{"gene":"LILRB1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1998,"finding":"LILRB1 (LIR-1) binds HLA-A, -B, and -C alleles and, upon phosphorylation, recruits the tyrosine phosphatase SHP-1; coligation of LILRB1 with FcγRI inhibits tyrosine phosphorylation of the Fc receptor γ-chain and Syk, and blocks intracellular calcium mobilization in monocytes.","method":"Co-ligation assay, phosphorylation assay, SHP-1 co-immunoprecipitation, calcium flux measurement in primary monocytes","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical assays (phosphorylation, co-IP of SHP-1, functional calcium assay) in primary cells, replicated across LIR-1 and LIR-2","pmids":["9842885"],"is_preprint":false},{"year":1999,"finding":"ILT2/LILRB1 directly recognizes and binds HLA-G1 on target cells, as shown by ILT2-Ig fusion protein binding to HLA-G1-expressing (HLA-E-negative) transfectants and blocking with receptor- and ligand-specific antibodies.","method":"ILT2-Ig fusion protein binding assay, antibody blocking cytotoxicity assay, site-directed mutagenesis of HLA-G1 leader sequence to ablate HLA-E surface expression","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct fusion-protein binding assay with mutagenesis controls distinguishing ILT2–HLA-G1 from CD94/NKG2A–HLA-E interactions","pmids":["9933109"],"is_preprint":false},{"year":2000,"finding":"The crystal structure of LILRB1 D1D2 at 2.1 Å resolution reveals two immunoglobulin-like domains arranged at an acute angle; the UL18-binding site maps to a portion of D1 distant from the interdomain hinge, distinct from the KIR binding site.","method":"X-ray crystallography (2.1 Å), UL18 binding localization by structural analysis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure with functional binding site localization","pmids":["11114384"],"is_preprint":false},{"year":2000,"finding":"HLA-F directly interacts with LILRB1 (ILT2) and ILT4; HLA-F tetramers stain monocytes and B cells, and this binding is conferred on non-binding cells by transfection with ILT2 or ILT4. Direct molecular interaction confirmed by surface plasmon resonance.","method":"HLA-F tetramer staining, cell transfection, surface plasmon resonance (SPR), immunoprecipitation","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — SPR demonstrates direct molecular interaction; tetramer staining and transfection provide orthogonal functional confirmation","pmids":["11169396"],"is_preprint":false},{"year":2000,"finding":"LILRB1 (CD85j/ILT2) is present in the cytoplasm of all T lymphocytes and is tyrosine-phosphorylated; it inhibits CD3/TCR-mediated activation in CD4+ and CD8+ clones, down-regulates antigen recognition by CD8+ cells, reduces cytolytic activity, and inhibits intracellular Ca2+ mobilization.","method":"Flow cytometry, Western blot, biochemical phosphorylation analysis, RT-PCR, cytolytic assay, Ca2+ mobilization assay in T cell clones","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (cytotoxicity, Ca2+ flux, proliferation) in primary T cell clones with blocking and cross-linking antibodies","pmids":["11034379"],"is_preprint":false},{"year":2001,"finding":"ILT2/LILRB1 inhibits TCR signaling by recruiting SHP-1 upon co-ligation with the TCR; this requires Src tyrosine kinase p56(lck) for ILT2 phosphorylation and results in reduced TCRζ phosphorylation, reduced TCRζ-ZAP70 complex formation, reduced ERK1/2 activation, and inhibition of actin cytoskeleton rearrangement. Both TCR and ILT2 polarize toward the APC upon engagement.","method":"Co-immunoprecipitation, phosphorylation assay, ERK activation assay, actin cytoskeleton imaging, confocal microscopy in primary CTLs and transfected T cell lines","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical and imaging methods (co-IP, phosphorylation, ERK assay, cytoskeleton imaging) in both primary and transfected cells","pmids":["11160312"],"is_preprint":false},{"year":2002,"finding":"Mutational analysis of LILRB1 ITIMs identified Y644 (SIYATL) and Y614 (VTYAQL) as the SHP-1 docking sites required for inhibitory function; Y533 (NLYAAV) plays a regulatory role required for tyrosine phosphorylation of the receptor and subsequent SHP-1 recruitment; mutation of Y562 (VTYAEV) did not alter receptor function.","method":"Site-directed mutagenesis, SHP-1 binding assay (co-IP), FcεR-induced serotonin release inhibition assay in rat basophilic leukemia cells, transfection in COS-7 cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis of all four ITIMs with both biochemical (SHP-1 binding) and functional (serotonin release) readouts","pmids":["11907092"],"is_preprint":false},{"year":2004,"finding":"UL18 on HCMV-infected cells interacts with CD85j/LILRB1 on CD8+ T cells to trigger MHC-unrestricted lysis of infected cells; this activation is independent of CD3/TCR engagement. Soluble recombinant UL18-Fc immunoprecipitated CD85j from T cells, and lysis was specifically blocked by anti-CD85j and anti-UL18 antibodies.","method":"Cytolysis assay, co-immunoprecipitation with recombinant UL18-Fc, antibody blocking, UL18-deficient HCMV mutant comparison","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct co-IP with recombinant protein, blocking experiments, UL18-null virus mutant, multiple cell types tested","pmids":["15100307"],"is_preprint":false},{"year":2004,"finding":"C-terminal Src kinase (Csk) is recruited to the LILRB1 cytoplasmic tail in a phosphotyrosine-dependent manner; yeast three-hybrid screening identified this interaction, confirmed by co-immunoprecipitation in mammalian cells. Mutational analysis suggests Csk SH2 domain preferentially binds ITIM Y562, though mutation of Y533, Y614, and Y644 also reduces Csk recruitment. Csk and SHP-1 do not co-precipitate together with LILRB1.","method":"Yeast three-hybrid screen, co-immunoprecipitation, Western blot, phospho-peptide mapping, site-directed mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast screen confirmed by mammalian co-IP with mutagenesis, but single lab and negative result for SHP-1/Csk co-precipitation with LILRB1","pmids":["15474475"],"is_preprint":false},{"year":2004,"finding":"ILT2/CD85j (LILRB1) is expressed on 40–55% of CMV-, EBV-, and HIV-specific CD8+ T cells on perforin+ CD27- effector cells; blocking ILT2 engagement increases antiviral IFN-γ production approximately threefold in both normal and HIV-infected donors, but does not appreciably affect cytotoxicity.","method":"Tetramer staining, antibody blocking, IFN-γ ELISPOT, cytotoxicity assay in primary human T cells","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking in primary human cells with two orthogonal readouts (IFN-γ and cytotoxicity), single lab","pmids":["15270723"],"is_preprint":false},{"year":2005,"finding":"LILRB1 must engage β2m-associated (conformationally intact) HLA-G for inhibitory signaling; β2m-free HLA-G heavy chain complexes expressed on the cell surface are not recognized by CD85j/LILRB1 and may interfere with CD85j–HLA-G interaction.","method":"Flow cytometry with LILRB1-Ig fusion protein, anti-HLA-G antibodies distinguishing β2m-associated vs. free heavy chains, transfected cell lines","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with LILRB1-Ig fusion protein discriminating conformational forms, single lab","pmids":["16210588"],"is_preprint":false},{"year":2005,"finding":"LILRB1 (CD85j) cross-linking on immature dendritic cells abolishes Ca2+ flux and strongly reduces IL-8 and IL-12 production induced by hOSCAR (human osteoclast-associated receptor) activation; it counteracts the hOSCAR-dependent anti-apoptotic effect by reducing Bcl-2 expression, and impairs DC-enhanced antigen-specific T cell proliferation.","method":"Ca2+ flux assay, cytokine ELISA, apoptosis assay, Bcl-2 Western blot, T cell proliferation assay in monocyte-derived DCs","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in primary human DCs, single lab","pmids":["15905516"],"is_preprint":false},{"year":2005,"finding":"LILRB1 cross-linking on B cells inhibits IgG and IgE class switching, reduces percentages of IgG- and IgE-expressing B cells, and down-regulates IL-8, IL-10, and TNF-α production across multiple stimulatory pathways (recall antigens, CD40L plus IL-4, LPS plus IL-4).","method":"Antibody cross-linking, flow cytometry, ELISA for cytokines and immunoglobulins, multiple B-cell stimulatory conditions","journal":"Clinical and diagnostic laboratory immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with multiple stimulatory pathways, single lab","pmids":["15939744"],"is_preprint":false},{"year":2005,"finding":"LILRB1-MHC class I binding is entropically driven (−TΔS = −9.4 to −6.6 kcal/mol) with low heat capacity changes; kinetic studies show fast association and dissociation rates; crystal structures reveal elbow-angle variation between D1 and D2 domains indicating interdomain flexibility, and NMR directly demonstrates conformational changes in LILRB1 upon MHCI binding.","method":"Surface plasmon resonance (kinetics), isothermal titration calorimetry (thermodynamics), X-ray crystallography (multiple crystal forms), NMR spectroscopy","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — four orthogonal biophysical methods (SPR, ITC, crystallography, NMR) in one rigorous study","pmids":["16305801"],"is_preprint":false},{"year":2005,"finding":"LILRB1 polymorphisms in the ligand-binding domains alter surface expression on lymphocytes and monocytes; PE01 haplotype carriers show significantly decreased LILRB1 surface expression without gross differences in crystal structures, thermostability, or binding affinities to HLA class I ligands among PE01–03 haplotype products.","method":"SNP analysis, crystal structures of PE01–03 products, thermostability assay, binding affinity measurements (SPR), flow cytometry of primary cells","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural, biophysical, and expression analyses across multiple polymorphic variants with functional correlation","pmids":["16014635"],"is_preprint":false},{"year":2005,"finding":"ILT2/LILRB1 signals in an inhibitory KIR-dependent manner in NK92 cells: mutant KIR lacking ITIM can inhibit via ILT2 engagement with the α3 domain of HLA class I, revealing functional cooperation between KIR and ILT2 signaling pathways. This KIR-dependent signaling requires catalytically active SHP-1.","method":"Transfection of KIR mutants into NK92 cells, antibody blocking of KIR–HLA-C and ILT2–HLA-I interactions, catalytically inactive SHP-1 overexpression assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional genetics (mutant KIR, dominant-negative SHP-1) with receptor-specific blocking antibodies, single lab","pmids":["16210603"],"is_preprint":false},{"year":2006,"finding":"Human ILT2/LILRB1 associates in vivo with murine MHC class I molecule H-2Db in ILT2-transgenic mice; this association inhibits TCR proximal signaling, affects thymocyte development, and results in long-term acceptance of skin allografts.","method":"Transgenic mouse model, co-immunoprecipitation (H-2Db with human ILT2), thymocyte development analysis, skin allograft model","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with co-IP evidence of receptor–ligand association and functional allograft outcome","pmids":["16897816"],"is_preprint":false},{"year":2006,"finding":"Spontaneous mutations in HCMV UL18 (clinical strains vs. AD169) in the α3 domain and α1 domain alter LIR-1/LILRB1 binding; α3 domain mutations are critical for LIR-1 binding; these two independent UL18 regions (α3 tip and α1 loops) contribute to LIR-1 recognition.","method":"Cytotoxicity assays, flow cytometry binding assays, Biacore (SPR), ELISA with soluble LIR-1 and UL18 variants from clinical strains","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biophysical binding assays with natural variants; single lab","pmids":["16479538"],"is_preprint":false},{"year":2007,"finding":"HCMV UL18 inhibits cytotoxicity of LIR-1+ NKL cells and LIR-1+ primary NK cells through a direct LIR-1–UL18 interaction (demonstrated by antibody blocking); LIR-1- NK cells are activated by UL18 through a LIR-1-independent mechanism.","method":"Cytolysis assay with adenoviral UL18 transduction and UL18-null HCMV mutant, antibody blocking, CD107 mobilization assay, IFN-α-activated NK bulk cultures, single NK cell clones","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple experimental systems (NKL line, primary NK bulk cultures, NK clones, UL18-null virus mutant), antibody blocking, consistent results across donors","pmids":["17372005"],"is_preprint":false},{"year":2007,"finding":"Continuous ligation of LILRB1 during monocyte-to-DC differentiation produces DCs with a unique phenotype, profound resistance to CD95-mediated death, inhibited secretion of IL-10, IL-12p70, and TGF-β, poor stimulatory activity for T-cell proliferation (reversed by CD80/CTLA-4 blockade or Treg depletion), and stable resistance to LPS activation.","method":"In vitro DC differentiation with continuous LILRB1 ligation, flow cytometry, cytokine ELISA, T-cell proliferation assay, CD95-mediated death assay, LPS stimulation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional readouts in a defined DC differentiation system with mechanistic rescue experiments","pmids":["18094328"],"is_preprint":false},{"year":2008,"finding":"CD85j+ NK cells (but not CD85j- NK cells) potently suppress HIV-1 replication in autologous monocyte-derived DCs in a cell-contact-dependent manner; this inhibition is abolished by blocking the CD85j receptor with recombinant CD85j protein, but only partially counteracted by anti-HLA class I antibodies, suggesting a non-HLA class I ligand on HIV-1-infected MDDCs mediates this interaction.","method":"NK/DC coculture, NK subset sorting (CD85j+ vs. CD85j-), HIV-1 replication assay, receptor blocking with recombinant CD85j and anti-HLA class I antibodies, recombinant CD85j staining of MDDCs","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-contact dependence and receptor blocking established, but identity of non-HLA ligand not determined; single lab","pmids":["18398485"],"is_preprint":false},{"year":2008,"finding":"LILRB1/ILT2 (CD85j) inhibits IFN-γ mRNA expression and secretion by NK cells in response to HLA class I-expressing targets, poly(I:C), and immature dendritic cells, and inhibits IFN-γ by ILT2+ T cells in response to superantigen, establishing HLA class I–ILT2 interaction as a specific regulator of IFN-γ at the mRNA and protein levels.","method":"NK-92 line and primary NK cell functional assays, IFN-γ mRNA and protein measurement (ELISA, qPCR), blocking with anti-ILT2 and anti-HLA class I antibodies, NK/DC coculture","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple stimulatory conditions, mRNA and protein readouts, receptor/ligand blocking, NK line and primary cells","pmids":["18684926"],"is_preprint":false},{"year":2010,"finding":"Cell-type-specific surface density of CD85j/LILRB1 is controlled by two distinct promoters (lymphocyte promoter 13 kb upstream of monocyte promoter) and a translational repression element in the 5'-UTR exon unique to the lymphocyte transcript; this sequence reduces protein translation without affecting mRNA levels, explaining the lower surface expression in lymphocytes vs. monocytes.","method":"Promoter mapping, reporter assay, 5'-UTR deletion analysis, Western blot, flow cytometry, ChIP in multiple hematopoietic cell types","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic promoter mapping, translational repression element identified by reporter assay and mutagenesis, orthogonal confirmation by Western blot and flow cytometry","pmids":["20194892"],"is_preprint":false},{"year":2013,"finding":"S100A9 is a non-HLA class I ligand for CD85j/LILRB1; direct interaction was demonstrated by co-immunoprecipitation. HIV-1 infection of MDDCs induces surface modulation of S100A9, influencing CD85j+ NK cell anti-HIV activity. Exogenous S100A9 stimulation of NK cells via CD85j ligation enhances control of HIV-1 infection in CD4+ T cells.","method":"Co-immunoprecipitation of LILRB1 and S100A9, flow cytometry, HIV-1 replication assay, NK/MDDC coculture, exogenous S100A9 stimulation","journal":"Retrovirology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifies novel ligand with functional confirmation in HIV suppression assay; single lab","pmids":["24156302"],"is_preprint":false},{"year":2016,"finding":"Intracellular Cys residues and HLA-I dimerization enhance LILRB1 recognition; classical HLA class Ia dimers (detected in exosomes and after type I IFN treatment of monocytes) show increased LILRB1 binding compared to monomers. Type I IFN increases LILRB1 recognition of monocyte HLA-I disproportionate to the increase in HLA-I surface expression.","method":"LILRB1-Fc fusion protein binding assay, cellular reporter system (LILRB1-ζ chimera), transfected 721.221 cells, flow cytometry, IFN-α stimulation of primary monocytes","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal receptor binding systems (fusion protein and chimeric receptor reporter) with defined ligand variants, single lab","pmids":["27109306"],"is_preprint":false},{"year":2017,"finding":"M2 macrophages upregulate CD85j (ILT2/LILRB1) on NK cells through a mechanism involving HLA-G (expressed at higher levels on M2 than M1); CD85j upregulation on CD56dim NK cells accounts for hyporesponsive degranulation and cytotoxicity, while soluble TGF-β and CD85j upregulation together account for diminished IFN-γ by CD56bright NK cells. Hyporesponsiveness to degranulation was not reversed upon short-term removal of M2.","method":"NK/macrophage coculture, flow cytometry, IFN-γ intracellular staining, CD107a degranulation assay, TGF-β neutralization, anti-CD85j blocking antibody, HLA-G measurement by ELISA and flow cytometry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (cytotoxicity, degranulation, IFN-γ), receptor/ligand blocking and neutralization, mechanistic dissection of TGF-β vs. CD85j contributions","pmids":["29282306"],"is_preprint":false},{"year":2018,"finding":"LILRB1 polymorphisms in regulatory regions and ligand-binding domains affect functional recognition of HCMV UL18 and classical MHCI (but not HLA-G) by NK cells; four nonsynonymous substitutions in the first two Ig domains each contribute to differential binding. One polymorphism controls addition of an N-linked glycan whose removal enhances binding to UL18 and alters binding to all tested ligands.","method":"Clinical cohort HCMV outcome analysis, NK cell functional assays with LILRB1 variants, SPR binding assays, glycosylation site mutagenesis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure–function analysis of natural variants with SPR binding, mutagenesis of glycosylation site, functional NK assays, and clinical correlation","pmids":["29528338"],"is_preprint":false},{"year":2019,"finding":"LILRB1 is expressed by a distinct CD8+PD-1- intratumoral T cell subset; HLA-G on tumor cells specifically inhibits CD8+ILT2+ (but not CD8+ILT2- or CD8+PD-1+) T cell cytotoxicity and IFN-γ production, and this inhibition is counteracted by blocking the HLA-G/ILT2 interaction.","method":"Transcriptomics, flow cytometry, ex vivo cytotoxicity assay with primary TILs and PBMCs, anti-ILT2/anti-HLA-G blocking experiments","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ex vivo functional assays with primary TILs from cancer patients, receptor/ligand blocking, multiple orthogonal methods","pmids":["31451484"],"is_preprint":false},{"year":2019,"finding":"LILRB1 engagement by HLA-G on tumor cells significantly inhibits BiTE molecule-induced CD8+ effector T cell activation; LILRB1 and PD-1 are expressed by distinct CD8+ T cell populations, and combined LILRB1 + PD-1 blockade induces greater activation than either alone.","method":"Flow cytometry, BiTE molecule stimulation assay, LILRB1/HLA-G blocking, anti-PD-1 blocking, T cell activation assays with primary human CD8+ T cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking with defined ligand, two orthogonal checkpoint blockade conditions, single lab","pmids":["31253728"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of four-domain LILRB1 in complex with HLA-G1 shows that D1D2 is responsible for HLA-I binding while D3D4 acts as a structural scaffold; staggered assembly of the four Ig-like domains shows limited flexibility. Structure supports models for both cis and trans HLA-I binding, and dimeric LILRB1 geometry suggests enhanced inhibitory signal transduction.","method":"X-ray crystallography of four-domain LILRB1 and LILRB1/HLA-G1 complex, structural analysis of domain angles and assembly","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structures of full ectodomain and receptor–ligand complex with functional domain assignment","pmids":["31273318"],"is_preprint":false},{"year":2020,"finding":"A RIFIN from Plasmodium falciparum mimics the binding mode of MHC class I to activate LILRB1 signaling; the crystal structure of RIFIN bound to LILRB1 reveals this mimicry; a single mutation in the RIFIN disrupts the complex, blocks LILRB1 binding of all tested RIFINs, and abolishes signaling in a reporter assay. In a supported lipid bilayer NK cell system, RIFIN suppresses NK cell perforin mobilization similarly to MHC.","method":"X-ray crystallography of RIFIN–LILRB1 complex, LILRB1 reporter assay, site-directed mutagenesis of RIFIN, supported lipid bilayer NK cell assay (ADCC model), perforin mobilization measurement","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus reporter assay plus functional NK assay; mechanistically rigorous and published in Nature","pmids":["32650338"],"is_preprint":false},{"year":2021,"finding":"RIFIN proteins from Plasmodium falciparum bind to LILRB1 domain 3 (D3); crystal and cryo-EM structures of RIFIN in complex with LILRB1 D3D4 and a D3D4-containing antibody Fab reveal that RIFIN–LILRB1 D3 interaction is similar to RIFIN–LAIR1; DNA insertions encoding LILRB1 D3D4 or D3 into the VH-CH1 elbow of antibody genes generate RIFIN-specific antibodies in malaria-exposed donors.","method":"Cryo-EM and crystal structure determination, SPR/binding assays, mass spectrometry, B cell clone isolation, antibody gene sequencing","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic structures (crystal + cryo-EM), binding assays, and naturally occurring human antibody discovery with structural validation","pmids":["33790470"],"is_preprint":false},{"year":2022,"finding":"LILRB1 blockade (Fc-silent anti-LILRB1 antibody LILRB1-IgGσ) significantly enhances antibody-dependent cellular phagocytosis (ADCP) of lymphoma cells by macrophages when combined with rituximab and CD47 blockade; LILRB1-IgGσ promotes serial engulfment and potentiates ADCP by M0, M1, and M2 macrophages, but requires CD47 co-blockade and CD20 antibody. LILRB2 blockade was not effective.","method":"In vitro ADCP assay, macrophage polarization, patient-derived CLL/lymphoma cell ADCP, antibody engineering (Fc-silent variants), serial engulfment imaging","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple macrophage polarization states and patient-derived cells tested; single lab; LILRB2 negative control strengthens specificity","pmids":["36389667"],"is_preprint":false},{"year":2024,"finding":"LILRB1 forms a complex with the low-density lipoprotein receptor (LDLR) and LDLR adapter protein 1 (LDLRAP1) to facilitate LDL/cholesterol uptake in multiple myeloma cells; loss of LILRB1 impairs cholesterol uptake but activates de novo cholesterol synthesis, decreasing anti-ferroptotic squalene and promoting ferroptosis.","method":"Co-immunoprecipitation (LILRB1–LDLR–LDLRAP1 complex), in vivo LILRB1 knockout (MM mouse model), cholesterol uptake assay, squalene measurement, ferroptosis assay, gene expression profiling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP identifies novel complex, in vivo knockout model, multiple metabolic readouts (cholesterol, squalene), ferroptosis mechanistic link; multiple orthogonal methods","pmids":["38982045"],"is_preprint":false}],"current_model":"LILRB1 (ILT2/LIR-1/CD85j) is an inhibitory immunoreceptor whose extracellular Ig-like D1D2 domains bind MHC class I molecules (classical HLA-A/B/C, non-classical HLA-G, HLA-F, and the HCMV homolog UL18) as well as non-MHC ligands (S100A9, Plasmodium falciparum RIFINs); upon ligand engagement, its cytoplasmic ITIMs (particularly Y614 and Y644) are phosphorylated—requiring Lck and ITIM Y533 as a regulatory site—leading to recruitment of SHP-1 and Csk, which suppress downstream kinase cascades (TCRζ/ZAP70, ERK, Ca2+ mobilization) and inhibit effector functions (cytotoxicity, IFN-γ secretion, degranulation, phagocytosis) in T cells, NK cells, B cells, monocytes, macrophages, and dendritic cells; cell-type-specific expression levels are set by alternative promoter usage and a 5'-UTR translational repressor element; additionally, LILRB1 forms a complex with LDLR and LDLRAP1 to facilitate cholesterol uptake in myeloma cells, protecting them from ferroptosis."},"narrative":{"mechanistic_narrative":"LILRB1 (ILT2/LIR-1/CD85j) is an inhibitory immunoreceptor that restrains effector functions across T cells, NK cells, B cells, monocytes, dendritic cells, and macrophages following recognition of MHC class I [PMID:9842885, PMID:11034379]. Its membrane-distal D1D2 Ig-like domains constitute the ligand-binding module, engaging classical HLA-A/B/C [PMID:9842885], non-classical HLA-G in a β2-microglobulin-dependent conformation [PMID:9933109, PMID:16210588], HLA-F [PMID:11169396], and the HCMV MHC-I homolog UL18 [PMID:11114384, PMID:15100307], while the membrane-proximal D3D4 domains form a structural scaffold and contribute a distinct binding surface exploited by Plasmodium falciparum RIFINs [PMID:31273318, PMID:33790470]. Crystallographic, calorimetric, and NMR analyses show the receptor engages MHC-I through an entropically driven, fast-on/fast-off interaction accompanied by interdomain flexibility and conformational change [PMID:16305801, PMID:31273318]. Upon ligand engagement, LILRB1 phosphorylation—dependent on Src kinase p56lck and the regulatory ITIM Y533—drives recruitment of SHP-1 to docking sites Y614 and Y644 and of Csk to Y562, which suppresses proximal activation cascades including TCRζ/ZAP70 coupling, ERK1/2 activation, calcium mobilization, and actin reorganization [PMID:11160312, PMID:11907092, PMID:15474475]. Through these signals LILRB1 inhibits cytotoxicity and IFN-γ secretion by T and NK cells [PMID:15270723, PMID:18684926, PMID:31451484], antibody class switching and cytokine output by B cells [PMID:15939744], dendritic cell maturation and stimulatory capacity [PMID:15905516, PMID:18094328], and macrophage phagocytosis [PMID:36389667]. Cell-type-specific surface density is set by dual promoter usage and a lymphocyte-specific 5'-UTR translational repressor element [PMID:20194892], and natural polymorphisms—including one controlling an N-linked glycan—tune ligand recognition [PMID:16014635, PMID:29528338]. Beyond immune signaling, LILRB1 assembles with LDLR and LDLRAP1 to drive cholesterol uptake in multiple myeloma cells, protecting them from ferroptosis [PMID:38982045].","teleology":[{"year":1998,"claim":"Established LILRB1 as an MHC class I-binding inhibitory receptor that recruits SHP-1 and dampens activating Fc receptor signaling, defining its core inhibitory logic.","evidence":"Co-ligation with FcγRI, SHP-1 co-IP, and calcium flux in primary monocytes","pmids":["9842885"],"confidence":"High","gaps":["ITIM residues mediating SHP-1 docking not yet mapped","Kinase responsible for receptor phosphorylation not identified"]},{"year":1999,"claim":"Demonstrated direct recognition of the non-classical ligand HLA-G1, broadening the ligand repertoire beyond classical HLA.","evidence":"ILT2-Ig fusion binding to HLA-G1 transfectants with antibody blocking and leader-sequence mutagenesis","pmids":["9933109"],"confidence":"High","gaps":["Conformational requirements of HLA-G not addressed","Downstream signaling in target cells not quantified"]},{"year":2000,"claim":"Solved the D1D2 structure and mapped the UL18-binding site, distinguishing LILRB1's engagement mode from KIRs.","evidence":"X-ray crystallography at 2.1 Å with binding-site localization","pmids":["11114384"],"confidence":"High","gaps":["Full ectodomain (D3D4) architecture not resolved","MHC-bound complex geometry not yet determined"]},{"year":2000,"claim":"Extended ligand recognition to HLA-F and confirmed direct molecular binding, and showed LILRB1 inhibits TCR-driven T cell activation.","evidence":"HLA-F tetramer staining, transfection, SPR; cytolytic and Ca2+ assays in T cell clones","pmids":["11169396","11034379"],"confidence":"High","gaps":["Physiological consequence of HLA-F engagement unclear","Signaling intermediates downstream of TCR inhibition not dissected"]},{"year":2001,"claim":"Defined the TCR-inhibitory mechanism: co-ligation recruits SHP-1, requires p56lck, and blocks TCRζ-ZAP70 coupling, ERK activation, and actin remodeling.","evidence":"Co-IP, phosphorylation, ERK and cytoskeleton imaging in CTLs and transfected T cells","pmids":["11160312"],"confidence":"High","gaps":["Stoichiometry of receptor clustering at the synapse not resolved","Role of other ITIMs not yet tested"]},{"year":2002,"claim":"Assigned functional roles to individual ITIMs, identifying Y614/Y644 as SHP-1 docking sites and Y533 as a regulatory phosphorylation site.","evidence":"Systematic ITIM mutagenesis with SHP-1 binding and serotonin-release readouts in RBL and COS-7 cells","pmids":["11907092"],"confidence":"High","gaps":["Y562 function unresolved at this stage","Kinetics of sequential ITIM phosphorylation not measured"]},{"year":2004,"claim":"Identified Csk as a second phosphotyrosine-dependent effector recruited to the LILRB1 tail, indicating a SHP-1-independent inhibitory arm.","evidence":"Yeast three-hybrid screen confirmed by mammalian co-IP and ITIM mutagenesis","pmids":["15474475"],"confidence":"Medium","gaps":["Single lab; Csk/SHP-1 do not co-precipitate with LILRB1, leaving spatial coordination unclear","Functional weight of Csk arm in primary cells not established"]},{"year":2004,"claim":"Showed UL18-LILRB1 engagement can paradoxically trigger MHC-unrestricted lysis of HCMV-infected cells, and characterized viral exploitation of the receptor.","evidence":"Cytolysis assays, UL18-Fc co-IP, antibody blocking, UL18-null virus in CD8+ T and NK cells","pmids":["15100307","17372005"],"confidence":"High","gaps":["Signaling switch between inhibition and activation not mechanistically resolved","In vivo relevance during HCMV infection not established"]},{"year":2005,"claim":"Characterized the biophysics of MHC-I recognition (entropy-driven, flexible, fast kinetics), conformational requirements (β2m-associated HLA-G), polymorphic control of expression, and functional cross-talk with KIRs.","evidence":"SPR, ITC, crystallography, NMR; LILRB1-Ig conformational binding; SNP/structure analysis; KIR mutant transfection in NK92","pmids":["16305801","16210588","16014635","16210603"],"confidence":"High","gaps":["Functional impact of interdomain flexibility on signaling untested","Mechanism by which polymorphisms alter surface expression not defined"]},{"year":2005,"claim":"Extended inhibitory function to dendritic cells and B cells, showing LILRB1 suppresses cytokine production, class switching, and DC stimulatory activity.","evidence":"Cross-linking with Ca2+, cytokine ELISA, Bcl-2 blot, T cell proliferation and Ig switching assays in primary DCs and B cells","pmids":["15905516","15939744"],"confidence":"Medium","gaps":["Single lab for each cell type","Physiological ligand driving these effects in vivo not identified"]},{"year":2006,"claim":"Provided in vivo evidence that LILRB1 engagement of MHC-I inhibits TCR signaling, shapes thymocyte development, and promotes allograft tolerance.","evidence":"ILT2-transgenic mice, H-2Db co-IP, thymocyte analysis, skin allograft model","pmids":["16897816"],"confidence":"Medium","gaps":["Cross-species receptor-ligand pairing limits physiological interpretation","Cell-intrinsic vs systemic contributions to tolerance not separated"]},{"year":2008,"claim":"Revealed a contact-dependent, non-HLA-mediated CD85j role in NK suppression of HIV-1 replication in dendritic cells, pointing to an unidentified ligand.","evidence":"NK/DC coculture, CD85j subset sorting, recombinant CD85j and anti-HLA blocking","pmids":["18398485"],"confidence":"Medium","gaps":["Non-HLA ligand identity unknown at this stage","Single lab"]},{"year":2008,"claim":"Established LILRB1 as a specific transcriptional and secretory regulator of IFN-γ in NK and T cells responding to HLA-I and dendritic cells.","evidence":"IFN-γ mRNA/protein assays, blocking antibodies in NK-92 and primary NK cells, NK/DC coculture","pmids":["18684926"],"confidence":"High","gaps":["Transcriptional machinery linking LILRB1 signaling to IFN-γ mRNA not defined"]},{"year":2010,"claim":"Explained cell-type-specific receptor density via dual promoters and a lymphocyte-specific 5'-UTR translational repressor element.","evidence":"Promoter mapping, reporter and 5'-UTR deletion assays, ChIP, Western, flow across hematopoietic cells","pmids":["20194892"],"confidence":"High","gaps":["Trans-acting factors binding the repressor element not identified","Signal-dependent regulation of promoter choice not addressed"]},{"year":2013,"claim":"Identified S100A9 as a non-HLA ligand linking LILRB1 to NK-mediated control of HIV infection.","evidence":"LILRB1-S100A9 co-IP, HIV replication assays, exogenous S100A9 stimulation of NK cells","pmids":["24156302"],"confidence":"Medium","gaps":["Structural basis of S100A9 binding not determined","Single lab"]},{"year":2016,"claim":"Showed HLA-I dimerization and intracellular cysteines enhance LILRB1 recognition, with type I IFN boosting recognition beyond surface HLA increases.","evidence":"LILRB1-Fc and LILRB1-ζ chimera reporter binding, transfected 721.221 cells, IFN-α stimulation of monocytes","pmids":["27109306"],"confidence":"Medium","gaps":["In vivo prevalence of HLA-I dimers uncertain","Single lab"]},{"year":2017,"claim":"Linked M2 macrophage HLA-G to LILRB1 upregulation on NK cells driving durable NK hyporesponsiveness.","evidence":"NK/macrophage coculture, degranulation and IFN-γ assays, TGF-β neutralization, anti-CD85j blocking","pmids":["29282306"],"confidence":"High","gaps":["Mechanism of irreversibility of degranulation hyporesponsiveness unresolved"]},{"year":2018,"claim":"Demonstrated that natural LILRB1 polymorphisms, including a glycosylation-controlling variant, tune ligand recognition and correlate with HCMV outcomes.","evidence":"Clinical cohort, NK functional assays, SPR, glycosylation-site mutagenesis","pmids":["29528338"],"confidence":"High","gaps":["Mechanism by which glycan alters binding geometry not structurally resolved"]},{"year":2019,"claim":"Established LILRB1/HLA-G as a tumor immune checkpoint on a distinct PD-1-negative CD8+ T cell subset, additive with PD-1 blockade and limiting BiTE efficacy.","evidence":"Transcriptomics, ex vivo TIL cytotoxicity/IFN-γ assays, BiTE stimulation, combined LILRB1/PD-1 blockade","pmids":["31451484","31253728"],"confidence":"High","gaps":["Determinants of the LILRB1+ vs PD-1+ subset divergence unknown","In vivo efficacy of LILRB1 blockade not established"]},{"year":2019,"claim":"Resolved the full four-domain ectodomain bound to HLA-G1, assigning D1D2 as the ligand interface and D3D4 as a scaffold and supporting cis/trans and dimeric signaling models.","evidence":"X-ray crystallography of four-domain LILRB1 and LILRB1/HLA-G1 complex","pmids":["31273318"],"confidence":"High","gaps":["Functional validation of dimeric signaling model lacking","Cis vs trans engagement in cells not directly demonstrated"]},{"year":2020,"claim":"Revealed molecular mimicry whereby P. falciparum RIFINs activate LILRB1 inhibitory signaling like MHC, suppressing NK perforin mobilization.","evidence":"RIFIN-LILRB1 crystal structure, reporter assay, RIFIN mutagenesis, supported lipid bilayer NK assay","pmids":["32650338"],"confidence":"High","gaps":["In vivo contribution to malaria immune evasion not quantified"]},{"year":2021,"claim":"Showed a subset of RIFINs binds LILRB1 D3 (mimicking LAIR1 engagement) and that humans generate anti-RIFIN antibodies via genomic insertion of LILRB1 D3D4 into antibody elbows.","evidence":"Crystal and cryo-EM structures, SPR, B cell clone isolation and antibody sequencing","pmids":["33790470"],"confidence":"High","gaps":["Signaling consequences of D3 engagement vs D1D2 engagement not compared"]},{"year":2022,"claim":"Demonstrated LILRB1 acts as a macrophage phagocytosis checkpoint whose blockade enhances antibody-dependent phagocytosis of lymphoma when combined with CD47 and CD20 antibodies.","evidence":"In vitro and patient-derived ADCP assays, Fc-silent anti-LILRB1, macrophage polarization, serial engulfment imaging","pmids":["36389667"],"confidence":"Medium","gaps":["Dependence on CD47 co-blockade limits standalone utility","Single lab; in vivo efficacy untested"]},{"year":2024,"claim":"Uncovered a non-immune role: LILRB1 partners with LDLR and LDLRAP1 to drive cholesterol uptake and protect myeloma cells from ferroptosis.","evidence":"LILRB1-LDLR-LDLRAP1 co-IP, in vivo knockout, cholesterol/squalene/ferroptosis assays","pmids":["38982045"],"confidence":"High","gaps":["Whether this complex functions outside myeloma not established","Relationship between immune and metabolic functions unclear"]},{"year":null,"claim":"How LILRB1 toggles between inhibitory and activating outcomes, how its dimeric/cis-trans geometry is functionally deployed, and how its immune-signaling and cholesterol-uptake functions are integrated remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Structural model of signaling-competent receptor clusters not validated functionally","Spatial coordination of SHP-1 and Csk arms unresolved","Generality of the LDLR/LDLRAP1 complex beyond myeloma unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,6,9,21,27]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3,5,30]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[7,18,30]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,8,33]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,22,29]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,5,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,4,5,9,21,27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,18,30,33]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[33]}],"complexes":["LILRB1–LDLR–LDLRAP1 complex","LILRB1–HLA-G1 receptor–ligand complex"],"partners":["SHP-1","CSK","LCK","HLA-G","UL18","S100A9","LDLR","LDLRAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NHL6","full_name":"Leukocyte immunoglobulin-like receptor subfamily B member 1","aliases":["CD85 antigen-like family member J","Immunoglobulin-like transcript 2","ILT-2","Monocyte/macrophage immunoglobulin-like receptor 7","MIR-7"],"length_aa":650,"mass_kda":70.8,"function":"Receptor for class I MHC antigens. Recognizes a broad spectrum of HLA-A, HLA-B, HLA-C, HLA-G and HLA-F alleles (PubMed:16455647, PubMed:28636952). Receptor for H301/UL18, a human cytomegalovirus class I MHC homolog. Ligand binding results in inhibitory signals and down-regulation of the immune response. Engagement of LILRB1 present on natural killer cells or T-cells by class I MHC molecules protects the target cells from lysis. Interaction with HLA-B or HLA-E leads to inhibition of FCER1A signaling and serotonin release. Inhibits FCGR1A-mediated phosphorylation of cellular proteins and mobilization of intracellular calcium ions (PubMed:11907092, PubMed:9285411, PubMed:9842885). Recognizes HLA-G in complex with B2M/beta-2 microglobulin and a nonamer self-peptide (PubMed:16455647). Upon interaction with peptide-bound HLA-G-B2M complex, triggers secretion of growth-promoting factors by decidual NK cells (PubMed:19304799, PubMed:29262349). Reprograms B cells toward an immune suppressive phenotype (PubMed:24453251)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q8NHL6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LILRB1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LILRB1","total_profiled":1310},"omim":[{"mim_id":"611162","title":"MALARIA, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/611162"},{"mim_id":"607517","title":"LEUKOCYTE IMMUNOGLOBULIN-LIKE RECEPTOR, SUBFAMILY A, MEMBER 4; LILRA4","url":"https://www.omim.org/entry/607517"},{"mim_id":"605699","title":"UL16-BINDING PROTEIN 3; ULBP3","url":"https://www.omim.org/entry/605699"},{"mim_id":"605698","title":"UL16-BINDING PROTEIN 2; ULBP2","url":"https://www.omim.org/entry/605698"},{"mim_id":"605697","title":"UL16-BINDING PROTEIN 1; ULBP1","url":"https://www.omim.org/entry/605697"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":48.0}],"url":"https://www.proteinatlas.org/search/LILRB1"},"hgnc":{"alias_symbol":["LIR-1","ILT2","MIR-7","CD85","LIR1","CD85j","PIRB","PIR-B"],"prev_symbol":[]},"alphafold":{"accession":"Q8NHL6","domains":[{"cath_id":"2.60.40.10","chopping":"31-119","consensus_level":"high","plddt":92.1403,"start":31,"end":119},{"cath_id":"2.60.40.10","chopping":"124-220","consensus_level":"high","plddt":87.7845,"start":124,"end":220},{"cath_id":"2.60.40.10","chopping":"225-319","consensus_level":"high","plddt":92.2629,"start":225,"end":319},{"cath_id":"2.60.40.10","chopping":"324-421","consensus_level":"high","plddt":94.6444,"start":324,"end":421}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NHL6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NHL6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NHL6-F1-predicted_aligned_error_v6.png","plddt_mean":73.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LILRB1","jax_strain_url":"https://www.jax.org/strain/search?query=LILRB1"},"sequence":{"accession":"Q8NHL6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NHL6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NHL6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NHL6"}},"corpus_meta":[{"pmid":"24014594","id":"PMC_24014594","title":"Circular RNA and miR-7 in cancer.","date":"2013","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24014594","citation_count":799,"is_preprint":false},{"pmid":"29549306","id":"PMC_29549306","title":"CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29549306","citation_count":500,"is_preprint":false},{"pmid":"9933109","id":"PMC_9933109","title":"The ILT2(LIR1) and CD94/NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells.","date":"1999","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9933109","citation_count":300,"is_preprint":false},{"pmid":"9842885","id":"PMC_9842885","title":"The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-mediated signaling in monocytes.","date":"1998","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9842885","citation_count":173,"is_preprint":false},{"pmid":"11169396","id":"PMC_11169396","title":"Functional characterization of HLA-F and binding of HLA-F tetramers to ILT2 and ILT4 receptors.","date":"2000","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11169396","citation_count":159,"is_preprint":false},{"pmid":"31832068","id":"PMC_31832068","title":"MiR-7-5p suppresses tumor metastasis of non-small cell lung cancer by targeting NOVA2.","date":"2019","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31832068","citation_count":126,"is_preprint":false},{"pmid":"25511742","id":"PMC_25511742","title":"miR-7-5p suppresses cell proliferation and induces apoptosis of breast cancer cells mainly by targeting REGγ.","date":"2014","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/25511742","citation_count":125,"is_preprint":false},{"pmid":"11114384","id":"PMC_11114384","title":"Crystal structure and ligand binding properties of the D1D2 region of the inhibitory receptor LIR-1 (ILT2).","date":"2000","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/11114384","citation_count":118,"is_preprint":false},{"pmid":"11034379","id":"PMC_11034379","title":"The CD85/LIR-1/ILT2 inhibitory receptor is expressed by all human T lymphocytes and down-regulates their functions.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11034379","citation_count":115,"is_preprint":false},{"pmid":"17372005","id":"PMC_17372005","title":"The human cytomegalovirus MHC class I homolog UL18 inhibits LIR-1+ but activates LIR-1- NK cells.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17372005","citation_count":115,"is_preprint":false},{"pmid":"11160312","id":"PMC_11160312","title":"Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) inhibits TCR signaling and actin cytoskeleton reorganization.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11160312","citation_count":110,"is_preprint":false},{"pmid":"34648132","id":"PMC_34648132","title":"METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis.","date":"2021","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/34648132","citation_count":96,"is_preprint":false},{"pmid":"16210588","id":"PMC_16210588","title":"The CD85J/leukocyte inhibitory receptor-1 distinguishes between conformed and beta 2-microglobulin-free HLA-G molecules.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16210588","citation_count":94,"is_preprint":false},{"pmid":"18094328","id":"PMC_18094328","title":"The inhibitory receptor LILRB1 modulates the differentiation and regulatory potential of human dendritic cells.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18094328","citation_count":84,"is_preprint":false},{"pmid":"29282306","id":"PMC_29282306","title":"Human M2 Macrophages Limit NK Cell Effector Functions through Secretion of TGF-β and Engagement of CD85j.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/29282306","citation_count":79,"is_preprint":false},{"pmid":"23793934","id":"PMC_23793934","title":"Identification of miR-7 as an oncogene in renal cell carcinoma.","date":"2013","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/23793934","citation_count":78,"is_preprint":false},{"pmid":"29714132","id":"PMC_29714132","title":"miR-7 Replacement Therapy in Parkinson's Disease.","date":"2018","source":"Current gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29714132","citation_count":75,"is_preprint":false},{"pmid":"15939744","id":"PMC_15939744","title":"Inhibitory receptors CD85j, LAIR-1, and CD152 down-regulate immunoglobulin and cytokine production by human B lymphocytes.","date":"2005","source":"Clinical and diagnostic laboratory immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15939744","citation_count":73,"is_preprint":false},{"pmid":"24570594","id":"PMC_24570594","title":"miR-7 inhibits colorectal cancer cell proliferation and induces apoptosis by targeting XRCC2.","date":"2014","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/24570594","citation_count":68,"is_preprint":false},{"pmid":"15094202","id":"PMC_15094202","title":"Immunoglobulin-like transcripts ILT2, ILT3 and ILT7 are expressed by human dendritic cells and down-regulated following activation.","date":"2004","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/15094202","citation_count":67,"is_preprint":false},{"pmid":"32962742","id":"PMC_32962742","title":"Long non-coding RNA LPP-AS2 promotes glioma tumorigenesis via miR-7-5p/EGFR/PI3K/AKT/c-MYC feedback loop.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/32962742","citation_count":67,"is_preprint":false},{"pmid":"16014635","id":"PMC_16014635","title":"Extensive polymorphisms of LILRB1 (ILT2, LIR1) and their association with HLA-DRB1 shared epitope negative rheumatoid arthritis.","date":"2005","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16014635","citation_count":65,"is_preprint":false},{"pmid":"31451484","id":"PMC_31451484","title":"CD8+PD-1-ILT2+ T Cells Are an Intratumoral Cytotoxic Population Selectively Inhibited by the Immune-Checkpoint HLA-G.","date":"2019","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/31451484","citation_count":63,"is_preprint":false},{"pmid":"15748215","id":"PMC_15748215","title":"Does memory improve with age? CD85j (ILT-2/LIR-1) expression on CD8 T cells correlates with 'memory inflation' in human cytomegalovirus infection.","date":"2005","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15748215","citation_count":60,"is_preprint":false},{"pmid":"30783079","id":"PMC_30783079","title":"Dihydroartemisinin inhibits prostate cancer via JARID2/miR-7/miR-34a-dependent downregulation of Axl.","date":"2019","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/30783079","citation_count":59,"is_preprint":false},{"pmid":"25181544","id":"PMC_25181544","title":"MiR-7 promotes epithelial cell transformation by targeting the tumor suppressor KLF4.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25181544","citation_count":52,"is_preprint":false},{"pmid":"32771992","id":"PMC_32771992","title":"Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells.","date":"2020","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32771992","citation_count":51,"is_preprint":false},{"pmid":"31267559","id":"PMC_31267559","title":"The MHC class I-LILRB1 signalling axis as a promising target in cancer therapy.","date":"2019","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31267559","citation_count":51,"is_preprint":false},{"pmid":"31401755","id":"PMC_31401755","title":"HIV-1 Tat-Induced Astrocytic Extracellular Vesicle miR-7 Impairs Synaptic Architecture.","date":"2019","source":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31401755","citation_count":50,"is_preprint":false},{"pmid":"22242197","id":"PMC_22242197","title":"Dynamic shift from CD85j/ILT-2 to NKG2D NK receptor expression pattern on human decidual NK during the first trimester of pregnancy.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22242197","citation_count":50,"is_preprint":false},{"pmid":"12672315","id":"PMC_12672315","title":"LIR-1 expression on lymphocytes, and cytomegalovirus disease in lung-transplant recipients.","date":"2003","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/12672315","citation_count":49,"is_preprint":false},{"pmid":"28181130","id":"PMC_28181130","title":"MicroRNAs miR-7 and miR-340 predict response to neoadjuvant chemotherapy in breast cancer.","date":"2017","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/28181130","citation_count":48,"is_preprint":false},{"pmid":"11907092","id":"PMC_11907092","title":"Mutational analysis of immunoreceptor tyrosine-based inhibition motifs of the Ig-like transcript 2 (CD85j) leukocyte receptor.","date":"2002","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11907092","citation_count":48,"is_preprint":false},{"pmid":"33806891","id":"PMC_33806891","title":"MiR-7 in Cancer Development.","date":"2021","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/33806891","citation_count":47,"is_preprint":false},{"pmid":"15270723","id":"PMC_15270723","title":"Increased expression of the natural killer cell inhibitory receptor CD85j/ILT2 on antigen-specific effector CD8 T cells and its impact on CD8 T-cell function.","date":"2004","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15270723","citation_count":47,"is_preprint":false},{"pmid":"24156302","id":"PMC_24156302","title":"S100A9 protein is a novel ligand for the CD85j receptor and its interaction is implicated in the control of HIV-1 replication by NK cells.","date":"2013","source":"Retrovirology","url":"https://pubmed.ncbi.nlm.nih.gov/24156302","citation_count":45,"is_preprint":false},{"pmid":"15100307","id":"PMC_15100307","title":"Specific recognition of the viral protein UL18 by CD85j/LIR-1/ILT2 on CD8+ T cells mediates the non-MHC-restricted lysis of human cytomegalovirus-infected cells.","date":"2004","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15100307","citation_count":45,"is_preprint":false},{"pmid":"33497805","id":"PMC_33497805","title":"Exosomes-transmitted miR-7 reverses gefitinib resistance by targeting YAP in non-small-cell lung cancer.","date":"2021","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/33497805","citation_count":45,"is_preprint":false},{"pmid":"25726929","id":"PMC_25726929","title":"Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade.","date":"2015","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25726929","citation_count":44,"is_preprint":false},{"pmid":"31273318","id":"PMC_31273318","title":"Structures of the four Ig-like domain LILRB2 and the four-domain LILRB1 and HLA-G1 complex.","date":"2019","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31273318","citation_count":44,"is_preprint":false},{"pmid":"32650338","id":"PMC_32650338","title":"Structural basis for RIFIN-mediated activation of LILRB1 in malaria.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32650338","citation_count":43,"is_preprint":false},{"pmid":"31908478","id":"PMC_31908478","title":"miR-7 Reverses Breast Cancer Resistance To Chemotherapy By Targeting MRP1 And BCL2.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31908478","citation_count":43,"is_preprint":false},{"pmid":"31253728","id":"PMC_31253728","title":"LILRB1 Blockade Enhances Bispecific T Cell Engager Antibody-Induced Tumor Cell Killing by Effector CD8+ T Cells.","date":"2019","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/31253728","citation_count":43,"is_preprint":false},{"pmid":"30619281","id":"PMC_30619281","title":"Ig-Like Transcript 2 (ILT2) Blockade and Lenalidomide Restore NK Cell Function in Chronic Lymphocytic Leukemia.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30619281","citation_count":42,"is_preprint":false},{"pmid":"32708846","id":"PMC_32708846","title":"Combinatory Treatment with miR-7-5p and Drug-Loaded Cubosomes Effectively Impairs Cancer Cells.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32708846","citation_count":42,"is_preprint":false},{"pmid":"18684926","id":"PMC_18684926","title":"HLA class I molecules regulate IFN-gamma production induced in NK cells by target cells, viral products, or immature dendritic cells through the inhibitory receptor ILT2/CD85j.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18684926","citation_count":41,"is_preprint":false},{"pmid":"36096532","id":"PMC_36096532","title":"BND-22, a first-in-class humanized ILT2-blocking antibody, promotes antitumor immunity and tumor regression.","date":"2022","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36096532","citation_count":41,"is_preprint":false},{"pmid":"20194892","id":"PMC_20194892","title":"Promoter choice and translational repression determine cell type-specific cell surface density of the inhibitory receptor CD85j expressed on different hematopoietic lineages.","date":"2010","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/20194892","citation_count":40,"is_preprint":false},{"pmid":"35251919","id":"PMC_35251919","title":"miR-7/TGF-β2 axis sustains acidic tumor microenvironment-induced lung cancer metastasis.","date":"2021","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/35251919","citation_count":40,"is_preprint":false},{"pmid":"15905516","id":"PMC_15905516","title":"CD85j (leukocyte Ig-like receptor-1/Ig-like transcript 2) inhibits human osteoclast-associated receptor-mediated activation of human dendritic cells.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15905516","citation_count":39,"is_preprint":false},{"pmid":"32640511","id":"PMC_32640511","title":"miR-7 Regulates GLP-1-Mediated Insulin Release by Targeting β-Arrestin 1.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32640511","citation_count":39,"is_preprint":false},{"pmid":"36389667","id":"PMC_36389667","title":"Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophages.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36389667","citation_count":39,"is_preprint":false},{"pmid":"17601702","id":"PMC_17601702","title":"Analysis of expression and function of the inhibitory receptor ILT2 (CD85j/LILRB1/LIR-1) in peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE).","date":"2007","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/17601702","citation_count":38,"is_preprint":false},{"pmid":"30675243","id":"PMC_30675243","title":"miR-7-5p inhibits cell migration and invasion in glioblastoma through targeting SATB1.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30675243","citation_count":38,"is_preprint":false},{"pmid":"15474475","id":"PMC_15474475","title":"Recruitment of C-terminal Src kinase by the leukocyte inhibitory receptor CD85j.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15474475","citation_count":37,"is_preprint":false},{"pmid":"37781391","id":"PMC_37781391","title":"Perspectives of targeting LILRB1 in innate and adaptive immune checkpoint therapy of cancer.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37781391","citation_count":36,"is_preprint":false},{"pmid":"18398485","id":"PMC_18398485","title":"The CD85j+ NK cell subset potently controls HIV-1 replication in autologous dendritic cells.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18398485","citation_count":36,"is_preprint":false},{"pmid":"32019988","id":"PMC_32019988","title":"Simultaneous downregulation of miR-21 and upregulation of miR-7 has anti-tumor efficacy.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32019988","citation_count":36,"is_preprint":false},{"pmid":"16897816","id":"PMC_16897816","title":"Human ILT2 receptor associates with murine MHC class I molecules in vivo and impairs T cell function.","date":"2006","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16897816","citation_count":35,"is_preprint":false},{"pmid":"16479538","id":"PMC_16479538","title":"Spontaneous mutations in the human CMV HLA class I homologue UL18 affect its binding to the inhibitory receptor LIR-1/ILT2/CD85j.","date":"2006","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16479538","citation_count":35,"is_preprint":false},{"pmid":"28659925","id":"PMC_28659925","title":"Immune Checkpoint Function of CD85j in CD8 T Cell Differentiation and Aging.","date":"2017","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28659925","citation_count":34,"is_preprint":false},{"pmid":"32353178","id":"PMC_32353178","title":"lncRNA Neat1 Stimulates Osteoclastogenesis Via Sponging miR-7.","date":"2020","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/32353178","citation_count":34,"is_preprint":false},{"pmid":"33125780","id":"PMC_33125780","title":"C/EBPα/miR-7 Controls CD4+ T-Cell Activation and Function and Orchestrates Experimental Autoimmune Hepatitis in Mice.","date":"2021","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/33125780","citation_count":34,"is_preprint":false},{"pmid":"36012357","id":"PMC_36012357","title":"Role of MicroRNA-7 (MiR-7) in Cancer Physiopathology.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36012357","citation_count":33,"is_preprint":false},{"pmid":"32810522","id":"PMC_32810522","title":"MiR-7 mediates mitochondrial impairment to trigger apoptosis and necroptosis in Rhabdomyosarcoma.","date":"2020","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32810522","citation_count":32,"is_preprint":false},{"pmid":"20600445","id":"PMC_20600445","title":"LILRB1 polymorphism and surface phenotypes of natural killer cells.","date":"2010","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20600445","citation_count":32,"is_preprint":false},{"pmid":"38982045","id":"PMC_38982045","title":"Leukocyte immunoglobulin-like receptor B1 (LILRB1) protects human multiple myeloma cells from ferroptosis by maintaining cholesterol homeostasis.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38982045","citation_count":31,"is_preprint":false},{"pmid":"11553539","id":"PMC_11553539","title":"CD85/LIR-1/ILT2 and CD152 (cytotoxic T lymphocyte antigen 4) inhibitory molecules down-regulate the cytolytic activity of human CD4+ T-cell clones specific for Mycobacterium tuberculosis.","date":"2001","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/11553539","citation_count":31,"is_preprint":false},{"pmid":"32201226","id":"PMC_32201226","title":"Antagonizing miR-7 suppresses B cell hyperresponsiveness and inhibits lupus development.","date":"2020","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/32201226","citation_count":30,"is_preprint":false},{"pmid":"16210603","id":"PMC_16210603","title":"Killer cell Ig-like receptor-dependent signaling by Ig-like transcript 2 (ILT2/CD85j/LILRB1/LIR-1).","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16210603","citation_count":29,"is_preprint":false},{"pmid":"29528338","id":"PMC_29528338","title":"LILRB1 polymorphisms influence posttransplant HCMV susceptibility and ligand interactions.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/29528338","citation_count":29,"is_preprint":false},{"pmid":"36732504","id":"PMC_36732504","title":"MiR-7-5p/KLF4 signaling inhibits stemness and radioresistance in colorectal cancer.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/36732504","citation_count":28,"is_preprint":false},{"pmid":"37238734","id":"PMC_37238734","title":"Serum and Exosomal miR-7-1-5p and miR-223-3p as Possible Biomarkers for Parkinson's Disease.","date":"2023","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37238734","citation_count":28,"is_preprint":false},{"pmid":"23007163","id":"PMC_23007163","title":"Decreased miR-7 expression in the skin and sera of patients with dermatomyositis.","date":"2013","source":"Acta dermato-venereologica","url":"https://pubmed.ncbi.nlm.nih.gov/23007163","citation_count":28,"is_preprint":false},{"pmid":"16305801","id":"PMC_16305801","title":"Entropically driven MHC class I recognition by human inhibitory receptor leukocyte Ig-like receptor B1 (LILRB1/ILT2/CD85j).","date":"2005","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16305801","citation_count":27,"is_preprint":false},{"pmid":"25089088","id":"PMC_25089088","title":"Regulation of Human PAX6 Expression by miR-7.","date":"2014","source":"Evolutionary bioinformatics online","url":"https://pubmed.ncbi.nlm.nih.gov/25089088","citation_count":27,"is_preprint":false},{"pmid":"32637582","id":"PMC_32637582","title":"miR-7 Reduces Breast Cancer Stem Cell Metastasis via Inhibiting RELA to Decrease ESAM Expression.","date":"2020","source":"Molecular therapy oncolytics","url":"https://pubmed.ncbi.nlm.nih.gov/32637582","citation_count":27,"is_preprint":false},{"pmid":"22844324","id":"PMC_22844324","title":"Impact of the NK cell receptor LIR-1 (ILT-2/CD85j/LILRB1) on cytotoxicity against multiple myeloma.","date":"2012","source":"Clinical & developmental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22844324","citation_count":25,"is_preprint":false},{"pmid":"34629037","id":"PMC_34629037","title":"miR-7/EGFR/MEGF9 axis regulates cartilage degradation in osteoarthritis via PI3K/AKT/mTOR signaling pathway.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34629037","citation_count":25,"is_preprint":false},{"pmid":"34149719","id":"PMC_34149719","title":"Circulating and Tumor-Infiltrating NK Cells From Clear Cell Renal Cell Carcinoma Patients Exhibit a Predominantly Inhibitory Phenotype Characterized by Overexpression of CD85j, CD45, CD48 and PD-1.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34149719","citation_count":25,"is_preprint":false},{"pmid":"28793250","id":"PMC_28793250","title":"miR-7 Buffers Differentiation in the Developing Drosophila Visual System.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28793250","citation_count":25,"is_preprint":false},{"pmid":"32183236","id":"PMC_32183236","title":"miR-7 Controls the Dopaminergic/Oligodendroglial Fate through Wnt/β-catenin Signaling Regulation.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32183236","citation_count":23,"is_preprint":false},{"pmid":"33392188","id":"PMC_33392188","title":"miR-7-5p Affects Brain Edema After Intracerebral Hemorrhage and Its Possible Mechanism.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33392188","citation_count":23,"is_preprint":false},{"pmid":"37094666","id":"PMC_37094666","title":"The miR-7/EGFR axis controls the epithelial cell immunomodulation and regeneration and orchestrates the pathology in inflammatory bowel disease.","date":"2023","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/37094666","citation_count":23,"is_preprint":false},{"pmid":"31044367","id":"PMC_31044367","title":"MicroRNA miR-7 and miR-17-92 in the Arcuate Nucleus of Mouse Hypothalamus Regulate Sex-Specific Diet-Induced Obesity.","date":"2019","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/31044367","citation_count":23,"is_preprint":false},{"pmid":"12130517","id":"PMC_12130517","title":"Engagement of ILT2/CD85j in Sézary syndrome cells inhibits their CD3/TCR signaling.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12130517","citation_count":22,"is_preprint":false},{"pmid":"35952464","id":"PMC_35952464","title":"Low shear stress inhibits endothelial mitophagy via caveolin-1/miR-7-5p/SQSTM1 signaling pathway.","date":"2022","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/35952464","citation_count":22,"is_preprint":false},{"pmid":"29531171","id":"PMC_29531171","title":"Loss of the Immune Checkpoint CD85j/LILRB1 on Malignant Plasma Cells Contributes to Immune Escape in Multiple Myeloma.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/29531171","citation_count":22,"is_preprint":false},{"pmid":"33790470","id":"PMC_33790470","title":"Structural basis of malaria RIFIN binding by LILRB1-containing antibodies.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/33790470","citation_count":22,"is_preprint":false},{"pmid":"35736212","id":"PMC_35736212","title":"LncRNA OIP5-AS1-directed miR-7 degradation promotes MYMX production during human myogenesis.","date":"2022","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/35736212","citation_count":21,"is_preprint":false},{"pmid":"32175684","id":"PMC_32175684","title":"Long noncoding RNA LINC00115 promotes breast cancer metastasis by inhibiting miR-7.","date":"2020","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/32175684","citation_count":21,"is_preprint":false},{"pmid":"31562534","id":"PMC_31562534","title":"High-throughput screening identified miR-7-2-3p and miR-29c-3p as metastasis suppressors in gallbladder carcinoma.","date":"2019","source":"Journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/31562534","citation_count":21,"is_preprint":false},{"pmid":"38831125","id":"PMC_38831125","title":"miR-7 controls glutamatergic transmission and neuronal connectivity in a Cdr1as-dependent manner.","date":"2024","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/38831125","citation_count":20,"is_preprint":false},{"pmid":"27109306","id":"PMC_27109306","title":"Interaction of the LILRB1 inhibitory receptor with HLA class Ia dimers.","date":"2016","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27109306","citation_count":20,"is_preprint":false},{"pmid":"33748999","id":"PMC_33748999","title":"circHIPK3 regulates proliferation and differentiation of myoblast through the miR-7/TCF12 pathway.","date":"2021","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33748999","citation_count":20,"is_preprint":false},{"pmid":"26973020","id":"PMC_26973020","title":"Possible Role of HLA-G, LILRB1 and KIR2DL4 Gene Polymorphisms in Spontaneous Miscarriage.","date":"2016","source":"Archivum immunologiae et therapiae experimentalis","url":"https://pubmed.ncbi.nlm.nih.gov/26973020","citation_count":20,"is_preprint":false},{"pmid":"34551195","id":"PMC_34551195","title":"Circular RNA WHSC1 exerts oncogenic properties by regulating miR-7/TAB2 in lung cancer.","date":"2021","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34551195","citation_count":19,"is_preprint":false},{"pmid":"32918786","id":"PMC_32918786","title":"Leukocyte immunoglobulin-like receptor B1 and B4 (LILRB1 and LILRB4): Highly sensitive and specific markers of acute myeloid leukemia with monocytic differentiation.","date":"2020","source":"Cytometry. Part B, Clinical cytometry","url":"https://pubmed.ncbi.nlm.nih.gov/32918786","citation_count":19,"is_preprint":false},{"pmid":"24157932","id":"PMC_24157932","title":"MiR-7-1 potentiated estrogen receptor agonists for functional neuroprotection in VSC4.1 motoneurons.","date":"2013","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24157932","citation_count":19,"is_preprint":false},{"pmid":"28483648","id":"PMC_28483648","title":"Oleic Acid Induces MiR-7 Processing through Remodeling of Pri-MiR-7/Protein Complex.","date":"2017","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28483648","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51713,"output_tokens":9511,"usd":0.148902,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19158,"output_tokens":6655,"usd":0.131082,"stage2_stop_reason":"end_turn"},"total_usd":0.279984,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical LILRB1 protein (also known as LIR-1, ILT2, MIR-7, LIR1, CD85j). The vast majority of papers in this corpus are about miR-7 (a microRNA), not LILRB1. I need to carefully distinguish:\n\n- Papers about LILRB1/ILT2/LIR-1/CD85j (the protein) → INCLUDE\n- Papers about miR-7 (a microRNA that is NOT the LILRB1 protein) → EXCLUDE\n- Note: \"MIR-7\" is listed as an alias for LILRB1, but this appears to be an old protein alias (not the microRNA). The corpus context shows the miR-7 papers are all about a microRNA involved in cancer/neurological contexts, which is fundamentally incompatible with LILRB1's known biology. These are symbol collisions.\n\nPapers clearly about LILRB1 protein: [3], [4], [5], [8], [9], [10], [11], [13], [14], [15], [20], [22], [23], [24], [27], [28], [33], [35], [36], [37], [39], [40], [41], [43], [44], [46], [47], [48], [50], [52], [55], [57], [59], [60], [61], [67], [68], [70], [71], [75], [78], [86], [88], [89], [94], [98]\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"LILRB1 (LIR-1) binds HLA-A, -B, and -C alleles and, upon phosphorylation, recruits the tyrosine phosphatase SHP-1; coligation of LILRB1 with FcγRI inhibits tyrosine phosphorylation of the Fc receptor γ-chain and Syk, and blocks intracellular calcium mobilization in monocytes.\",\n      \"method\": \"Co-ligation assay, phosphorylation assay, SHP-1 co-immunoprecipitation, calcium flux measurement in primary monocytes\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical assays (phosphorylation, co-IP of SHP-1, functional calcium assay) in primary cells, replicated across LIR-1 and LIR-2\",\n      \"pmids\": [\"9842885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ILT2/LILRB1 directly recognizes and binds HLA-G1 on target cells, as shown by ILT2-Ig fusion protein binding to HLA-G1-expressing (HLA-E-negative) transfectants and blocking with receptor- and ligand-specific antibodies.\",\n      \"method\": \"ILT2-Ig fusion protein binding assay, antibody blocking cytotoxicity assay, site-directed mutagenesis of HLA-G1 leader sequence to ablate HLA-E surface expression\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct fusion-protein binding assay with mutagenesis controls distinguishing ILT2–HLA-G1 from CD94/NKG2A–HLA-E interactions\",\n      \"pmids\": [\"9933109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The crystal structure of LILRB1 D1D2 at 2.1 Å resolution reveals two immunoglobulin-like domains arranged at an acute angle; the UL18-binding site maps to a portion of D1 distant from the interdomain hinge, distinct from the KIR binding site.\",\n      \"method\": \"X-ray crystallography (2.1 Å), UL18 binding localization by structural analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure with functional binding site localization\",\n      \"pmids\": [\"11114384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HLA-F directly interacts with LILRB1 (ILT2) and ILT4; HLA-F tetramers stain monocytes and B cells, and this binding is conferred on non-binding cells by transfection with ILT2 or ILT4. Direct molecular interaction confirmed by surface plasmon resonance.\",\n      \"method\": \"HLA-F tetramer staining, cell transfection, surface plasmon resonance (SPR), immunoprecipitation\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SPR demonstrates direct molecular interaction; tetramer staining and transfection provide orthogonal functional confirmation\",\n      \"pmids\": [\"11169396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"LILRB1 (CD85j/ILT2) is present in the cytoplasm of all T lymphocytes and is tyrosine-phosphorylated; it inhibits CD3/TCR-mediated activation in CD4+ and CD8+ clones, down-regulates antigen recognition by CD8+ cells, reduces cytolytic activity, and inhibits intracellular Ca2+ mobilization.\",\n      \"method\": \"Flow cytometry, Western blot, biochemical phosphorylation analysis, RT-PCR, cytolytic assay, Ca2+ mobilization assay in T cell clones\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (cytotoxicity, Ca2+ flux, proliferation) in primary T cell clones with blocking and cross-linking antibodies\",\n      \"pmids\": [\"11034379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ILT2/LILRB1 inhibits TCR signaling by recruiting SHP-1 upon co-ligation with the TCR; this requires Src tyrosine kinase p56(lck) for ILT2 phosphorylation and results in reduced TCRζ phosphorylation, reduced TCRζ-ZAP70 complex formation, reduced ERK1/2 activation, and inhibition of actin cytoskeleton rearrangement. Both TCR and ILT2 polarize toward the APC upon engagement.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, ERK activation assay, actin cytoskeleton imaging, confocal microscopy in primary CTLs and transfected T cell lines\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical and imaging methods (co-IP, phosphorylation, ERK assay, cytoskeleton imaging) in both primary and transfected cells\",\n      \"pmids\": [\"11160312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mutational analysis of LILRB1 ITIMs identified Y644 (SIYATL) and Y614 (VTYAQL) as the SHP-1 docking sites required for inhibitory function; Y533 (NLYAAV) plays a regulatory role required for tyrosine phosphorylation of the receptor and subsequent SHP-1 recruitment; mutation of Y562 (VTYAEV) did not alter receptor function.\",\n      \"method\": \"Site-directed mutagenesis, SHP-1 binding assay (co-IP), FcεR-induced serotonin release inhibition assay in rat basophilic leukemia cells, transfection in COS-7 cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis of all four ITIMs with both biochemical (SHP-1 binding) and functional (serotonin release) readouts\",\n      \"pmids\": [\"11907092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"UL18 on HCMV-infected cells interacts with CD85j/LILRB1 on CD8+ T cells to trigger MHC-unrestricted lysis of infected cells; this activation is independent of CD3/TCR engagement. Soluble recombinant UL18-Fc immunoprecipitated CD85j from T cells, and lysis was specifically blocked by anti-CD85j and anti-UL18 antibodies.\",\n      \"method\": \"Cytolysis assay, co-immunoprecipitation with recombinant UL18-Fc, antibody blocking, UL18-deficient HCMV mutant comparison\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct co-IP with recombinant protein, blocking experiments, UL18-null virus mutant, multiple cell types tested\",\n      \"pmids\": [\"15100307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"C-terminal Src kinase (Csk) is recruited to the LILRB1 cytoplasmic tail in a phosphotyrosine-dependent manner; yeast three-hybrid screening identified this interaction, confirmed by co-immunoprecipitation in mammalian cells. Mutational analysis suggests Csk SH2 domain preferentially binds ITIM Y562, though mutation of Y533, Y614, and Y644 also reduces Csk recruitment. Csk and SHP-1 do not co-precipitate together with LILRB1.\",\n      \"method\": \"Yeast three-hybrid screen, co-immunoprecipitation, Western blot, phospho-peptide mapping, site-directed mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast screen confirmed by mammalian co-IP with mutagenesis, but single lab and negative result for SHP-1/Csk co-precipitation with LILRB1\",\n      \"pmids\": [\"15474475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ILT2/CD85j (LILRB1) is expressed on 40–55% of CMV-, EBV-, and HIV-specific CD8+ T cells on perforin+ CD27- effector cells; blocking ILT2 engagement increases antiviral IFN-γ production approximately threefold in both normal and HIV-infected donors, but does not appreciably affect cytotoxicity.\",\n      \"method\": \"Tetramer staining, antibody blocking, IFN-γ ELISPOT, cytotoxicity assay in primary human T cells\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking in primary human cells with two orthogonal readouts (IFN-γ and cytotoxicity), single lab\",\n      \"pmids\": [\"15270723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LILRB1 must engage β2m-associated (conformationally intact) HLA-G for inhibitory signaling; β2m-free HLA-G heavy chain complexes expressed on the cell surface are not recognized by CD85j/LILRB1 and may interfere with CD85j–HLA-G interaction.\",\n      \"method\": \"Flow cytometry with LILRB1-Ig fusion protein, anti-HLA-G antibodies distinguishing β2m-associated vs. free heavy chains, transfected cell lines\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with LILRB1-Ig fusion protein discriminating conformational forms, single lab\",\n      \"pmids\": [\"16210588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LILRB1 (CD85j) cross-linking on immature dendritic cells abolishes Ca2+ flux and strongly reduces IL-8 and IL-12 production induced by hOSCAR (human osteoclast-associated receptor) activation; it counteracts the hOSCAR-dependent anti-apoptotic effect by reducing Bcl-2 expression, and impairs DC-enhanced antigen-specific T cell proliferation.\",\n      \"method\": \"Ca2+ flux assay, cytokine ELISA, apoptosis assay, Bcl-2 Western blot, T cell proliferation assay in monocyte-derived DCs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in primary human DCs, single lab\",\n      \"pmids\": [\"15905516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LILRB1 cross-linking on B cells inhibits IgG and IgE class switching, reduces percentages of IgG- and IgE-expressing B cells, and down-regulates IL-8, IL-10, and TNF-α production across multiple stimulatory pathways (recall antigens, CD40L plus IL-4, LPS plus IL-4).\",\n      \"method\": \"Antibody cross-linking, flow cytometry, ELISA for cytokines and immunoglobulins, multiple B-cell stimulatory conditions\",\n      \"journal\": \"Clinical and diagnostic laboratory immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with multiple stimulatory pathways, single lab\",\n      \"pmids\": [\"15939744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LILRB1-MHC class I binding is entropically driven (−TΔS = −9.4 to −6.6 kcal/mol) with low heat capacity changes; kinetic studies show fast association and dissociation rates; crystal structures reveal elbow-angle variation between D1 and D2 domains indicating interdomain flexibility, and NMR directly demonstrates conformational changes in LILRB1 upon MHCI binding.\",\n      \"method\": \"Surface plasmon resonance (kinetics), isothermal titration calorimetry (thermodynamics), X-ray crystallography (multiple crystal forms), NMR spectroscopy\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — four orthogonal biophysical methods (SPR, ITC, crystallography, NMR) in one rigorous study\",\n      \"pmids\": [\"16305801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LILRB1 polymorphisms in the ligand-binding domains alter surface expression on lymphocytes and monocytes; PE01 haplotype carriers show significantly decreased LILRB1 surface expression without gross differences in crystal structures, thermostability, or binding affinities to HLA class I ligands among PE01–03 haplotype products.\",\n      \"method\": \"SNP analysis, crystal structures of PE01–03 products, thermostability assay, binding affinity measurements (SPR), flow cytometry of primary cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural, biophysical, and expression analyses across multiple polymorphic variants with functional correlation\",\n      \"pmids\": [\"16014635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ILT2/LILRB1 signals in an inhibitory KIR-dependent manner in NK92 cells: mutant KIR lacking ITIM can inhibit via ILT2 engagement with the α3 domain of HLA class I, revealing functional cooperation between KIR and ILT2 signaling pathways. This KIR-dependent signaling requires catalytically active SHP-1.\",\n      \"method\": \"Transfection of KIR mutants into NK92 cells, antibody blocking of KIR–HLA-C and ILT2–HLA-I interactions, catalytically inactive SHP-1 overexpression assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional genetics (mutant KIR, dominant-negative SHP-1) with receptor-specific blocking antibodies, single lab\",\n      \"pmids\": [\"16210603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human ILT2/LILRB1 associates in vivo with murine MHC class I molecule H-2Db in ILT2-transgenic mice; this association inhibits TCR proximal signaling, affects thymocyte development, and results in long-term acceptance of skin allografts.\",\n      \"method\": \"Transgenic mouse model, co-immunoprecipitation (H-2Db with human ILT2), thymocyte development analysis, skin allograft model\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with co-IP evidence of receptor–ligand association and functional allograft outcome\",\n      \"pmids\": [\"16897816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Spontaneous mutations in HCMV UL18 (clinical strains vs. AD169) in the α3 domain and α1 domain alter LIR-1/LILRB1 binding; α3 domain mutations are critical for LIR-1 binding; these two independent UL18 regions (α3 tip and α1 loops) contribute to LIR-1 recognition.\",\n      \"method\": \"Cytotoxicity assays, flow cytometry binding assays, Biacore (SPR), ELISA with soluble LIR-1 and UL18 variants from clinical strains\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biophysical binding assays with natural variants; single lab\",\n      \"pmids\": [\"16479538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HCMV UL18 inhibits cytotoxicity of LIR-1+ NKL cells and LIR-1+ primary NK cells through a direct LIR-1–UL18 interaction (demonstrated by antibody blocking); LIR-1- NK cells are activated by UL18 through a LIR-1-independent mechanism.\",\n      \"method\": \"Cytolysis assay with adenoviral UL18 transduction and UL18-null HCMV mutant, antibody blocking, CD107 mobilization assay, IFN-α-activated NK bulk cultures, single NK cell clones\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple experimental systems (NKL line, primary NK bulk cultures, NK clones, UL18-null virus mutant), antibody blocking, consistent results across donors\",\n      \"pmids\": [\"17372005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Continuous ligation of LILRB1 during monocyte-to-DC differentiation produces DCs with a unique phenotype, profound resistance to CD95-mediated death, inhibited secretion of IL-10, IL-12p70, and TGF-β, poor stimulatory activity for T-cell proliferation (reversed by CD80/CTLA-4 blockade or Treg depletion), and stable resistance to LPS activation.\",\n      \"method\": \"In vitro DC differentiation with continuous LILRB1 ligation, flow cytometry, cytokine ELISA, T-cell proliferation assay, CD95-mediated death assay, LPS stimulation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional readouts in a defined DC differentiation system with mechanistic rescue experiments\",\n      \"pmids\": [\"18094328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD85j+ NK cells (but not CD85j- NK cells) potently suppress HIV-1 replication in autologous monocyte-derived DCs in a cell-contact-dependent manner; this inhibition is abolished by blocking the CD85j receptor with recombinant CD85j protein, but only partially counteracted by anti-HLA class I antibodies, suggesting a non-HLA class I ligand on HIV-1-infected MDDCs mediates this interaction.\",\n      \"method\": \"NK/DC coculture, NK subset sorting (CD85j+ vs. CD85j-), HIV-1 replication assay, receptor blocking with recombinant CD85j and anti-HLA class I antibodies, recombinant CD85j staining of MDDCs\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-contact dependence and receptor blocking established, but identity of non-HLA ligand not determined; single lab\",\n      \"pmids\": [\"18398485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LILRB1/ILT2 (CD85j) inhibits IFN-γ mRNA expression and secretion by NK cells in response to HLA class I-expressing targets, poly(I:C), and immature dendritic cells, and inhibits IFN-γ by ILT2+ T cells in response to superantigen, establishing HLA class I–ILT2 interaction as a specific regulator of IFN-γ at the mRNA and protein levels.\",\n      \"method\": \"NK-92 line and primary NK cell functional assays, IFN-γ mRNA and protein measurement (ELISA, qPCR), blocking with anti-ILT2 and anti-HLA class I antibodies, NK/DC coculture\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple stimulatory conditions, mRNA and protein readouts, receptor/ligand blocking, NK line and primary cells\",\n      \"pmids\": [\"18684926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cell-type-specific surface density of CD85j/LILRB1 is controlled by two distinct promoters (lymphocyte promoter 13 kb upstream of monocyte promoter) and a translational repression element in the 5'-UTR exon unique to the lymphocyte transcript; this sequence reduces protein translation without affecting mRNA levels, explaining the lower surface expression in lymphocytes vs. monocytes.\",\n      \"method\": \"Promoter mapping, reporter assay, 5'-UTR deletion analysis, Western blot, flow cytometry, ChIP in multiple hematopoietic cell types\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic promoter mapping, translational repression element identified by reporter assay and mutagenesis, orthogonal confirmation by Western blot and flow cytometry\",\n      \"pmids\": [\"20194892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"S100A9 is a non-HLA class I ligand for CD85j/LILRB1; direct interaction was demonstrated by co-immunoprecipitation. HIV-1 infection of MDDCs induces surface modulation of S100A9, influencing CD85j+ NK cell anti-HIV activity. Exogenous S100A9 stimulation of NK cells via CD85j ligation enhances control of HIV-1 infection in CD4+ T cells.\",\n      \"method\": \"Co-immunoprecipitation of LILRB1 and S100A9, flow cytometry, HIV-1 replication assay, NK/MDDC coculture, exogenous S100A9 stimulation\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifies novel ligand with functional confirmation in HIV suppression assay; single lab\",\n      \"pmids\": [\"24156302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Intracellular Cys residues and HLA-I dimerization enhance LILRB1 recognition; classical HLA class Ia dimers (detected in exosomes and after type I IFN treatment of monocytes) show increased LILRB1 binding compared to monomers. Type I IFN increases LILRB1 recognition of monocyte HLA-I disproportionate to the increase in HLA-I surface expression.\",\n      \"method\": \"LILRB1-Fc fusion protein binding assay, cellular reporter system (LILRB1-ζ chimera), transfected 721.221 cells, flow cytometry, IFN-α stimulation of primary monocytes\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal receptor binding systems (fusion protein and chimeric receptor reporter) with defined ligand variants, single lab\",\n      \"pmids\": [\"27109306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"M2 macrophages upregulate CD85j (ILT2/LILRB1) on NK cells through a mechanism involving HLA-G (expressed at higher levels on M2 than M1); CD85j upregulation on CD56dim NK cells accounts for hyporesponsive degranulation and cytotoxicity, while soluble TGF-β and CD85j upregulation together account for diminished IFN-γ by CD56bright NK cells. Hyporesponsiveness to degranulation was not reversed upon short-term removal of M2.\",\n      \"method\": \"NK/macrophage coculture, flow cytometry, IFN-γ intracellular staining, CD107a degranulation assay, TGF-β neutralization, anti-CD85j blocking antibody, HLA-G measurement by ELISA and flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (cytotoxicity, degranulation, IFN-γ), receptor/ligand blocking and neutralization, mechanistic dissection of TGF-β vs. CD85j contributions\",\n      \"pmids\": [\"29282306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LILRB1 polymorphisms in regulatory regions and ligand-binding domains affect functional recognition of HCMV UL18 and classical MHCI (but not HLA-G) by NK cells; four nonsynonymous substitutions in the first two Ig domains each contribute to differential binding. One polymorphism controls addition of an N-linked glycan whose removal enhances binding to UL18 and alters binding to all tested ligands.\",\n      \"method\": \"Clinical cohort HCMV outcome analysis, NK cell functional assays with LILRB1 variants, SPR binding assays, glycosylation site mutagenesis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure–function analysis of natural variants with SPR binding, mutagenesis of glycosylation site, functional NK assays, and clinical correlation\",\n      \"pmids\": [\"29528338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LILRB1 is expressed by a distinct CD8+PD-1- intratumoral T cell subset; HLA-G on tumor cells specifically inhibits CD8+ILT2+ (but not CD8+ILT2- or CD8+PD-1+) T cell cytotoxicity and IFN-γ production, and this inhibition is counteracted by blocking the HLA-G/ILT2 interaction.\",\n      \"method\": \"Transcriptomics, flow cytometry, ex vivo cytotoxicity assay with primary TILs and PBMCs, anti-ILT2/anti-HLA-G blocking experiments\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ex vivo functional assays with primary TILs from cancer patients, receptor/ligand blocking, multiple orthogonal methods\",\n      \"pmids\": [\"31451484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LILRB1 engagement by HLA-G on tumor cells significantly inhibits BiTE molecule-induced CD8+ effector T cell activation; LILRB1 and PD-1 are expressed by distinct CD8+ T cell populations, and combined LILRB1 + PD-1 blockade induces greater activation than either alone.\",\n      \"method\": \"Flow cytometry, BiTE molecule stimulation assay, LILRB1/HLA-G blocking, anti-PD-1 blocking, T cell activation assays with primary human CD8+ T cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking with defined ligand, two orthogonal checkpoint blockade conditions, single lab\",\n      \"pmids\": [\"31253728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of four-domain LILRB1 in complex with HLA-G1 shows that D1D2 is responsible for HLA-I binding while D3D4 acts as a structural scaffold; staggered assembly of the four Ig-like domains shows limited flexibility. Structure supports models for both cis and trans HLA-I binding, and dimeric LILRB1 geometry suggests enhanced inhibitory signal transduction.\",\n      \"method\": \"X-ray crystallography of four-domain LILRB1 and LILRB1/HLA-G1 complex, structural analysis of domain angles and assembly\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structures of full ectodomain and receptor–ligand complex with functional domain assignment\",\n      \"pmids\": [\"31273318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A RIFIN from Plasmodium falciparum mimics the binding mode of MHC class I to activate LILRB1 signaling; the crystal structure of RIFIN bound to LILRB1 reveals this mimicry; a single mutation in the RIFIN disrupts the complex, blocks LILRB1 binding of all tested RIFINs, and abolishes signaling in a reporter assay. In a supported lipid bilayer NK cell system, RIFIN suppresses NK cell perforin mobilization similarly to MHC.\",\n      \"method\": \"X-ray crystallography of RIFIN–LILRB1 complex, LILRB1 reporter assay, site-directed mutagenesis of RIFIN, supported lipid bilayer NK cell assay (ADCC model), perforin mobilization measurement\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus reporter assay plus functional NK assay; mechanistically rigorous and published in Nature\",\n      \"pmids\": [\"32650338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RIFIN proteins from Plasmodium falciparum bind to LILRB1 domain 3 (D3); crystal and cryo-EM structures of RIFIN in complex with LILRB1 D3D4 and a D3D4-containing antibody Fab reveal that RIFIN–LILRB1 D3 interaction is similar to RIFIN–LAIR1; DNA insertions encoding LILRB1 D3D4 or D3 into the VH-CH1 elbow of antibody genes generate RIFIN-specific antibodies in malaria-exposed donors.\",\n      \"method\": \"Cryo-EM and crystal structure determination, SPR/binding assays, mass spectrometry, B cell clone isolation, antibody gene sequencing\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic structures (crystal + cryo-EM), binding assays, and naturally occurring human antibody discovery with structural validation\",\n      \"pmids\": [\"33790470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LILRB1 blockade (Fc-silent anti-LILRB1 antibody LILRB1-IgGσ) significantly enhances antibody-dependent cellular phagocytosis (ADCP) of lymphoma cells by macrophages when combined with rituximab and CD47 blockade; LILRB1-IgGσ promotes serial engulfment and potentiates ADCP by M0, M1, and M2 macrophages, but requires CD47 co-blockade and CD20 antibody. LILRB2 blockade was not effective.\",\n      \"method\": \"In vitro ADCP assay, macrophage polarization, patient-derived CLL/lymphoma cell ADCP, antibody engineering (Fc-silent variants), serial engulfment imaging\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple macrophage polarization states and patient-derived cells tested; single lab; LILRB2 negative control strengthens specificity\",\n      \"pmids\": [\"36389667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LILRB1 forms a complex with the low-density lipoprotein receptor (LDLR) and LDLR adapter protein 1 (LDLRAP1) to facilitate LDL/cholesterol uptake in multiple myeloma cells; loss of LILRB1 impairs cholesterol uptake but activates de novo cholesterol synthesis, decreasing anti-ferroptotic squalene and promoting ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation (LILRB1–LDLR–LDLRAP1 complex), in vivo LILRB1 knockout (MM mouse model), cholesterol uptake assay, squalene measurement, ferroptosis assay, gene expression profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP identifies novel complex, in vivo knockout model, multiple metabolic readouts (cholesterol, squalene), ferroptosis mechanistic link; multiple orthogonal methods\",\n      \"pmids\": [\"38982045\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LILRB1 (ILT2/LIR-1/CD85j) is an inhibitory immunoreceptor whose extracellular Ig-like D1D2 domains bind MHC class I molecules (classical HLA-A/B/C, non-classical HLA-G, HLA-F, and the HCMV homolog UL18) as well as non-MHC ligands (S100A9, Plasmodium falciparum RIFINs); upon ligand engagement, its cytoplasmic ITIMs (particularly Y614 and Y644) are phosphorylated—requiring Lck and ITIM Y533 as a regulatory site—leading to recruitment of SHP-1 and Csk, which suppress downstream kinase cascades (TCRζ/ZAP70, ERK, Ca2+ mobilization) and inhibit effector functions (cytotoxicity, IFN-γ secretion, degranulation, phagocytosis) in T cells, NK cells, B cells, monocytes, macrophages, and dendritic cells; cell-type-specific expression levels are set by alternative promoter usage and a 5'-UTR translational repressor element; additionally, LILRB1 forms a complex with LDLR and LDLRAP1 to facilitate cholesterol uptake in myeloma cells, protecting them from ferroptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LILRB1 (ILT2/LIR-1/CD85j) is an inhibitory immunoreceptor that restrains effector functions across T cells, NK cells, B cells, monocytes, dendritic cells, and macrophages following recognition of MHC class I [#0, #4]. Its membrane-distal D1D2 Ig-like domains constitute the ligand-binding module, engaging classical HLA-A/B/C [#0], non-classical HLA-G in a β2-microglobulin-dependent conformation [#1, #10], HLA-F [#3], and the HCMV MHC-I homolog UL18 [#2, #7], while the membrane-proximal D3D4 domains form a structural scaffold and contribute a distinct binding surface exploited by Plasmodium falciparum RIFINs [#29, #31]. Crystallographic, calorimetric, and NMR analyses show the receptor engages MHC-I through an entropically driven, fast-on/fast-off interaction accompanied by interdomain flexibility and conformational change [#13, #29]. Upon ligand engagement, LILRB1 phosphorylation—dependent on Src kinase p56lck and the regulatory ITIM Y533—drives recruitment of SHP-1 to docking sites Y614 and Y644 and of Csk to Y562, which suppresses proximal activation cascades including TCRζ/ZAP70 coupling, ERK1/2 activation, calcium mobilization, and actin reorganization [#5, #6, #8]. Through these signals LILRB1 inhibits cytotoxicity and IFN-γ secretion by T and NK cells [#9, #21, #27], antibody class switching and cytokine output by B cells [#12], dendritic cell maturation and stimulatory capacity [#11, #19], and macrophage phagocytosis [#32]. Cell-type-specific surface density is set by dual promoter usage and a lymphocyte-specific 5'-UTR translational repressor element [#22], and natural polymorphisms—including one controlling an N-linked glycan—tune ligand recognition [#14, #26]. Beyond immune signaling, LILRB1 assembles with LDLR and LDLRAP1 to drive cholesterol uptake in multiple myeloma cells, protecting them from ferroptosis [#33].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established LILRB1 as an MHC class I-binding inhibitory receptor that recruits SHP-1 and dampens activating Fc receptor signaling, defining its core inhibitory logic.\",\n      \"evidence\": \"Co-ligation with FcγRI, SHP-1 co-IP, and calcium flux in primary monocytes\",\n      \"pmids\": [\"9842885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ITIM residues mediating SHP-1 docking not yet mapped\", \"Kinase responsible for receptor phosphorylation not identified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated direct recognition of the non-classical ligand HLA-G1, broadening the ligand repertoire beyond classical HLA.\",\n      \"evidence\": \"ILT2-Ig fusion binding to HLA-G1 transfectants with antibody blocking and leader-sequence mutagenesis\",\n      \"pmids\": [\"9933109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational requirements of HLA-G not addressed\", \"Downstream signaling in target cells not quantified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Solved the D1D2 structure and mapped the UL18-binding site, distinguishing LILRB1's engagement mode from KIRs.\",\n      \"evidence\": \"X-ray crystallography at 2.1 Å with binding-site localization\",\n      \"pmids\": [\"11114384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full ectodomain (D3D4) architecture not resolved\", \"MHC-bound complex geometry not yet determined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Extended ligand recognition to HLA-F and confirmed direct molecular binding, and showed LILRB1 inhibits TCR-driven T cell activation.\",\n      \"evidence\": \"HLA-F tetramer staining, transfection, SPR; cytolytic and Ca2+ assays in T cell clones\",\n      \"pmids\": [\"11169396\", \"11034379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of HLA-F engagement unclear\", \"Signaling intermediates downstream of TCR inhibition not dissected\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the TCR-inhibitory mechanism: co-ligation recruits SHP-1, requires p56lck, and blocks TCRζ-ZAP70 coupling, ERK activation, and actin remodeling.\",\n      \"evidence\": \"Co-IP, phosphorylation, ERK and cytoskeleton imaging in CTLs and transfected T cells\",\n      \"pmids\": [\"11160312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of receptor clustering at the synapse not resolved\", \"Role of other ITIMs not yet tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Assigned functional roles to individual ITIMs, identifying Y614/Y644 as SHP-1 docking sites and Y533 as a regulatory phosphorylation site.\",\n      \"evidence\": \"Systematic ITIM mutagenesis with SHP-1 binding and serotonin-release readouts in RBL and COS-7 cells\",\n      \"pmids\": [\"11907092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Y562 function unresolved at this stage\", \"Kinetics of sequential ITIM phosphorylation not measured\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified Csk as a second phosphotyrosine-dependent effector recruited to the LILRB1 tail, indicating a SHP-1-independent inhibitory arm.\",\n      \"evidence\": \"Yeast three-hybrid screen confirmed by mammalian co-IP and ITIM mutagenesis\",\n      \"pmids\": [\"15474475\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; Csk/SHP-1 do not co-precipitate with LILRB1, leaving spatial coordination unclear\", \"Functional weight of Csk arm in primary cells not established\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed UL18-LILRB1 engagement can paradoxically trigger MHC-unrestricted lysis of HCMV-infected cells, and characterized viral exploitation of the receptor.\",\n      \"evidence\": \"Cytolysis assays, UL18-Fc co-IP, antibody blocking, UL18-null virus in CD8+ T and NK cells\",\n      \"pmids\": [\"15100307\", \"17372005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling switch between inhibition and activation not mechanistically resolved\", \"In vivo relevance during HCMV infection not established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Characterized the biophysics of MHC-I recognition (entropy-driven, flexible, fast kinetics), conformational requirements (β2m-associated HLA-G), polymorphic control of expression, and functional cross-talk with KIRs.\",\n      \"evidence\": \"SPR, ITC, crystallography, NMR; LILRB1-Ig conformational binding; SNP/structure analysis; KIR mutant transfection in NK92\",\n      \"pmids\": [\"16305801\", \"16210588\", \"16014635\", \"16210603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional impact of interdomain flexibility on signaling untested\", \"Mechanism by which polymorphisms alter surface expression not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended inhibitory function to dendritic cells and B cells, showing LILRB1 suppresses cytokine production, class switching, and DC stimulatory activity.\",\n      \"evidence\": \"Cross-linking with Ca2+, cytokine ELISA, Bcl-2 blot, T cell proliferation and Ig switching assays in primary DCs and B cells\",\n      \"pmids\": [\"15905516\", \"15939744\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab for each cell type\", \"Physiological ligand driving these effects in vivo not identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided in vivo evidence that LILRB1 engagement of MHC-I inhibits TCR signaling, shapes thymocyte development, and promotes allograft tolerance.\",\n      \"evidence\": \"ILT2-transgenic mice, H-2Db co-IP, thymocyte analysis, skin allograft model\",\n      \"pmids\": [\"16897816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cross-species receptor-ligand pairing limits physiological interpretation\", \"Cell-intrinsic vs systemic contributions to tolerance not separated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed a contact-dependent, non-HLA-mediated CD85j role in NK suppression of HIV-1 replication in dendritic cells, pointing to an unidentified ligand.\",\n      \"evidence\": \"NK/DC coculture, CD85j subset sorting, recombinant CD85j and anti-HLA blocking\",\n      \"pmids\": [\"18398485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-HLA ligand identity unknown at this stage\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established LILRB1 as a specific transcriptional and secretory regulator of IFN-γ in NK and T cells responding to HLA-I and dendritic cells.\",\n      \"evidence\": \"IFN-γ mRNA/protein assays, blocking antibodies in NK-92 and primary NK cells, NK/DC coculture\",\n      \"pmids\": [\"18684926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional machinery linking LILRB1 signaling to IFN-γ mRNA not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Explained cell-type-specific receptor density via dual promoters and a lymphocyte-specific 5'-UTR translational repressor element.\",\n      \"evidence\": \"Promoter mapping, reporter and 5'-UTR deletion assays, ChIP, Western, flow across hematopoietic cells\",\n      \"pmids\": [\"20194892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trans-acting factors binding the repressor element not identified\", \"Signal-dependent regulation of promoter choice not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified S100A9 as a non-HLA ligand linking LILRB1 to NK-mediated control of HIV infection.\",\n      \"evidence\": \"LILRB1-S100A9 co-IP, HIV replication assays, exogenous S100A9 stimulation of NK cells\",\n      \"pmids\": [\"24156302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of S100A9 binding not determined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed HLA-I dimerization and intracellular cysteines enhance LILRB1 recognition, with type I IFN boosting recognition beyond surface HLA increases.\",\n      \"evidence\": \"LILRB1-Fc and LILRB1-ζ chimera reporter binding, transfected 721.221 cells, IFN-α stimulation of monocytes\",\n      \"pmids\": [\"27109306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo prevalence of HLA-I dimers uncertain\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked M2 macrophage HLA-G to LILRB1 upregulation on NK cells driving durable NK hyporesponsiveness.\",\n      \"evidence\": \"NK/macrophage coculture, degranulation and IFN-γ assays, TGF-β neutralization, anti-CD85j blocking\",\n      \"pmids\": [\"29282306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of irreversibility of degranulation hyporesponsiveness unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that natural LILRB1 polymorphisms, including a glycosylation-controlling variant, tune ligand recognition and correlate with HCMV outcomes.\",\n      \"evidence\": \"Clinical cohort, NK functional assays, SPR, glycosylation-site mutagenesis\",\n      \"pmids\": [\"29528338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which glycan alters binding geometry not structurally resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established LILRB1/HLA-G as a tumor immune checkpoint on a distinct PD-1-negative CD8+ T cell subset, additive with PD-1 blockade and limiting BiTE efficacy.\",\n      \"evidence\": \"Transcriptomics, ex vivo TIL cytotoxicity/IFN-γ assays, BiTE stimulation, combined LILRB1/PD-1 blockade\",\n      \"pmids\": [\"31451484\", \"31253728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of the LILRB1+ vs PD-1+ subset divergence unknown\", \"In vivo efficacy of LILRB1 blockade not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the full four-domain ectodomain bound to HLA-G1, assigning D1D2 as the ligand interface and D3D4 as a scaffold and supporting cis/trans and dimeric signaling models.\",\n      \"evidence\": \"X-ray crystallography of four-domain LILRB1 and LILRB1/HLA-G1 complex\",\n      \"pmids\": [\"31273318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional validation of dimeric signaling model lacking\", \"Cis vs trans engagement in cells not directly demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed molecular mimicry whereby P. falciparum RIFINs activate LILRB1 inhibitory signaling like MHC, suppressing NK perforin mobilization.\",\n      \"evidence\": \"RIFIN-LILRB1 crystal structure, reporter assay, RIFIN mutagenesis, supported lipid bilayer NK assay\",\n      \"pmids\": [\"32650338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution to malaria immune evasion not quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed a subset of RIFINs binds LILRB1 D3 (mimicking LAIR1 engagement) and that humans generate anti-RIFIN antibodies via genomic insertion of LILRB1 D3D4 into antibody elbows.\",\n      \"evidence\": \"Crystal and cryo-EM structures, SPR, B cell clone isolation and antibody sequencing\",\n      \"pmids\": [\"33790470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling consequences of D3 engagement vs D1D2 engagement not compared\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated LILRB1 acts as a macrophage phagocytosis checkpoint whose blockade enhances antibody-dependent phagocytosis of lymphoma when combined with CD47 and CD20 antibodies.\",\n      \"evidence\": \"In vitro and patient-derived ADCP assays, Fc-silent anti-LILRB1, macrophage polarization, serial engulfment imaging\",\n      \"pmids\": [\"36389667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dependence on CD47 co-blockade limits standalone utility\", \"Single lab; in vivo efficacy untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a non-immune role: LILRB1 partners with LDLR and LDLRAP1 to drive cholesterol uptake and protect myeloma cells from ferroptosis.\",\n      \"evidence\": \"LILRB1-LDLR-LDLRAP1 co-IP, in vivo knockout, cholesterol/squalene/ferroptosis assays\",\n      \"pmids\": [\"38982045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this complex functions outside myeloma not established\", \"Relationship between immune and metabolic functions unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LILRB1 toggles between inhibitory and activating outcomes, how its dimeric/cis-trans geometry is functionally deployed, and how its immune-signaling and cholesterol-uptake functions are integrated remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural model of signaling-competent receptor clusters not validated functionally\", \"Spatial coordination of SHP-1 and Csk arms unresolved\", \"Generality of the LDLR/LDLRAP1 complex beyond myeloma unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 6, 9, 21, 27]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3, 5, 30]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [7, 18, 30]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 8, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 22, 29]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 4, 5, 9, 21, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 18, 30, 33]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [33]}\n    ],\n    \"complexes\": [\n      \"LILRB1–LDLR–LDLRAP1 complex\",\n      \"LILRB1–HLA-G1 receptor–ligand complex\"\n    ],\n    \"partners\": [\n      \"SHP-1\",\n      \"Csk\",\n      \"LCK\",\n      \"HLA-G\",\n      \"UL18\",\n      \"S100A9\",\n      \"LDLR\",\n      \"LDLRAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}