{"gene":"HLA-B","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1976,"finding":"HLA-B specificities (e.g., HLA-B7, HLA-B12) and the Bw4/Bw6 diallelic system are distinct antigenic determinants located on the same polypeptide chain, demonstrated by sequential immunoprecipitation of papain-solubilized membrane proteins with alloantisera to HLA-B7, HLA-B12, w4 and w6.","method":"Sequential immunoprecipitation of 125I-labeled papain-solubilized lymphoblastoid cell membrane proteins with HLA-B and Bw4/Bw6 alloantisera","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical reconstitution/co-purification with orthogonal antisera; foundational result","pmids":["63373"],"is_preprint":false},{"year":1991,"finding":"Crystal structure of HLA-B27 reveals that nonameric self-peptides are bound in an extended conformation within the antigen-binding cleft, with peptide termini anchored in pockets and side chains at defined positions (especially Arg at position 2) contacting allele-specific pockets.","method":"X-ray crystallography","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with direct visualization of peptide-binding mode","pmids":["1922337"],"is_preprint":false},{"year":1992,"finding":"The 2.1 Å crystal structure of HLA-B27 shows that tight peptide binding results from extensive contacts at both ends of the peptide cleft between main-chain atoms and conserved MHC side chains, and that the Arg anchor at peptide position 2 inserts into an HLA-B27-specific pocket, suggesting a general mechanism for peptide binding.","method":"X-ray crystallography at 2.1 Å resolution","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with mechanistic interpretation, foundational paper","pmids":["1525820"],"is_preprint":false},{"year":1994,"finding":"Transcriptional suppression of HLA-B expression by c-Myc overexpression is mediated through the core promoter region (a 43 bp fragment containing CCAAT and TATA elements), independently of enhancer A or enhancer B regions, indicating c-Myc interferes with basal transcription initiation.","method":"Transfection of HLA-B reporter constructs with variable promoter deletions into melanoma cell lines with high/low c-myc expression; heterologous enhancer coupling assay","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 — promoter deletion mapping and heterologous enhancer experiments in a single lab","pmids":["8206526"],"is_preprint":false},{"year":1996,"finding":"HIV-1 Nef protein induces rapid endocytosis of MHC class I molecules (including HLA-B) from the cell surface of lymphoid, monocytic and epithelial cells; Nef does not affect MHC-I synthesis or transport through the ER/cis-Golgi but causes surface MHC-I to accumulate in endosomal vesicles and undergo degradation.","method":"Expression of HIV-1 Nef in multiple cell types; immunofluorescence, subcellular fractionation, flow cytometry to track MHC-I trafficking","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple cell types, multiple methods, widely replicated; foundational mechanistic paper","pmids":["8612235"],"is_preprint":false},{"year":1997,"finding":"In TAP-deficient patients, the majority of cell-surface class I molecules are HLA-B products; two peptides eluted from these HLA-B molecules are derived from cytosolic proteins presented via a TAP-independent pathway, and an EBV LMP2-specific cytotoxic CD8+ T cell clone recognizes LMP2 presented by HLA-B on TAP-deficient cells.","method":"Cytofluorometry, biochemical analysis, peptide elution and sequencing from TAP-deficient EBV-transformed B-LCL, CTL cloning and cytotoxicity assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — direct peptide elution plus functional CTL assay, multiple orthogonal methods","pmids":["9144467"],"is_preprint":false},{"year":1997,"finding":"HLA-B*1501 presents a defined set of peptides with a consistent binding signature identified by large-scale production using hollow-fiber bioreactors combined with mass spectrometry, establishing that individual HLA-B alleles have allele-specific peptide-binding repertoires.","method":"Hollow-fiber bioreactor scale production of HLA-B*1501 plus bound peptides; mass spectrometry peptide mapping","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 1 — direct biochemical isolation and MS identification of natural ligands; single lab","pmids":["9089095"],"is_preprint":false},{"year":1997,"finding":"HLA-B*4801 selects nonamer peptides with Gln or Lys at position 2 and Leu at the C-terminus (defined by pool sequence analysis), and binds CD8α homodimers weakly due to Thr245 in the α3 domain; a Thr245Ala mutation restores CD8 binding to normal levels, yet alloreactive T cells recognizing B*4801 are still inhibited by anti-CD8 antibodies.","method":"Endogenous peptide pool sequencing from HLA-class-I-deficient 221 cell transfectants; in vitro cell-cell CD8 binding assay; site-directed mutagenesis of Thr245Ala; flow cytometry","journal":"Tissue antigens","confidence":"High","confidence_rationale":"Tier 1-2 — peptide motif definition, mutagenesis of CD8-contact residue, functional CD8-binding assay in same study","pmids":["9331948"],"is_preprint":false},{"year":1998,"finding":"Wild-type p53 represses the HLA-B core promoter, and c-Myc-induced HLA-B downregulation is independent of p53 because c-Myc suppresses the basal HLA-B promoter even in p53-null cell lines, demonstrating that c-Myc and p53 repress the minimal HLA-B promoter through independent mechanisms.","method":"Transfection of HLA-B core promoter reporter constructs in p53-null melanoma lines with and without c-myc; co-transfection of wild-type p53","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assays in p53-null lines plus p53 cotransfection; single lab, moderate evidence","pmids":["9839551"],"is_preprint":false},{"year":1999,"finding":"HIV-1 Nef selectively downregulates HLA-A and HLA-B but not HLA-C or HLA-E from the cell surface; residues in the cytoplasmic tails of HLA-C and HLA-E protect them from Nef-mediated downregulation, allowing HIV-infected cells to escape NK cell lysis while evading CTL.","method":"Flow cytometry of HIV-1-infected lymphoid cells expressing defined HLA molecules; domain-swap and mutagenesis to identify protective HLA cytoplasmic tail residues; NK cell cytotoxicity assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of cytoplasmic tail residues plus functional NK and CTL assays; widely replicated","pmids":["10403641"],"is_preprint":false},{"year":2004,"finding":"Crystal structure of HLA-B*3501 at 1.5 Å bound to an unusually long 14-mer peptide shows that the N- and C-termini are embedded in the A and F pockets (as for normal-length peptides) while the central region bulges flexibly out of the groove; two peptide variants with Ala substitutions at P2 or P2+P9 show altered flexibility and conformation and reduced T cell activation, implicating both peptide conformation and MHC α-helical dynamics in TCR engagement.","method":"X-ray crystallography at 1.5 Å; site-directed mutagenesis of peptide positions; T cell activation assays with CTL clones","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis plus functional T cell assay in one study","pmids":["15494511"],"is_preprint":false},{"year":2010,"finding":"Large-scale direct biochemical analysis of HLA-B*2705-bound peptides (the 'peptidome') using recombinant soluble HLA-B27 secreted from chondrocytic and HeLa cells, combined with tandem MS, identified 1,268 B27 peptides and refined the B27 binding motif including a propensity for long peptides whose central residues bulge from the groove; candidate molecular mimicry peptides were found between human cartilage proteins and bacterial sequences.","method":"Recombinant soluble HLA-B*2705 immunoaffinity purification from cell lines; capillary LC-MS/MS; SILAC and iTRAQ quantitation","journal":"Arthritis and rheumatism","confidence":"High","confidence_rationale":"Tier 1 — large-scale direct biochemical peptide identification with stable isotope validation","pmids":["20112406"],"is_preprint":false},{"year":2012,"finding":"Direct physical interaction between HLA-B*1502 protein (loaded with endogenous peptides) and carbamazepine (CBZ) activates CBZ-specific CTLs without intracellular drug metabolism or antigen processing; surface plasmon resonance and peptide-binding assays showed the HLA-B*1502/peptide/β2m complex binds CBZ and analogs sharing the 5-carboxamide tricyclic ring; site-directed mutagenesis identified three key residues in the peptide-binding groove (Asn63, Ile95, Leu156) with Asn63 being essential; computer modeling revealed preferred binding at the B pocket via Arg62 interaction.","method":"In vitro CTL expansion and activation; surface plasmon resonance; peptide-binding assay; site-directed mutagenesis; molecular dynamics modeling","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (SPR, mutagenesis, peptide binding, functional CTL assay) in one study","pmids":["22322005"],"is_preprint":false},{"year":2014,"finding":"HLA-B polymorphisms profoundly influence the assembly characteristics of HLA-B molecules and the stability of their peptide-deficient forms; dependence on the assembly factor tapasin varies markedly among allotypes, with several polymorphic residues near the C-terminal end of the peptide groove being key determinants of tapasin-independent assembly; tapasin-independent allotypes refold more readily with peptides in vitro and show less aggregation during refolding.","method":"Flow cytometry of HLA-B surface expression in tapasin-deficient cells; in vitro refolding assays with defined peptides; aggregation assays; comparison across multiple HLA-B allotypes","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical refolding assays plus cell-based expression in tapasin-KO cells; multiple allotypes tested","pmids":["24790147"],"is_preprint":false},{"year":2015,"finding":"KIR3DS1 recognition of HLA-B*57:01 is peptide-dependent; structure-guided screening identified HIV-derived peptide epitopes presented by HLA-B*57:01 that facilitate productive KIR3DS1 binding, demonstrating that changes in the peptide repertoire during viral infection can trigger KIR3DS1 engagement and NK cell activation.","method":"Structure-driven peptide screening; binding assays between KIR3DS1 and HLA-B*57:01-peptide complexes; functional NK cell assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — structure-guided approach plus binding and functional NK assays; single lab","pmids":["25740999"],"is_preprint":false},{"year":2016,"finding":"Phosphorylation at peptide position 4 (P4) predominates in HLA-B-associated phosphopeptide ligands across multiple HLA-B alleles, dictated by the conserved Arg62 residue in the HLA-B heavy chain; crystal structures of HLA-B*40 bound to a phosphopeptide versus its non-phosphorylated counterpart confirmed structural accommodation of phospho-P4 by Arg62; preference for basic residues at P1 is allotype-dependent and linked to A-pocket structure.","method":"Immunopeptidomics (peptidomic workflow); peptide-binding assays; X-ray crystallography of HLA-B*40/phosphopeptide complex","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus peptidomics plus binding assays in one study","pmids":["27920218"],"is_preprint":false},{"year":2016,"finding":"Conformational flexibility is elevated in disease-associated HLA-B*27 subtypes (B*27:04 and B*27:05) compared to non-disease-associated subtypes (B*27:06 and B*27:09), as measured by isotope-edited IR spectroscopy; crystal structures of pVIPR-B*27:04 and pVIPR-B*27:06 show that B*27:04 presents the peptide in a single conventional conformation while B*27:06 shows dual conformation, separating dual peptide conformation from increased molecular dynamics as distinct structural features.","method":"X-ray crystallography; isotope-edited infrared (IR) spectroscopy to probe molecular dynamics","journal":"Arthritis & rheumatology","confidence":"High","confidence_rationale":"Tier 1 — crystal structures plus biophysical dynamics measurement in same study","pmids":["26748477"],"is_preprint":false},{"year":2016,"finding":"HIV-1 Nef downregulates HLA-B less efficiently than HLA-A from the surface of HIV-infected cells; the differential effect maps to Nef codon 202 (confirmed by site-directed mutagenesis) and to C-terminal CKV residues present in HLA-A but absent in HLA-B cytoplasmic tails; the degree of HLA-B relative resistance correlates inversely with the ability of HIV-specific T cells to recognize infected cells.","method":"Flow cytometry of 46 patient-derived Nef clones; Nef site-directed mutagenesis; coculture T cell recognition assay; in silico Nef codon function analysis","journal":"mBio","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of Nef-202 and HLA cytoplasmic tail, functional T cell recognition assay, multiple patient clones","pmids":["26787826"],"is_preprint":false},{"year":2017,"finding":"HLA-B*46:01, formed by intergenic mini-conversion between HLA-B*15:01 and HLA-C*01:02, carries the C1 epitope and is recognized by NK receptor KIR2DL3; high-resolution MS showed B*46:01 has a low-diversity peptidome distinct from its parental alleles; a minority (21%) of B*46:01 peptides sharing C-terminal characteristics serve as KIR2DL3 ligands, linking peptidome composition to NK receptor recognition.","method":"High-resolution mass spectrometry immunopeptidomics; KIR2DL3 binding assays; sequence analysis of mini-conversion","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — direct biochemical peptidome characterization plus NK receptor binding functional assay","pmids":["28514659"],"is_preprint":false},{"year":2018,"finding":"Multiple HLA-B allotypes (~15% of 27 tested) are expressed at relatively high levels on the surface of TAP1- or TAP2-deficient cells and occur in partially peptide-receptive and EndoH-sensitive forms, indicating TAP-independent assembly; synergy between high peptide-loading efficiency, broad specificity for peptides from unconventional sources, and high intrinsic stability of the empty form underlies TAP-independent assembly of certain HLA-B*35, B*57 and B*15 alleles; TAP-independent allotypes are more resistant to viral TAP inhibitor-induced HLA-I downmodulation.","method":"Flow cytometry of 27 HLA-B alleles in TAP1/TAP2-deficient cells; EndoH sensitivity assay; peptide-binding/loading efficiency assays; viral TAP inhibitor experiments; NK cell activation assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1-2 — systematic survey of 27 alleles with biochemical and functional assays across multiple methods","pmids":["29995954"],"is_preprint":false},{"year":2018,"finding":"In HLA-B*27:05, empty or suboptimally loaded molecules can escape intracellular retention and reach the cell surface as β2m-free heavy chains; an artificial disulfide bond between residues 84 and 139 confers enhanced conformational stability to suboptimally loaded molecules; a general quality control mechanism in the early secretory pathway (conserved between mouse and human cells) distinguishes poorly loaded from optimally loaded MHC-I, but is allotype-specifically permissive for HLA-B*27:05.","method":"Cell-based transport/trafficking assays; disulfide bond engineering (Cys84-Cys139 mutagenesis); flow cytometry; comparison of murine and human cell lines","journal":"PLoS one","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis plus cell-based trafficking; single lab but multiple orthogonal approaches","pmids":["30071035"],"is_preprint":false},{"year":2019,"finding":"Pro-inflammatory cytokines TNFα and IFNγ increase HLA-B allomorph expression in lung cancer cells, and elevated HLA-B expression independently drives significant changes in the HLA-bound immunopeptidome beyond those attributable to proteome changes alone.","method":"Quantitative immunopeptidomics; proteomics; cytokine stimulation; flow cytometry of HLA-B surface levels","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — immunopeptidomics plus quantitative proteomics; single lab, moderate evidence","pmids":["30833945"],"is_preprint":false},{"year":2021,"finding":"Flucloxacillin (FLX) directly modifies HLA-B*57:01 at Lys146 (covalent haptenation), alters anchor residue frequencies in the immunopeptidome (enriching peptides with C-terminal Trp and FLX-haptenated Lys), and haptenated peptides at P4 and P6 induce drug-specific CD8+ T cells in HLA-B*57:01-transgenic mice; FLX modification at K146 may also impair KIR-3DL or peptide interactions.","method":"Mass spectrometry-based immunopeptidomics; in vivo immunization of HLA-B*57:01-Tg mice with drug-haptenated peptides; CD8+ T cell assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 1-2 — direct MS identification of haptenated peptides plus in vivo functional assay; single lab","pmids":["33633747"],"is_preprint":false},{"year":2022,"finding":"CD8+ T cells bearing disease-associated public TCRs (BV9-CDR3β motif with AV21 pairing) clonally expanded in joint (AS) and eye (AAU) of HLA-B*27 patients recognize self-peptides and microbial peptides presented by HLA-B*27:05 but not B*27:09; structural analysis revealed that TCR cross-reactivity is rooted in a shared binding motif at the peptide-MHC interface engaged by the BV9-CDR3β TCRs; HLA-B*27:05 yeast display peptide libraries identified the activating peptides.","method":"HLA-B*27:05 yeast display peptide library screening; crystal structure of TCR–HLA-B*27:05–peptide complexes; T cell cloning from joint/eye; TCR sequencing","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus functional T cell activation plus yeast display library; replicated across patient cohorts","pmids":["36477533"],"is_preprint":false},{"year":2015,"finding":"N-glycosylation of HLA-B*57:01 is required for efficient KIR3DL1 binding; tunicamycin treatment (blocking the first step of N-glycosylation) significantly reduces KIR3DL1-Fc binding to HLA-B*57:01-expressing cells despite sustained HLA-B*57:01 surface expression, and decreases KIR3DL1ζ+ Jurkat reporter activation while increasing degranulation of primary KIR3DL1+ NK cell clones.","method":"Glycosylation enzyme inhibitor panel; KIR3DL1-Fc binding assay by flow cytometry; KIR3DL1ζ+ Jurkat reporter assay; primary NK cell degranulation assay","journal":"PLoS one","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological glycosylation inhibition with multiple functional readouts; single lab","pmids":["26680341"],"is_preprint":false}],"current_model":"HLA-B is a highly polymorphic MHC class I heavy chain that assembles in the endoplasmic reticulum with β2-microglobulin and peptides (8–14 mers) via a tapasin-dependent or -independent pathway depending on allotype, presents them at the cell surface for CD8+ T cell and NK cell (KIR3DL1/KIR3DS1) surveillance, with peptide binding governed by allele-specific pockets (especially a conserved Arg62 that accommodates phospho-P4 residues), N-glycosylation facilitating KIR binding, and expression controlled at the transcriptional level by c-Myc and p53 acting independently on the core promoter, while HIV-1 Nef exploits allele-specific cytoplasmic tail differences to preferentially downregulate HLA-A over HLA-B via endocytosis, and certain alleles (B*27, B*57, B*1502, B*5801) confer disease susceptibility or drug hypersensitivity through direct drug–peptide–HLA interactions and presentation of arthritogenic or drug-haptenated peptides to autoreactive CD8+ T cells."},"narrative":{"teleology":[{"year":1976,"claim":"Establishing that HLA-B allotypic specificities and the Bw4/Bw6 serological epitopes reside on the same polypeptide chain resolved the molecular identity of HLA-B gene products and enabled subsequent structural analysis.","evidence":"Sequential immunoprecipitation of radiolabeled papain-solubilized lymphoblastoid membrane proteins with allele-specific and Bw4/Bw6 alloantisera","pmids":["63373"],"confidence":"High","gaps":["No structural information on the chain architecture","Bw4/Bw6 epitope location on the polypeptide unknown"]},{"year":1992,"claim":"Crystal structures of HLA-B*27 revealed the molecular basis of peptide binding: nonameric peptides lie extended in the groove with termini anchored in conserved pockets and an Arg at P2 inserted into a B-allele-specific pocket, establishing the paradigm for allele-specific peptide selection.","evidence":"X-ray crystallography of HLA-B*27 at 2.1 Å resolution with bound self-peptides","pmids":["1922337","1525820"],"confidence":"High","gaps":["Structures limited to B*27; generalizability to other HLA-B alleles not yet tested","Dynamics and conformational flexibility not captured by static crystal structures"]},{"year":1997,"claim":"Demonstration that HLA-B can present peptides via a TAP-independent pathway in TAP-deficient patients, and that HLA-B allotypes differ in peptide motifs and CD8-binding efficiency due to α3 domain polymorphisms, expanded the functional scope of HLA-B beyond the classical TAP-dependent pathway.","evidence":"Peptide elution and CTL assays from TAP-deficient B-LCL; peptide pool sequencing and CD8-binding mutagenesis (Thr245Ala) in 221-cell transfectants","pmids":["9144467","9331948","9089095"],"confidence":"High","gaps":["Molecular mechanism of TAP-independent peptide loading unknown","CD8-binding polymorphism tested for only one allotype"]},{"year":1998,"claim":"Mapping transcriptional regulation showed that c-Myc and p53 each independently repress the HLA-B core promoter through the CCAAT/TATA region, providing a mechanism for MHC-I downregulation in tumors with oncogene activation or p53 overexpression.","evidence":"HLA-B promoter-reporter deletion constructs transfected into melanoma cells with varying c-Myc/p53 status","pmids":["8206526","9839551"],"confidence":"Medium","gaps":["Direct transcription-factor–DNA binding not demonstrated","Relevance to endogenous HLA-B mRNA levels not confirmed in primary tumors","Chromatin context not assessed"]},{"year":1999,"claim":"HIV-1 Nef was shown to selectively downregulate HLA-A and HLA-B (but not HLA-C/E) by inducing endocytosis; the differential susceptibility maps to cytoplasmic tail differences, explaining how HIV evades CTL while sparing NK-inhibitory ligands.","evidence":"Flow cytometry, immunofluorescence, and subcellular fractionation in Nef-expressing cells; domain-swap and tail mutagenesis; NK and CTL cytotoxicity assays","pmids":["8612235","10403641"],"confidence":"High","gaps":["Precise Nef–HLA-B tail interaction interface not structurally resolved","Relative contribution of endosomal degradation versus lysosomal routing unclear"]},{"year":2004,"claim":"A 1.5 Å structure of HLA-B*35:01 bound to a 14-mer peptide showed that long peptides are accommodated by central bulging while termini remain anchored, and that peptide conformation modulates TCR engagement, broadening understanding of peptide-length flexibility.","evidence":"X-ray crystallography of HLA-B*3501 with 14-mer and Ala-substituted peptide variants; CTL activation assays","pmids":["15494511"],"confidence":"High","gaps":["Generalizability of bulging mechanism to other HLA-B alleles not tested","Structural basis of TCR contact with bulged peptides not resolved"]},{"year":2012,"claim":"Direct binding of carbamazepine to the HLA-B*15:02/peptide complex without antigen processing, and identification of key groove residues (Asn63, Ile95, Leu156) including conserved Arg62, established a structural mechanism for drug hypersensitivity mediated by drug–peptide–MHC interaction.","evidence":"SPR binding, peptide-binding assays, site-directed mutagenesis of HLA-B*1502, and CTL activation assays","pmids":["22322005"],"confidence":"High","gaps":["No crystal structure of CBZ bound in the groove","In vivo relevance in patient tissue not confirmed"]},{"year":2014,"claim":"Systematic comparison across HLA-B allotypes revealed that polymorphic residues near the C-terminal groove determine tapasin dependence, and that tapasin-independent alleles refold more readily and resist viral TAP-inhibitor-mediated downregulation, explaining allotype-specific variation in antigen presentation efficiency.","evidence":"Surface expression in tapasin-deficient cells; in vitro refolding and aggregation assays across 27 HLA-B alleles; viral TAP-inhibitor experiments","pmids":["24790147","29995954"],"confidence":"High","gaps":["Structural basis for tapasin interaction specificity not determined at atomic level","Clinical impact of tapasin independence on immune control not quantified"]},{"year":2016,"claim":"Discovery that the conserved Arg62 in HLA-B accommodates phosphopeptides at P4, combined with biophysical evidence that conformational dynamics differ between disease-associated (B*27:05) and non-disease-associated (B*27:09) subtypes, linked both peptide chemistry and heavy-chain dynamics to disease susceptibility.","evidence":"Immunopeptidomics and crystal structures of HLA-B*40/phosphopeptide; isotope-edited IR spectroscopy comparing B*27 subtypes; crystal structures of pVIPR–B*27:04 and B*27:06","pmids":["27920218","26748477"],"confidence":"High","gaps":["Functional consequence of increased dynamics for TCR recognition not directly tested","Role of phosphopeptide presentation in immune surveillance in vivo unknown"]},{"year":2016,"claim":"Refined analysis of HIV Nef selectivity showed HLA-B is downregulated less efficiently than HLA-A, mapping the difference to Nef codon 202 and the absence of C-terminal CKV residues in HLA-B's cytoplasmic tail, revealing an allele-specific immune evasion hierarchy.","evidence":"Flow cytometry with 46 patient-derived Nef clones; Nef-202 mutagenesis; coculture T cell recognition assays","pmids":["26787826"],"confidence":"High","gaps":["Crystal structure of Nef bound to HLA-B tail not available","Impact of differential downregulation on in vivo viral control not prospectively tested"]},{"year":2017,"claim":"HLA-B*46:01, formed by gene conversion between HLA-B and HLA-C, presents a uniquely low-diversity peptidome and engages KIR2DL3 in a peptide-dependent manner, illustrating how gene conversion events reshape both peptide repertoire and NK receptor recognition.","evidence":"High-resolution MS immunopeptidomics; KIR2DL3 binding assays","pmids":["28514659"],"confidence":"High","gaps":["Structural basis of KIR2DL3 engagement by B*46:01 not determined","In vivo NK cell functional consequence not characterized"]},{"year":2022,"claim":"Identification of public cross-reactive TCRs (BV9-CDR3β/AV21) in HLA-B*27:05+ ankylosing spondylitis and uveitis patients, recognizing both self and microbial peptides presented by B*27:05 but not B*27:09, provided structural evidence that molecular mimicry through a shared TCR-binding motif underlies B*27-associated autoimmunity.","evidence":"HLA-B*27:05 yeast-display peptide library; TCR–pMHC crystal structures; T cell cloning from affected joint and eye tissues","pmids":["36477533"],"confidence":"High","gaps":["Triggering microbial infection initiating disease not identified in patients","Whether targeting these public TCRs is therapeutically feasible is untested"]},{"year":null,"claim":"Key unresolved questions include: the atomic-resolution structure of the tapasin–HLA-B editing complex; how conformational dynamics of disease-associated subtypes translate into altered TCR triggering thresholds in vivo; and the structural basis of Nef–HLA-B cytoplasmic tail interaction.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No atomic structure of tapasin–HLA-B complex","In vivo dynamics–TCR signaling relationship unresolved","Nef–HLA-B tail co-structure lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,2,10,12,14,15,23]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,7,9,17,19,24]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[13,19,20]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,5,9,10,12,14,15,17,18,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[13,19,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,9,17,22,23]}],"complexes":["MHC class I peptide-loading complex","HLA-B/β2-microglobulin/peptide heterotrimer"],"partners":["B2M","KIR3DL1","KIR3DS1","KIR2DL3","TAPBP","TAP1","TAP2"],"other_free_text":[]},"mechanistic_narrative":"HLA-B is a highly polymorphic MHC class I heavy chain that assembles with β2-microglobulin and short peptides in the endoplasmic reticulum—via tapasin-dependent or tapasin-independent pathways depending on allotype—and presents these peptide ligands at the cell surface for surveillance by CD8+ T cells and NK cells through TCR and KIR receptors [PMID:1525820, PMID:24790147, PMID:29995954]. Allele-specific pockets in the peptide-binding groove, defined by high-resolution crystal structures, dictate the peptide repertoire: an Arg anchor at P2 governs HLA-B*27 binding, a conserved Arg62 accommodates phosphopeptides at P4 across many alleles, and the overall peptidome diversity varies markedly among allotypes [PMID:1922337, PMID:27920218, PMID:28514659]. N-glycosylation of HLA-B is required for efficient KIR3DL1 engagement, and KIR3DS1 recognition of HLA-B*57:01 is peptide-dependent, linking viral peptide presentation to NK cell activation [PMID:26680341, PMID:25740999]. Certain alleles confer disease susceptibility—HLA-B*27:05 presents self- and microbial peptides to cross-reactive public TCRs in ankylosing spondylitis and acute anterior uveitis, while HLA-B*15:02 and HLA-B*57:01 directly bind drugs (carbamazepine, flucloxacillin) to activate drug-specific CD8+ T cells in hypersensitivity reactions [PMID:36477533, PMID:22322005, PMID:33633747]."},"prefetch_data":{"uniprot":{"accession":"P01889","full_name":"HLA class I histocompatibility antigen, B alpha chain","aliases":["Human leukocyte antigen B","HLA-B"],"length_aa":362,"mass_kda":40.5,"function":"Antigen-presenting major histocompatibility complex class I (MHCI) molecule. In complex with B2M/beta 2 microglobulin displays primarily viral and tumor-derived peptides on antigen-presenting cells for recognition by alpha-beta T cell receptor (TCR) on HLA-B-restricted CD8-positive T cells, guiding antigen-specific T cell immune response to eliminate infected or transformed cells (PubMed:23209413, PubMed:25808313, PubMed:29531227, PubMed:9620674). May also present self-peptides derived from the signal sequence of secreted or membrane proteins, although T cells specific for these peptides are usually inactivated to prevent autoreactivity (PubMed:18991276, PubMed:7743181). Both the peptide and the MHC molecule are recognized by TCR, the peptide is responsible for the fine specificity of antigen recognition and MHC residues account for the MHC restriction of T cells (PubMed:24600035, PubMed:29531227, PubMed:9620674). Typically presents intracellular peptide antigens of 8 to 13 amino acids that arise from cytosolic proteolysis via constitutive proteasome and IFNG-induced immunoproteasome (PubMed:23209413). Can bind different peptides containing allele-specific binding motifs, which are mainly defined by anchor residues at position 2 and 9 (PubMed:25808313, PubMed:29531227) Allele B*07:02: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and mainly a Leu anchor residue at the C-terminus (PubMed:7743181). Presents a long peptide (APRGPHGGAASGL) derived from the cancer-testis antigen CTAG1A/NY-ESO-1, eliciting a polyclonal CD8-positive T cell response against tumor cells (PubMed:29531227). Presents viral epitopes derived from HIV-1 gag-pol (TPQDLNTML) and Nef (RPQVPLRPM) (PubMed:25808313). Presents an immunodominant epitope derived from SARS-CoV-2 N/nucleoprotein (SPRWYFYYL) (PubMed:32887977). Displays self-peptides including a peptide derived from the signal sequence of HLA-DPB1 (APRTVALTA) (PubMed:7743181) Allele B*08:01: Presents to CD8-positive T cells viral epitopes derived from EBV/HHV-4 EBNA3 (QAKWRLQTL), eliciting cytotoxic T cell response Allele B*13:02: Presents multiple HIV-1 epitopes derived from gag (RQANFLGKI, GQMREPRGSDI), nef (RQDILDLWI), gag-pol (RQYDQILIE, GQGQWTYQI) and rev (LQLPPLERL), all having in common a Gln residue at position 2 and mainly hydrophobic amino acids Leu, Ile or Val at the C-terminus. Associated with successful control of HIV-1 infection Allele B*18:01: Preferentially presents octameric and nonameric peptides sharing a common motif, namely a Glu at position 2 and Phe or Tyr anchor residues at the C-terminus (PubMed:14978097, PubMed:18991276, PubMed:23749632). Presents an EBV/HHV-4 epitope derived from BZLF1 (SELEIKRY) (PubMed:23749632). May present to CD8-positive T cells an antigenic peptide derived from MAGEA3 (MEVDPIGHLY), triggering an anti-tumor immune response (PubMed:12366779). May display a broad repertoire of self-peptides with a preference for peptides derived from RNA-binding proteins (PubMed:14978097) Allele B*27:05: Presents to CD8-positive T cells immunodominant viral epitopes derived from HCV POLG (ARMILMTHF), HIV-1 gag (KRWIILGLNK), IAV NP (SRYWAIRTR), SARS-CoV-2 N/nucleoprotein (QRNAPRITF), EBV/HHV-4 EBNA4 (HRCQAIRKK) and EBV/HHV-4 EBNA6 (RRIYDLIEL), conferring longterm protection against viral infection (PubMed:15113903, PubMed:18385228, PubMed:19139562, PubMed:32887977, PubMed:9620674). Can present self-peptides derived from cytosolic and nuclear proteins. All peptides carry an Arg at position 2 (PubMed:1922338). The peptide-bound form interacts with NK cell inhibitory receptor KIR3DL1 and inhibits NK cell activation in a peptide-specific way, being particularly sensitive to the nature of the amino acid side chain at position 8 of the antigenic peptide (PubMed:15657948, PubMed:8879234). KIR3DL1 fails to recognize HLA-B*27:05 in complex with B2M and EBV/HHV-4 EBNA6 (RRIYDLIEL) peptide, which can lead to increased activation of NK cells during infection (PubMed:15657948). May present an altered repertoire of peptides in the absence of TAP1-TAP2 and TAPBPL (PubMed:9620674) Allele B*40:01: Presents immunodominant viral epitopes derived from EBV/HHV-4 LMP2 (IEDPPFNSL) and SARS-CoV-2 N/nucleoprotein (MEVTPSGTWL), triggering memory CD8-positive T cell response (PubMed:18991276, PubMed:32887977). Displays self-peptides sharing a signature motif, namely a Glu at position 2 and a Leu anchor residue at the C-terminus (PubMed:18991276) Allele B*41:01: Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Ala or Pro anchor residues at the C-terminus Allele B*44:02: Presents immunodominant viral epitopes derived from EBV/HHV-4 EBNA4 (VEITPYKPTW) and EBNA6 (AEGGVGWRHW, EENLLDFVRF), triggering memory CD8-positive T cell response (PubMed:18991276, PubMed:9620674). Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Phe, Tyr or Trp anchor residues at the C-terminus (PubMed:18991276) Allele B*45:01: Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Ala or Pro anchor residues at the C-terminus Allele B*46:01: Preferentially presents nonameric peptides sharing a signature motif, namely Ala and Leu at position 2 and Tyr, Phe, Leu, or Met anchor residues at the C-terminus. The peptide-bound form interacts with KIR2DL3 and inhibits NK cell cytotoxic response in a peptide-specific way Allele B*47:01: Displays self-peptides sharing a signature motif, namely an Asp at position 2 and Leu or Met anchor residues at the C-terminus Allele B*49:01: Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Ile or Val anchor residues at the C-terminus Allele B*50:01: Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Ala or Pro anchor residues at the C-terminus Allele B*51:01: Presents an octameric HIV-1 epitope derived from gag-pol (TAFTIPSI) to the public TRAV17/TRBV7-3 TCR clonotype, strongly suppressing HIV-1 replication Allele B*54:01: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and Ala anchor residue at the C-terminus Allele B*55:01: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and Ala anchor residue at the C-terminus Allele B*56:01: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and Ala anchor residue at the C-terminus Allele B*57:01: The peptide-bound form recognizes KIR3DL1 and inhibits NK cell cytotoxic response. Presents HIV gag peptides (immunodominant KAFSPEVIPMF and subdominant KALGPAATL epitopes) predominantly to CD8-positive T cell clones expressing a TRAV41-containing TCR, triggering HLA-B-restricted T cell responses Allele B*67:01: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and Leu anchor residue at the C-terminus","subcellular_location":"Cell membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P01889/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HLA-B","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HLA-B","total_profiled":1310},"omim":[{"mim_id":"620778","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, THREE DOMAINS, SHORT CYTOPLASMIC TAIL, 1; KIR3DS1","url":"https://www.omim.org/entry/620778"},{"mim_id":"619920","title":"ANKYRIN REPEAT- AND DEATH DOMAIN-CONTAINING PROTEIN 1B; ANKDD1B","url":"https://www.omim.org/entry/619920"},{"mim_id":"615746","title":"ZXD FAMILY ZINC FINGER PROTEIN C; ZXDC","url":"https://www.omim.org/entry/615746"},{"mim_id":"614374","title":"BLOOD GROUP, CHIDO/RODGERS SYSTEM","url":"https://www.omim.org/entry/614374"},{"mim_id":"613927","title":"COMPLEMENT COMPONENT 2; C2","url":"https://www.omim.org/entry/613927"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":2350.0}],"url":"https://www.proteinatlas.org/search/HLA-B"},"hgnc":{"alias_symbol":[],"prev_symbol":["AS"]},"alphafold":{"accession":"P01889","domains":[{"cath_id":"3.30.500.10","chopping":"24-203","consensus_level":"high","plddt":97.2323,"start":24,"end":203},{"cath_id":"2.60.40.10","chopping":"209-296","consensus_level":"high","plddt":97.1534,"start":209,"end":296}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P01889","model_url":"https://alphafold.ebi.ac.uk/files/AF-P01889-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P01889-F1-predicted_aligned_error_v6.png","plddt_mean":88.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HLA-B","jax_strain_url":"https://www.jax.org/strain/search?query=HLA-B"},"sequence":{"accession":"P01889","fasta_url":"https://rest.uniprot.org/uniprotkb/P01889.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P01889/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P01889"}},"corpus_meta":[{"pmid":"12134147","id":"PMC_12134147","title":"Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS.","date":"2002","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12134147","citation_count":928,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17496894","id":"PMC_17496894","title":"Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17496894","citation_count":613,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21428768","id":"PMC_21428768","title":"Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan.","date":"2011","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21428768","citation_count":494,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15024131","id":"PMC_15024131","title":"Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15024131","citation_count":336,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1317015","id":"PMC_1317015","title":"Unusual HLA-B alleles in two tribes of Brazilian Indians.","date":"1992","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/1317015","citation_count":258,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22322005","id":"PMC_22322005","title":"Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome.","date":"2012","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22322005","citation_count":225,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23695185","id":"PMC_23695185","title":"Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing.","date":"2013","source":"Clinical pharmacology and therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/23695185","citation_count":160,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7792765","id":"PMC_7792765","title":"Comprehensive, serologically equivalent DNA typing for HLA-B by PCR using sequence-specific primers (PCR-SSP).","date":"1995","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/7792765","citation_count":125,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36477533","id":"PMC_36477533","title":"Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/36477533","citation_count":122,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17892322","id":"PMC_17892322","title":"Immunodominant tuberculosis CD8 antigens preferentially restricted by HLA-B.","date":"2007","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/17892322","citation_count":121,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28520526","id":"PMC_28520526","title":"KIR3DL1/HLA-B Subtypes Govern Acute Myelogenous Leukemia Relapse After Hematopoietic Cell Transplantation.","date":"2017","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28520526","citation_count":118,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10513813","id":"PMC_10513813","title":"Association analysis between the MIC-A and HLA-B alleles in Japanese patients with Behçet's disease.","date":"1999","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/10513813","citation_count":84,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24790147","id":"PMC_24790147","title":"Distinct assembly profiles of HLA-B molecules.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24790147","citation_count":78,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9331945","id":"PMC_9331945","title":"Episodic evolution and turnover of HLA-B in the indigenous human populations of the Americas.","date":"1997","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/9331945","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"63373","id":"PMC_63373","title":"HLA-B specificities and w4, w6 specificities are on the same polypeptide.","date":"1976","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/63373","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25740999","id":"PMC_25740999","title":"Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/25740999","citation_count":69,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15494511","id":"PMC_15494511","title":"Conformational restraints and flexibility of 14-meric peptides in complex with HLA-B*3501.","date":"2004","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15494511","citation_count":69,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9089095","id":"PMC_9089095","title":"Large-scale production of class I bound peptides: assigning a signature to HLA-B*1501.","date":"1997","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/9089095","citation_count":61,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20112406","id":"PMC_20112406","title":"The HLA-B*2705 peptidome.","date":"2010","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/20112406","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12428239","id":"PMC_12428239","title":"Association of ankylosing spondylitis with HLA-B*1403 in a West African population.","date":"2002","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/12428239","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29782330","id":"PMC_29782330","title":"A transgenic mouse model for HLA-B*57:01-linked abacavir drug tolerance and reactivity.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/29782330","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22238317","id":"PMC_22238317","title":"Impact of HLA-B*81-associated mutations in HIV-1 Gag on viral replication capacity.","date":"2012","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/22238317","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16698437","id":"PMC_16698437","title":"Diversity of MICA and linkage disequilibrium with HLA-B in two North American populations.","date":"2006","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16698437","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7524186","id":"PMC_7524186","title":"The HLA-B73 antigen has a most unusual structure that defines a second lineage of HLA-B alleles.","date":"1994","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/7524186","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27920218","id":"PMC_27920218","title":"A Molecular Basis for the Presentation of Phosphorylated Peptides by HLA-B Antigens.","date":"2016","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/27920218","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12209364","id":"PMC_12209364","title":"A weak association of HLA-B*2702 with Behçet's disease.","date":"2002","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/12209364","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7846047","id":"PMC_7846047","title":"Rational design of nonnatural peptides as high-affinity ligands for the HLA-B*2705 human leukocyte antigen.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7846047","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9951811","id":"PMC_9951811","title":"Association of clinical manifestations with HLA-B alleles in Takayasu arteritis.","date":"1998","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/9951811","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30833945","id":"PMC_30833945","title":"Pro-inflammatory Cytokines Alter the Immunopeptidome Landscape by Modulation of HLA-B Expression.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30833945","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15220037","id":"PMC_15220037","title":"Transmission of HIV-1 and HLA-B allele-sharing within serodiscordant heterosexual Zambian couples.","date":"2004","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15220037","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28247302","id":"PMC_28247302","title":"An Update on the Genetic Polymorphism of HLA-B*27 With 213 Alleles Encompassing 160 Subtypes (and Still Counting).","date":"2017","source":"Current rheumatology reports","url":"https://pubmed.ncbi.nlm.nih.gov/28247302","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28386763","id":"PMC_28386763","title":"Ankylosing Spondylitis: HLA-B*27-Positive Versus HLA-B*27-Negative Disease.","date":"2017","source":"Current rheumatology reports","url":"https://pubmed.ncbi.nlm.nih.gov/28386763","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28514659","id":"PMC_28514659","title":"The Intergenic Recombinant HLA-B∗46:01 Has a Distinctive Peptidome that Includes KIR2DL3 Ligands.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28514659","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30509441","id":"PMC_30509441","title":"The role of HLA-B*27 in spondyloarthritis.","date":"2018","source":"Best practice & research. Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/30509441","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21059238","id":"PMC_21059238","title":"Evolution of the HIV-1 nef gene in HLA-B*57 positive elite suppressors.","date":"2010","source":"Retrovirology","url":"https://pubmed.ncbi.nlm.nih.gov/21059238","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9144467","id":"PMC_9144467","title":"Human peptide transporter deficiency: importance of HLA-B in the presentation of TAP-independent EBV antigens.","date":"1997","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9144467","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29995954","id":"PMC_29995954","title":"Selected HLA-B allotypes are resistant to inhibition or deficiency of the transporter associated with antigen processing (TAP).","date":"2018","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/29995954","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7871521","id":"PMC_7871521","title":"Analysis of HLA-B*44 alleles encoded on extended HLA haplotypes by direct automated sequencing.","date":"1994","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/7871521","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1350870","id":"PMC_1350870","title":"Sequence differences between HLA-B and TNF distinguish different MHC ancestral haplotypes.","date":"1992","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/1350870","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25139336","id":"PMC_25139336","title":"KIR diversity in Māori and Polynesians: populations in which HLA-B is not a significant KIR ligand.","date":"2014","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/25139336","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9694251","id":"PMC_9694251","title":"Familial psoriasis and HLA-B: unambiguous support for linkage in 97 published families.","date":"1998","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/9694251","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8206526","id":"PMC_8206526","title":"Transcriptional suppression of HLA-B expression by c-Myc is mediated through the core promoter elements.","date":"1994","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/8206526","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1563985","id":"PMC_1563985","title":"Haplospecific polymorphism between HLA B and tumor necrosis factor.","date":"1992","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1563985","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25019531","id":"PMC_25019531","title":"Epistatic interaction of ERAP1 and HLA-B in Behçet disease: a replication study in the Spanish population.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25019531","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33633747","id":"PMC_33633747","title":"Alterations in the HLA-B*57:01 Immunopeptidome by Flucloxacillin and Immunogenicity of Drug-Haptenated Peptides.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33633747","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11862403","id":"PMC_11862403","title":"MICA genetic polymorphism and linkage disequilibrium with HLA-B in 29 African-American families.","date":"2001","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/11862403","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14551603","id":"PMC_14551603","title":"MICA, HLA-B haplotypic variation in five population groups of sub-Saharan African ancestry.","date":"2003","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/14551603","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9110928","id":"PMC_9110928","title":"Strong association between microsatellites and an HLA-B, DR haplotype (B18-DR3): implication for microsatellite evolution.","date":"1996","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/9110928","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26748477","id":"PMC_26748477","title":"Increased Conformational Flexibility of HLA-B*27 Subtypes Associated With Ankylosing Spondylitis.","date":"2016","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/26748477","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27666425","id":"PMC_27666425","title":"HLA-B*40:02 and DRB1*04:03 are risk factors for oxcarbazepine-induced maculopapular eruption.","date":"2016","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/27666425","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32726429","id":"PMC_32726429","title":"Identification of Flucloxacillin-Haptenated HLA-B*57:01 Ligands: Evidence of Antigen Processing and Presentation.","date":"2020","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/32726429","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10090615","id":"PMC_10090615","title":"Evolutionary relationships between HLA-B alleles as indicated by an analysis of intron sequences.","date":"1999","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/10090615","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29803000","id":"PMC_29803000","title":"HLA-B*27 subtypes and their implications in the pathogenesis of ankylosing spondylitis.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29803000","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10980349","id":"PMC_10980349","title":"DNA sequencing of HLA-B alleles in Mexican patients with Takayasu arteritis.","date":"2000","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/10980349","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12618907","id":"PMC_12618907","title":"Distribution of HLA-B alleles in Mexican Amerindian populations.","date":"2003","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/12618907","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28968792","id":"PMC_28968792","title":"Control of HIV-1 by an HLA-B*52:01-C*12:02 Protective Haplotype.","date":"2017","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/28968792","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29037440","id":"PMC_29037440","title":"Novel genetic loci associated HLA-B*08:01 positive myasthenia gravis.","date":"2017","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/29037440","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29437277","id":"PMC_29437277","title":"Identification of Native and Posttranslationally Modified HLA-B*57:01-Restricted HIV Envelope Derived Epitopes Using Immunoproteomics.","date":"2018","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/29437277","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9331948","id":"PMC_9331948","title":"Interactions of HLA-B*4801 with peptide and CD8.","date":"1997","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/9331948","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11585536","id":"PMC_11585536","title":"Rapid determination of HLA B*07 ligands from the West Nile virus NY99 genome.","date":"2001","source":"Emerging infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/11585536","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10323345","id":"PMC_10323345","title":"Identification, sequencing and serology of HLA-B*3527.","date":"1999","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/10323345","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7666396","id":"PMC_7666396","title":"Allelic associations and homozygosity at loci from HLA-B to D6S299 in genetic haemochromatosis.","date":"1995","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7666396","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32619904","id":"PMC_32619904","title":"Polymorphisms of HLA-B: influences on assembly and immunity.","date":"2020","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32619904","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26355081","id":"PMC_26355081","title":"Consequences of HLA-B*13-Associated Escape Mutations on HIV-1 Replication and Nef Function.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/26355081","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7826137","id":"PMC_7826137","title":"HLA-B alleles and complotypes in Mexican patients with seronegative spondyloarthropathies.","date":"1994","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/7826137","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33481054","id":"PMC_33481054","title":"The enigmatic role of HLA-B*27 in spondyloarthritis pathogenesis.","date":"2021","source":"Seminars in immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/33481054","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27028549","id":"PMC_27028549","title":"MICA, MICB Polymorphisms and Linkage Disequilibrium with HLA-B in a Chinese Mongolian Population.","date":"2016","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27028549","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25330014","id":"PMC_25330014","title":"Time to seroconversion in HIV-exposed subjects carrying protective versus non protective KIR3DS1/L1 and HLA-B genotypes.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25330014","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23921616","id":"PMC_23921616","title":"HLA B*5701 status, disease progression, and response to antiretroviral therapy.","date":"2013","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23921616","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37950822","id":"PMC_37950822","title":"HLA-B*27 and Ankylosing Spondylitis: 50 Years of Insights and Discoveries.","date":"2023","source":"Current rheumatology reports","url":"https://pubmed.ncbi.nlm.nih.gov/37950822","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24010680","id":"PMC_24010680","title":"HIV subtype influences HLA-B*07:02-associated HIV disease outcome.","date":"2013","source":"AIDS research and human retroviruses","url":"https://pubmed.ncbi.nlm.nih.gov/24010680","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9839551","id":"PMC_9839551","title":"Repression of the minimal HLA-B promoter by c-myc and p53 occurs through independent mechanisms.","date":"1998","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9839551","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9583813","id":"PMC_9583813","title":"Complete coding sequence of HLA-B*2712: a serologic B27-negative antigen associated to Bw6.","date":"1998","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/9583813","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29760718","id":"PMC_29760718","title":"Multiplexed Nanopore Sequencing of HLA-B Locus in Māori and Pacific Island Samples.","date":"2018","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29760718","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19364518","id":"PMC_19364518","title":"MICA-HLA-B haplotype diversity and linkage disequilibrium in a population of Jewish descent from Majorca (the Balearic Islands).","date":"2009","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19364518","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12074714","id":"PMC_12074714","title":"Distribution of HLA-B alleles in nasopharyngeal carcinoma patients and normal controls in Thailand.","date":"2002","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/12074714","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25257159","id":"PMC_25257159","title":"Detection of HLA-B*58:01 with TaqMan assay and its association with allopurinol-induced sCADR.","date":"2015","source":"Clinical chemistry and laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25257159","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23929683","id":"PMC_23929683","title":"Increased expression of intrinsic antiviral genes in HLA-B*57-positive individuals.","date":"2013","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/23929683","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3871424","id":"PMC_3871424","title":"Complotype genetic loci segregate more frequently with HLA-DR than with HLA-B.","date":"1985","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/3871424","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39024572","id":"PMC_39024572","title":"Mucosal signatures of pathogenic T cells in HLA-B*27+ anterior uveitis and axial spondyloarthritis.","date":"2024","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/39024572","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11380950","id":"PMC_11380950","title":"Non-expression of HLA-B*5111N is caused by an insertion into the cytosine island at exon 4 creating a frameshift stop codon.","date":"2001","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/11380950","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26787826","id":"PMC_26787826","title":"Relative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences.","date":"2016","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/26787826","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10748881","id":"PMC_10748881","title":"HLA-B*27 typing by sequence specific amplification without DNA extraction.","date":"1999","source":"Molecular pathology : MP","url":"https://pubmed.ncbi.nlm.nih.gov/10748881","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35169303","id":"PMC_35169303","title":"HLA-B*07:02 and HLA-C*07:02 are associated with trimethoprim-sulfamethoxazole respiratory failure.","date":"2022","source":"The pharmacogenomics journal","url":"https://pubmed.ncbi.nlm.nih.gov/35169303","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10395111","id":"PMC_10395111","title":"HLA-B*4703: sequence confirmation, serology and distribution.","date":"1999","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/10395111","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34925382","id":"PMC_34925382","title":"The HLA Ligandome Comprises a Limited Repertoire of O-GlcNAcylated Antigens Preferentially Associated With HLA-B*07:02.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34925382","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9008312","id":"PMC_9008312","title":"Molecular analysis of HLA-B in the Malaysian aborigines.","date":"1996","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/9008312","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29021373","id":"PMC_29021373","title":"A Specialist Macaque MHC Class I Molecule with HLA-B*27-like Peptide-Binding Characteristics.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/29021373","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16893385","id":"PMC_16893385","title":"MICA-STR, HLA-B haplotypic diversity and linkage disequilibrium in the Hunan Han population of southern China.","date":"2006","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/16893385","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31784043","id":"PMC_31784043","title":"CD39+ regulatory T cells modulate the immune response to carbamazepine in HLA-B*15:02 carriers.","date":"2019","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/31784043","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21896406","id":"PMC_21896406","title":"HLA-B*27 allele associated to Behçet's disease and to anterior uveitis in Moroccan patients.","date":"2011","source":"Annales de biologie clinique","url":"https://pubmed.ncbi.nlm.nih.gov/21896406","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32817371","id":"PMC_32817371","title":"A Shared TCR Bias toward an Immunogenic EBV Epitope Dominates in HLA-B*07:02-Expressing Individuals.","date":"2020","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/32817371","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10674978","id":"PMC_10674978","title":"HLA-B*4021: hybrid linking the B15 and B40 families.","date":"1999","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/10674978","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30514861","id":"PMC_30514861","title":"Epistatic Interaction of ERAP1 and HLA-B*51 in Iranian Patients with Behçet's Disease.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30514861","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30071035","id":"PMC_30071035","title":"Distinct mechanisms survey the structural integrity of HLA-B*27:05 intracellularly and at the surface.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30071035","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8896172","id":"PMC_8896172","title":"Ligation based HLA-B*27 typing.","date":"1996","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/8896172","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26680341","id":"PMC_26680341","title":"Influence of Glycosylation Inhibition on the Binding of KIR3DL1 to HLA-B*57:01.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26680341","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17610423","id":"PMC_17610423","title":"The nature of recombination in HLA-B*4207.","date":"2007","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/17610423","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8988545","id":"PMC_8988545","title":"A novel recombinant HLA-B*39 allele (B*3910) in a South African Zulu.","date":"1996","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/8988545","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37306379","id":"PMC_37306379","title":"TAP2 Drives HLA-B∗13:01‒Linked Dapsone Hypersensitivity Syndrome Tolerance and Reactivity.","date":"2022","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/37306379","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19571811","id":"PMC_19571811","title":"Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.","date":"2009","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/19571811","citation_count":3645,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10426993","id":"PMC_10426993","title":"Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.","date":"1999","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/10426993","citation_count":2377,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2420472","id":"PMC_2420472","title":"The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides.","date":"1986","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/2420472","citation_count":1673,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16751776","id":"PMC_16751776","title":"A germline-specific class of small RNAs binds mammalian Piwi proteins.","date":"2006","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16751776","citation_count":1362,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18256392","id":"PMC_18256392","title":"HLA-B*5701 screening for hypersensitivity to abacavir.","date":"2008","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18256392","citation_count":1292,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15057820","id":"PMC_15057820","title":"Medical genetics: a marker for Stevens-Johnson syndrome.","date":"2004","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15057820","citation_count":1267,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17641165","id":"PMC_17641165","title":"A whole-genome association study of major determinants for host control of HIV-1.","date":"2007","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/17641165","citation_count":1010,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11888582","id":"PMC_11888582","title":"Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.","date":"2002","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11888582","citation_count":1007,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17785583","id":"PMC_17785583","title":"High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17785583","citation_count":1004,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21051598","id":"PMC_21051598","title":"The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.","date":"2010","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21051598","citation_count":985,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15743917","id":"PMC_15743917","title":"HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15743917","citation_count":955,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8612235","id":"PMC_8612235","title":"Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein.","date":"1996","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8612235","citation_count":874,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19483685","id":"PMC_19483685","title":"HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin.","date":"2009","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19483685","citation_count":750,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22286218","id":"PMC_22286218","title":"Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis.","date":"2012","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22286218","citation_count":737,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17353931","id":"PMC_17353931","title":"Large-scale mapping of human protein-protein interactions by mass spectrometry.","date":"2007","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/17353931","citation_count":733,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21743469","id":"PMC_21743469","title":"Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21743469","citation_count":729,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12519789","id":"PMC_12519789","title":"Proteomic and biochemical analyses of human B cell-derived exosomes. Potential implications for their function and multivesicular body formation.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12519789","citation_count":708,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10403641","id":"PMC_10403641","title":"The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells.","date":"1999","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/10403641","citation_count":704,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1922337","id":"PMC_1922337","title":"The structure of HLA-B27 reveals nonamer self-peptides bound in an extended conformation.","date":"1991","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/1922337","citation_count":688,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14718574","id":"PMC_14718574","title":"The human plasma proteome: a nonredundant list developed by combination of four separate sources.","date":"2004","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/14718574","citation_count":658,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19525953","id":"PMC_19525953","title":"Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci.","date":"2009","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19525953","citation_count":639,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1525820","id":"PMC_1525820","title":"The three-dimensional structure of HLA-B27 at 2.1 A resolution suggests a general mechanism for tight peptide binding to MHC.","date":"1992","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/1525820","citation_count":615,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12029127","id":"PMC_12029127","title":"Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level.","date":"2002","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12029127","citation_count":610,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19056867","id":"PMC_19056867","title":"Large-scale proteomics and phosphoproteomics of urinary exosomes.","date":"2008","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/19056867","citation_count":607,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50659,"output_tokens":6514,"usd":0.124843},"stage2":{"model":"claude-opus-4-6","input_tokens":10156,"output_tokens":4585,"usd":0.248108},"total_usd":0.727288,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":62960,"output_tokens":6559,"usd":0.143632},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":10454,"output_tokens":3528,"usd":0.210705}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1976,\n      \"finding\": \"HLA-B specificities and the Bw4/Bw6 supertypic specificities are located on the same polypeptide chain, demonstrated by sequential immunoprecipitation of papain-solubilized membrane proteins showing that HLA-B7 and w6, and HLA-B12 and w4, are distinct antigenic determinants on the same molecule.\",\n      \"method\": \"Sequential immunoprecipitation of radiolabeled, papain-solubilized lymphoblastoid cell line membrane proteins with alloantisera to HLA-B7, HLA-B12, w4, and w6\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical reconstitution (immunoprecipitation) demonstrating co-purification of determinants on the same polypeptide\",\n      \"pmids\": [\"63373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"c-Myc oncoprotein transcriptionally suppresses HLA-B expression through the core promoter region (a -68 to +13 bp fragment encompassing the CCAAT and TATA elements), independently of the enhancer A or enhancer B regions, as demonstrated by reporter transfection assays in melanoma cells.\",\n      \"method\": \"HLA-B promoter-reporter construct transfection in melanoma cell lines with varying c-Myc expression; deletion analysis mapping the responsive region to the 43 bp core promoter\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reporter assay with deletion mapping and functional c-Myc overexpression/low-expression comparison\",\n      \"pmids\": [\"8206526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"HLA-B molecules (HLA-B*4801) present peptides with glutamine or lysine at position 2 and leucine at the C-terminus, and the B*4801 heavy chain binds CD8α homodimers weakly due to a threonine at position 245 in the α3 domain; mutation of Thr245 to Ala restores CD8 binding to levels of other HLA class I allotypes.\",\n      \"method\": \"Pool sequencing of endogenously bound peptides from HLA class I-deficient 221 cells transfected with B*4801 cDNA; in vitro cell-cell binding assay with CD8α homodimers; site-directed mutagenesis of residue 245\",\n      \"journal\": \"Tissue antigens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro assay plus mutagenesis demonstrating CD8-binding mechanism\",\n      \"pmids\": [\"9331948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"In TAP-deficient individuals, HLA-B molecules are the predominant class I products expressed on the cell surface and can present peptides (including a TAP-independent EBV LMP2 epitope) to CD8+ cytotoxic T cells via a TAP-independent processing pathway.\",\n      \"method\": \"Cytofluorometry, biochemical analysis of cell-surface HLA-I expression on TAP-deficient EBV B-LCLs; peptide elution and sequencing; isolation and functional testing of CD8+ T cell clones\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical analysis plus functional T cell cloning with defined phenotypic readout\",\n      \"pmids\": [\"9144467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Wild-type p53 represses the HLA-B core promoter, but c-Myc suppression of HLA-B operates through a p53-independent mechanism, as c-Myc still suppresses the basal HLA-B promoter in p53-null cell lines.\",\n      \"method\": \"Transfection of wild-type p53 and c-Myc into p53-null and p53-expressing cell lines; HLA-B promoter-reporter assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis-type experiment using null cell lines plus reporter assay, single lab\",\n      \"pmids\": [\"9839551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The crystal structure of HLA-B*3501 at 1.5 Å resolution shows that a 14-mer peptide is anchored at its N and C termini in the A and F pockets, with the central portion bulging flexibly out of the groove; substitutions at P2 or P2/P9 alter peptide conformation and MHC α-helical regions, reducing T cell activation.\",\n      \"method\": \"X-ray crystallography of HLA-B*3501/14-mer peptide complex at 1.5 Å; peptide variants with Ala substitutions tested for T cell activation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation by mutagenesis and T cell assays\",\n      \"pmids\": [\"15494511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HLA-B*15:02 directly binds carbamazepine (CBZ) in a peptide-dependent manner without requiring intracellular drug metabolism or antigen processing; three residues (Asn63, Ile95, Leu156) in the peptide-binding groove are critical for CBZ presentation and CTL activation, with Asn63 being the key residue shared by the disease-associated HLA-B75 family.\",\n      \"method\": \"Surface plasmon resonance, peptide-binding assay, site-directed mutagenesis of HLA-B*15:02, CTL activation assays, computer modeling of CBZ docking into HLA-B*15:02 peptide-binding groove\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted binding with SPR, mutagenesis identifying key residues, and functional CTL readout\",\n      \"pmids\": [\"22322005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HLA-B polymorphisms profoundly influence assembly characteristics and peptide-loading efficiency; dependence on the assembly factor tapasin is highly variable across HLA-B allotypes, with certain polymorphic residues near the C-terminal end of the peptide-binding groove being key determinants of tapasin-independent assembly.\",\n      \"method\": \"In vitro refolding assays of 27 HLA-B allotypes; TAP-deficient cell expression; aggregation and stability measurements; comparison to HIV disease outcome data\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — broad in vitro allotype survey with reconstitution and mechanistic follow-up linking tapasin dependence to assembly and disease\",\n      \"pmids\": [\"24790147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIR3DS1 recognition of HLA-B*57:01 is peptide-dependent; specific HIV-derived peptide epitopes presented by HLA-B*57:01 facilitate productive interactions between HLA-B*57:01 and the activating NK receptor KIR3DS1, identified through a structure-driven approach.\",\n      \"method\": \"Structure-guided identification of peptide characteristics enabling KIR3DS1 interaction; functional binding assays with HLA-B*57:01/peptide complexes and KIR3DS1\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structure-driven approach with functional validation demonstrating peptide-dependent KIR3DS1 engagement\",\n      \"pmids\": [\"25740999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"N-glycosylation of HLA-B*57:01 is required for KIR3DL1 binding; inhibition of N-glycosylation with tunicamycin significantly reduces KIR3DL1-Fc binding to HLA-B*57:01 on cell surfaces, decreases KIR3DL1ζ+ Jurkat reporter activation, and increases degranulation of primary KIR3DL1+ NK cells.\",\n      \"method\": \"Glycosylation inhibitor panel on HLA-B*57:01-expressing 721.221 cells; flow cytometric KIR3DL1-Fc binding assay; KIR3DL1ζ+ Jurkat reporter assay; primary NK cell degranulation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays showing mechanism of glycosylation-dependent KIR binding\",\n      \"pmids\": [\"26680341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HIV-1 Nef downregulates HLA-B less efficiently than HLA-A due to absence of C-terminal Cys-Lys-Val residues in HLA-B; Nef codon 202 is a key polymorphic site modulating differential HLA-A versus HLA-B downregulation, confirmed by site-directed mutagenesis.\",\n      \"method\": \"Flow cytometry of Nef-mediated HLA downregulation using 46 patient-derived Nef clones; site-directed mutagenesis of Nef-202; in silico analysis of HLA cytoplasmic tail interactions; luciferase reporter T cell co-culture assay\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — patient-derived Nef library plus mutagenesis with functional immune recognition readout\",\n      \"pmids\": [\"26787826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HLA-B molecules present phosphorylated peptides predominantly with phosphorylation at peptide position 4 (P4), dictated by the conserved Arg62 residue in the HLA-B heavy chain; crystal structure of HLA-B*40 with a phosphopeptide explains why this structural feature is shared across most HLA-B alleles.\",\n      \"method\": \"Immunopeptidomics mass spectrometry of four HLA-B allotypes; peptide binding assays; crystal structure determination of HLA-B*40 with phosphorylated and non-phosphorylated ligands\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus peptidomics plus binding assays providing mechanistic explanation\",\n      \"pmids\": [\"27920218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HLA-B*46:01, formed by intergenic recombination introducing HLA-C1 epitope into an HLA-B allotype, has a distinctive low-diversity peptidome; a minority (21%) of its peptides with specific C-terminal characteristics function as KIR2DL3 ligands, making HLA-B*46:01 the only common HLA-B allotype recognized by the C1-specific NK receptor KIR2DL3.\",\n      \"method\": \"High-resolution mass spectrometry peptidome analysis; KIR2DL3 ligand prediction and validation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — high-resolution peptidome mapping with functional KIR binding characterization\",\n      \"pmids\": [\"28514659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Approximately 15% of HLA-B allotypes (including certain HLA-B*35, B*57, and B*15 alleles) are expressed at relatively high levels on TAP1- or TAP2-deficient cell surfaces; TAP-independent expression requires synergy between high peptide loading efficiency, broad peptide specificity from unconventional sources, and high intrinsic stability of the empty form. These TAP-independent allotypes are more resistant to viral TAP inhibitor-induced HLA-I downmodulation.\",\n      \"method\": \"Expression testing of 27 HLA-B alleles in TAP1/TAP2-deficient cells; Endoglycosidase H sensitivity assay; NK cell activation assay with viral TAP inhibitors\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic broad allotype survey with multiple orthogonal assays and functional NK/T cell readouts\",\n      \"pmids\": [\"29995954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HLA-B*57:01 transgenic mice tolerate abacavir in vivo through CD4+ T cell-dependent induction of anergy-like CD8+ T cell phenotype; depletion of CD4+ T cells prior to abacavir administration instead leads to DC maturation and generation of HLA-B*57:01-restricted, systemic effector CD8+ T cells with skin-homing phenotype, and B7 costimulatory blockade prevents this CD8+ T cell activation.\",\n      \"method\": \"HLA-B*57:01 transgenic mouse model; in vivo CD4+ T cell depletion; DC maturation assay; B7 blockade; flow cytometric characterization of CD8+ T cell phenotype and skin biopsy\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic mouse model with multiple experimental interventions defining CD4-CD8-DC pathway\",\n      \"pmids\": [\"29782330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HLA-B*27 subtypes associated with ankylosing spondylitis (B*27:04 and B*27:05) exhibit increased conformational flexibility compared to non-associated subtypes (B*27:06 and B*27:09), as measured by isotope-edited infrared spectroscopy; crystal structures show that the single-amino-acid differences between subtypes result in subtype-dependent peptide binding conformations.\",\n      \"method\": \"X-ray crystallography of pVIPR-peptide/HLA-B*27:04 and pVIPR-peptide/HLA-B*27:06 complexes; isotope-edited infrared spectroscopy to probe molecular dynamics\",\n      \"journal\": \"Arthritis & rheumatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus biophysical spectroscopy identifying structural mechanism differentiating disease-associated subtypes\",\n      \"pmids\": [\"26748477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HLA-B*27:05 in the absence of peptide is structurally unstable; empty or suboptimally loaded HLA-B*27:05 can escape intracellular retention and appear on the cell surface as β2m-free heavy chains; an artificially introduced disulfide bond between residues 84 and 139 confers enhanced conformational stability to suboptimally loaded molecules.\",\n      \"method\": \"Intracellular transport and folding assays; cell surface expression analysis; engineered disulfide bond mutagenesis; comparison between murine and human early secretory pathways\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis plus cell biology experiments demonstrating quality-control mechanism for HLA-B*27:05\",\n      \"pmids\": [\"30071035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Pro-inflammatory cytokines TNFα and IFNγ increase HLA-B expression in lung cancer cells, and increased HLA-B allomorph levels independently drive significant changes in the HLA-bound immunopeptidome, beyond the changes attributable to overall proteome remodeling.\",\n      \"method\": \"Cytokine stimulation of lung cancer cells; quantitative immunopeptidomics by mass spectrometry; proteome analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative immunopeptidomics with cytokine perturbation, single lab\",\n      \"pmids\": [\"30833945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Flucloxacillin (FLX) covalently modifies multiple proteins in immune cells and generates haptenated peptides presented by HLA-B*57:01; six putative FLX-modified HLA-B*57:01 ligands were identified by immunopeptidomics, including peptides with FLX-modified lysine residues, establishing antigen processing and neoantigen formation as the mechanism of HLA-B*57:01-linked FLX-induced liver injury.\",\n      \"method\": \"Mass spectrometry-based immunopeptidomics of FLX-treated C1R-B*57:01 cells; characterization of FLX-protein adducts\",\n      \"journal\": \"Toxicological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical identification of drug-haptenated HLA ligands by immunopeptidomics\",\n      \"pmids\": [\"32726429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FLX treatment of HLA-B*57:01-expressing cells enriches the immunopeptidome with peptides containing C-terminal tryptophan and FLX-haptenated lysine residues; FLX-modified peptides with drug at P4 or P6 induce drug-specific CD8+ T cells in vivo in HLA-B*57:01 transgenic mice; FLX also directly modifies the HLA-B Lys146 residue, potentially interfering with KIR-3DL or peptide interactions.\",\n      \"method\": \"Immunopeptidomics by mass spectrometry; in vivo immunization of HLA-B*57:01 transgenic mice with FLX-modified peptides; CD8+ T cell response assays; identification of covalent FLX modification on HLA-B K146\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo and in vitro mechanistic studies with mass spectrometry and functional T cell assays\",\n      \"pmids\": [\"33633747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Autoimmunity-associated public TCRs bearing a BV9-CDR3β motif with consistent AV21 chain pairing are clonally expanded in joints (ankylosing spondylitis) and eyes (acute anterior uveitis) of HLA-B*27 patients; HLA-B*27:05 yeast display peptide libraries identified shared self-peptides and microbial peptides that activate these TCRs, and structural analysis revealed a shared binding motif present in both self- and microbial antigens engaging BV9-CDR3β TCRs.\",\n      \"method\": \"TCR isolation from blood and synovial fluid/eye; HLA-B*27:05 yeast display peptide libraries; structural analysis of TCR-pMHC complex\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — yeast display library screening plus structural analysis identifying shared TCR-pHLA-B*27 binding motif across self and microbial antigens\",\n      \"pmids\": [\"36477533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TAP2 (and TAP1) expression levels regulate the efficiency of antigen processing and presentation by HLA-B*13:01, with higher TAP1/TAP2 mRNA levels in dapsone hypersensitivity syndrome (DHS) patients (all HLA-B*13:01+) and enhanced capacity to activate dapsone-specific T cells; TAP functional impairment blocks dapsone-specific T cell activation.\",\n      \"method\": \"GWAS; genome-wide DNA methylation analysis; quantitative PCR of TAP1/TAP2; in vitro antigen presentation and T cell activation assays with TAP inhibition\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional in vitro experiments with TAP inhibition and direct T cell activation readout linking TAP to HLA-B*13:01 presentation\",\n      \"pmids\": [\"37306379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KIR3DL1 allotypes vary in NK cell expression and inhibitory capacity upon binding HLA-B Bw4 molecules; different KIR3DL1/HLA-B allelic combinations generate discrete hierarchies of NK cell inhibition, with genetically predicted weak or non-inhibitory combinations correlating with lower AIDS progression rates in over 1,500 HIV+ individuals.\",\n      \"method\": \"Genetic epistasis analysis in large HIV+ cohort; correlation with previously defined functional KIR3DL1 allotype differences\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large-scale epistasis analysis with functional correlate data across >1500 patients replicating functional allotype hierarchy\",\n      \"pmids\": [\"17496894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"An epistatic interaction between the activating NK receptor KIR3DS1 and HLA-B alleles encoding Bw4-80Ile delays AIDS progression; neither locus alone shows a consistent protective effect, indicating that KIR3DS1 functionally engages HLA-B Bw4-80Ile ligands to mediate NK cell protection against HIV-1.\",\n      \"method\": \"Genetic epistasis analysis across multiple HIV+ cohorts; statistical interaction testing between KIR3DS1 and HLA-B Bw4-80Ile alleles for AIDS outcomes\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis across multiple cohorts demonstrating ligand-receptor functional interaction\",\n      \"pmids\": [\"12134147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YeiH-specific CD8+ T cells recognizing an enteric bacterial peptide (YeiH) presented by HLA-B*27 express a mucosal gene set and surface proteins consistent with intestinal differentiation (CD161, integrin α4β7, CCR6), and are clonally expanded in blood of axSpA and B27AAU patients compared to controls, suggesting early antigen priming occurs in the gastrointestinal tract.\",\n      \"method\": \"Ocular, synovial, and blood T cell analysis; tetramer staining with HLA-B*27/YeiH; flow cytometry for mucosal markers; clonal expansion analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional T cell characterization with antigen-specific tetramer and mucosal marker profiling, single study\",\n      \"pmids\": [\"39024572\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HLA-B is a highly polymorphic MHC class I heavy chain that assembles in the endoplasmic reticulum—in a tapasin-dependent or tapasin-independent manner depending on allotype—with β2-microglobulin and peptides derived from the cytosol (via TAP or TAP-independent routes), presents them at the cell surface to CD8+ T cells and NK cell receptors (KIR3DL1/S1, KIR2DL3), and mediates immune surveillance whose specificity and efficiency are determined by allotype-specific peptide-binding groove architecture, N-glycosylation, conformational stability, and susceptibility to viral immune evasion (e.g., HIV Nef-mediated downregulation); specific allotypes directly bind small-molecule drugs (e.g., carbamazepine to HLA-B*15:02 via Asn63 in the peptide-binding groove) or present drug-haptenated peptides (HLA-B*57:01 with abacavir/flucloxacillin) to trigger CD8+ T cell-mediated hypersensitivity, while disease-associated allotypes such as HLA-B*27:05 exhibit increased conformational flexibility and present self/microbial peptides to autoreactive public TCRs implicated in spondyloarthritis.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1976,\n      \"finding\": \"HLA-B specificities (e.g., HLA-B7, HLA-B12) and the Bw4/Bw6 diallelic system are distinct antigenic determinants located on the same polypeptide chain, demonstrated by sequential immunoprecipitation of papain-solubilized membrane proteins with alloantisera to HLA-B7, HLA-B12, w4 and w6.\",\n      \"method\": \"Sequential immunoprecipitation of 125I-labeled papain-solubilized lymphoblastoid cell membrane proteins with HLA-B and Bw4/Bw6 alloantisera\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical reconstitution/co-purification with orthogonal antisera; foundational result\",\n      \"pmids\": [\"63373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Crystal structure of HLA-B27 reveals that nonameric self-peptides are bound in an extended conformation within the antigen-binding cleft, with peptide termini anchored in pockets and side chains at defined positions (especially Arg at position 2) contacting allele-specific pockets.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with direct visualization of peptide-binding mode\",\n      \"pmids\": [\"1922337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The 2.1 Å crystal structure of HLA-B27 shows that tight peptide binding results from extensive contacts at both ends of the peptide cleft between main-chain atoms and conserved MHC side chains, and that the Arg anchor at peptide position 2 inserts into an HLA-B27-specific pocket, suggesting a general mechanism for peptide binding.\",\n      \"method\": \"X-ray crystallography at 2.1 Å resolution\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with mechanistic interpretation, foundational paper\",\n      \"pmids\": [\"1525820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Transcriptional suppression of HLA-B expression by c-Myc overexpression is mediated through the core promoter region (a 43 bp fragment containing CCAAT and TATA elements), independently of enhancer A or enhancer B regions, indicating c-Myc interferes with basal transcription initiation.\",\n      \"method\": \"Transfection of HLA-B reporter constructs with variable promoter deletions into melanoma cell lines with high/low c-myc expression; heterologous enhancer coupling assay\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter deletion mapping and heterologous enhancer experiments in a single lab\",\n      \"pmids\": [\"8206526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"HIV-1 Nef protein induces rapid endocytosis of MHC class I molecules (including HLA-B) from the cell surface of lymphoid, monocytic and epithelial cells; Nef does not affect MHC-I synthesis or transport through the ER/cis-Golgi but causes surface MHC-I to accumulate in endosomal vesicles and undergo degradation.\",\n      \"method\": \"Expression of HIV-1 Nef in multiple cell types; immunofluorescence, subcellular fractionation, flow cytometry to track MHC-I trafficking\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell types, multiple methods, widely replicated; foundational mechanistic paper\",\n      \"pmids\": [\"8612235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"In TAP-deficient patients, the majority of cell-surface class I molecules are HLA-B products; two peptides eluted from these HLA-B molecules are derived from cytosolic proteins presented via a TAP-independent pathway, and an EBV LMP2-specific cytotoxic CD8+ T cell clone recognizes LMP2 presented by HLA-B on TAP-deficient cells.\",\n      \"method\": \"Cytofluorometry, biochemical analysis, peptide elution and sequencing from TAP-deficient EBV-transformed B-LCL, CTL cloning and cytotoxicity assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct peptide elution plus functional CTL assay, multiple orthogonal methods\",\n      \"pmids\": [\"9144467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"HLA-B*1501 presents a defined set of peptides with a consistent binding signature identified by large-scale production using hollow-fiber bioreactors combined with mass spectrometry, establishing that individual HLA-B alleles have allele-specific peptide-binding repertoires.\",\n      \"method\": \"Hollow-fiber bioreactor scale production of HLA-B*1501 plus bound peptides; mass spectrometry peptide mapping\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical isolation and MS identification of natural ligands; single lab\",\n      \"pmids\": [\"9089095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"HLA-B*4801 selects nonamer peptides with Gln or Lys at position 2 and Leu at the C-terminus (defined by pool sequence analysis), and binds CD8α homodimers weakly due to Thr245 in the α3 domain; a Thr245Ala mutation restores CD8 binding to normal levels, yet alloreactive T cells recognizing B*4801 are still inhibited by anti-CD8 antibodies.\",\n      \"method\": \"Endogenous peptide pool sequencing from HLA-class-I-deficient 221 cell transfectants; in vitro cell-cell CD8 binding assay; site-directed mutagenesis of Thr245Ala; flow cytometry\",\n      \"journal\": \"Tissue antigens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — peptide motif definition, mutagenesis of CD8-contact residue, functional CD8-binding assay in same study\",\n      \"pmids\": [\"9331948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Wild-type p53 represses the HLA-B core promoter, and c-Myc-induced HLA-B downregulation is independent of p53 because c-Myc suppresses the basal HLA-B promoter even in p53-null cell lines, demonstrating that c-Myc and p53 repress the minimal HLA-B promoter through independent mechanisms.\",\n      \"method\": \"Transfection of HLA-B core promoter reporter constructs in p53-null melanoma lines with and without c-myc; co-transfection of wild-type p53\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assays in p53-null lines plus p53 cotransfection; single lab, moderate evidence\",\n      \"pmids\": [\"9839551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HIV-1 Nef selectively downregulates HLA-A and HLA-B but not HLA-C or HLA-E from the cell surface; residues in the cytoplasmic tails of HLA-C and HLA-E protect them from Nef-mediated downregulation, allowing HIV-infected cells to escape NK cell lysis while evading CTL.\",\n      \"method\": \"Flow cytometry of HIV-1-infected lymphoid cells expressing defined HLA molecules; domain-swap and mutagenesis to identify protective HLA cytoplasmic tail residues; NK cell cytotoxicity assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of cytoplasmic tail residues plus functional NK and CTL assays; widely replicated\",\n      \"pmids\": [\"10403641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structure of HLA-B*3501 at 1.5 Å bound to an unusually long 14-mer peptide shows that the N- and C-termini are embedded in the A and F pockets (as for normal-length peptides) while the central region bulges flexibly out of the groove; two peptide variants with Ala substitutions at P2 or P2+P9 show altered flexibility and conformation and reduced T cell activation, implicating both peptide conformation and MHC α-helical dynamics in TCR engagement.\",\n      \"method\": \"X-ray crystallography at 1.5 Å; site-directed mutagenesis of peptide positions; T cell activation assays with CTL clones\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis plus functional T cell assay in one study\",\n      \"pmids\": [\"15494511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Large-scale direct biochemical analysis of HLA-B*2705-bound peptides (the 'peptidome') using recombinant soluble HLA-B27 secreted from chondrocytic and HeLa cells, combined with tandem MS, identified 1,268 B27 peptides and refined the B27 binding motif including a propensity for long peptides whose central residues bulge from the groove; candidate molecular mimicry peptides were found between human cartilage proteins and bacterial sequences.\",\n      \"method\": \"Recombinant soluble HLA-B*2705 immunoaffinity purification from cell lines; capillary LC-MS/MS; SILAC and iTRAQ quantitation\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — large-scale direct biochemical peptide identification with stable isotope validation\",\n      \"pmids\": [\"20112406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Direct physical interaction between HLA-B*1502 protein (loaded with endogenous peptides) and carbamazepine (CBZ) activates CBZ-specific CTLs without intracellular drug metabolism or antigen processing; surface plasmon resonance and peptide-binding assays showed the HLA-B*1502/peptide/β2m complex binds CBZ and analogs sharing the 5-carboxamide tricyclic ring; site-directed mutagenesis identified three key residues in the peptide-binding groove (Asn63, Ile95, Leu156) with Asn63 being essential; computer modeling revealed preferred binding at the B pocket via Arg62 interaction.\",\n      \"method\": \"In vitro CTL expansion and activation; surface plasmon resonance; peptide-binding assay; site-directed mutagenesis; molecular dynamics modeling\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (SPR, mutagenesis, peptide binding, functional CTL assay) in one study\",\n      \"pmids\": [\"22322005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HLA-B polymorphisms profoundly influence the assembly characteristics of HLA-B molecules and the stability of their peptide-deficient forms; dependence on the assembly factor tapasin varies markedly among allotypes, with several polymorphic residues near the C-terminal end of the peptide groove being key determinants of tapasin-independent assembly; tapasin-independent allotypes refold more readily with peptides in vitro and show less aggregation during refolding.\",\n      \"method\": \"Flow cytometry of HLA-B surface expression in tapasin-deficient cells; in vitro refolding assays with defined peptides; aggregation assays; comparison across multiple HLA-B allotypes\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical refolding assays plus cell-based expression in tapasin-KO cells; multiple allotypes tested\",\n      \"pmids\": [\"24790147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIR3DS1 recognition of HLA-B*57:01 is peptide-dependent; structure-guided screening identified HIV-derived peptide epitopes presented by HLA-B*57:01 that facilitate productive KIR3DS1 binding, demonstrating that changes in the peptide repertoire during viral infection can trigger KIR3DS1 engagement and NK cell activation.\",\n      \"method\": \"Structure-driven peptide screening; binding assays between KIR3DS1 and HLA-B*57:01-peptide complexes; functional NK cell assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structure-guided approach plus binding and functional NK assays; single lab\",\n      \"pmids\": [\"25740999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Phosphorylation at peptide position 4 (P4) predominates in HLA-B-associated phosphopeptide ligands across multiple HLA-B alleles, dictated by the conserved Arg62 residue in the HLA-B heavy chain; crystal structures of HLA-B*40 bound to a phosphopeptide versus its non-phosphorylated counterpart confirmed structural accommodation of phospho-P4 by Arg62; preference for basic residues at P1 is allotype-dependent and linked to A-pocket structure.\",\n      \"method\": \"Immunopeptidomics (peptidomic workflow); peptide-binding assays; X-ray crystallography of HLA-B*40/phosphopeptide complex\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus peptidomics plus binding assays in one study\",\n      \"pmids\": [\"27920218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Conformational flexibility is elevated in disease-associated HLA-B*27 subtypes (B*27:04 and B*27:05) compared to non-disease-associated subtypes (B*27:06 and B*27:09), as measured by isotope-edited IR spectroscopy; crystal structures of pVIPR-B*27:04 and pVIPR-B*27:06 show that B*27:04 presents the peptide in a single conventional conformation while B*27:06 shows dual conformation, separating dual peptide conformation from increased molecular dynamics as distinct structural features.\",\n      \"method\": \"X-ray crystallography; isotope-edited infrared (IR) spectroscopy to probe molecular dynamics\",\n      \"journal\": \"Arthritis & rheumatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures plus biophysical dynamics measurement in same study\",\n      \"pmids\": [\"26748477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HIV-1 Nef downregulates HLA-B less efficiently than HLA-A from the surface of HIV-infected cells; the differential effect maps to Nef codon 202 (confirmed by site-directed mutagenesis) and to C-terminal CKV residues present in HLA-A but absent in HLA-B cytoplasmic tails; the degree of HLA-B relative resistance correlates inversely with the ability of HIV-specific T cells to recognize infected cells.\",\n      \"method\": \"Flow cytometry of 46 patient-derived Nef clones; Nef site-directed mutagenesis; coculture T cell recognition assay; in silico Nef codon function analysis\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of Nef-202 and HLA cytoplasmic tail, functional T cell recognition assay, multiple patient clones\",\n      \"pmids\": [\"26787826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HLA-B*46:01, formed by intergenic mini-conversion between HLA-B*15:01 and HLA-C*01:02, carries the C1 epitope and is recognized by NK receptor KIR2DL3; high-resolution MS showed B*46:01 has a low-diversity peptidome distinct from its parental alleles; a minority (21%) of B*46:01 peptides sharing C-terminal characteristics serve as KIR2DL3 ligands, linking peptidome composition to NK receptor recognition.\",\n      \"method\": \"High-resolution mass spectrometry immunopeptidomics; KIR2DL3 binding assays; sequence analysis of mini-conversion\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical peptidome characterization plus NK receptor binding functional assay\",\n      \"pmids\": [\"28514659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Multiple HLA-B allotypes (~15% of 27 tested) are expressed at relatively high levels on the surface of TAP1- or TAP2-deficient cells and occur in partially peptide-receptive and EndoH-sensitive forms, indicating TAP-independent assembly; synergy between high peptide-loading efficiency, broad specificity for peptides from unconventional sources, and high intrinsic stability of the empty form underlies TAP-independent assembly of certain HLA-B*35, B*57 and B*15 alleles; TAP-independent allotypes are more resistant to viral TAP inhibitor-induced HLA-I downmodulation.\",\n      \"method\": \"Flow cytometry of 27 HLA-B alleles in TAP1/TAP2-deficient cells; EndoH sensitivity assay; peptide-binding/loading efficiency assays; viral TAP inhibitor experiments; NK cell activation assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic survey of 27 alleles with biochemical and functional assays across multiple methods\",\n      \"pmids\": [\"29995954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In HLA-B*27:05, empty or suboptimally loaded molecules can escape intracellular retention and reach the cell surface as β2m-free heavy chains; an artificial disulfide bond between residues 84 and 139 confers enhanced conformational stability to suboptimally loaded molecules; a general quality control mechanism in the early secretory pathway (conserved between mouse and human cells) distinguishes poorly loaded from optimally loaded MHC-I, but is allotype-specifically permissive for HLA-B*27:05.\",\n      \"method\": \"Cell-based transport/trafficking assays; disulfide bond engineering (Cys84-Cys139 mutagenesis); flow cytometry; comparison of murine and human cell lines\",\n      \"journal\": \"PLoS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis plus cell-based trafficking; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"30071035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Pro-inflammatory cytokines TNFα and IFNγ increase HLA-B allomorph expression in lung cancer cells, and elevated HLA-B expression independently drives significant changes in the HLA-bound immunopeptidome beyond those attributable to proteome changes alone.\",\n      \"method\": \"Quantitative immunopeptidomics; proteomics; cytokine stimulation; flow cytometry of HLA-B surface levels\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — immunopeptidomics plus quantitative proteomics; single lab, moderate evidence\",\n      \"pmids\": [\"30833945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Flucloxacillin (FLX) directly modifies HLA-B*57:01 at Lys146 (covalent haptenation), alters anchor residue frequencies in the immunopeptidome (enriching peptides with C-terminal Trp and FLX-haptenated Lys), and haptenated peptides at P4 and P6 induce drug-specific CD8+ T cells in HLA-B*57:01-transgenic mice; FLX modification at K146 may also impair KIR-3DL or peptide interactions.\",\n      \"method\": \"Mass spectrometry-based immunopeptidomics; in vivo immunization of HLA-B*57:01-Tg mice with drug-haptenated peptides; CD8+ T cell assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — direct MS identification of haptenated peptides plus in vivo functional assay; single lab\",\n      \"pmids\": [\"33633747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD8+ T cells bearing disease-associated public TCRs (BV9-CDR3β motif with AV21 pairing) clonally expanded in joint (AS) and eye (AAU) of HLA-B*27 patients recognize self-peptides and microbial peptides presented by HLA-B*27:05 but not B*27:09; structural analysis revealed that TCR cross-reactivity is rooted in a shared binding motif at the peptide-MHC interface engaged by the BV9-CDR3β TCRs; HLA-B*27:05 yeast display peptide libraries identified the activating peptides.\",\n      \"method\": \"HLA-B*27:05 yeast display peptide library screening; crystal structure of TCR–HLA-B*27:05–peptide complexes; T cell cloning from joint/eye; TCR sequencing\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus functional T cell activation plus yeast display library; replicated across patient cohorts\",\n      \"pmids\": [\"36477533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"N-glycosylation of HLA-B*57:01 is required for efficient KIR3DL1 binding; tunicamycin treatment (blocking the first step of N-glycosylation) significantly reduces KIR3DL1-Fc binding to HLA-B*57:01-expressing cells despite sustained HLA-B*57:01 surface expression, and decreases KIR3DL1ζ+ Jurkat reporter activation while increasing degranulation of primary KIR3DL1+ NK cell clones.\",\n      \"method\": \"Glycosylation enzyme inhibitor panel; KIR3DL1-Fc binding assay by flow cytometry; KIR3DL1ζ+ Jurkat reporter assay; primary NK cell degranulation assay\",\n      \"journal\": \"PLoS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological glycosylation inhibition with multiple functional readouts; single lab\",\n      \"pmids\": [\"26680341\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HLA-B is a highly polymorphic MHC class I heavy chain that assembles in the endoplasmic reticulum with β2-microglobulin and peptides (8–14 mers) via a tapasin-dependent or -independent pathway depending on allotype, presents them at the cell surface for CD8+ T cell and NK cell (KIR3DL1/KIR3DS1) surveillance, with peptide binding governed by allele-specific pockets (especially a conserved Arg62 that accommodates phospho-P4 residues), N-glycosylation facilitating KIR binding, and expression controlled at the transcriptional level by c-Myc and p53 acting independently on the core promoter, while HIV-1 Nef exploits allele-specific cytoplasmic tail differences to preferentially downregulate HLA-A over HLA-B via endocytosis, and certain alleles (B*27, B*57, B*1502, B*5801) confer disease susceptibility or drug hypersensitivity through direct drug–peptide–HLA interactions and presentation of arthritogenic or drug-haptenated peptides to autoreactive CD8+ T cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HLA-B encodes a highly polymorphic MHC class I heavy chain that assembles with β2-microglobulin and peptide in the endoplasmic reticulum and presents endogenous peptides—including phosphopeptides anchored via the conserved Arg62 residue at position 4—to CD8+ T cells and NK cell receptors (KIR3DL1, KIR3DS1, KIR2DL3) at the cell surface [PMID:27920218, PMID:17496894, PMID:28514659]. Allotype-specific polymorphisms in the peptide-binding groove govern peptide repertoire, tapasin dependence during assembly, TAP-independent surface expression, conformational stability of the empty heavy chain, CD8 co-receptor engagement, and N-glycosylation-dependent KIR recognition [PMID:24790147, PMID:29995954, PMID:9331948, PMID:26680341]. Specific allotypes directly bind small-molecule drugs (carbamazepine to HLA-B*15:02 via Asn63) or present drug-haptenated peptides (flucloxacillin- and abacavir-modified neoantigens by HLA-B*57:01) to elicit CD8+ T cell–mediated hypersensitivity reactions, while disease-associated HLA-B*27:05 exhibits increased conformational flexibility and presents shared self/microbial peptide motifs to clonally expanded public TCRs implicated in ankylosing spondylitis and acute anterior uveitis [PMID:22322005, PMID:33633747, PMID:26748477, PMID:36477533].\",\n  \"teleology\": [\n    {\n      \"year\": 1976,\n      \"claim\": \"Establishing that HLA-B private specificities and Bw4/Bw6 supertypic determinants reside on the same polypeptide chain resolved a fundamental question about the molecular identity of HLA-B gene products.\",\n      \"evidence\": \"Sequential immunoprecipitation of radiolabeled papain-solubilized membrane proteins from lymphoblastoid cell lines\",\n      \"pmids\": [\"63373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural information on where Bw4/Bw6 epitopes map on the three-dimensional molecule\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstration that HLA-B molecules are the predominant MHC class I expressed on TAP-deficient cells and can present viral epitopes to CD8+ T cells via TAP-independent pathways established that HLA-B has an alternative antigen-loading route, later shown to involve intrinsic stability and broad peptide specificity of specific allotypes.\",\n      \"evidence\": \"Flow cytometry, peptide elution, and CD8+ CTL cloning from TAP-deficient EBV B-LCLs; later systematic survey of 27 allotypes in TAP1/2-deficient cells\",\n      \"pmids\": [\"9144467\", \"29995954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the TAP-independent peptide source compartment remains unclear\", \"Relative contribution of signal peptide-derived versus other peptides in TAP-independent loading not fully delineated\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification that a single residue (Thr245) in the α3 domain of HLA-B*4801 weakens CD8α binding—restored by Thr245Ala mutation—revealed that allotypic polymorphism outside the peptide-binding groove modulates co-receptor engagement.\",\n      \"evidence\": \"Pool peptide sequencing, cell-cell CD8α binding assay, and site-directed mutagenesis in HLA class I–deficient 221 cells\",\n      \"pmids\": [\"9331948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional impact on in vivo CTL responses for low-CD8-binding allotypes not tested\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Mapping c-Myc–mediated transcriptional repression to a 43-bp core promoter (CCAAT/TATA region) of HLA-B, and separately showing p53 repression through a distinct mechanism, defined how oncogenic transcription factors independently downregulate HLA-B to promote immune evasion.\",\n      \"evidence\": \"Promoter-reporter deletion analysis and c-Myc overexpression in melanoma cells; epistasis with p53-null lines\",\n      \"pmids\": [\"8206526\", \"9839551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin occupancy of c-Myc or p53 at the HLA-B promoter not demonstrated\", \"Whether these mechanisms operate in non-melanoma tumors in vivo is unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Discovery of epistatic protection against AIDS progression by KIR3DS1 with HLA-B Bw4-80Ile, and later demonstration that KIR3DL1 allotype–HLA-B Bw4 combinations create inhibition hierarchies predicting HIV outcomes, established that HLA-B is a functionally relevant ligand for NK cell receptors in infectious disease.\",\n      \"evidence\": \"Genetic epistasis analysis across multiple large HIV+ cohorts for KIR3DS1/HLA-B Bw4-80Ile and KIR3DL1/HLA-B Bw4 combinations\",\n      \"pmids\": [\"12134147\", \"17496894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biophysical binding of KIR3DS1 to Bw4-80Ile was not shown in these genetic studies\", \"Mechanism by which specific KIR3DL1 allotype expression levels translate to graded inhibition is incompletely defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The 1.5 Å crystal structure of HLA-B*3501 with a 14-mer peptide revealed how long peptides bulge from the groove while anchored at termini, and showed that P2/P9 substitutions alter α-helix conformation and T cell recognition, providing a structural framework for understanding peptide-length flexibility in antigen presentation.\",\n      \"evidence\": \"X-ray crystallography of HLA-B*3501/14-mer complex; Ala-substituted peptide variants tested for T cell activation\",\n      \"pmids\": [\"15494511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of bulged peptide in solution not captured by static crystal structure\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification that carbamazepine binds directly to HLA-B*15:02 in a peptide-dependent manner—with Asn63 as the critical groove residue—provided the first mechanistic explanation for pharmacogenomic drug hypersensitivity mediated by specific HLA-B allotypes.\",\n      \"evidence\": \"SPR binding, peptide-binding assays, site-directed mutagenesis of Asn63/Ile95/Leu156, CTL activation, and computational docking\",\n      \"pmids\": [\"22322005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full atomic structure of CBZ bound in the HLA-B*15:02 groove not determined experimentally\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Systematic survey of 27 HLA-B allotypes demonstrated that tapasin dependence varies dramatically across alleles and is governed by polymorphic residues near the C-terminal end of the peptide-binding groove, linking assembly pathway variation to allotype-specific immune function.\",\n      \"evidence\": \"In vitro refolding, TAP-deficient cell expression, stability and aggregation measurements for 27 allotypes\",\n      \"pmids\": [\"24790147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of tapasin interaction with specific HLA-B groove residues not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing that KIR3DS1 recognition of HLA-B*57:01 is peptide-dependent, and that N-glycosylation is required for KIR3DL1 binding, revealed post-translational and peptide-repertoire layers of regulation governing NK receptor engagement with HLA-B.\",\n      \"evidence\": \"Structure-guided peptide identification with functional KIR3DS1 binding; tunicamycin glycosylation inhibition with KIR3DL1-Fc binding and NK degranulation assays\",\n      \"pmids\": [\"25740999\", \"26680341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of KIR3DS1 bound to HLA-B*57:01/peptide complex not available at time of study\", \"Glycan composition required for KIR3DL1 engagement not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Structural and biophysical comparison of HLA-B*27 subtypes showed that disease-associated B*27:04 and B*27:05 have increased conformational flexibility relative to non-associated B*27:06 and B*27:09, and that instability of empty B*27:05 allows β2m-free heavy chains to reach the cell surface, linking molecular dynamics to spondyloarthritis pathogenesis.\",\n      \"evidence\": \"X-ray crystallography of B*27:04 and B*27:06 with pVIPR peptide; isotope-edited infrared spectroscopy; engineered disulfide stabilization of B*27:05\",\n      \"pmids\": [\"26748477\", \"30071035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether surface β2m-free heavy chains directly activate innate immune receptors in vivo remains unproven\", \"Role of ER stress from misfolded B*27:05 versus surface free heavy chains in disease not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Crystal structure of HLA-B*40 with a phosphopeptide explained why phosphorylation at peptide P4 is a conserved feature of HLA-B ligands: the near-universally conserved Arg62 in HLA-B coordinates the phosphate group, distinguishing HLA-B from HLA-A in phosphopeptide presentation.\",\n      \"evidence\": \"X-ray crystallography; immunopeptidomics of four HLA-B allotypes; peptide-binding assays\",\n      \"pmids\": [\"27920218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional T cell recognition of phosphopeptides on HLA-B in tumor immunity not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstration that HIV Nef downregulates HLA-B less efficiently than HLA-A—due to absence of C-terminal Cys-Lys-Val residues in HLA-B cytoplasmic tail and Nef codon-202 polymorphism—explained why HLA-B-restricted CTL responses dominate HIV immune control.\",\n      \"evidence\": \"Flow cytometry with 46 patient-derived Nef clones; Nef-202 mutagenesis; luciferase T cell co-culture assay\",\n      \"pmids\": [\"26787826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of Nef interaction with HLA-B cytoplasmic tail not resolved\", \"Whether other viral evasion proteins show similar differential HLA-A/B targeting is unexplored\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Characterization of HLA-B*46:01—a recombinant allotype carrying HLA-C1 epitope—as having a uniquely low-diversity peptidome with a subset functioning as KIR2DL3 ligands revealed that intergenic recombination can create novel NK receptor specificities on HLA-B molecules.\",\n      \"evidence\": \"High-resolution mass spectrometry peptidome analysis; KIR2DL3 ligand prediction and validation\",\n      \"pmids\": [\"28514659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional impact on NK cell education and viral susceptibility in B*46:01 carriers not fully defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"In vivo studies in HLA-B*57:01 transgenic mice showed that abacavir tolerance depends on CD4+ T cell–mediated suppression of CD8+ effectors, and that CD4 depletion plus B7 costimulation unleashes drug-reactive CD8+ T cells with skin-homing phenotype, defining the cellular circuit of HLA-B*57:01-restricted drug hypersensitivity.\",\n      \"evidence\": \"HLA-B*57:01 transgenic mice; in vivo CD4 depletion; DC maturation; B7 costimulatory blockade; flow cytometry\",\n      \"pmids\": [\"29782330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same CD4-dependent tolerance mechanism operates in human abacavir hypersensitivity is unconfirmed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of flucloxacillin-haptenated peptides presented by HLA-B*57:01—and demonstration that these neoantigens with FLX-modified lysines at P4 or P6 activate drug-specific CD8+ T cells in vivo—established covalent drug modification and antigen processing as the mechanism of HLA-B*57:01-linked drug-induced liver injury.\",\n      \"evidence\": \"Immunopeptidomics of FLX-treated C1R-B*57:01 cells; in vivo immunization of HLA-B*57:01 transgenic mice; CD8+ T cell assays; FLX adduct characterization including K146 on HLA-B heavy chain\",\n      \"pmids\": [\"32726429\", \"33633747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FLX modification of HLA-B K146 itself alters KIR3DL1 recognition in vivo is unknown\", \"Liver-specific antigen processing contribution not directly tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Yeast display peptide library screening identified shared self and microbial peptide motifs presented by HLA-B*27:05 that activate clonally expanded public BV9-CDR3β/AV21 TCRs found in both joints and eyes of spondyloarthritis and uveitis patients, providing a molecular explanation for cross-reactive autoimmunity in HLA-B*27-associated disease.\",\n      \"evidence\": \"TCR isolation from blood, synovial fluid, and aqueous humor; HLA-B*27:05 yeast display library; structural analysis of TCR-pMHC\",\n      \"pmids\": [\"36477533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether molecular mimicry is sufficient or whether free heavy chain pathology contributes independently remains unresolved\", \"Mucosal priming of these public TCRs inferred but not directly visualized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of HLA-B*27-restricted enteric bacterial peptide (YeiH)-specific CD8+ T cells with mucosal homing markers expanded in spondyloarthritis patients suggested that gastrointestinal antigen priming drives pathogenic T cell responses in HLA-B*27-associated disease.\",\n      \"evidence\": \"HLA-B*27/YeiH tetramer staining; flow cytometry for mucosal markers (CD161, α4β7, CCR6); clonal expansion analysis in blood\",\n      \"pmids\": [\"39024572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of gut priming (e.g., intestinal biopsy T cell isolation) not performed\", \"Whether YeiH-specific T cells are pathogenic or bystanders in joint/eye inflammation is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of tapasin interaction with diverse HLA-B allotypes, whether β2m-free HLA-B*27 heavy chains directly activate innate receptors in vivo, the relative contribution of ER stress versus surface free heavy chains in B*27-associated disease, and whether pharmacogenomic tolerance mechanisms defined in mouse models translate to human drug hypersensitivity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic-resolution structure of tapasin engaged with any HLA-B allotype\", \"In vivo disease models that distinguish free heavy chain signaling from cross-reactive T cell pathology are lacking\", \"Human validation of CD4-dependent drug tolerance mechanism is needed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [8, 9, 22, 23]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5, 11, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 9, 10, 13, 16]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 5, 6, 8, 9, 11, 14, 20, 22, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 16, 20, 24]}\n    ],\n    \"complexes\": [\n      \"MHC class I peptide-loading complex\",\n      \"HLA-B/β2-microglobulin/peptide trimeric complex\"\n    ],\n    \"partners\": [\n      \"B2M\",\n      \"KIR3DL1\",\n      \"KIR3DS1\",\n      \"KIR2DL3\",\n      \"CD8A\",\n      \"TAPBP\",\n      \"TAP1\",\n      \"TAP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"HLA-B is a highly polymorphic MHC class I heavy chain that assembles with β2-microglobulin and short peptides in the endoplasmic reticulum—via tapasin-dependent or tapasin-independent pathways depending on allotype—and presents these peptide ligands at the cell surface for surveillance by CD8+ T cells and NK cells through TCR and KIR receptors [PMID:1525820, PMID:24790147, PMID:29995954]. Allele-specific pockets in the peptide-binding groove, defined by high-resolution crystal structures, dictate the peptide repertoire: an Arg anchor at P2 governs HLA-B*27 binding, a conserved Arg62 accommodates phosphopeptides at P4 across many alleles, and the overall peptidome diversity varies markedly among allotypes [PMID:1922337, PMID:27920218, PMID:28514659]. N-glycosylation of HLA-B is required for efficient KIR3DL1 engagement, and KIR3DS1 recognition of HLA-B*57:01 is peptide-dependent, linking viral peptide presentation to NK cell activation [PMID:26680341, PMID:25740999]. Certain alleles confer disease susceptibility—HLA-B*27:05 presents self- and microbial peptides to cross-reactive public TCRs in ankylosing spondylitis and acute anterior uveitis, while HLA-B*15:02 and HLA-B*57:01 directly bind drugs (carbamazepine, flucloxacillin) to activate drug-specific CD8+ T cells in hypersensitivity reactions [PMID:36477533, PMID:22322005, PMID:33633747].\",\n  \"teleology\": [\n    {\n      \"year\": 1976,\n      \"claim\": \"Establishing that HLA-B allotypic specificities and the Bw4/Bw6 serological epitopes reside on the same polypeptide chain resolved the molecular identity of HLA-B gene products and enabled subsequent structural analysis.\",\n      \"evidence\": \"Sequential immunoprecipitation of radiolabeled papain-solubilized lymphoblastoid membrane proteins with allele-specific and Bw4/Bw6 alloantisera\",\n      \"pmids\": [\"63373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural information on the chain architecture\", \"Bw4/Bw6 epitope location on the polypeptide unknown\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Crystal structures of HLA-B*27 revealed the molecular basis of peptide binding: nonameric peptides lie extended in the groove with termini anchored in conserved pockets and an Arg at P2 inserted into a B-allele-specific pocket, establishing the paradigm for allele-specific peptide selection.\",\n      \"evidence\": \"X-ray crystallography of HLA-B*27 at 2.1 Å resolution with bound self-peptides\",\n      \"pmids\": [\"1922337\", \"1525820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures limited to B*27; generalizability to other HLA-B alleles not yet tested\", \"Dynamics and conformational flexibility not captured by static crystal structures\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstration that HLA-B can present peptides via a TAP-independent pathway in TAP-deficient patients, and that HLA-B allotypes differ in peptide motifs and CD8-binding efficiency due to α3 domain polymorphisms, expanded the functional scope of HLA-B beyond the classical TAP-dependent pathway.\",\n      \"evidence\": \"Peptide elution and CTL assays from TAP-deficient B-LCL; peptide pool sequencing and CD8-binding mutagenesis (Thr245Ala) in 221-cell transfectants\",\n      \"pmids\": [\"9144467\", \"9331948\", \"9089095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of TAP-independent peptide loading unknown\", \"CD8-binding polymorphism tested for only one allotype\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapping transcriptional regulation showed that c-Myc and p53 each independently repress the HLA-B core promoter through the CCAAT/TATA region, providing a mechanism for MHC-I downregulation in tumors with oncogene activation or p53 overexpression.\",\n      \"evidence\": \"HLA-B promoter-reporter deletion constructs transfected into melanoma cells with varying c-Myc/p53 status\",\n      \"pmids\": [\"8206526\", \"9839551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcription-factor–DNA binding not demonstrated\", \"Relevance to endogenous HLA-B mRNA levels not confirmed in primary tumors\", \"Chromatin context not assessed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"HIV-1 Nef was shown to selectively downregulate HLA-A and HLA-B (but not HLA-C/E) by inducing endocytosis; the differential susceptibility maps to cytoplasmic tail differences, explaining how HIV evades CTL while sparing NK-inhibitory ligands.\",\n      \"evidence\": \"Flow cytometry, immunofluorescence, and subcellular fractionation in Nef-expressing cells; domain-swap and tail mutagenesis; NK and CTL cytotoxicity assays\",\n      \"pmids\": [\"8612235\", \"10403641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise Nef–HLA-B tail interaction interface not structurally resolved\", \"Relative contribution of endosomal degradation versus lysosomal routing unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"A 1.5 Å structure of HLA-B*35:01 bound to a 14-mer peptide showed that long peptides are accommodated by central bulging while termini remain anchored, and that peptide conformation modulates TCR engagement, broadening understanding of peptide-length flexibility.\",\n      \"evidence\": \"X-ray crystallography of HLA-B*3501 with 14-mer and Ala-substituted peptide variants; CTL activation assays\",\n      \"pmids\": [\"15494511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability of bulging mechanism to other HLA-B alleles not tested\", \"Structural basis of TCR contact with bulged peptides not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Direct binding of carbamazepine to the HLA-B*15:02/peptide complex without antigen processing, and identification of key groove residues (Asn63, Ile95, Leu156) including conserved Arg62, established a structural mechanism for drug hypersensitivity mediated by drug–peptide–MHC interaction.\",\n      \"evidence\": \"SPR binding, peptide-binding assays, site-directed mutagenesis of HLA-B*1502, and CTL activation assays\",\n      \"pmids\": [\"22322005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of CBZ bound in the groove\", \"In vivo relevance in patient tissue not confirmed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Systematic comparison across HLA-B allotypes revealed that polymorphic residues near the C-terminal groove determine tapasin dependence, and that tapasin-independent alleles refold more readily and resist viral TAP-inhibitor-mediated downregulation, explaining allotype-specific variation in antigen presentation efficiency.\",\n      \"evidence\": \"Surface expression in tapasin-deficient cells; in vitro refolding and aggregation assays across 27 HLA-B alleles; viral TAP-inhibitor experiments\",\n      \"pmids\": [\"24790147\", \"29995954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for tapasin interaction specificity not determined at atomic level\", \"Clinical impact of tapasin independence on immune control not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that the conserved Arg62 in HLA-B accommodates phosphopeptides at P4, combined with biophysical evidence that conformational dynamics differ between disease-associated (B*27:05) and non-disease-associated (B*27:09) subtypes, linked both peptide chemistry and heavy-chain dynamics to disease susceptibility.\",\n      \"evidence\": \"Immunopeptidomics and crystal structures of HLA-B*40/phosphopeptide; isotope-edited IR spectroscopy comparing B*27 subtypes; crystal structures of pVIPR–B*27:04 and B*27:06\",\n      \"pmids\": [\"27920218\", \"26748477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of increased dynamics for TCR recognition not directly tested\", \"Role of phosphopeptide presentation in immune surveillance in vivo unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Refined analysis of HIV Nef selectivity showed HLA-B is downregulated less efficiently than HLA-A, mapping the difference to Nef codon 202 and the absence of C-terminal CKV residues in HLA-B's cytoplasmic tail, revealing an allele-specific immune evasion hierarchy.\",\n      \"evidence\": \"Flow cytometry with 46 patient-derived Nef clones; Nef-202 mutagenesis; coculture T cell recognition assays\",\n      \"pmids\": [\"26787826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of Nef bound to HLA-B tail not available\", \"Impact of differential downregulation on in vivo viral control not prospectively tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"HLA-B*46:01, formed by gene conversion between HLA-B and HLA-C, presents a uniquely low-diversity peptidome and engages KIR2DL3 in a peptide-dependent manner, illustrating how gene conversion events reshape both peptide repertoire and NK receptor recognition.\",\n      \"evidence\": \"High-resolution MS immunopeptidomics; KIR2DL3 binding assays\",\n      \"pmids\": [\"28514659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of KIR2DL3 engagement by B*46:01 not determined\", \"In vivo NK cell functional consequence not characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of public cross-reactive TCRs (BV9-CDR3β/AV21) in HLA-B*27:05+ ankylosing spondylitis and uveitis patients, recognizing both self and microbial peptides presented by B*27:05 but not B*27:09, provided structural evidence that molecular mimicry through a shared TCR-binding motif underlies B*27-associated autoimmunity.\",\n      \"evidence\": \"HLA-B*27:05 yeast-display peptide library; TCR–pMHC crystal structures; T cell cloning from affected joint and eye tissues\",\n      \"pmids\": [\"36477533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Triggering microbial infection initiating disease not identified in patients\", \"Whether targeting these public TCRs is therapeutically feasible is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the atomic-resolution structure of the tapasin–HLA-B editing complex; how conformational dynamics of disease-associated subtypes translate into altered TCR triggering thresholds in vivo; and the structural basis of Nef–HLA-B cytoplasmic tail interaction.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No atomic structure of tapasin–HLA-B complex\", \"In vivo dynamics–TCR signaling relationship unresolved\", \"Nef–HLA-B tail co-structure lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 2, 10, 12, 14, 15, 23]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 7, 9, 17, 19, 24]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [13, 19, 20]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 5, 9, 10, 12, 14, 15, 17, 18, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [13, 19, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 9, 17, 22, 23]}\n    ],\n    \"complexes\": [\n      \"MHC class I peptide-loading complex\",\n      \"HLA-B/β2-microglobulin/peptide heterotrimer\"\n    ],\n    \"partners\": [\n      \"B2M\",\n      \"KIR3DL1\",\n      \"KIR3DS1\",\n      \"KIR2DL3\",\n      \"TAPBP\",\n      \"TAP1\",\n      \"TAP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}