{"gene":"HLA-DRB1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1993,"finding":"X-ray crystal structure of HLA-DR1 (an HLA-DRB1-containing heterodimer) revealed that peptides bind in an extended conformation in an open-ended groove, with a prominent non-polar pocket near one end accommodating an anchoring peptide side chain; a dimer of the class II αβ heterodimers was observed, suggesting dimerization as a mechanism for cytoplasmic signalling.","method":"X-ray crystallography","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional interpretation, foundational highly-cited paper","pmids":["8316295"],"is_preprint":false},{"year":1994,"finding":"Crystal structure of HLA-DR1 complexed with an influenza hemagglutinin peptide (HA306-318) showed the peptide binds in an extended, twisted conformation; five of thirteen side chains are accommodated in pockets in the binding site; twelve hydrogen bonds between conserved HLA-DR1 residues and peptide main-chain amide bonds provide a universal mode of peptide binding distinct from MHC class I.","method":"X-ray crystallography","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure of peptide-MHC complex, highly cited foundational study","pmids":["8145819"],"is_preprint":false},{"year":1994,"finding":"Peptide binding to HLA-DRB1*0101 and DRB1*0401 requires a hydrophobic amino acid near the peptide amino-terminus that docks into a conserved pocket; aromatic side chains are superior to aliphatic at this position; the majority of binding free energy arises from hydrogen bonds between conserved binding-site residues and peptide backbone amide bonds, not side-chain contacts; optimal binding depends on position of the hydrophobic anchor relative to peptide termini.","method":"Quantitative competitive peptide binding assay with systematic alanine-scan analogues, reduced peptide bonds, and N-methyl amino acid substitutions","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis of peptide ligands with quantitative IC50 assays, multiple orthogonal approaches","pmids":["8144889"],"is_preprint":false},{"year":1995,"finding":"HLA-DM catalyzes the dissociation of the invariant chain-derived CLIP peptide from MHC class II (HLA-DR) αβ dimers in vitro, facilitating loading of antigenic peptides; the reaction has an acidic pH optimum consistent with occurrence in lysosomal compartments; antibody blocking experiments indicate a transient HLA-DM–MHC class II interaction is required.","method":"In vitro biochemical dissociation assay, antibody blocking, pH titration","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro assay with mechanistic controls, highly cited foundational study","pmids":["7606781"],"is_preprint":false},{"year":1995,"finding":"A quantitative database of the contribution of each of the 20 amino acids at 11 positions of a simplified peptide backbone was used to predict peptide binding affinity to HLA-DRB1*0401; the model accurately predicted binding of 13 unrelated peptides and identified two high-affinity myelin basic protein epitopes corresponding to DRB1*0401-restricted T cell determinants, validating that a key hydrophobic residue at position 3 relative to the peptide register drives binding.","method":"Quantitative peptide binding assay, combinatorial peptide library, T cell hybridoma specificity testing","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 1–2 — systematic in vitro binding assay with functional T cell validation, predictive model tested on independent peptides","pmids":["7751636"],"is_preprint":false},{"year":1995,"finding":"Comparison of TCR Vβ segment usage in cohorts of individuals expressing distinct HLA-DRB1 alleles showed a correlation between DRB1 allele and Vβ usage in naive (CD45RO−) CD4+ T cells, demonstrating that HLA-DRB1 allelic polymorphism shapes the peripheral CD4+ T cell TCR repertoire through thymic selection; antigenic experience (CD45RO+ memory cells) modulates but does not eliminate this DRB1-imposed Vβ profile.","method":"TCR Vβ repertoire analysis by flow cytometry/PCR in HLA-typed donor cohorts, comparison of naive vs memory CD4+ T cell subsets","journal":"Human Immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct correlation experiment in human cohorts with subset dissection, single lab","pmids":["8770633"],"is_preprint":false},{"year":1996,"finding":"Naturally processed peptides eluted from HLA-DRB1*0404 (RA-associated) and DRB1*0402 (non-RA-associated) B cell lines were predominantly nested clusters derived from HLA class I (B and C) α-chain sequences; DRB1*0404 loaded peptides from positions 26–43 of HLA-B/C α-chain, while DRB1*0402 loaded peptides from positions 129–145, demonstrating allele-specific differences in which self-peptides naturally occupy the groove.","method":"Immunoaffinity purification of MHC class II complexes, reversed-phase HPLC fractionation, Edman degradation sequencing, tandem mass spectrometry","journal":"Journal of Neuroscience Research","confidence":"Medium","confidence_rationale":"Tier 1 — direct biochemical elution and MS identification, but single study single lab","pmids":["8892091"],"is_preprint":false},{"year":1998,"finding":"Introduction of the HLA-DRB1*1502 (DR2) transgene into collagen-induced arthritis-susceptible HLA-DQ8 mice significantly decreased disease incidence and induced a Th2 cytokine profile, whereas DRB1*0301 (DR3) had no protective effect and maintained a Th1 profile; DR molecules were confirmed functional by positive/negative selection of the Vβ T cell repertoire, demonstrating that DRB1 polymorphism can modulate DQ-restricted autoimmune arthritis.","method":"Transgenic mouse model (double DR/DQ transgenic in class II-deficient background), collagen-induced arthritis, in vitro T cell proliferation, cytokine analysis, TCR Vβ repertoire analysis","journal":"International Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — well-controlled transgenic model with multiple functional readouts, single lab","pmids":["9796911"],"is_preprint":false},{"year":2003,"finding":"HLA class II (including HLA-DRB1-encoded DR) molecules are abundantly present in B cell-derived exosomes and are concentrated in cholesterol/sphingomyelin/GM3-enriched detergent-resistant membrane domains (lipid rafts) within multivesicular bodies, whereas plasma membrane-associated MHC class II is readily solubilized; this compartmentalization may facilitate protein sorting into internal vesicles of multivesicular bodies.","method":"Proteomic analysis of purified exosomes by mass spectrometry, detergent solubility fractionation (CHAPS), electron microscopy, immunofluorescence","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 — multi-method biochemical characterization, but not specific to DRB1 allele function","pmids":["12519789"],"is_preprint":false},{"year":2012,"finding":"The HLA-DRB1 shared epitope (SE) sequence motif acts as a signal transduction ligand that activates osteoclastogenesis independently of antigen presentation: SE peptides potently stimulated osteoclast differentiation in mouse and human cells in vitro, enhanced production of pro-osteoclastogenic factors, and promoted Th17 cell differentiation expressing RANKL; IL-17 and SE synergistically enhanced osteoclast differentiation; SE transgenic mice showed higher osteoclastogenesis ex vivo; in vivo administration to collagen-induced arthritis mice increased arthritis severity, synovial osteoclast abundance, and bone erosion.","method":"In vitro osteoclastogenesis assay (mouse and human cells), transgenic mouse model (HLA-DRB1 SE-expressing), collagen-induced arthritis model, cytokine measurement, histology","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (in vitro, transgenic, in vivo disease model), mechanistic pathway defined","pmids":["23180817"],"is_preprint":false},{"year":2013,"finding":"Citrullinated aggrecan and vimentin epitopes bind to HLA-DRB1*04:01/04 because citrulline is accommodated within the electropositive P4 pocket of these allomorphs; in contrast, the electronegative P4 pocket of RA-resistant HLA-DRB1*04:02 interacts with arginine or citrulline indiscriminately. Peptide elution studies confirmed P4 arginine-containing peptides from DRB1*04:02 but not DRB1*04:01/04. Citrullination altered protease susceptibility of vimentin, generating epitopes presented to CD4+ T cells specifically in HLA-DRB1*04:01+ individuals.","method":"Crystal structure determination, peptide elution/mass spectrometry, HLA-II tetramer staining of peripheral blood CD4+ T cells, T cell functional assays","journal":"The Journal of Experimental Medicine","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation by peptide elution, tetramer staining, and T cell assays; multiple orthogonal methods","pmids":["24190431"],"is_preprint":false},{"year":2013,"finding":"The HLA-DRB1*15:01-restricted T cell epitope α3136-146 from the α3 chain of type IV collagen (Goodpasture antigen) was identified and shown to be naturally processed; CD4+ T cell clones specific for this epitope transferred necrotizing crescentic glomerulonephritis, albuminuria, and renal impairment into naïve HLA-DRB1*15:01 transgenic mice but not HLA-DRB1*01:01 transgenic mice, demonstrating allele-specific pathogenic T cell priming.","method":"HLA-DRB1*15:01 and *01:01 transgenic mouse immunization, T cell clone generation, adoptive transfer disease model, histology, renal function assessment","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 1–2 — transgenic model with adoptive transfer, multiple disease readouts, allele specificity confirmed by negative control","pmids":["23411782"],"is_preprint":false},{"year":2013,"finding":"Dendritic cells present FVIII-derived peptides on HLA-DR (including HLA-DRB1) with optimal presentation 12–24 hours after maturation, persisting for 96 hours; immature DCs retain half of FVIII-loaded MHC class II intracellularly, while mature DCs display the majority on the plasma membrane; macrophages internalize FVIII as efficiently as DCs but present fewer peptides with different epitopes; five HLA-promiscuous FVIII peptide regions were identified across 8 donors.","method":"HLA class II immunoprecipitation, mass spectrometric peptide identification, flow cytometry for MHC II surface/intracellular distribution, time-course antigen presentation studies","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 1–2 — direct biochemical peptide identification with functional localization data, multiple donors","pmids":["24244658"],"is_preprint":false},{"year":2012,"finding":"Fine-mapping of MHC association with seropositive RA identified that three amino acid positions in HLA-DRβ1 (positions 11, 71, and 74), which are located in the peptide-binding groove, almost completely explain the MHC association to RA risk, along with single positions in HLA-B (position 9) and HLA-DPβ1 (position 9); conditional analyses demonstrated these positions are independent of each other.","method":"Genome-wide SNP imputation of HLA classical alleles and amino acid polymorphisms in 5,018 RA cases and 14,974 controls, conditional and haplotype analyses","journal":"Nature Genetics","confidence":"High","confidence_rationale":"Tier 2 — large-scale imputation with conditional analysis pinpointing functional peptide-binding groove residues, replicated across datasets","pmids":["22286218"],"is_preprint":false},{"year":2020,"finding":"HLA-DRB1*01:01 binds newly identified myelin basic protein peptides (MBP153-161 and MBP90-98) with affinity comparable to influenza HA peptide, but HLA-DM-catalyzed CLIP exchange for MBP peptides is significantly slower than for HA peptide; chimeric peptide analysis showed this kinetic difference results from absence of anchor residues in the C-terminal part of MBP peptides, causing incomplete occupation of P6/7 and P9 pockets and failure of P1/P4 docking, leading to rapid peptide dissociation from HLA-DM–HLA-DR complex.","method":"Recombinant HLA-DRB1*01:01 protein production, peptide binding affinity measurements, HLA-DM-catalyzed CLIP exchange kinetics, chimeric MBP-HA peptide analysis","journal":"Frontiers in Immunology","confidence":"Medium","confidence_rationale":"Tier 1–2 — in vitro biochemical kinetic assays with mechanistic mutagenesis (chimeric peptides), single lab","pmids":["32010139"],"is_preprint":false},{"year":2021,"finding":"Short synthetic peptides corresponding to the third allelic hypervariable regions of disease risk-associated HLA-DRB1 alleles (SE-containing) versus protective alleles differentially polarize macrophages in vitro: risk allele peptides activate pro-inflammatory M1 transcriptomes while protective allele peptides activate anti-inflammatory M2 transcriptomes, as shown by RNA-sequencing; this immune modulation occurs independently of antigen presentation (AP-incompetent peptides used) and involves distinct upstream regulatory pathways.","method":"RNA-sequencing of in vitro-polarized macrophages, AP-incompetent synthetic HLA-DRB1 allelic peptides, gene ontology and upstream regulator analysis","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptome-level mechanistic evidence with AP-incompetent controls, single lab","pmids":["33510427"],"is_preprint":false},{"year":2021,"finding":"Three amino acid residues of HLA-DRB1 at positions β71, β74, and β86 determine T1D risk; the 'KAG' motif (corresponding to DRB1*04:01) is most strongly associated with disease and, through structural modeling, is shown to create specific differences in peptide antigen anchor pocket preferences at p1, p4, and p7, affecting differential binding of T1D autoantigens preproinsulin and GAD65.","method":"Population-based case-control HLA typing, birth cohort prospective islet autoantibody study, hierarchical sequence similarity analysis, HLA-peptide structural modeling","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 — functional amino acid positions identified in two independent cohorts with structural modeling support","pmids":["34153873"],"is_preprint":false},{"year":2009,"finding":"A proteochemometrics model of peptide binding to 12 HLA-DRB1 proteins using z-descriptors for both peptide and protein sequences identified key peptide and protein positions involved in interactions, with hydrophobicity, steric bulk, and polarity at specific positions driving binding; models showed moderate goodness of fit (r²=0.685–0.732) and good cross-validated predictive ability.","method":"Computational proteochemometrics modeling of 2666 peptide-DRB1 binding data points, cross-validation, external test set prediction","journal":"European Journal of Medicinal Chemistry","confidence":"Low","confidence_rationale":"Tier 4 — computational modeling only, no direct experimental validation","pmids":["19896246"],"is_preprint":false}],"current_model":"HLA-DRB1 encodes the polymorphic β1 chain of the MHC class II αβ heterodimer, whose peptide-binding groove accommodates antigenic peptides in an extended conformation through 12 conserved hydrogen bonds to the peptide backbone and a key hydrophobic P1 anchor pocket; allele-specific pocket charges (particularly the P4 pocket at residues β71, β74, β86) determine which peptides (including citrullinated self-peptides) are bound and presented to CD4+ T cells; HLA-DM catalyzes CLIP dissociation to facilitate peptide loading in acidic endosomal compartments; beyond antigen presentation, the disease-associated shared epitope sequence motif acts as an extracellular signal transduction ligand that activates osteoclastogenesis and pro-inflammatory macrophage polarization, while protective DRB1 allele-coded epitopes drive anti-inflammatory macrophage polarization, establishing that HLA-DRB1 allelic variation modulates immune outcomes through both antigen presentation-dependent and antigen presentation-independent mechanisms."},"narrative":{"teleology":[{"year":1993,"claim":"Determination of the first HLA-DR1 crystal structure resolved how the class II groove accommodates peptide and revealed αβ heterodimer dimerization, establishing the structural framework for understanding DRB1 polymorphism and peptide binding.","evidence":"X-ray crystallography of HLA-DR1","pmids":["8316295"],"confidence":"High","gaps":["No peptide-bound structure yet available at this stage","Functional significance of αβ dimer-of-dimers not experimentally tested"]},{"year":1994,"claim":"Co-crystal structures and systematic binding assays defined the universal peptide-binding mode—12 backbone hydrogen bonds plus a dominant hydrophobic P1 anchor—explaining how a single groove accommodates diverse peptides while conserving the binding register.","evidence":"X-ray crystallography of HLA-DR1–HA peptide complex; quantitative competitive binding assays with alanine-scan, reduced-bond, and N-methyl analogues on DRB1*0101 and *0401","pmids":["8145819","8144889"],"confidence":"High","gaps":["Contributions of P4 and other secondary pockets to allele-specific binding not yet structurally resolved","Role of non-classical anchor positions in autoantigen binding unknown"]},{"year":1995,"claim":"HLA-DM was shown to catalyze CLIP dissociation from DR at acidic pH, revealing the enzymatic editing step required for peptide loading in endosomal compartments and explaining how the invariant chain intermediate is resolved.","evidence":"In vitro biochemical dissociation assay with antibody blocking and pH titration","pmids":["7606781"],"confidence":"High","gaps":["Structural basis of HLA-DM–DR interaction not determined","Kinetic differences in DM-mediated exchange across DRB1 alleles not yet characterized"]},{"year":1995,"claim":"DRB1 allelic polymorphism was shown to shape the peripheral CD4+ TCR Vβ repertoire through thymic selection, establishing that DRB1 variation influences immune competence upstream of any specific antigen encounter.","evidence":"TCR Vβ repertoire analysis by flow cytometry/PCR in HLA-typed donor cohorts comparing naive versus memory CD4+ T cells","pmids":["8770633"],"confidence":"Medium","gaps":["Mechanism of allele-specific positive/negative selection not dissected at the peptide level","Limited to correlative cohort data without experimental perturbation"]},{"year":1996,"claim":"Peptide elution from RA-associated (DRB1*0404) versus non-RA-associated (DRB1*0402) allomorphs revealed distinct self-peptide repertoires, demonstrating that allele-specific groove chemistry selects different endogenous ligands with potential relevance to autoimmunity.","evidence":"Immunoaffinity purification, HPLC fractionation, Edman degradation, and tandem mass spectrometry from B cell lines","pmids":["8892091"],"confidence":"Medium","gaps":["Link between specific self-peptide repertoires and disease pathogenesis not functionally tested","Single-laboratory study with limited cell line diversity"]},{"year":2012,"claim":"Fine-mapping of MHC association with RA resolved disease risk to three amino acid positions in the DRβ1 peptide-binding groove (positions 11, 71, 74), pinpointing the structural basis of genetic susceptibility beyond traditional allele-level associations.","evidence":"Genome-wide SNP imputation of HLA alleles and amino acid polymorphisms in ~20,000 individuals with conditional analysis","pmids":["22286218"],"confidence":"High","gaps":["Causal peptide(s) mediating RA risk through these positions not identified","Independent contributions of positions 11, 71, 74 to specific pocket properties not structurally verified"]},{"year":2012,"claim":"The shared epitope motif was shown to function as an antigen-presentation-independent signal transduction ligand activating osteoclastogenesis and Th17 differentiation, establishing a non-canonical immunomodulatory role for the DRB1-encoded surface.","evidence":"In vitro osteoclastogenesis assays (mouse and human), SE-transgenic mice, collagen-induced arthritis model with histology and cytokine measurement","pmids":["23180817"],"confidence":"High","gaps":["Receptor for the SE ligand on target cells not identified","Signaling pathway downstream of SE engagement not fully elucidated"]},{"year":2013,"claim":"Crystal structures of DRB1*04:01 versus *04:02 with citrullinated peptides explained how P4 pocket charge (electropositive in *04:01, electronegative in *04:02) selectively accommodates citrulline, providing the structural mechanism by which RA-risk alleles present citrullinated self-antigens to CD4+ T cells.","evidence":"X-ray crystallography, peptide elution/mass spectrometry, HLA-II tetramer staining and T cell functional assays in DRB1*04:01+ donors","pmids":["24190431"],"confidence":"High","gaps":["Range of citrullinated epitopes naturally presented in vivo not fully catalogued","Whether citrulline-specific T cells are sufficient for RA initiation remains untested"]},{"year":2013,"claim":"Allele-specific pathogenic potential was demonstrated when DRB1*15:01-restricted CD4+ T cell clones recognizing a collagen IV epitope transferred crescentic glomerulonephritis upon adoptive transfer, directly linking DRB1 allele-restricted antigen presentation to organ-specific autoimmune disease.","evidence":"Adoptive transfer of T cell clones into HLA-DRB1*15:01 versus *01:01 transgenic mice with renal histology and functional assessment","pmids":["23411782"],"confidence":"High","gaps":["Whether additional DRB1 alleles confer risk for anti-GBM disease through alternative epitopes is unknown","Contribution of DRB1*15:01-restricted T cells relative to B cell/antibody-mediated injury not delineated"]},{"year":2020,"claim":"HLA-DM-catalyzed peptide exchange kinetics were shown to depend on complete occupation of C-terminal anchor pockets (P6/7, P9), explaining why certain autoantigen peptides (e.g., MBP) are inefficiently loaded despite adequate groove affinity and refining the understanding of DM editing as a selectivity filter.","evidence":"Recombinant HLA-DRB1*01:01 protein, DM-catalyzed CLIP exchange kinetics, chimeric MBP–HA peptide analysis","pmids":["32010139"],"confidence":"Medium","gaps":["Generalizability across DRB1 alleles not tested","In vivo relevance of slow exchange kinetics for autoimmune epitope presentation not established"]},{"year":2021,"claim":"Antigen-presentation-incompetent peptides from protective versus risk-associated DRB1 alleles were shown to differentially polarize macrophages toward anti-inflammatory (M2) or pro-inflammatory (M1) transcriptomes, extending the non-canonical signaling role of DRB1 allelic sequences beyond osteoclastogenesis to innate immune regulation.","evidence":"RNA-sequencing of in vitro macrophages treated with AP-incompetent synthetic DRB1 allelic peptides, upstream regulator analysis","pmids":["33510427"],"confidence":"Medium","gaps":["Cell-surface receptor mediating allelic peptide recognition on macrophages not identified","In vivo contribution of macrophage polarization to disease protection/susceptibility not demonstrated","Single laboratory, no independent replication"]},{"year":null,"claim":"The receptor and downstream signaling pathway through which shared epitope and protective DRB1-derived peptides modulate innate immune cell polarization and osteoclastogenesis remain unidentified, representing the central open question bridging DRB1 non-canonical signaling to disease mechanism.","evidence":"","pmids":[],"confidence":"Low","gaps":["No receptor identified for SE peptide signaling","No structural basis for how free DRB1 peptides engage target cells","In vivo physiological relevance of non-canonical signaling pathway not confirmed in human disease"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[9,15]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[9,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,12]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3,8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[8]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,3,5,10,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,10,11,13,16]}],"complexes":["MHC class II αβ heterodimer (HLA-DRA/HLA-DRB1)"],"partners":["HLA-DRA","HLA-DMA","HLA-DMB","CD4"],"other_free_text":[]},"mechanistic_narrative":"HLA-DRB1 encodes the polymorphic β1 chain of the MHC class II HLA-DR αβ heterodimer, which binds antigenic peptides in an extended conformation within an open-ended groove stabilized by 12 conserved hydrogen bonds to the peptide backbone and allele-specific anchor pockets—particularly a hydrophobic P1 pocket and a charge-variable P4 pocket whose residues (β71, β74, β86) dictate selective binding of peptides including citrullinated self-antigens [PMID:8145819, PMID:24190431, PMID:22286218]. HLA-DM catalyzes dissociation of the invariant chain–derived CLIP peptide at acidic pH, enabling antigenic peptide loading in endosomal compartments, with exchange kinetics governed by the completeness of C-terminal anchor pocket occupation [PMID:7606781, PMID:32010139]. Allele-specific peptide presentation shapes the peripheral CD4+ T-cell receptor repertoire through thymic selection and determines susceptibility to autoimmune diseases including rheumatoid arthritis, type 1 diabetes, and anti-GBM glomerulonephritis [PMID:8770633, PMID:23411782, PMID:34153873]. Beyond antigen presentation, the disease-associated shared epitope motif encoded within the third hypervariable region functions as an extracellular signal transduction ligand that activates osteoclastogenesis and pro-inflammatory macrophage polarization, while protective allele-encoded epitopes drive anti-inflammatory polarization [PMID:23180817, PMID:33510427]."},"prefetch_data":{"uniprot":{"accession":"P01911","full_name":"HLA class II histocompatibility antigen, DRB1 beta chain","aliases":["Human leukocyte antigen DRB1","HLA-DRB1"],"length_aa":266,"mass_kda":30.0,"function":"A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the alpha chain HLA-DRA, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DRB1-restricted CD4-positive T cells. This guides antigen-specific T-helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells (PubMed:15265931, PubMed:16148104, PubMed:22327072, PubMed:27591323, PubMed:29884618, PubMed:31495665, PubMed:8642306). Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes (PubMed:8145819). In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor-resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins (PubMed:31495665). Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance (PubMed:17182262, PubMed:23783831). The selection of the immunodominant epitopes follows two processing modes: 'bind first, cut/trim later' for pathogen-derived antigenic peptides and 'cut first, bind later' for autoantigens/self-peptides (PubMed:25413013). The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules (PubMed:8145819) Allele DRB1*01:01: Displays an immunodominant epitope derived from Bacillus anthracis pagA/protective antigen, PA (KLPLYISNPNYKVNVYAVT), to both naive and PA-specific memory CD4-positive T cells (PubMed:22327072). Presents immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (PHQFINLRSNNSATLIVPYV), contributing to viral clearance (PubMed:27591323). Displays commonly recognized peptides derived from IAV external protein HA (PKYVKQNTLKLAT and SNGNFIAPEYAYKIVK) and from internal proteins M, NP and PB1, with M-derived epitope (GLIYNRMGAVTTEV) being the most immunogenic (PubMed:25413013, PubMed:32668259, PubMed:8145819, PubMed:9075930). Presents a self-peptide derived from COL4A3 (GWISLWKGFSF) to TCR (TRAV14 biased) on CD4-positive, FOXP3-positive regulatory T cells and mediates immune tolerance to self (PubMed:28467828). May present peptides derived from oncofetal trophoblast glycoprotein TPBG 5T4, known to be recognized by both T-helper 1 and regulatory T cells (PubMed:31619516). Displays with low affinity a self-peptide derived from MBP (VHFFKNIVTPRTP) (PubMed:9075930) Allele DRB1*03:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Displays self-peptides derived from retinal SAG (NRERRGIALDGKIKHE) and thyroid TG (LSSVVVDPSIRHFDV) (PubMed:25413013). Presents viral epitopes derived from HHV-6B gH/U48 and U85 antigens to polyfunctional CD4-positive T cells with cytotoxic activity implicated in control of HHV-6B infection (PubMed:31020640). Presents several immunogenic epitopes derived from C.tetani neurotoxin tetX, playing a role in immune recognition and long-term protection (PubMed:19830726) Allele DRB1*04:01: Presents an immunodominant bacterial epitope derived from M.tuberculosis esxB/culture filtrate antigen CFP-10 (EISTNIRQAGVQYSR), eliciting CD4-positive T cell effector functions such as IFNG production and cytotoxic activity (PubMed:15265931). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Presents tumor epitopes derived from melanoma-associated TYR antigen (QNILLSNAPLGPQFP and DYSYLQDSDPDSFQD), triggering CD4-positive T cell effector functions such as GMCSF production (PubMed:8642306). Displays preferentially citrullinated self-peptides derived from VIM (GVYATR/citSSAVR and SAVRAR/citSSVPGVR) and ACAN (VVLLVATEGR/ CitVRVNSAYQDK) (PubMed:24190431). Displays self-peptides derived from COL2A1 (PubMed:9354468) Allele DRB1*04:02: Displays native or citrullinated self-peptides derived from VIM Allele DRB1*04:04: May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (HIVMQYMYVPPGAPIPTTRN) and VP2 (RGDSTITSQDVANAVVGYGV), contributing to viral clearance (PubMed:27591323). Displays preferentially citrullinated self-peptides derived from VIM (SAVRAR/citSSVPGVR) (PubMed:24190431) Allele DRB1*04:05: May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies Allele DRB1*05:01: Presents an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load Allele DRB1*07:01: Upon EBV infection, presents latent antigen EBNA2 peptide (PRSPTVFYNIPPMPLPPSQL) to CD4-positive T cells, driving oligoclonal expansion and selection of a dominant virus-specific memory T cell subset with cytotoxic potential to directly eliminate virus-infected B cells (PubMed:31308093). May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (VPYVNAVPMDSMVRHNNWSL), contributing to viral clearance (PubMed:27591323). In the context of tumor immunesurveillance, may present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (MTEYKLVVVGAVGVGKSALTIQLI), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:22929521). In metastatic epithelial tumors, presents to intratumoral CD4-positive T cells a KRAS neoantigen (MTEYKLVVVGAVGVGKSALTIQLI) carrying G12V hotspot driver mutation and may mediate tumor regression (PubMed:30282837) Allele DRB1*11:01: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SDRIIQITRGDSTITSQDVA), contributing to viral clearance (PubMed:27591323). Presents several immunogenic epitopes derived from C.tetani neurotoxin tetX, playing a role in immune recognition and longterm protection (PubMed:19830726). In the context of tumor immunesurveillance, may present tumor-derived neoantigens to CD4-positive T cells and trigger anti-tumor helper functions (PubMed:31495665) Allele DRB1*13:01: Presents viral epitopes derived from HHV-6B antigens to polyfunctional CD4-positive T cells implicated in control of HHV-6B infection Allele DRB1*15:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SNNSATLIVPYVNAVPMDSM), contributing to viral clearance (PubMed:27591323). Displays a self-peptide derived from MBP (ENPVVHFFKNIVTPR) (PubMed:25413013, PubMed:9782128). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies Allele DRB1*15:02: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:19120973) (Microbial infection) Acts as a receptor for Epstein-Barr virus on lymphocytes","subcellular_location":"Cell membrane; Endoplasmic reticulum membrane; Lysosome membrane; Late endosome membrane; Autolysosome membrane","url":"https://www.uniprot.org/uniprotkb/P01911/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HLA-DRB1","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HLA-DRB1","total_profiled":1310},"omim":[{"mim_id":"614590","title":"PODOCONIOSIS, SUSCEPTIBILITY TO; PDCOS","url":"https://www.omim.org/entry/614590"},{"mim_id":"614389","title":"PREGNANCY LOSS, RECURRENT, SUSCEPTIBILITY TO, 1; RPRGL1","url":"https://www.omim.org/entry/614389"},{"mim_id":"614380","title":"COMPLEMENT COMPONENT 4A DEFICIENCY; C4AD","url":"https://www.omim.org/entry/614380"},{"mim_id":"614379","title":"COMPLEMENT COMPONENT 4B DEFICIENCY; C4BD","url":"https://www.omim.org/entry/614379"},{"mim_id":"613883","title":"KELL BLOOD GROUP METALLOENDOPEPTIDASE; KEL","url":"https://www.omim.org/entry/613883"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":554.1},{"tissue":"lymphoid tissue","ntpm":574.2}],"url":"https://www.proteinatlas.org/search/HLA-DRB1"},"hgnc":{"alias_symbol":[],"prev_symbol":["HLA-DR1B"]},"alphafold":{"accession":"P01911","domains":[{"cath_id":"3.10.320.10","chopping":"37-117","consensus_level":"high","plddt":97.9932,"start":37,"end":117},{"cath_id":"2.60.40.10","chopping":"126-221","consensus_level":"high","plddt":94.328,"start":126,"end":221}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P01911","model_url":"https://alphafold.ebi.ac.uk/files/AF-P01911-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P01911-F1-predicted_aligned_error_v6.png","plddt_mean":88.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HLA-DRB1","jax_strain_url":"https://www.jax.org/strain/search?query=HLA-DRB1"},"sequence":{"accession":"P01911","fasta_url":"https://rest.uniprot.org/uniprotkb/P01911.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P01911/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P01911"}},"corpus_meta":[{"pmid":"1416553","id":"PMC_1416553","title":"The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis.","date":"1992","source":"Annals of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/1416553","citation_count":452,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24190431","id":"PMC_24190431","title":"A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis.","date":"2013","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24190431","citation_count":331,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16905561","id":"PMC_16905561","title":"Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis.","date":"2006","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16905561","citation_count":250,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10425186","id":"PMC_10425186","title":"Polymorphisms in the SOD2 and HLA-DRB1 genes are associated with nonfamilial idiopathic dilated cardiomyopathy in Japanese.","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10425186","citation_count":153,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1574800","id":"PMC_1574800","title":"Rapid HLA-DRB1 genotyping by nested PCR amplification.","date":"1992","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/1574800","citation_count":142,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17653284","id":"PMC_17653284","title":"HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis.","date":"2007","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/17653284","citation_count":138,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20061955","id":"PMC_20061955","title":"The rheumatoid arthritis HLA-DRB1 shared epitope.","date":"2010","source":"Current opinion in rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/20061955","citation_count":133,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8144889","id":"PMC_8144889","title":"Exploration of requirements for peptide binding to HLA DRB1*0101 and DRB1*0401.","date":"1994","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8144889","citation_count":127,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9500545","id":"PMC_9500545","title":"Recent origin of HLA-DRB1 alleles and implications for human evolution.","date":"1998","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9500545","citation_count":110,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1685264","id":"PMC_1685264","title":"HLA-DRB1*01 subtyping by allele-specific PCR amplification: a sensitive, specific and rapid technique.","date":"1991","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/1685264","citation_count":102,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7720475","id":"PMC_7720475","title":"HLA-DRB1*1502 allele, subtype of DR15, is associated with susceptibility to ulcerative colitis and its progression.","date":"1995","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/7720475","citation_count":99,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15529363","id":"PMC_15529363","title":"Increased susceptibility to rheumatoid arthritis in Koreans heterozygous for HLA-DRB1*0405 and *0901.","date":"2004","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/15529363","citation_count":94,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16463424","id":"PMC_16463424","title":"Chronic periaortitis and HLA-DRB1*03: another clue to an autoimmune origin.","date":"2006","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/16463424","citation_count":91,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27435705","id":"PMC_27435705","title":"HLA-DRB1 the notorious gene in the mosaic of autoimmunity.","date":"2017","source":"Immunologic research","url":"https://pubmed.ncbi.nlm.nih.gov/27435705","citation_count":90,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22807207","id":"PMC_22807207","title":"Association between Parkinson's disease and the HLA-DRB1 locus.","date":"2012","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/22807207","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32370106","id":"PMC_32370106","title":"Current Understanding of an Emerging Role of HLA-DRB1 Gene in Rheumatoid Arthritis-From Research to Clinical Practice.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32370106","citation_count":87,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23793098","id":"PMC_23793098","title":"Association of HLA-DRB1-restricted CD4⁺ T cell responses with HIV immune control.","date":"2013","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23793098","citation_count":83,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9572996","id":"PMC_9572996","title":"Clinical significance of HLA-DRB1*0410 in Japanese patients with idiopathic thrombocytopenic purpura.","date":"1998","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9572996","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20530326","id":"PMC_20530326","title":"Multiple sclerosis, vitamin D, and HLA-DRB1*15.","date":"2010","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/20530326","citation_count":67,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30038611","id":"PMC_30038611","title":"In Situ Humoral Immunity to Vimentin in HLA-DRB1*03+ Patients With Pulmonary Sarcoidosis.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30038611","citation_count":65,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18338763","id":"PMC_18338763","title":"Association of IL23R, TNFRSF1A, and HLA-DRB1*0103 allele variants with inflammatory bowel disease phenotypes in the Finnish population.","date":"2008","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/18338763","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23411782","id":"PMC_23411782","title":"The HLA-DRB1*15:01-restricted Goodpasture's T cell epitope induces GN.","date":"2013","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/23411782","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12022360","id":"PMC_12022360","title":"MICA rather than MICB, TNFA, or HLA-DRB1 is associated with susceptibility to psoriatic arthritis.","date":"2002","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/12022360","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10718431","id":"PMC_10718431","title":"HLA-DRB1, -DQA1, and -DQB1 genotypes in patients with nasal polyposis.","date":"2000","source":"The Laryngoscope","url":"https://pubmed.ncbi.nlm.nih.gov/10718431","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7751636","id":"PMC_7751636","title":"Prediction of peptide affinity to HLA DRB1*0401.","date":"1995","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7751636","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22127897","id":"PMC_22127897","title":"HLA-DRB1*15:01 and multiple sclerosis: a female association?","date":"2011","source":"Multiple sclerosis (Houndmills, Basingstoke, England)","url":"https://pubmed.ncbi.nlm.nih.gov/22127897","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15529352","id":"PMC_15529352","title":"Particular HLA-DRB1 shared epitope genotypes are strongly associated with rheumatoid vasculitis.","date":"2004","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/15529352","citation_count":54,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10784518","id":"PMC_10784518","title":"Systemic scleroderma in Greece: low mortality and strong linkage with HLA-DRB1*1104 allele.","date":"2000","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/10784518","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10332964","id":"PMC_10332964","title":"HLA-DRB1 genotype influences risk for and severity of rheumatoid arthritis.","date":"1999","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/10332964","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21280007","id":"PMC_21280007","title":"HLA-DRB1*0407 and *1304 are risk factors for scleroderma renal crisis.","date":"2011","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/21280007","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12618858","id":"PMC_12618858","title":"Dissecting the associations of endemic pemphigus foliaceus (Fogo Selvagem) with HLA-DRB1 alleles and genotypes.","date":"2003","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/12618858","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11196680","id":"PMC_11196680","title":"Independent contribution of HLA-DRB1 and TNF alpha promoter polymorphisms to the susceptibility to Crohn's disease.","date":"2000","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/11196680","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25506722","id":"PMC_25506722","title":"Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans.","date":"2015","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25506722","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19956544","id":"PMC_19956544","title":"Interaction of vitamin D receptor with HLA DRB1 0301 in type 1 diabetes patients from North India.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19956544","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27829665","id":"PMC_27829665","title":"The role of common protective alleles HLA-DRB1*13 among systemic autoimmune diseases.","date":"2016","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/27829665","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28822831","id":"PMC_28822831","title":"IFNA-AS1 regulates CD4+ T cell activation in myasthenia gravis though HLA-DRB1.","date":"2017","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/28822831","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21739420","id":"PMC_21739420","title":"Genetic variants in the HLA-DRB1 gene are associated with Kashin-Beck disease in the Tibetan population.","date":"2011","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/21739420","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19392788","id":"PMC_19392788","title":"HLA-DRB1 associations with disease susceptibility and clinical course in Australians with multiple sclerosis.","date":"2009","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/19392788","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32234402","id":"PMC_32234402","title":"Comprehensive meta-analysis reveals an association of the HLA-DRB1*1602 allele with autoimmune diseases mediated predominantly by autoantibodies.","date":"2020","source":"Autoimmunity reviews","url":"https://pubmed.ncbi.nlm.nih.gov/32234402","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24964187","id":"PMC_24964187","title":"The influence of HLA-DRB1*15 on motor cortical pathology in multiple sclerosis.","date":"2015","source":"Neuropathology and applied neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/24964187","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22509268","id":"PMC_22509268","title":"HLA-DRB1-DQB1 haplotypes confer susceptibility and resistance to multiple sclerosis in Sardinia.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22509268","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23380141","id":"PMC_23380141","title":"Association of HLA-DRB1 and TNF genotypes with dengue hemorrhagic fever.","date":"2013","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23380141","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9796911","id":"PMC_9796911","title":"Modulation of HLA-DQ-restricted collagen-induced arthritis by HLA-DRB1 polymorphism.","date":"1998","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9796911","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17328818","id":"PMC_17328818","title":"A new classification of HLA-DRB1 alleles differentiates predisposing and protective alleles for autoantibody production in rheumatoid arthritis.","date":"2007","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/17328818","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21716163","id":"PMC_21716163","title":"Association of HLA-DRB1 alleles and neuropsychological function in autism.","date":"2012","source":"Psychiatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21716163","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24244658","id":"PMC_24244658","title":"Limited promiscuity of HLA-DRB1 presented peptides derived of blood coagulation factor VIII.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24244658","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7906684","id":"PMC_7906684","title":"Influence of HLA-DRB1 gene variation on the clinical course of Vogt-Koyanagi-Harada disease.","date":"1994","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/7906684","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21924912","id":"PMC_21924912","title":"Association between HLA-DRB1 and myasthenia gravis in a northern Han Chinese population.","date":"2011","source":"Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia","url":"https://pubmed.ncbi.nlm.nih.gov/21924912","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7725310","id":"PMC_7725310","title":"High resolution HLA-DRB1 SSP typing for cadaveric donor transplantation.","date":"1995","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/7725310","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8851725","id":"PMC_8851725","title":"HLA-DRB1, DQA1, DQB1 DNA polymorphism in the Bulgarian population.","date":"1996","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/8851725","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22310063","id":"PMC_22310063","title":"Proinflammatory HLA-DRB1*01-haplotype predisposes to ST-elevation myocardial infarction.","date":"2012","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/22310063","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23180817","id":"PMC_23180817","title":"An HLA-DRB1-coded signal transduction ligand facilitates inflammatory arthritis: a new mechanism of autoimmunity.","date":"2012","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23180817","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16792590","id":"PMC_16792590","title":"HLA DRB1*15-DPB1*05 haplotype: a susceptible gene marker for isocyanate-induced occupational asthma?","date":"2006","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/16792590","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12878363","id":"PMC_12878363","title":"Molecular analyses of HLA-DRB1, -DPB1, and -DQB1 in Jing ethnic minority of Southwest China.","date":"2003","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12878363","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10566602","id":"PMC_10566602","title":"Relative HLA-DRB1*13 allele frequencies and DRB3 associations of unrelated individuals from five US populations.","date":"1999","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10566602","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1926126","id":"PMC_1926126","title":"HLA-DRB1, -DQA1, -DQB1, -DPA1 and -DPB1 genes in Japanese multiple sclerosis patients.","date":"1991","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/1926126","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16756466","id":"PMC_16756466","title":"Interaction of HLA-DRB1 alleles with CTLA-4 in the predisposition to Graves' disease: the impact of DRB1*07.","date":"2006","source":"Thyroid : official journal of the American Thyroid Association","url":"https://pubmed.ncbi.nlm.nih.gov/16756466","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29106035","id":"PMC_29106035","title":"Genetic association of HLA-DRB1 multiple polymorphisms with dermatomyositis in Chinese population.","date":"2017","source":"HLA","url":"https://pubmed.ncbi.nlm.nih.gov/29106035","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19210888","id":"PMC_19210888","title":"Role of HLA-DRB1 and PTPN22 genes in susceptibility to juvenile idiopathic arthritis in Hungarian patients.","date":"2008","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/19210888","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19243543","id":"PMC_19243543","title":"Anti-\"Mi(a)\" immunization is associated with HLA-DRB1*0901.","date":"2009","source":"Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/19243543","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24403192","id":"PMC_24403192","title":"A variant upstream of HLA-DRB1 and multiple variants in MICA influence susceptibility to cervical cancer in a Swedish population.","date":"2014","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24403192","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32010139","id":"PMC_32010139","title":"Protective Allele for Multiple Sclerosis HLA-DRB1*01:01 Provides Kinetic Discrimination of Myelin and Exogenous Antigenic Peptides.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32010139","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9433406","id":"PMC_9433406","title":"The effect of HLA-DRB1 disease susceptibility markers on the expression of RA.","date":"1997","source":"Scandinavian journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/9433406","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28981958","id":"PMC_28981958","title":"Pooled analysis of the HLA-DRB1 by smoking interaction in Parkinson disease.","date":"2017","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/28981958","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23404077","id":"PMC_23404077","title":"Association of HLA-DRB1*15:02 and DRB5*01:02 allele with the susceptibility to systemic sclerosis in Thai patients.","date":"2013","source":"Rheumatology international","url":"https://pubmed.ncbi.nlm.nih.gov/23404077","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17714903","id":"PMC_17714903","title":"Analysis of HLA-DRB1, DQA1, DQB1 haplotypes in Sardinian centenarians.","date":"2007","source":"Experimental gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/17714903","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23186557","id":"PMC_23186557","title":"Association of HLA-DRB1*1501 tagging rs3135388 gene polymorphism with multiple sclerosis.","date":"2012","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/23186557","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1293086","id":"PMC_1293086","title":"Generic HLA-DRB1 gene oligotyping by a nonradioactive reverse dot-blot methodology.","date":"1992","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1293086","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22578019","id":"PMC_22578019","title":"The genetic variants at the HLA-DRB1 gene are associated with primary IgA nephropathy in Han Chinese.","date":"2012","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22578019","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20303356","id":"PMC_20303356","title":"Human risk allele HLA-DRB1*0405 predisposes class II transgenic Ab0 NOD mice to autoimmune pancreatitis.","date":"2010","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/20303356","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23588515","id":"PMC_23588515","title":"HLA-DRB1 allele association with rheumatoid arthritis susceptibility and severity in Syria.","date":"2013","source":"Revista brasileira de reumatologia","url":"https://pubmed.ncbi.nlm.nih.gov/23588515","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11704286","id":"PMC_11704286","title":"HLA-DRB1*04 alleles in psoriatic arthritis: comparison with rheumatoid arthritis and healthy controls.","date":"2001","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11704286","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19046304","id":"PMC_19046304","title":"Association of aplastic anaemia and Fanconi's disease with HLA-DRB1 alleles.","date":"2008","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/19046304","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24278156","id":"PMC_24278156","title":"Diversity of extended HLA-DRB1 haplotypes in the Finnish population.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24278156","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17207714","id":"PMC_17207714","title":"Genetic variations of HLA-DRB1 and susceptibility to Kawasaki disease in Taiwanese children.","date":"2006","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17207714","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19896246","id":"PMC_19896246","title":"Peptide binding to the HLA-DRB1 supertype: a proteochemometrics analysis.","date":"2009","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19896246","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23180035","id":"PMC_23180035","title":"Genetics of ANCA-associated vasculitis in Japan: a role for HLA-DRB1*09:01 haplotype.","date":"2012","source":"Clinical and experimental nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/23180035","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10852382","id":"PMC_10852382","title":"HLA DRB1*1501 and intrathecal inflammation in multiple sclerosis.","date":"2000","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/10852382","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24666112","id":"PMC_24666112","title":"Evaluation of HLA-DRB1 imputation using a Finnish dataset.","date":"2014","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/24666112","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17767557","id":"PMC_17767557","title":"The nature of diversity of HLA-DRB1 exon 3.","date":"2007","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/17767557","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14769517","id":"PMC_14769517","title":"Shared-epitope HLA-DRB1 alleles and sex ratio in Italian patients with rheumatoid arthritis.","date":"2004","source":"Joint bone spine","url":"https://pubmed.ncbi.nlm.nih.gov/14769517","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27713139","id":"PMC_27713139","title":"Hypomethylation of HLA-DRB1 and its clinical significance in psoriasis.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27713139","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27214100","id":"PMC_27214100","title":"Brief Report: HLA-DRB1, DQA1, and DQB1 in Juvenile-Onset Systemic Sclerosis.","date":"2016","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/27214100","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33510427","id":"PMC_33510427","title":"HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33510427","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1353911","id":"PMC_1353911","title":"The significance of HLA-DRB1 matching in clinical renal transplantation.","date":"1992","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/1353911","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27503745","id":"PMC_27503745","title":"Association of HLA-DRB1 Gene Polymorphism with Risk of Asthma: A Meta-Analysis.","date":"2016","source":"Medical science monitor basic research","url":"https://pubmed.ncbi.nlm.nih.gov/27503745","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8892091","id":"PMC_8892091","title":"Analysis of naturally processed peptides eluted from HLA DRB1*0402 and *0404.","date":"1996","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/8892091","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31981624","id":"PMC_31981624","title":"Association of HLA-DRB1∗09:01 with tIgE levels among African-ancestry individuals with asthma.","date":"2020","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31981624","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25582808","id":"PMC_25582808","title":"Immune-related pathways including HLA-DRB1(∗)13:02 are associated with panic disorder.","date":"2015","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/25582808","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8770633","id":"PMC_8770633","title":"HLA-DRB1 molecules and antigenic experience shape the repertoire of CD4 T cells.","date":"1995","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8770633","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8525160","id":"PMC_8525160","title":"[HLA DRB1 polymorphism in rhizomelic pseudo-polyarthritis and Horton disease].","date":"1995","source":"La Revue de medecine interne","url":"https://pubmed.ncbi.nlm.nih.gov/8525160","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21497601","id":"PMC_21497601","title":"HLA DRB1*1503 allelic haplotype predominance and associated immunodysregulation in systemic lupus erythematosus.","date":"2011","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21497601","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21911185","id":"PMC_21911185","title":"HPV-16 and HLA-DRB1 alleles are associated with cervical carcinoma in Mexican Mestizo women.","date":"2011","source":"Archives of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/21911185","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26056112","id":"PMC_26056112","title":"Relationship of HLA-DRB1 gene polymorphism with susceptibility to pulmonary tuberculosis: updated meta-analysis.","date":"2015","source":"The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease","url":"https://pubmed.ncbi.nlm.nih.gov/26056112","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34153873","id":"PMC_34153873","title":"The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes.","date":"2021","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/34153873","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12870731","id":"PMC_12870731","title":"Association of the HLA-DRB1 gene locus with gastric adenocarcinoma in Japan.","date":"2003","source":"Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/12870731","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23413297","id":"PMC_23413297","title":"Assessing interactions between HLA-DRB1*15 and infectious mononucleosis on the risk of multiple sclerosis.","date":"2013","source":"Multiple sclerosis (Houndmills, Basingstoke, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23413297","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9933752","id":"PMC_9933752","title":"Association between HLA-DRB1*15 and Japanese patients with rheumatoid arthritis complicated by renal involvement.","date":"1999","source":"Nephron","url":"https://pubmed.ncbi.nlm.nih.gov/9933752","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12022354","id":"PMC_12022354","title":"Henoch-Schönlein purpura and cutaneous leukocytoclastic angiitis exhibit different HLA-DRB1 associations.","date":"2002","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/12022354","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30175673","id":"PMC_30175673","title":"Human leukocyte antigen (HLA)-DRB1 allele polymorphisms and systemic sclerosis.","date":"2019","source":"Modern rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/30175673","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11181995","id":"PMC_11181995","title":"The sequence of the human genome.","date":"2001","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11181995","citation_count":8428,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17554300","id":"PMC_17554300","title":"Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.","date":"2007","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/17554300","citation_count":7256,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23128233","id":"PMC_23128233","title":"Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23128233","citation_count":3725,"is_preprint":false,"source_track":"gene2pubmed"},{"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":"24162737","id":"PMC_24162737","title":"Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24162737","citation_count":3440,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8316295","id":"PMC_8316295","title":"Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1.","date":"1993","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/8316295","citation_count":2026,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24390342","id":"PMC_24390342","title":"Genetics of rheumatoid arthritis contributes to biology and drug discovery.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/24390342","citation_count":1778,"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":"8145819","id":"PMC_8145819","title":"Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide.","date":"1994","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/8145819","citation_count":1391,"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":"21297633","id":"PMC_21297633","title":"Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21297633","citation_count":1078,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20453842","id":"PMC_20453842","title":"Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.","date":"2010","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20453842","citation_count":1018,"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":"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":"20335276","id":"PMC_20335276","title":"PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations.","date":"2010","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20335276","citation_count":908,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19838193","id":"PMC_19838193","title":"Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus.","date":"2009","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19838193","citation_count":803,"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":"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":"17804836","id":"PMC_17804836","title":"TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide study.","date":"2007","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17804836","citation_count":675,"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":"18252895","id":"PMC_18252895","title":"HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families.","date":"2008","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/18252895","citation_count":622,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7606781","id":"PMC_7606781","title":"HLA-DM induces CLIP dissociation from MHC class II alpha beta dimers and facilitates peptide loading.","date":"1995","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/7606781","citation_count":597,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489916","id":"PMC_15489916","title":"Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15489916","citation_count":547,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15191952","id":"PMC_15191952","title":"Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.","date":"2004","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15191952","citation_count":544,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20018961","id":"PMC_20018961","title":"Genomewide association study of leprosy.","date":"2009","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20018961","citation_count":532,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21399633","id":"PMC_21399633","title":"Genome-wide association study identifies susceptibility loci for IgA nephropathy.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21399633","citation_count":522,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55903,"output_tokens":3831,"usd":0.112587},"stage2":{"model":"claude-opus-4-6","input_tokens":7255,"output_tokens":3112,"usd":0.171113},"total_usd":0.616585,"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":70218,"output_tokens":5727,"usd":0.14828},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":8774,"output_tokens":3168,"usd":0.184605}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"Peptide binding to HLA-DRB1*0101 and DRB1*0401 requires a key hydrophobic anchor residue near the amino-terminus; optimal binding depends on the position of this hydrophobic side chain relative to peptide termini, aromatic amino acids are superior to aliphatic side chains at this position, and a significant portion of binding free energy arises from hydrogen bonds between the class II binding site and the amide backbone of the ligand.\",\n      \"method\": \"Quantitative competitive peptide binding assay with polyalanine analogues, reduced peptide bonds, and N-methyl amino acid substitutions\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assay with systematic mutagenesis/analogue series; multiple orthogonal methods in single study\",\n      \"pmids\": [\"8144889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"A quantitative prediction matrix for peptide binding to HLA-DRB1*0401 was established by measuring the contribution of each of the 20 amino acids at 11 peptide positions; the P3 hydrophobic anchor is critical, and the model correctly predicted binding of unrelated peptides including myelin basic protein-derived peptides, allowing identification of T cell determinants.\",\n      \"method\": \"Quantitative peptide binding assay; prediction matrix validated on independent peptide sets and T cell hybridoma specificity\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic in vitro binding assay with predictive validation; multiple orthogonal confirmations\",\n      \"pmids\": [\"7751636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Citrullinated aggrecan and vimentin epitopes bind to HLA-DRB1*04:01/04 via accommodation of citrulline in the electropositive P4 pocket; the RA-resistant allomorph DRB1*04:02 has an electronegative P4 pocket that binds arginine-containing (but not exclusively citrullinated) peptides. Citrullination alters protease susceptibility of vimentin generating neo-epitopes presented by DRB1*04:01 to autoreactive CD4+ T cells detectable by HLA-II tetramers.\",\n      \"method\": \"Crystal structure / peptide elution studies; HLA-II tetramers; T cell functional assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural and functional validation with multiple orthogonal methods in one study\",\n      \"pmids\": [\"24190431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The HLA-DRB1-coded shared epitope (SE) sequence motif acts as a signal transduction ligand that activates osteoclastogenesis in vitro and in vivo, enhances production of pro-osteoclastogenic factors, promotes Th17 cell differentiation expressing RANKL, and synergizes with IL-17 to drive osteoclast differentiation; transgenic mice expressing SE-coding HLA-DRB1 alleles showed markedly higher osteoclastogenesis and bone degradation, and SE ligand administration in vivo increased arthritis severity and bone erosion.\",\n      \"method\": \"In vitro osteoclastogenesis assay with mouse and human cells; HLA-DRB1 transgenic mice; collagen-induced arthritis model; in vivo ligand administration\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo assays with transgenic model and functional readouts\",\n      \"pmids\": [\"23180817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HLA-DRB1*15:01 restricts a specific CD4+ T cell epitope (α3136-146) from the noncollagenous domain of type IV collagen α3-chain; CD4+ T cell clones specific for this epitope transferred necrotizing crescentic glomerulonephritis into naive HLA-DRB1*15:01 transgenic mice, whereas HLA-DRB1*01:01 transgenic mice were unaffected, demonstrating allele-restricted pathogenic T cell responses.\",\n      \"method\": \"HLA-DRB1 transgenic mouse immunization; adoptive T cell transfer; epitope mapping with overlapping peptides\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — transgenic mouse model with adoptive transfer and defined disease readout; multiple alleles compared\",\n      \"pmids\": [\"23411782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Introduction of HLA-DRB1*1502 (DR2) transgene into DQ8-susceptible mice significantly decreased collagen-induced arthritis incidence and promoted a Th2 cytokine profile, whereas DRB1*0301 (DR3) had no protective effect and yielded a Th1 profile, demonstrating that DRB1 polymorphism can modulate DQ-restricted autoimmune arthritis.\",\n      \"method\": \"HLA transgenic mouse model (CIA); T cell proliferation assay; cytokine profiling\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic mouse CIA model with functional immune readouts; single lab\",\n      \"pmids\": [\"9796911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human risk allele HLA-DRB1*0405, but not DRB1*0401 or DQ8, predisposes transgenic Ab0 NOD mice to autoimmune pancreatitis mediated by infiltrating CD4+ and CD8+ T cells, B cells, and macrophages, demonstrating that DRB1*0405 is an independent risk gene on the DRB1*0405/DQB1*0401 haplotype.\",\n      \"method\": \"HLA class II transgenic mouse model; irradiation and adoptive CD90+ T cell transfer; histopathology\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic mouse model with direct allele comparison; single lab\",\n      \"pmids\": [\"20303356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HLA-DRB1 allele variants stratify HIV viremia control via CD4+ T cell responses: DRB1*15:02 associated with low viremia and DRB1*03:01 with high viremia; alleles linked with low viremia promiscuously present a broader breadth of Gag and Nef peptides with lower functional avidity compared to high-viremia alleles.\",\n      \"method\": \"Peptide-DRB1 restriction mapping in functional T cell assays; cohort analysis of HLA-DRB1 effects on viremia\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional T cell assays combined with genetic analysis; single lab but large cohort\",\n      \"pmids\": [\"23793098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"HLA-DRB1 alleles shape the peripheral CD4+ TCR Vβ repertoire: a correlation between Vβ gene segment usage and HLA-DRB1 alleles was demonstrated in naive (CD45RO-) CD4+ T cells, with this HLA-imposed profile maintained but less pronounced in memory (CD45RO+) CD4+ T cells, indicating that antigen experience modulates the HLA-DRB1-shaped TCR repertoire.\",\n      \"method\": \"TCR Vβ usage analysis in sorted naive vs. memory CD4+ T cell populations from HLA-DRB1-typed cohorts\",\n      \"journal\": \"Human immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct repertoire analysis in HLA-typed human cohorts with naive/memory compartment comparison; single lab\",\n      \"pmids\": [\"8770633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Short synthetic peptides corresponding to the third hypervariable regions of disease-risk versus disease-protective HLA-DRB1 alleles differentially polarize macrophages: risk-allele peptides activate pro-inflammatory (M1) transcriptomes while protective-allele peptides activate anti-inflammatory (M2) transcriptomes, independently of antigen presentation.\",\n      \"method\": \"RNA-sequencing of in vitro-polarized macrophages treated with AP-incompetent HLA-DRB1-coded short peptides; gene ontology and upstream regulator analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq with functional peptide treatment; novel non-AP mechanism; single lab\",\n      \"pmids\": [\"33510427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Naturally processed peptides eluted from HLA-DRB1*0404 are nested clusters derived from positions 26-43 of the HLA-B and -C alpha-chain, while DRB1*0402 predominantly presents a nested cluster from positions 129-145 of the HLA-B alpha-chain, demonstrating that RA-associated and non-associated DR4 alleles present distinct endogenous peptide repertoires.\",\n      \"method\": \"Immunoaffinity purification of MHC class II/peptide complexes from homozygous B cell lines; reversed-phase HPLC; Edman degradation; tandem mass spectrometry\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — biochemical peptide elution with mass spectrometry; single lab, single study\",\n      \"pmids\": [\"8892091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HLA-DRB1*01:01 binds MBP-derived peptides (MBP153-161 and MBP90-98) with affinity comparable to the HA306-318 control peptide, but HLA-DM-catalyzed kinetic measurements reveal a significantly lower rate of CLIP exchange for MBP peptides due to incomplete occupation of P6/7 and P9 pockets caused by lack of anchor residues, leading to rapid dissociation; this kinetic discrimination between self (MBP) and exogenous peptides may underlie the protective effect of DRB1*01:01 in MS.\",\n      \"method\": \"In vitro binding assay with recombinant HLA-DRB1*01:01; HLA-DM-catalyzed CLIP exchange kinetics; chimeric MBP-HA peptide analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with kinetic measurements; single lab\",\n      \"pmids\": [\"32010139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A vitamin D response element (VDRE) present in the promoter region of HLA-DRB1*0301 mediates interaction between VDR and HLA-DRB1, with VDR high-producer alleles (F and T) interacting with DRB1*0301; DRB1*0301 expression is regulated by 1,25-(OH)2D3 through this VDRE, confirmed by flow cytometry and real-time PCR.\",\n      \"method\": \"Promoter sequence analysis; flow cytometry; real-time PCR; LD-based interaction statistics\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, promoter bioinformatics + flow cytometry/qPCR without full functional reconstitution\",\n      \"pmids\": [\"19956544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The lncRNA IFNG-AS1 negatively regulates HLA-DRB1 expression in myasthenia gravis, influencing CD4+ T cell activation; knockdown/overexpression experiments showed IFNG-AS1 reduced HLA-DRB expression and modulated CD40L levels and CD4+ T cell activation partly through effects on HLA-DRB1.\",\n      \"method\": \"lncRNA knockdown/overexpression in EAMG model; qPCR and functional T cell assays\",\n      \"journal\": \"Clinical immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, indirect regulation of HLA-DRB1 expression without direct mechanistic reconstitution\",\n      \"pmids\": [\"28822831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Three amino acid residues in HLA-DRB1 (β71, β74, β86) forming allele-specific motifs determine T1D risk by shaping peptide antigen anchor pocket preferences (p1, p4, p7 pockets); the 'KAG' motif (DRB1*04:01) most strongly predicts T1D risk and seroconversion, while 'REG'/'REV' motifs are protective, likely through differential binding of autoantigens preproinsulin and GAD65.\",\n      \"method\": \"Population-based case-control genotyping; birth cohort time-to-seroconversion analysis; HLA-peptide structural modeling\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — genetic association plus computational structural modeling; no direct binding reconstitution\",\n      \"pmids\": [\"34153873\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HLA-DRB1 encodes a highly polymorphic MHC class II beta chain that presents antigenic peptides to CD4+ T cells via allele-specific peptide-binding pockets (particularly P1 and P4), with distinct alleles determining peptide repertoire and binding kinetics; beyond antigen presentation, the shared epitope motif coded by risk alleles can act as a signal transduction ligand activating osteoclastogenesis and pro-inflammatory macrophage polarization, while protective alleles kinetically discriminate self from foreign peptides and promote anti-inflammatory immune responses, collectively explaining allele-specific contributions to autoimmune disease susceptibility and severity.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract mechanistic discoveries only from KEEP papers.\n\n**Classification summary:**\n- Papers about HLA-DRB1 disease associations (GWAS, epidemiology, genotyping methods): EXCLUDE (no mechanistic findings)\n- Papers with direct mechanistic experiments on HLA-DRB1 protein function: KEEP\n- Generic genome papers (human genome sequence, BioPlex interactome): EXCLUDE (not specific to HLA-DRB1)\n\n**KEEP papers with mechanistic content:**\n- PMID:24190431 — crystal/structural basis of citrullinated peptide binding to HLA-DRB1*04:01/04\n- PMID:8144889 — peptide binding requirements for DRB1*0101 and DRB1*0401 (in vitro binding assay)\n- PMID:7751636 — prediction/characterization of peptide binding to DRB1*0401\n- PMID:8316295 — crystal structure of HLA-DR1\n- PMID:8145819 — crystal structure of HLA-DR1 with peptide\n- PMID:7606781 — HLA-DM catalyzes CLIP dissociation from MHC class II (mechanistic)\n- PMID:23180817 — SE as signal transduction ligand activating osteoclastogenesis\n- PMID:33510427 — HLA-DRB1 allelic epitopes activate reciprocal macrophage polarization\n- PMID:9796911 — DRB1 polymorphism modulates DQ-restricted arthritis (transgenic mouse mechanistic)\n- PMID:8770633 — HLA-DRB1 shapes CD4+ T cell TCR Vβ repertoire\n- PMID:23411782 — HLA-DRB1*15:01-restricted T cell epitope induces GN (transgenic mouse)\n- PMID:32010139 — Kinetic discrimination of MBP vs exogenous peptides by HLA-DRB1*01:01\n- PMID:24244658 — FVIII peptide presentation on HLA-DR (dendritic cells/macrophages)\n- PMID:8892091 — Naturally processed peptides eluted from DRB1*0404 and *0402\n- PMID:12519789 — HLA class II in B cell exosomes (MHC class II enriched in detergent-resistant domains)\n- PMID:22286218 — Five amino acids in HLA-DRB1 explain MHC-RA association (fine mapping functional residues)\n- PMID:34153873 — KAG motif (β71, β74, β86) determines peptide binding pocket preferences\n- PMID:19243543 — HLA-DRB1*0901 presents Mi(a) antigen peptides (predicted epitopes)\n- PMID:19956544 — VDR interaction with HLA-DRB1*0301 via VDRE in promoter (flow cytometry, real-time PCR)\n- PMID:19896246 — proteochemometrics of peptide binding to HLA-DRB1 proteins\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"X-ray crystal structure of HLA-DR1 (an HLA-DRB1-containing heterodimer) revealed that peptides bind in an extended conformation in an open-ended groove, with a prominent non-polar pocket near one end accommodating an anchoring peptide side chain; a dimer of the class II αβ heterodimers was observed, suggesting dimerization as a mechanism for cytoplasmic signalling.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional interpretation, foundational highly-cited paper\",\n      \"pmids\": [\"8316295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Crystal structure of HLA-DR1 complexed with an influenza hemagglutinin peptide (HA306-318) showed the peptide binds in an extended, twisted conformation; five of thirteen side chains are accommodated in pockets in the binding site; twelve hydrogen bonds between conserved HLA-DR1 residues and peptide main-chain amide bonds provide a universal mode of peptide binding distinct from MHC class I.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure of peptide-MHC complex, highly cited foundational study\",\n      \"pmids\": [\"8145819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Peptide binding to HLA-DRB1*0101 and DRB1*0401 requires a hydrophobic amino acid near the peptide amino-terminus that docks into a conserved pocket; aromatic side chains are superior to aliphatic at this position; the majority of binding free energy arises from hydrogen bonds between conserved binding-site residues and peptide backbone amide bonds, not side-chain contacts; optimal binding depends on position of the hydrophobic anchor relative to peptide termini.\",\n      \"method\": \"Quantitative competitive peptide binding assay with systematic alanine-scan analogues, reduced peptide bonds, and N-methyl amino acid substitutions\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis of peptide ligands with quantitative IC50 assays, multiple orthogonal approaches\",\n      \"pmids\": [\"8144889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"HLA-DM catalyzes the dissociation of the invariant chain-derived CLIP peptide from MHC class II (HLA-DR) αβ dimers in vitro, facilitating loading of antigenic peptides; the reaction has an acidic pH optimum consistent with occurrence in lysosomal compartments; antibody blocking experiments indicate a transient HLA-DM–MHC class II interaction is required.\",\n      \"method\": \"In vitro biochemical dissociation assay, antibody blocking, pH titration\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro assay with mechanistic controls, highly cited foundational study\",\n      \"pmids\": [\"7606781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"A quantitative database of the contribution of each of the 20 amino acids at 11 positions of a simplified peptide backbone was used to predict peptide binding affinity to HLA-DRB1*0401; the model accurately predicted binding of 13 unrelated peptides and identified two high-affinity myelin basic protein epitopes corresponding to DRB1*0401-restricted T cell determinants, validating that a key hydrophobic residue at position 3 relative to the peptide register drives binding.\",\n      \"method\": \"Quantitative peptide binding assay, combinatorial peptide library, T cell hybridoma specificity testing\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — systematic in vitro binding assay with functional T cell validation, predictive model tested on independent peptides\",\n      \"pmids\": [\"7751636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Comparison of TCR Vβ segment usage in cohorts of individuals expressing distinct HLA-DRB1 alleles showed a correlation between DRB1 allele and Vβ usage in naive (CD45RO−) CD4+ T cells, demonstrating that HLA-DRB1 allelic polymorphism shapes the peripheral CD4+ T cell TCR repertoire through thymic selection; antigenic experience (CD45RO+ memory cells) modulates but does not eliminate this DRB1-imposed Vβ profile.\",\n      \"method\": \"TCR Vβ repertoire analysis by flow cytometry/PCR in HLA-typed donor cohorts, comparison of naive vs memory CD4+ T cell subsets\",\n      \"journal\": \"Human Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct correlation experiment in human cohorts with subset dissection, single lab\",\n      \"pmids\": [\"8770633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Naturally processed peptides eluted from HLA-DRB1*0404 (RA-associated) and DRB1*0402 (non-RA-associated) B cell lines were predominantly nested clusters derived from HLA class I (B and C) α-chain sequences; DRB1*0404 loaded peptides from positions 26–43 of HLA-B/C α-chain, while DRB1*0402 loaded peptides from positions 129–145, demonstrating allele-specific differences in which self-peptides naturally occupy the groove.\",\n      \"method\": \"Immunoaffinity purification of MHC class II complexes, reversed-phase HPLC fractionation, Edman degradation sequencing, tandem mass spectrometry\",\n      \"journal\": \"Journal of Neuroscience Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical elution and MS identification, but single study single lab\",\n      \"pmids\": [\"8892091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Introduction of the HLA-DRB1*1502 (DR2) transgene into collagen-induced arthritis-susceptible HLA-DQ8 mice significantly decreased disease incidence and induced a Th2 cytokine profile, whereas DRB1*0301 (DR3) had no protective effect and maintained a Th1 profile; DR molecules were confirmed functional by positive/negative selection of the Vβ T cell repertoire, demonstrating that DRB1 polymorphism can modulate DQ-restricted autoimmune arthritis.\",\n      \"method\": \"Transgenic mouse model (double DR/DQ transgenic in class II-deficient background), collagen-induced arthritis, in vitro T cell proliferation, cytokine analysis, TCR Vβ repertoire analysis\",\n      \"journal\": \"International Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — well-controlled transgenic model with multiple functional readouts, single lab\",\n      \"pmids\": [\"9796911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HLA class II (including HLA-DRB1-encoded DR) molecules are abundantly present in B cell-derived exosomes and are concentrated in cholesterol/sphingomyelin/GM3-enriched detergent-resistant membrane domains (lipid rafts) within multivesicular bodies, whereas plasma membrane-associated MHC class II is readily solubilized; this compartmentalization may facilitate protein sorting into internal vesicles of multivesicular bodies.\",\n      \"method\": \"Proteomic analysis of purified exosomes by mass spectrometry, detergent solubility fractionation (CHAPS), electron microscopy, immunofluorescence\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — multi-method biochemical characterization, but not specific to DRB1 allele function\",\n      \"pmids\": [\"12519789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The HLA-DRB1 shared epitope (SE) sequence motif acts as a signal transduction ligand that activates osteoclastogenesis independently of antigen presentation: SE peptides potently stimulated osteoclast differentiation in mouse and human cells in vitro, enhanced production of pro-osteoclastogenic factors, and promoted Th17 cell differentiation expressing RANKL; IL-17 and SE synergistically enhanced osteoclast differentiation; SE transgenic mice showed higher osteoclastogenesis ex vivo; in vivo administration to collagen-induced arthritis mice increased arthritis severity, synovial osteoclast abundance, and bone erosion.\",\n      \"method\": \"In vitro osteoclastogenesis assay (mouse and human cells), transgenic mouse model (HLA-DRB1 SE-expressing), collagen-induced arthritis model, cytokine measurement, histology\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (in vitro, transgenic, in vivo disease model), mechanistic pathway defined\",\n      \"pmids\": [\"23180817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Citrullinated aggrecan and vimentin epitopes bind to HLA-DRB1*04:01/04 because citrulline is accommodated within the electropositive P4 pocket of these allomorphs; in contrast, the electronegative P4 pocket of RA-resistant HLA-DRB1*04:02 interacts with arginine or citrulline indiscriminately. Peptide elution studies confirmed P4 arginine-containing peptides from DRB1*04:02 but not DRB1*04:01/04. Citrullination altered protease susceptibility of vimentin, generating epitopes presented to CD4+ T cells specifically in HLA-DRB1*04:01+ individuals.\",\n      \"method\": \"Crystal structure determination, peptide elution/mass spectrometry, HLA-II tetramer staining of peripheral blood CD4+ T cells, T cell functional assays\",\n      \"journal\": \"The Journal of Experimental Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation by peptide elution, tetramer staining, and T cell assays; multiple orthogonal methods\",\n      \"pmids\": [\"24190431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The HLA-DRB1*15:01-restricted T cell epitope α3136-146 from the α3 chain of type IV collagen (Goodpasture antigen) was identified and shown to be naturally processed; CD4+ T cell clones specific for this epitope transferred necrotizing crescentic glomerulonephritis, albuminuria, and renal impairment into naïve HLA-DRB1*15:01 transgenic mice but not HLA-DRB1*01:01 transgenic mice, demonstrating allele-specific pathogenic T cell priming.\",\n      \"method\": \"HLA-DRB1*15:01 and *01:01 transgenic mouse immunization, T cell clone generation, adoptive transfer disease model, histology, renal function assessment\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — transgenic model with adoptive transfer, multiple disease readouts, allele specificity confirmed by negative control\",\n      \"pmids\": [\"23411782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Dendritic cells present FVIII-derived peptides on HLA-DR (including HLA-DRB1) with optimal presentation 12–24 hours after maturation, persisting for 96 hours; immature DCs retain half of FVIII-loaded MHC class II intracellularly, while mature DCs display the majority on the plasma membrane; macrophages internalize FVIII as efficiently as DCs but present fewer peptides with different epitopes; five HLA-promiscuous FVIII peptide regions were identified across 8 donors.\",\n      \"method\": \"HLA class II immunoprecipitation, mass spectrometric peptide identification, flow cytometry for MHC II surface/intracellular distribution, time-course antigen presentation studies\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — direct biochemical peptide identification with functional localization data, multiple donors\",\n      \"pmids\": [\"24244658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Fine-mapping of MHC association with seropositive RA identified that three amino acid positions in HLA-DRβ1 (positions 11, 71, and 74), which are located in the peptide-binding groove, almost completely explain the MHC association to RA risk, along with single positions in HLA-B (position 9) and HLA-DPβ1 (position 9); conditional analyses demonstrated these positions are independent of each other.\",\n      \"method\": \"Genome-wide SNP imputation of HLA classical alleles and amino acid polymorphisms in 5,018 RA cases and 14,974 controls, conditional and haplotype analyses\",\n      \"journal\": \"Nature Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large-scale imputation with conditional analysis pinpointing functional peptide-binding groove residues, replicated across datasets\",\n      \"pmids\": [\"22286218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HLA-DRB1*01:01 binds newly identified myelin basic protein peptides (MBP153-161 and MBP90-98) with affinity comparable to influenza HA peptide, but HLA-DM-catalyzed CLIP exchange for MBP peptides is significantly slower than for HA peptide; chimeric peptide analysis showed this kinetic difference results from absence of anchor residues in the C-terminal part of MBP peptides, causing incomplete occupation of P6/7 and P9 pockets and failure of P1/P4 docking, leading to rapid peptide dissociation from HLA-DM–HLA-DR complex.\",\n      \"method\": \"Recombinant HLA-DRB1*01:01 protein production, peptide binding affinity measurements, HLA-DM-catalyzed CLIP exchange kinetics, chimeric MBP-HA peptide analysis\",\n      \"journal\": \"Frontiers in Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro biochemical kinetic assays with mechanistic mutagenesis (chimeric peptides), single lab\",\n      \"pmids\": [\"32010139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Short synthetic peptides corresponding to the third allelic hypervariable regions of disease risk-associated HLA-DRB1 alleles (SE-containing) versus protective alleles differentially polarize macrophages in vitro: risk allele peptides activate pro-inflammatory M1 transcriptomes while protective allele peptides activate anti-inflammatory M2 transcriptomes, as shown by RNA-sequencing; this immune modulation occurs independently of antigen presentation (AP-incompetent peptides used) and involves distinct upstream regulatory pathways.\",\n      \"method\": \"RNA-sequencing of in vitro-polarized macrophages, AP-incompetent synthetic HLA-DRB1 allelic peptides, gene ontology and upstream regulator analysis\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptome-level mechanistic evidence with AP-incompetent controls, single lab\",\n      \"pmids\": [\"33510427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Three amino acid residues of HLA-DRB1 at positions β71, β74, and β86 determine T1D risk; the 'KAG' motif (corresponding to DRB1*04:01) is most strongly associated with disease and, through structural modeling, is shown to create specific differences in peptide antigen anchor pocket preferences at p1, p4, and p7, affecting differential binding of T1D autoantigens preproinsulin and GAD65.\",\n      \"method\": \"Population-based case-control HLA typing, birth cohort prospective islet autoantibody study, hierarchical sequence similarity analysis, HLA-peptide structural modeling\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional amino acid positions identified in two independent cohorts with structural modeling support\",\n      \"pmids\": [\"34153873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A proteochemometrics model of peptide binding to 12 HLA-DRB1 proteins using z-descriptors for both peptide and protein sequences identified key peptide and protein positions involved in interactions, with hydrophobicity, steric bulk, and polarity at specific positions driving binding; models showed moderate goodness of fit (r²=0.685–0.732) and good cross-validated predictive ability.\",\n      \"method\": \"Computational proteochemometrics modeling of 2666 peptide-DRB1 binding data points, cross-validation, external test set prediction\",\n      \"journal\": \"European Journal of Medicinal Chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational modeling only, no direct experimental validation\",\n      \"pmids\": [\"19896246\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HLA-DRB1 encodes the polymorphic β1 chain of the MHC class II αβ heterodimer, whose peptide-binding groove accommodates antigenic peptides in an extended conformation through 12 conserved hydrogen bonds to the peptide backbone and a key hydrophobic P1 anchor pocket; allele-specific pocket charges (particularly the P4 pocket at residues β71, β74, β86) determine which peptides (including citrullinated self-peptides) are bound and presented to CD4+ T cells; HLA-DM catalyzes CLIP dissociation to facilitate peptide loading in acidic endosomal compartments; beyond antigen presentation, the disease-associated shared epitope sequence motif acts as an extracellular signal transduction ligand that activates osteoclastogenesis and pro-inflammatory macrophage polarization, while protective DRB1 allele-coded epitopes drive anti-inflammatory macrophage polarization, establishing that HLA-DRB1 allelic variation modulates immune outcomes through both antigen presentation-dependent and antigen presentation-independent mechanisms.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HLA-DRB1 encodes the polymorphic beta chain of the MHC class II heterodimer that presents antigenic peptides to CD4+ T cells, with allele-specific anchor pockets (P1, P3, P4, P6/7, P9) governing peptide repertoire, binding affinity, and kinetic stability of peptide–MHC complexes [PMID:8144889, PMID:7751636, PMID:24190431]. Allelic variation at the peptide-binding groove determines which endogenous and exogenous peptides are displayed, as demonstrated by distinct naturally processed peptide sets eluted from RA-associated versus non-associated DR4 subtypes and by HLA-DM-catalyzed kinetic discrimination between self and foreign peptides [PMID:8892091, PMID:32010139]. Beyond canonical antigen presentation, the shared epitope motif encoded by disease-risk DRB1 alleles functions as a signal transduction ligand that activates osteoclastogenesis and Th17 differentiation in vitro and in vivo, while short peptides from the third hypervariable region of risk versus protective alleles differentially polarize macrophages toward pro-inflammatory (M1) or anti-inflammatory (M2) transcriptomes [PMID:23180817, PMID:33510427]. Specific DRB1 alleles confer allele-restricted susceptibility to autoimmune diseases including rheumatoid arthritis, anti-GBM glomerulonephritis, autoimmune pancreatitis, and type 1 diabetes, as established by transgenic mouse adoptive-transfer experiments and population studies [PMID:24190431, PMID:23411782, PMID:20303356].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing the biophysical rules of peptide binding to HLA-DRB1 resolved how the class II groove engages ligands: a hydrophobic N-terminal anchor and backbone hydrogen bonds provide the dominant binding energy, defining the molecular basis of allele-specific peptide selection.\",\n      \"evidence\": \"Quantitative competitive binding assays using polyalanine analogues, reduced peptide bonds, and N-methyl amino acid substitutions with DRB1*0101 and DRB1*0401\",\n      \"pmids\": [\"8144889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Only two DRB1 alleles tested; generalizability to other alleles inferred but not shown\", \"No structural data at atomic resolution in this study\", \"Role of flanking residues outside the core binding register not addressed\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Construction of a quantitative peptide-binding prediction matrix for DRB1*0401 demonstrated that systematic residue preferences across 11 positions could predict T cell determinants, bridging molecular binding to immunological function.\",\n      \"evidence\": \"Systematic measurement of 20 amino acids at each peptide position; validated against independent peptide sets and T cell hybridoma specificities\",\n      \"pmids\": [\"7751636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Matrix derived for a single allele; transferability to other DRB1 alleles not demonstrated\", \"Does not account for HLA-DM editing or in vivo processing\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstration that HLA-DRB1 alleles shape the peripheral CD4+ TCR Vβ repertoire established that DRB1 polymorphism exerts a selecting force on T cell diversity beyond peptide binding.\",\n      \"evidence\": \"TCR Vβ usage analysis in sorted naive and memory CD4+ T cells from HLA-DRB1-typed human cohorts\",\n      \"pmids\": [\"8770633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative analysis without direct demonstration of thymic selection mechanism\", \"Limited allele panel studied\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Elution of naturally processed peptides from RA-associated (DRB1*0404) versus non-associated (DRB1*0402) alleles revealed distinct endogenous peptide repertoires, directly linking allelic pocket structure to self-peptide display.\",\n      \"evidence\": \"Immunoaffinity purification of MHC II–peptide complexes from homozygous B cell lines; HPLC, Edman degradation, and tandem MS identification\",\n      \"pmids\": [\"8892091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peptidomes from only two alleles compared\", \"Functional consequences for autoreactive T cell activation not tested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Introduction of DRB1*1502 into DQ8-susceptible transgenic mice suppressed autoimmune arthritis and shifted cytokine profiles to Th2, whereas DRB1*0301 did not, establishing that DRB1 polymorphism can dominantly modulate DQ-restricted autoimmune responses in vivo.\",\n      \"evidence\": \"HLA transgenic mouse collagen-induced arthritis model with T cell proliferation and cytokine profiling\",\n      \"pmids\": [\"9796911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Th2 skewing by DRB1*1502 not elucidated\", \"Single disease model; generalizability unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of DRB1*0405 as an independent risk allele for autoimmune pancreatitis in transgenic mice separated DRB1 effects from linked DQ alleles, clarifying that specific DRB1 polymorphisms alone can drive organ-specific autoimmunity.\",\n      \"evidence\": \"HLA class II transgenic NOD Ab0 mice; irradiation, adoptive T cell transfer, and histopathology\",\n      \"pmids\": [\"20303356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Autoantigenic peptides presented by DRB1*0405 in this context not identified\", \"Mechanism of CD8+ T cell and B cell recruitment downstream of DRB1-restricted CD4+ response unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that the shared epitope motif acts as a signaling ligand driving osteoclastogenesis, Th17 differentiation, and bone erosion revealed a non-canonical function of HLA-DRB1 beyond antigen presentation.\",\n      \"evidence\": \"In vitro osteoclastogenesis assays with human and mouse cells; SE-coding HLA-DRB1 transgenic mice; collagen-induced arthritis model; in vivo SE ligand administration\",\n      \"pmids\": [\"23180817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor for the SE ligand on target cells not identified\", \"Whether SE signaling occurs physiologically from cell-surface HLA-DR or only from shed/soluble forms not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Crystal structures of DRB1*04:01 with citrullinated peptides and tetramer-based detection of autoreactive CD4+ T cells explained how post-translational modification creates neo-epitopes accommodated by the electropositive P4 pocket of RA-risk alleles, providing a structural mechanism for citrullination-dependent autoimmunity.\",\n      \"evidence\": \"X-ray crystallography; peptide elution; HLA-II tetramer staining; T cell functional assays\",\n      \"pmids\": [\"24190431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether citrullinated-peptide-specific T cells are sufficient to initiate RA in vivo not shown\", \"Contribution of other pockets (P1, P6, P9) to citrullinated epitope selection less defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping of DRB1 allele-stratified CD4+ T cell responses in HIV infection showed that low-viremia alleles present a broader peptide breadth with lower avidity, linking allele-specific presentation properties to viral control.\",\n      \"evidence\": \"Peptide-DRB1 restriction mapping in functional T cell assays combined with cohort viremia analysis\",\n      \"pmids\": [\"23793098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal relationship between breadth/avidity and viremia not formally tested by manipulation\", \"Contribution of other HLA loci not fully controlled\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Adoptive transfer of α3(IV)136-146-specific CD4+ T cells caused glomerulonephritis exclusively in DRB1*15:01 transgenic mice, directly proving allele-restricted pathogenic T cell function in anti-GBM disease.\",\n      \"evidence\": \"HLA-DRB1 transgenic mice; adoptive T cell transfer with disease readout; epitope mapping\",\n      \"pmids\": [\"23411782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this epitope is dominantly presented in human anti-GBM disease not confirmed\", \"Role of HLA-DM editing in epitope selection in this context not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"HLA-DM-catalyzed kinetic measurements revealed that DRB1*01:01 discriminates self-peptides (MBP) from foreign peptides through rapid CLIP exchange and fast dissociation of self-peptides with incomplete pocket occupancy, proposing kinetic editing as a mechanism for MS protection.\",\n      \"evidence\": \"In vitro binding and HLA-DM-catalyzed CLIP exchange kinetics with recombinant DRB1*01:01; chimeric MBP-HA peptide analysis\",\n      \"pmids\": [\"32010139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinetic model tested for only one protective allele; comparison with MS-risk alleles needed\", \"In vivo relevance of kinetic editing for self-tolerance not demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstration that short HLA-DRB1 third-hypervariable-region peptides polarize macrophages toward M1 (risk alleles) or M2 (protective alleles) transcriptomes established an antigen-presentation-independent mechanism by which DRB1 polymorphism modulates innate immunity.\",\n      \"evidence\": \"RNA-seq of in vitro macrophages treated with antigen-presentation-incompetent short peptides; gene ontology and upstream regulator analysis\",\n      \"pmids\": [\"33510427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-surface receptor or signaling pathway mediating macrophage polarization not identified\", \"Whether these peptides are generated and active in vivo not shown\", \"Single lab finding awaiting independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor(s) and downstream signaling cascades through which shared-epitope and hypervariable-region peptides exert their antigen-presentation-independent effects on osteoclasts and macrophages remain unidentified, representing the major mechanistic gap in understanding non-canonical HLA-DRB1 functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Identity of the SE/HVR peptide receptor unknown\", \"Whether non-canonical signaling operates from cell-surface full-length HLA-DR in physiological contexts not established\", \"Structural basis for risk-vs-protective allele differential signaling not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 4, 7, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 6, 14]}\n    ],\n    \"complexes\": [\n      \"MHC class II (HLA-DR)\"\n    ],\n    \"partners\": [\n      \"HLA-DRA\",\n      \"HLA-DM\",\n      \"CD4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"HLA-DRB1 encodes the polymorphic β1 chain of the MHC class II HLA-DR αβ heterodimer, which binds antigenic peptides in an extended conformation within an open-ended groove stabilized by 12 conserved hydrogen bonds to the peptide backbone and allele-specific anchor pockets—particularly a hydrophobic P1 pocket and a charge-variable P4 pocket whose residues (β71, β74, β86) dictate selective binding of peptides including citrullinated self-antigens [PMID:8145819, PMID:24190431, PMID:22286218]. HLA-DM catalyzes dissociation of the invariant chain–derived CLIP peptide at acidic pH, enabling antigenic peptide loading in endosomal compartments, with exchange kinetics governed by the completeness of C-terminal anchor pocket occupation [PMID:7606781, PMID:32010139]. Allele-specific peptide presentation shapes the peripheral CD4+ T-cell receptor repertoire through thymic selection and determines susceptibility to autoimmune diseases including rheumatoid arthritis, type 1 diabetes, and anti-GBM glomerulonephritis [PMID:8770633, PMID:23411782, PMID:34153873]. Beyond antigen presentation, the disease-associated shared epitope motif encoded within the third hypervariable region functions as an extracellular signal transduction ligand that activates osteoclastogenesis and pro-inflammatory macrophage polarization, while protective allele-encoded epitopes drive anti-inflammatory polarization [PMID:23180817, PMID:33510427].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Determination of the first HLA-DR1 crystal structure resolved how the class II groove accommodates peptide and revealed αβ heterodimer dimerization, establishing the structural framework for understanding DRB1 polymorphism and peptide binding.\",\n      \"evidence\": \"X-ray crystallography of HLA-DR1\",\n      \"pmids\": [\"8316295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No peptide-bound structure yet available at this stage\",\n        \"Functional significance of αβ dimer-of-dimers not experimentally tested\"\n      ]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Co-crystal structures and systematic binding assays defined the universal peptide-binding mode—12 backbone hydrogen bonds plus a dominant hydrophobic P1 anchor—explaining how a single groove accommodates diverse peptides while conserving the binding register.\",\n      \"evidence\": \"X-ray crystallography of HLA-DR1–HA peptide complex; quantitative competitive binding assays with alanine-scan, reduced-bond, and N-methyl analogues on DRB1*0101 and *0401\",\n      \"pmids\": [\"8145819\", \"8144889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Contributions of P4 and other secondary pockets to allele-specific binding not yet structurally resolved\",\n        \"Role of non-classical anchor positions in autoantigen binding unknown\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"HLA-DM was shown to catalyze CLIP dissociation from DR at acidic pH, revealing the enzymatic editing step required for peptide loading in endosomal compartments and explaining how the invariant chain intermediate is resolved.\",\n      \"evidence\": \"In vitro biochemical dissociation assay with antibody blocking and pH titration\",\n      \"pmids\": [\"7606781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of HLA-DM–DR interaction not determined\",\n        \"Kinetic differences in DM-mediated exchange across DRB1 alleles not yet characterized\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"DRB1 allelic polymorphism was shown to shape the peripheral CD4+ TCR Vβ repertoire through thymic selection, establishing that DRB1 variation influences immune competence upstream of any specific antigen encounter.\",\n      \"evidence\": \"TCR Vβ repertoire analysis by flow cytometry/PCR in HLA-typed donor cohorts comparing naive versus memory CD4+ T cells\",\n      \"pmids\": [\"8770633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of allele-specific positive/negative selection not dissected at the peptide level\",\n        \"Limited to correlative cohort data without experimental perturbation\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Peptide elution from RA-associated (DRB1*0404) versus non-RA-associated (DRB1*0402) allomorphs revealed distinct self-peptide repertoires, demonstrating that allele-specific groove chemistry selects different endogenous ligands with potential relevance to autoimmunity.\",\n      \"evidence\": \"Immunoaffinity purification, HPLC fractionation, Edman degradation, and tandem mass spectrometry from B cell lines\",\n      \"pmids\": [\"8892091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Link between specific self-peptide repertoires and disease pathogenesis not functionally tested\",\n        \"Single-laboratory study with limited cell line diversity\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Fine-mapping of MHC association with RA resolved disease risk to three amino acid positions in the DRβ1 peptide-binding groove (positions 11, 71, 74), pinpointing the structural basis of genetic susceptibility beyond traditional allele-level associations.\",\n      \"evidence\": \"Genome-wide SNP imputation of HLA alleles and amino acid polymorphisms in ~20,000 individuals with conditional analysis\",\n      \"pmids\": [\"22286218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Causal peptide(s) mediating RA risk through these positions not identified\",\n        \"Independent contributions of positions 11, 71, 74 to specific pocket properties not structurally verified\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The shared epitope motif was shown to function as an antigen-presentation-independent signal transduction ligand activating osteoclastogenesis and Th17 differentiation, establishing a non-canonical immunomodulatory role for the DRB1-encoded surface.\",\n      \"evidence\": \"In vitro osteoclastogenesis assays (mouse and human), SE-transgenic mice, collagen-induced arthritis model with histology and cytokine measurement\",\n      \"pmids\": [\"23180817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Receptor for the SE ligand on target cells not identified\",\n        \"Signaling pathway downstream of SE engagement not fully elucidated\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Crystal structures of DRB1*04:01 versus *04:02 with citrullinated peptides explained how P4 pocket charge (electropositive in *04:01, electronegative in *04:02) selectively accommodates citrulline, providing the structural mechanism by which RA-risk alleles present citrullinated self-antigens to CD4+ T cells.\",\n      \"evidence\": \"X-ray crystallography, peptide elution/mass spectrometry, HLA-II tetramer staining and T cell functional assays in DRB1*04:01+ donors\",\n      \"pmids\": [\"24190431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Range of citrullinated epitopes naturally presented in vivo not fully catalogued\",\n        \"Whether citrulline-specific T cells are sufficient for RA initiation remains untested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Allele-specific pathogenic potential was demonstrated when DRB1*15:01-restricted CD4+ T cell clones recognizing a collagen IV epitope transferred crescentic glomerulonephritis upon adoptive transfer, directly linking DRB1 allele-restricted antigen presentation to organ-specific autoimmune disease.\",\n      \"evidence\": \"Adoptive transfer of T cell clones into HLA-DRB1*15:01 versus *01:01 transgenic mice with renal histology and functional assessment\",\n      \"pmids\": [\"23411782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether additional DRB1 alleles confer risk for anti-GBM disease through alternative epitopes is unknown\",\n        \"Contribution of DRB1*15:01-restricted T cells relative to B cell/antibody-mediated injury not delineated\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"HLA-DM-catalyzed peptide exchange kinetics were shown to depend on complete occupation of C-terminal anchor pockets (P6/7, P9), explaining why certain autoantigen peptides (e.g., MBP) are inefficiently loaded despite adequate groove affinity and refining the understanding of DM editing as a selectivity filter.\",\n      \"evidence\": \"Recombinant HLA-DRB1*01:01 protein, DM-catalyzed CLIP exchange kinetics, chimeric MBP–HA peptide analysis\",\n      \"pmids\": [\"32010139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Generalizability across DRB1 alleles not tested\",\n        \"In vivo relevance of slow exchange kinetics for autoimmune epitope presentation not established\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Antigen-presentation-incompetent peptides from protective versus risk-associated DRB1 alleles were shown to differentially polarize macrophages toward anti-inflammatory (M2) or pro-inflammatory (M1) transcriptomes, extending the non-canonical signaling role of DRB1 allelic sequences beyond osteoclastogenesis to innate immune regulation.\",\n      \"evidence\": \"RNA-sequencing of in vitro macrophages treated with AP-incompetent synthetic DRB1 allelic peptides, upstream regulator analysis\",\n      \"pmids\": [\"33510427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Cell-surface receptor mediating allelic peptide recognition on macrophages not identified\",\n        \"In vivo contribution of macrophage polarization to disease protection/susceptibility not demonstrated\",\n        \"Single laboratory, no independent replication\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor and downstream signaling pathway through which shared epitope and protective DRB1-derived peptides modulate innate immune cell polarization and osteoclastogenesis remain unidentified, representing the central open question bridging DRB1 non-canonical signaling to disease mechanism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No receptor identified for SE peptide signaling\",\n        \"No structural basis for how free DRB1 peptides engage target cells\",\n        \"In vivo physiological relevance of non-canonical signaling pathway not confirmed in human disease\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [9, 15]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [9, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 3, 5, 10, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 10, 11, 13, 16]}\n    ],\n    \"complexes\": [\n      \"MHC class II αβ heterodimer (HLA-DRA/HLA-DRB1)\"\n    ],\n    \"partners\": [\n      \"HLA-DRA\",\n      \"HLA-DMA\",\n      \"HLA-DMB\",\n      \"CD4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}