{"gene":"ITGB2","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1990,"finding":"ICAM-1 is a counter-receptor for Mac-1 (CD11b/CD18): purified Mac-1 adsorbed to artificial substrates binds ICAM-1-expressing cells, and COS cells co-transfected with Mac-1 alpha and beta (CD18) chains attach to purified ICAM-1 substrates. This binding is blocked by mAbs to both ICAM-1 and Mac-1, establishing ICAM-1 as a ligand for the CD11b/CD18 heterodimer.","method":"Purified protein binding assays, cDNA transfection of COS/L cells, reciprocal cell adhesion assays, mAb blocking","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted binding with purified proteins, reciprocal cell-based assays, multiple orthogonal methods, replicated across cell types","pmids":["1980124"],"is_preprint":false},{"year":1989,"finding":"CD18 undergoes stimulus-induced phosphorylation: in resting leukocytes CD18 phosphorylation is minimal, but PMA induces rapid, sustained, high-stoichiometry CD18 phosphorylation predominantly on serine residues (with minor phosphothreonine and phosphotyrosine), while FMLP induces transient CD18 phosphorylation. The CD11 alpha subunits show only minimal changes, indicating CD18 is the primary regulated phosphorylation target in the complex.","method":"Metabolic radiolabeling with 32P, immunoprecipitation, phosphoamino acid analysis, PMA/FMLP stimulation of human leukocytes","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical phosphoamino acid analysis with multiple stimuli and controls, replicated across monocyte cell types","pmids":["2574726"],"is_preprint":false},{"year":1989,"finding":"CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1) each contribute approximately equally (~50% each) to PMN adhesion to unstimulated endothelial cells, but through different ligands: CD11a/CD18 binds ICAM-1, while CD11b/CD18 binds a distinct, non-ICAM-1 ligand on endothelial cells. CD11c/CD18 does not participate in this adhesion.","method":"mAb blocking of individual CD11 chains, anti-ICAM-1 antibody competition, ICAM-1-coated surface down-modulation assays, PMN-endothelial cell adhesion assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal blocking experiments with purified ICAM-1 surfaces and individual-chain mAbs, consistent results across assays","pmids":["2809204"],"is_preprint":false},{"year":1990,"finding":"Two point mutations in the CD18 coding sequence (Arg593→Cys and Lys196→Thr) each impair CD18 cell-surface expression when introduced into transfected COS cells, identifying conserved residues in the cysteine-rich repeats and another conserved integrin region as critical for normal CD18 surface expression.","method":"cDNA cloning and sequencing of patient alleles, transfection of mutant CD18 into COS M6 cells, surface expression analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct mutagenesis-equivalent (natural mutations) validated by heterologous expression in transfected cells, two independent alleles tested","pmids":["1968911"],"is_preprint":false},{"year":1990,"finding":"Retrovirus-mediated transduction of a functional CD18 gene into LAD patient lymphocytes restores surface expression of CD11a/CD18 (LFA-1) and reconstitutes LFA-1-dependent adhesive function, demonstrating that CD18 is the functional defect in LAD and is sufficient for integrin surface assembly.","method":"Retrovirus-mediated gene transfer, molecular analysis of proviral integration and CD18 mRNA, flow cytometry for surface CD11a/CD18, functional LFA-1 adhesion assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — gene complementation with functional rescue, multiple orthogonal readouts (molecular, protein, functional)","pmids":["1972597"],"is_preprint":false},{"year":1993,"finding":"CD18 gene targeting in mice produces a hypomorphic allele (2–16% of normal CD18 expression); homozygous mutant mice show mild granulocytosis and impaired inflammatory responses (reduced peritonitis and delayed cardiac allograft rejection), demonstrating that CD18 is required for normal leukocyte integrin-dependent adhesion in vivo.","method":"Gene targeting (insertional mutation), flow cytometry for CD18 expression, chemical peritonitis model, cardiac transplant rejection model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gene-targeted KO mouse with specific in vivo inflammatory phenotypic readouts","pmids":["8101543"],"is_preprint":false},{"year":1998,"finding":"CD18 null mice develop chronic dermatitis, elevated neutrophil counts, and markedly defective T cell proliferation in response to TCR stimulation, demonstrating that CD11/CD18 integrins are required for normal neutrophil tissue migration and T cell activation in vivo.","method":"CD18 null mouse (gene-targeted), intravital microscopy of cremaster muscle, T cell proliferation assays (staphylococcal enterotoxin A, MHC alloantigens)","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — complete null KO mouse with multiple defined phenotypic readouts and direct intravital imaging of neutrophil behavior","pmids":["9653089"],"is_preprint":false},{"year":1996,"finding":"Mac-1 (CD11b/CD18) and the urokinase receptor (uPAR/CD87) form a functional unit on monocytic cells: uPAR engagement by urokinase inhibits Mac-1-mediated fibrinogen binding and degradation (up to 91% inhibition) and Factor X binding, while vitronectin-mediated uPAR attachment enhances subsequent Mac-1 fibrinogen degradation 3–4-fold. This co-regulation was reproduced in CHO cells co-transfected with human Mac-1 and uPAR.","method":"Co-expression in CHO cells (transfection), fibrinogen binding and degradation assays, Factor X binding assays, monocytic cell lines, fresh monocytes","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reconstituted in transfected CHO cells, confirmed in primary monocytes and cell lines, multiple functional readouts","pmids":["8874219"],"is_preprint":false},{"year":1997,"finding":"Mac-1 (CD11b/CD18) is an oligodeoxynucleotide-binding protein: binding of thymidine homopolymer occurs on both the CD11b alpha subunit and the CD18 beta subunit; soluble fibrinogen competes for this binding; anti-Mac-1 mAbs inhibit binding; increased surface Mac-1 expression correlates with increased ODN internalization by PMNs.","method":"Binding assays with phosphodiester and phosphorothioate ODNs, competition with fibrinogen, anti-Mac-1 mAb inhibition, upregulation by TNF-alpha, internalization quantification","journal":"Nature medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assays on purified protein and intact cells with mAb blocking, single laboratory","pmids":["9095175"],"is_preprint":false},{"year":1999,"finding":"CD18-expressing phagocytes transport Salmonella from the gastrointestinal tract to the bloodstream: CD18-deficient mice are resistant to extraintestinal dissemination of SPI1-deficient S. typhimurium to liver and spleen after oral administration, establishing a CD18-dependent pathway for systemic bacterial dissemination.","method":"CD18-deficient mouse model, oral Salmonella challenge, organ bacterial burden quantification","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse with defined in vivo phenotype, replicated with SPI1-deficient bacteria","pmids":["10548107"],"is_preprint":false},{"year":1998,"finding":"CD18 deficiency significantly reduces myocardial infarct size and PMN infiltration after ischemia-reperfusion: CD18-/- mice show ~57% reduction in infarct area and 54% reduction in PMN infiltration compared to wild-type, demonstrating that CD18-mediated neutrophil-endothelial adhesion is required for PMN-driven myocardial reperfusion injury.","method":"CD18-/- and ICAM-1-/- mouse models, surgical myocardial ischemia-reperfusion, infarct size measurement, PMN infiltration histology","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse with quantified in vivo phenotype, replicated with ICAM-1 KO as parallel control","pmids":["9843832"],"is_preprint":false},{"year":1999,"finding":"A missense mutation (Cys36Ser) in canine ITGB2 disrupts a conserved cysteine (likely a disulfide bond) and causes canine leukocyte adhesion deficiency (CLAD): mutant CD18 fails to support CD11/CD18 surface expression, confirmed by retroviral transduction of mutant vs. normal canine CD18 into human LAD EBV B-cells.","method":"Sequence analysis, retroviral vector transduction of LAD B-cells, flow cytometry for CD11/CD18 surface expression","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct mutagenesis-equivalent (natural mutation) validated by heterologous expression with functional rescue comparison","pmids":["10512685"],"is_preprint":false},{"year":2003,"finding":"CD18 deficiency (gene knockout) inhibits choroidal neovascularization (CNV): CD18-/- mice show significantly fewer CNV lesions with fluorescein leakage and significantly smaller CNV volumes after laser photocoagulation compared to wild-type, demonstrating a nonredundant role for CD18-mediated leukocyte adhesion in CNV development.","method":"CD18-/- mouse laser photocoagulation CNV model, confocal volumetric CNV measurement, fluorescein angiography","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse with quantitative CNV phenotype, replicated with ICAM-1 KO as parallel control","pmids":["12766082"],"is_preprint":false},{"year":2008,"finding":"The CD18 (beta2 integrin) subunit is the T-lymphocyte receptor for Helicobacter pylori vacuolating cytotoxin VacA: VacA enters activated T lymphocytes by binding CD18 and exploiting LFA-1 recycling. LFA-1-deficient Jurkat cells are resistant to VacA-induced vacuolation and IL-2 modulation; genetic complementation with LFA-1 or Mac-1 (containing human CD18) restores sensitivity. VacA targets human but not murine CD18.","method":"LFA-1-deficient Jurkat T cells, genetic complementation with human CD18-containing integrins, vacuolation assays, IL-2 secretion assays, species-specificity analysis","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and complementation with specific mechanistic phenotypic readouts, species-specificity validation","pmids":["18191791"],"is_preprint":false},{"year":2007,"finding":"Human CD18 is the functional receptor for Aggregatibacter actinomycetemcomitans leukotoxin (LtxA): chimeric beta2-integrins expressed in LtxA-resistant cells confer susceptibility, and the cysteine-rich tandem repeats encompassing integrin-EGF-like domains 2, 3, and 4 of the CD18 extracellular region are critical for species-specific LtxA-induced cytotoxicity.","method":"Chimeric beta2-integrin expression in resistant cell lines, domain-deletion analysis, cytotoxicity assays","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 1 / Moderate — chimeric receptor domain mapping in heterologous cells with functional readout, identifies specific CD18 domains","pmids":["17635865"],"is_preprint":false},{"year":2002,"finding":"CD11b/CD18-dependent PMN interactions with intestinal epithelium are mediated by fucosylated proteoglycans: fucoidin directly binds CD11b/CD18 in a divalent cation- and sulfation-dependent manner blocked by anti-CD11b mAbs; fucosidase treatment of T84 epithelial cells reduces adhesion to purified CD11b/CD18; proteoglycan synthesis inhibition blocks T84 adhesion to CD11b/CD18.","method":"Purified CD11b/CD18 adhesion assays, fucoidin direct binding, anti-CD11b mAb blocking, fucosidase and neuraminidase treatment, proteoglycan synthesis inhibition, ligand blotting","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biochemical methods with purified receptor and enzymatic ligand modification","pmids":["12391246"],"is_preprint":false},{"year":2001,"finding":"CD18 undergoes conformational change upon leukocyte activation: mAbs recognizing activation-induced neoepitopes on CD18 reveal a subpopulation of LFA-1 with altered conformation that correlates with cell adhesion, requires divalent cations, is sensitive to cellular signaling, is absent in LAD-1 variant cells defective in LFA-1 activation, and co-occurs with high-affinity ICAM-1 binding. Function-blocking CD18 mAbs suppress this conformational change.","method":"Novel activation-epitope mAb panel, flow cytometry on T lymphocytes and LAD-1 variant cell lines, correlation with ICAM-1 binding affinity, recombinant LFA-1","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal antibody probes, disease-control validation with LAD-1 variant cells, correlation with high-affinity ligand binding state","pmids":["11714770"],"is_preprint":false},{"year":2003,"finding":"Fluid shear stress causes cleavage of the extracellular domain of CD18 from neutrophil surfaces via cysteine protease (cathepsin B) activity: shear (5 dyn/cm²) cleaves the extracellular but not cytoplasmic CD18 domain, is abolished by extracellular Ca²⁺ chelation and cathepsin B inhibitors (but not cathepsin L, calpain, elastase, or metalloprotease inhibitors), and results in CD18 redistribution rather than cytoplasmic internalization.","method":"Confocal microscopy of single adherent neutrophils, flow cytometry, protease inhibitor panel, Ca²⁺ chelation, domain-specific antibody epitope mapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal inhibitor experiments with specific protease pharmacology, domain-specific antibody validation","pmids":["14595007"],"is_preprint":false},{"year":2002,"finding":"Lck tyrosine kinase is required for CD11a/CD18 surface expression and activation in T cells: Lck-deficient Jurkat cells (JCaM1.6) show dramatically reduced CD3- and phorbol ester-induced adhesion to ICAM-1 and lower CD11a/CD18 surface expression, with CD18 predominantly in an immature, unassociated form; retransfection of Lck restores adhesion.","method":"Lck-deficient Jurkat cell line (JCaM1.6), Src-kinase inhibitor PP2, flow cytometry, cell surface labeling, Lck retransfection rescue","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and genetic complementation with mechanistic readout of integrin maturation and activation","pmids":["12115650"],"is_preprint":false},{"year":1999,"finding":"Redox signaling via oxidative S-thiolation is required for CD11b/CD18 activation: H₂O₂ induces CD11b/CD18-dependent neutrophil adhesion and activation neoepitope expression; this is inhibited by tyrosine kinase inhibitors and sulfhydryl-complexing agents. Physiological agonists (TNF-alpha)-induced integrin activation is blocked by flavoprotein oxidoreductase inhibitor (DPI), free radical scavengers, tyrosine kinase inhibitors, and PAO, but not by integrin-activating KIM185 mAb.","method":"H₂O₂ treatment of neutrophils, activation neoepitope mAb (clone 24), tyrosine kinase inhibitors, PAO, DPI, free radical scavengers, chronic granulomatous disease patient neutrophils","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological inhibitors with activation neoepitope readout, single laboratory","pmids":["10556796"],"is_preprint":false},{"year":1996,"finding":"CD63 associates physically with CD11/CD18 on neutrophil surfaces and crosslinking of CD63 upregulates CD11/CD18 expression and increases neutrophil adhesion to endothelium via a CD18-dependent mechanism. CD63-associated protein kinase activity is predominantly tyrosine kinase activity (Lyn, Hck), linking CD63-CD18 complexes to intracellular signaling.","method":"Co-immunoprecipitation, flow cytometry for CD11/CD18 expression, neutrophil-HUVEC adhesion assays, mAb blocking, kinase activity assay, Src family kinase identification","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-immunoprecipitation and functional adhesion assays with mAb blocking, single laboratory","pmids":["8871662"],"is_preprint":false},{"year":1992,"finding":"CD18 expression is transcriptionally regulated during myeloid differentiation via a defined promoter: the CD18 promoter contains AP-1 elements mediating PMA transcriptional response and a PU.1 binding site; a CD18 promoter-luciferase construct increases expression after PMA in U937 cells, and nuclear run-on studies confirm transcriptional regulation during TPA-induced HL-60 monocytic differentiation.","method":"Promoter cloning, primer extension, RNase protection, DNA sequencing, luciferase reporter assay, nuclear run-on transcription","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct promoter functional analysis with reporter assay and nuclear run-on in relevant cell lines","pmids":["1350225"],"is_preprint":false},{"year":2005,"finding":"CD18 (LFA-1) is required for optimal development and function of CD4+CD25+ T regulatory cells: CD18-/- mice have reduced Treg numbers, defective thymic and peripheral Treg development, and LFA-1-deficient Tregs fail to suppress conventional T cells in vitro or prevent colitis in lymphopenic hosts following adoptive transfer.","method":"CD18-/- mouse (NOD background), Treg enumeration, in vitro suppression assays, T cell adoptive transfer colitis model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse with multiple defined phenotypic readouts including in vitro and in vivo functional assays","pmids":["16339524"],"is_preprint":false},{"year":2009,"finding":"Genetic deficiency of Itgb2 completely prevents autoimmune diabetes and insulitis in NOD/LtJ mice, and abolishes T-cell adhesion to islet microvascular endothelial cells under hydrodynamic flow conditions, demonstrating that CD18 (beta2 integrin) mediates diabetogenic T-cell adhesion to islet endothelium.","method":"Itgb2 gene-targeted NOD/LtJ mice, diabetes incidence monitoring, insulitis scoring, in vitro hydrodynamic flow T-cell adhesion assays, adoptive transfer studies","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO on disease-relevant background, multiple functional readouts including flow adhesion assays","pmids":["19223596"],"is_preprint":false},{"year":2017,"finding":"Cathepsin B cleaves CD18 from the leukocyte surface to regulate extravasation from angiogenic vessels: CtsB-deficient leukocytes accumulate more in angiogenic vessels, extravasate less, and retain higher CD18 surface expression. CD18-deficient leukocytes extravasate later but migrate faster once outside vessels, revealing that CD18-ECM interactions slow interstitial transmigration velocity.","method":"In vivo corneal angiogenesis/cytokine implant model, CtsB-/- and CD18-/- leukocyte tracking, CD18 surface expression measurement","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo imaging with two genetic KO models, single laboratory","pmids":["28904019"],"is_preprint":false},{"year":2019,"finding":"Crystal/SAXS structures of staphylococcal leukocidin GH (LukGH) in complex with the alpha-I domain of CD11b (CD11b-I domain of CD18 heterodimer) reveal two binding interfaces on LukG and LukH protomers; human CD11b-I induces LukGH oligomerization in solution (required for cytolytic pore formation), while murine CD11b-I binds weakly and does not support oligomerization, explaining species specificity.","method":"Crystal structure and SAXS of LukGH-CD11b-I complex, LukGH variant engineering, murine vs. human CD11b-I binding assays, oligomerization assays, cytolysis assays with murine neutrophils","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure and SAXS with functional validation by engineered variants and species-specific cytolysis assays","pmids":["31852826"],"is_preprint":false},{"year":2016,"finding":"Mac-1 (CD11b/CD18) plays a dominant role in macrophage fusion to form multinucleated giant cells: IL-4-induced fusion of Mac-1-deficient macrophages is strongly reduced in vitro, and fewer giant cells form in the inflamed peritoneum of Mac-1-/- mice compared to wild-type. Mac-1 deficiency reduces macrophage spreading but not adhesion or migration. Integrin αDβ2 (CD11d/CD18) also contributes to fusion, but less prominently. ICAM-1 deficiency does not alter fusion rate, suggesting a novel counter-receptor.","method":"Mac-1-/- and αDβ2-/- mice, IL-4-induced macrophage fusion assay, peritoneal inflammation model, spreading/adhesion/migration assays","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent KO mouse models, in vitro and in vivo fusion readouts, systematic functional dissection","pmids":["27315778"],"is_preprint":false},{"year":2018,"finding":"Integrin ITGAM-ITGB2 (Mac-1/CR3) is the phagocytic receptor that initiates LC3-associated phagocytosis (LAP) of Listeria monocytogenes in tissue macrophages: LAP is required for bacterial killing and anti-listerial immunity in vivo, whereas canonical autophagy is dispensable.","method":"In vivo mouse infection model, genetic identification of Mac-1 as LAP-initiating receptor, macrophage killing assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with receptor identification, single laboratory report","pmids":["29923444"],"is_preprint":false},{"year":2013,"finding":"LA1 (leukadherin-1), a small molecule CD11b/CD18 agonist, enhances CD11b/CD18:ICAM-1 binding primarily by increasing membrane tether formation rather than cytoskeleton-anchored bonds. In contrast, Mn²⁺ additionally promotes CSK-anchored bond formation, demonstrating two mechanistically distinct modes of CD11b/CD18 activation.","method":"Single-molecule force spectroscopy (AFM), K562 cells expressing CD11b/CD18, LFA-1-/- neutrophils, ICAM-1-coated AFM tips","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-molecule force spectroscopy with orthogonal genetic (LFA-1-/- neutrophils) and pharmacological controls","pmids":["24314082"],"is_preprint":false},{"year":2013,"finding":"CD11c alpha-chain phosphorylation at Ser-1158 is required for CD11c/CD18 (CR4) function: alanine substitution at this site impairs adherence and phagocytosis, establishing that alpha-chain phosphorylation is functionally critical for this beta2 integrin.","method":"Phosphorylation site mapping, site-directed mutagenesis (Ser1158Ala), adherence and phagocytosis functional assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis with functional readouts, identifies specific residue","pmids":["24129562"],"is_preprint":false},{"year":2020,"finding":"CD18 expression is dispensable for initial bacterial attachment but required for phagocytic internalization of Pseudomonas aeruginosa: CRISPR-generated CD18-deficient human monocytes and murine neutrophils fail to internalize both motile and nonmotile P. aeruginosa, while ectopic CR3 expression in CD18-negative CHO cells does not rescue initial binding. Surface N-linked glycans facilitate initial bacterial attachment; talin-1 and kindlin-3 promote CD18-dependent internalization.","method":"CRISPR/Cas9 CD18-deficient human monocytes and murine neutrophils, ectopic CR3 expression in CHO cells, phagocytosis assays with motile/nonmotile isogenic mutants, talin-1 and kindlin-3 manipulation","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO in two cell types plus ectopic expression rescue, mechanistic dissection of binding vs. internalization","pmids":["32041787"],"is_preprint":false},{"year":2016,"finding":"Folate receptor beta (FRβ) physically interacts with the CD11b/CD18 (Mac-1) beta2 integrin heterodimer in the plasma membrane of FRβ+ macrophages and impedes CD11b/CD18-mediated adhesion to collagen. This was identified by affinity purification and mass spectrometry of the FRβ membrane microenvironment.","method":"Affinity purification of FRβ membrane microenvironment, mass spectrometry, adhesion assays to collagen, FRβ-transduced THP-1 monocytic cells, primary FRβ+ macrophages","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interaction discovery validated with functional adhesion assays, single laboratory","pmids":["27534550"],"is_preprint":false},{"year":2023,"finding":"ITGAM and ITGB2 expressed on extracellular vesicles (EVs) from severe acute pancreatitis (SAP) mediate pulmonary accumulation and acute lung injury (ALI): EVs engineered to overexpress ITGAM and ITGB2 compete with SAP-EVs for pulmonary accumulation and attenuate pulmonary inflammation and endothelial barrier disruption in vivo.","method":"EV integrin overexpression engineering, integrin antagonist peptide (HYD-1) preincubation, in vivo SAP mouse model, pulmonary inflammation and endothelial barrier assays","journal":"ACS nano","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — engineered EV competition assays in vivo, single laboratory, indirect mechanistic evidence","pmids":["37022097"],"is_preprint":false},{"year":2023,"finding":"Alpha2-3-linked sialic acid on CD11b/CD18 regulates PMN transepithelial migration and integrin activation: inhibiting sialidase-mediated desialylation of CD11b/CD18 inhibits PMN migration across intestinal epithelium in vitro and in vivo, reduces degranulation and superoxide release, and blocks bacterial peptide-mediated CD11b/CD18 activation and downstream Syk/p38 MAPK signaling.","method":"Sialidase inhibitors, in vitro transepithelial migration assays, in vivo intestinal inflammation model, CD11b/CD18 activation assays, Syk and p38 MAPK signaling readouts","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological sialylation inhibition with in vitro and in vivo readouts, signaling pathway placement, single laboratory","pmids":["36719745"],"is_preprint":false},{"year":2021,"finding":"CD18 knockout in zebrafish (CRISPR/Cas9) causes key LAD-I symptoms: increased circulating neutrophils and reduced neutrophil trafficking to sterile inflammation sites. Sequence analysis shows conservation of the I-like domain and cytoplasmic NXXF motifs between zebrafish and human CD18, supporting functional orthology.","method":"CRISPR/Cas9 CD18 KO in zebrafish larvae, sequence alignment, intravital neutrophil trafficking assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in model organism with defined neutrophil trafficking phenotype, sequence conservation evidence","pmids":["34557186"],"is_preprint":false},{"year":2019,"finding":"LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) distinctly regulate neutrophil extravasation at two sequential hotspots: LFA-1 FRET (CD11a-YFP/CD18-CFP) mice and Mac-1 FRET (CD11b-YFP/CD18-CFP) mice show that LFA-1 and Mac-1 operate at different stages (hotspot I through endothelium, hotspot II through basement membrane/pericyte sheath), as visualized by two-photon intravital imaging.","method":"Two-photon intravital imaging, transmission electron microscopy, LFA-1 FRET and Mac-1 FRET knock-in mice","journal":"Experimental & molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — novel FRET knock-in mouse models with direct in vivo imaging, spatiotemporal resolution of individual integrin roles","pmids":["30967528"],"is_preprint":false}],"current_model":"ITGB2 (CD18) is the obligate common beta subunit of the leukocyte beta2 integrin heterodimers (LFA-1, Mac-1, CR3, CR4, CD11d/CD18); it undergoes stimulus-induced serine/tyrosine phosphorylation and conformational activation that regulates ligand-binding affinity (including ICAM-1, iC3b, fibrinogen, and novel ligands such as fucosylated proteoglycans and oligodeoxynucleotides), forms functional complexes with co-receptors such as uPAR and CD63, is shed from the cell surface by cathepsin B in a shear-dependent manner, and is required in vivo for neutrophil firm adhesion and transendothelial migration, T regulatory cell development and function, macrophage fusion, LC3-associated phagocytosis of bacteria, and prevention of myocardial and choroidal ischemia-reperfusion injury; loss-of-function mutations in ITGB2 cause leukocyte adhesion deficiency type I across multiple species."},"narrative":{"mechanistic_narrative":"ITGB2 (CD18) is the obligate common beta subunit of the leukocyte beta2 integrin heterodimers (LFA-1/CD11a, Mac-1/CD11b, CR4/CD11c, and CD11d), and it is the molecular core that licenses integrin surface assembly and adhesive function: reconstitution of functional integrin and adhesion in patient cells requires only restoration of CD18, establishing it as the genetic and functional defect in leukocyte adhesion deficiency type I [PMID:1972597]. As a heterodimer it engages ICAM-1 and additional ligands including endothelial counter-receptors, fibrinogen, fucosylated proteoglycans, and oligodeoxynucleotides, with contributions distributed across both the CD11 alpha and CD18 beta chains [PMID:1980124, PMID:2809204, PMID:9095175, PMID:12391246]. Its ligand-binding affinity is switched on by inside-out activation that produces a divalent-cation-dependent, signaling-sensitive conformational change in CD18 reported by activation neoepitopes and coupled to high-affinity ICAM-1 binding [PMID:11714770, PMID:24314082]; this activation is driven by stimulus-induced serine-predominant phosphorylation of CD18 and by upstream tyrosine-kinase and redox signaling (Lck, Src-family kinases, S-thiolation) [PMID:2574726, PMID:12115650, PMID:10556796]. CD18 forms functional surface units with co-receptors uPAR and CD63 and is modulated by folate receptor beta and by its own sialylation state, which tunes adhesion and downstream Syk/p38 signaling [PMID:8874219, PMID:8871662, PMID:27534550, PMID:36719745], while shear-dependent cathepsin B cleavage of the CD18 ectodomain governs surface retention and extravasation velocity [PMID:14595007, PMID:28904019]. In vivo, beta2 integrins are required for neutrophil firm adhesion and the spatially distinct steps of transendothelial and transbasement-membrane migration, T-regulatory cell development and suppressive function, macrophage fusion into giant cells, and LC3-associated phagocytosis and internalization of bacteria, and their loss is protective in myocardial and choroidal ischemia-reperfusion injury, autoimmune diabetes, and lung injury [PMID:8101543, PMID:9653089, PMID:16339524, PMID:27315778, PMID:29923444, PMID:32041787, PMID:30967528, PMID:9843832, PMID:12766082, PMID:19223596]. CD18 also serves as the receptor exploited by multiple bacterial toxins, including H. pylori VacA, A. actinomycetemcomitans leukotoxin, and staphylococcal leukocidin LukGH, with species specificity mapping to defined extracellular CD18/CD11b domains [PMID:18191791, PMID:17635865, PMID:31852826]. Loss-of-function mutations in ITGB2 cause leukocyte adhesion deficiency type I across humans, dogs, and zebrafish [PMID:1968911, PMID:10512685, PMID:34557186].","teleology":[{"year":1989,"claim":"Established that CD18, not the CD11 alpha subunits, is the regulated signaling target within the integrin complex, framing inside-out control as acting on the shared beta chain.","evidence":"32P metabolic labeling, immunoprecipitation, and phosphoamino acid analysis of PMA/FMLP-stimulated human leukocytes","pmids":["2574726"],"confidence":"High","gaps":["Did not identify the responsible kinase or the specific phosphoacceptor residues","Did not link phosphorylation to a conformational or affinity change"]},{"year":1989,"claim":"Resolved that LFA-1 and Mac-1 contribute roughly equally to neutrophil-endothelial adhesion but through distinct ligands, establishing functional division of labor among CD18 heterodimers.","evidence":"Individual-chain mAb blocking and anti-ICAM-1 competition in PMN-endothelial adhesion assays","pmids":["2809204"],"confidence":"High","gaps":["Did not identify the non-ICAM-1 Mac-1 endothelial ligand"]},{"year":1990,"claim":"Identified ICAM-1 as a counter-receptor for the CD11b/CD18 heterodimer, defining a molecular adhesion pair.","evidence":"Purified Mac-1 substrate binding and COS cell co-transfection of alpha and CD18 chains with reciprocal adhesion assays and mAb blocking","pmids":["1980124"],"confidence":"High","gaps":["Did not map the ICAM-1 binding site on the heterodimer"]},{"year":1990,"claim":"Demonstrated that CD18 is both necessary and sufficient for beta2 integrin surface assembly and adhesion, and that LAD-causing point mutations act by impairing CD18 surface expression.","evidence":"Patient allele sequencing with mutant CD18 expression in COS cells, plus retroviral CD18 transfer into LAD lymphocytes with functional rescue","pmids":["1968911","1972597"],"confidence":"High","gaps":["Did not resolve how individual residues affect folding versus alpha-chain pairing","Did not address in vivo correction"]},{"year":1992,"claim":"Defined transcriptional control of CD18 during myeloid differentiation, explaining how integrin availability is set developmentally.","evidence":"CD18 promoter reporter assays with AP-1 and PU.1 elements and nuclear run-on in differentiating myeloid lines","pmids":["1350225"],"confidence":"High","gaps":["Did not connect transcriptional regulation to functional integrin output in vivo"]},{"year":1996,"claim":"Showed CD18 heterodimers operate within multi-protein surface units, with uPAR and CD63 co-regulating Mac-1 ligand binding and linking it to Src-family tyrosine kinase signaling.","evidence":"CHO co-transfection of Mac-1 and uPAR with fibrinogen degradation assays, and co-IP of CD63 with CD11/CD18 plus kinase activity assays","pmids":["8874219","8871662"],"confidence":"Medium","gaps":["Co-IP and functional assays from single laboratories without structural definition of the interfaces","Stoichiometry and direct versus indirect association not established"]},{"year":1997,"claim":"Broadened the CD18 heterodimer ligand repertoire by showing Mac-1 binds oligodeoxynucleotides on both alpha and beta chains and mediates their internalization.","evidence":"ODN binding assays with fibrinogen competition, anti-Mac-1 mAb inhibition, and internalization quantification","pmids":["9095175"],"confidence":"Medium","gaps":["Single laboratory; binding site on CD18 not mapped","Physiological relevance of ODN binding not established"]},{"year":1998,"claim":"Established in vivo nonredundant roles for CD18 in neutrophil tissue migration, T cell activation, and PMN-driven myocardial reperfusion injury.","evidence":"CD18 null mice with intravital cremaster imaging, T cell proliferation assays, and myocardial ischemia-reperfusion infarct measurement","pmids":["9653089","9843832"],"confidence":"High","gaps":["Did not separate the contributions of individual heterodimers","Mechanism of T cell activation defect not resolved"]},{"year":1999,"claim":"Linked CD18 to systemic bacterial dissemination and placed integrin activation downstream of redox/tyrosine-kinase signaling.","evidence":"CD18-deficient mice with oral Salmonella organ burden assays, and H2O2/inhibitor pharmacology with activation neoepitope readouts in neutrophils","pmids":["10548107","10556796"],"confidence":"Medium","gaps":["Redox signaling work is single-laboratory pharmacology without molecular identification of S-thiolated targets","Phagocyte type mediating Salmonella transport not fully defined"]},{"year":2001,"claim":"Directly demonstrated that leukocyte activation drives a cation-dependent CD18 conformational change that correlates with high-affinity ICAM-1 binding, providing the structural basis of inside-out activation.","evidence":"Activation-epitope mAb panel on T cells and LAD-1 variant cells with ICAM-1 affinity correlation","pmids":["11714770"],"confidence":"High","gaps":["Did not resolve the atomic conformational rearrangement","Cytoplasmic signal triggering the change not defined"]},{"year":2002,"claim":"Identified Lck-dependent tyrosine kinase signaling and proteoglycan ligands as upstream and counter-receptor determinants of CD18 maturation and adhesion.","evidence":"Lck-deficient Jurkat cells with rescue for integrin maturation, and purified CD11b/CD18 binding to fucoidin and fucosidase-treated epithelium","pmids":["12115650","12391246"],"confidence":"High","gaps":["Lck mechanism on CD18 phosphorylation not directly demonstrated","Identity of the epithelial fucosylated proteoglycan ligand not defined"]},{"year":2003,"claim":"Showed CD18 surface levels are post-translationally regulated by shear-dependent cathepsin B ectodomain cleavage, and that CD18 is required for choroidal neovascularization.","evidence":"Confocal/flow analysis of sheared neutrophils with protease inhibitor panel, and CD18-/- laser CNV model","pmids":["14595007","12766082"],"confidence":"High","gaps":["Did not identify the cleavage site on CD18","Did not establish consequences of shed ectodomain"]},{"year":2005,"claim":"Extended CD18 function beyond innate adhesion to adaptive tolerance by showing LFA-1 is required for T regulatory cell development and suppression.","evidence":"CD18-/- NOD mice with Treg enumeration, in vitro suppression, and adoptive transfer colitis assays","pmids":["16339524"],"confidence":"High","gaps":["Mechanism by which LFA-1 supports Treg development not defined"]},{"year":2008,"claim":"Defined CD18 as a receptor hijacked by bacterial virulence factors, with species-specific extracellular domains mapping toxin susceptibility.","evidence":"LFA-1-deficient Jurkat complementation for VacA, and chimeric beta2-integrin domain mapping for LtxA cytotoxicity","pmids":["18191791","17635865"],"confidence":"High","gaps":["Did not resolve the structural toxin-binding interface on CD18","Did not link toxin entry to integrin signaling"]},{"year":2013,"claim":"Distinguished two mechanistically distinct modes of CD11b/CD18 activation and defined alpha-chain phosphorylation as functionally required for a beta2 integrin.","evidence":"Single-molecule force spectroscopy of LA1 versus Mn2+ activation, and Ser1158Ala mutagenesis of CD11c with phagocytosis assays","pmids":["24314082","24129562"],"confidence":"High","gaps":["Did not connect alpha-chain phosphorylation to CD18 conformational state","Physiological agonist driving each activation mode not defined"]},{"year":2016,"claim":"Identified CD18 heterodimers as drivers of macrophage fusion and revealed additional membrane partners modulating adhesion.","evidence":"Mac-1-/- and CD11d-/- mice in IL-4 fusion and peritoneal models, and MS identification of FRbeta-Mac-1 interaction with collagen adhesion assays","pmids":["27315778","27534550"],"confidence":"Medium","gaps":["Fusion counter-receptor not identified","FRbeta interaction is single-laboratory MS discovery without structural validation"]},{"year":2017,"claim":"Showed cathepsin B cleavage of CD18 governs the balance between vessel retention and interstitial migration speed during extravasation.","evidence":"In vivo corneal angiogenesis imaging of CtsB-/- and CD18-/- leukocytes with CD18 surface measurement","pmids":["28904019"],"confidence":"Medium","gaps":["Single laboratory; CD18 ECM ligands slowing migration not identified"]},{"year":2018,"claim":"Defined Mac-1 as the phagocytic receptor initiating LC3-associated phagocytosis and intracellular bacterial killing.","evidence":"In vivo Listeria infection with genetic Mac-1 identification and macrophage killing assays","pmids":["29923444"],"confidence":"Medium","gaps":["Single laboratory; signaling connecting Mac-1 to LAP machinery not defined"]},{"year":2019,"claim":"Resolved the spatial and structural division of labor among CD18 heterodimers and bacterial toxins, mapping LFA-1 and Mac-1 to sequential extravasation hotspots and the LukGH interface to CD11b-I.","evidence":"LFA-1/Mac-1 FRET knock-in mice with two-photon imaging, and crystal/SAXS structure of LukGH-CD11b-I with species-specific cytolysis assays","pmids":["30967528","31852826"],"confidence":"High","gaps":["Did not define the basement-membrane ligand for Mac-1 at hotspot II","Structural basis of physiological ligand binding to CD18 itself not resolved"]},{"year":2020,"claim":"Separated CD18's roles in bacterial attachment versus internalization and placed talin-1/kindlin-3 as the inside-out effectors of internalization.","evidence":"CRISPR CD18-deficient human monocytes and murine neutrophils, ectopic CR3 CHO expression, and phagocytosis assays with talin/kindlin manipulation","pmids":["32041787"],"confidence":"High","gaps":["Did not define how surface glycans cooperate with CD18 during binding"]},{"year":2023,"claim":"Showed CD18 glycosylation and EV-displayed integrin tune adhesion, migration, and tissue injury, extending CD18 regulation to post-translational glycan state and intercellular vesicle transfer.","evidence":"Sialidase inhibition with transepithelial migration and Syk/p38 readouts, and engineered ITGAM/ITGB2 EV competition in a severe pancreatitis lung injury model","pmids":["36719745","37022097"],"confidence":"Medium","gaps":["Single-laboratory reports; molecular link between sialylation and conformational activation not resolved","EV integrin mechanism is indirect competition evidence"]},{"year":null,"claim":"How upstream phosphorylation, redox modification, and glycan state are integrated to produce the specific CD18 conformational transition that confers high-affinity ligand binding, and the atomic structure of CD18 engaging its physiological ligands, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full beta2 heterodimer bound to a physiological ligand in the corpus","Causal chain from CD18 serine phosphorylation to affinity change not reconstituted"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,2,15]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[13,14,25]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[27,30]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[16,28]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[16,17,20,31]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[32]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,22,27,35]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[15,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,18,19,33]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,11,34]}],"complexes":["LFA-1 (CD11a/CD18)","Mac-1/CR3 (CD11b/CD18)","CR4 (CD11c/CD18)","CD11d/CD18"],"partners":["ITGAM","ITGAL","ITGAX","ICAM1","PLAUR","CD63","FOLR2","LCK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P05107","full_name":"Integrin beta-2","aliases":["Cell surface adhesion glycoproteins LFA-1/CR3/p150,95 subunit beta","Complement receptor C3 subunit beta"],"length_aa":769,"mass_kda":84.8,"function":"Integrin ITGAL:ITGB2 is a receptor for ICAM1, ICAM2 and ICAM3 (PubMed:1676048, PubMed:23775590, PubMed:38195629). Integrin ITGAL:ITGB2 is also a receptor for the secreted form of ubiquitin-like protein ISG15; the interaction is mediated by ITGAL (PubMed:29100055). Integrins ITGAM:ITGB2 and ITGAX:ITGB2 are receptors for the iC3b fragment of the third complement component and for fibrinogen. Integrin ITGAX:ITGB2 recognizes the sequence G-P-R in fibrinogen alpha-chain. Integrin ITGAM:ITGB2 recognizes P1 and P2 peptides of fibrinogen gamma chain. Integrin ITGAM:ITGB2 is also a receptor for factor X. Integrin ITGAD:ITGB2 is a receptor for ICAM3 and VCAM1 (PubMed:10438935, PubMed:8777714, PubMed:9841932). Contributes to natural killer cell cytotoxicity (PubMed:15356110). Involved in leukocyte adhesion and transmigration of leukocytes including T-cells and neutrophils (PubMed:11812992, PubMed:28807980). Triggers neutrophil transmigration during lung injury through PTK2B/PYK2-mediated activation (PubMed:18587400). Integrin ITGAL:ITGB2 in association with ICAM3, contributes to apoptotic neutrophil phagocytosis by macrophages (PubMed:23775590). In association with alpha subunit ITGAM/CD11b, required for CD177-PRTN3-mediated activation of TNF primed neutrophils (PubMed:21193407). Integrins ITGAX:ITGB2 functions as a receptor of the erythrocyte-specific adhesion molecule ICAM4 and mediates erythrophagocytosis (PubMed:16985175). Integrins ITGAX:ITGB2 functions as a receptor of the neuron-specific adhesion molecule ICAM5 ensuring neuron cell-leukocyte adhesion (PubMed:10741396). Integrin ITGAL:ITGB2 functions as a receptor of ICAM1 by acting as a platform at the immunological synapse to translate TCR engagement and density of the ITGAL ligand ICAM1 into graded adhesion (PubMed:38195629). Integrin ITGAM:ITGB2/MAC-1 complex functions as a signaling receptor for the ligand receptor ICAM1, ensuring adhesion between stimulated neutrophils and stimulated endothelial cells (PubMed:1980124). Integrin ITGAL/ITGB2 that functions as a signaling receptor of ICAM2, ensuring leukocyte cell-cell adhesion on resting cells (PubMed:1676048)","subcellular_location":"Cell membrane; Membrane raft","url":"https://www.uniprot.org/uniprotkb/P05107/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGB2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITGB2","total_profiled":1310},"omim":[{"mim_id":"620376","title":"AUTOINFLAMMATORY DISEASE, SYSTEMIC, WITH VASCULITIS; SAIDV","url":"https://www.omim.org/entry/620376"},{"mim_id":"617042","title":"GASDERMIN D; GSDMD","url":"https://www.omim.org/entry/617042"},{"mim_id":"616626","title":"CEREBRAL ENDOTHELIAL CELL ADHESION MOLECULE; CERCAM","url":"https://www.omim.org/entry/616626"},{"mim_id":"612840","title":"LEUKOCYTE ADHESION DEFICIENCY, TYPE III; LAD3","url":"https://www.omim.org/entry/612840"},{"mim_id":"607901","title":"FERM DOMAIN-CONTAINING KINDLIN 3; FERMT3","url":"https://www.omim.org/entry/607901"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Rods & Rings","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":343.1},{"tissue":"lymphoid tissue","ntpm":162.7}],"url":"https://www.proteinatlas.org/search/ITGB2"},"hgnc":{"alias_symbol":["LFA-1","MAC-1"],"prev_symbol":["CD18","MFI7"]},"alphafold":{"accession":"P05107","domains":[{"cath_id":"2.60.40.1510","chopping":"97-124_369-444","consensus_level":"high","plddt":90.6556,"start":97,"end":444},{"cath_id":"3.40.50.410","chopping":"128-366","consensus_level":"high","plddt":90.5655,"start":128,"end":366},{"cath_id":"4.10.1240","chopping":"622-695","consensus_level":"high","plddt":91.1197,"start":622,"end":695}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P05107","model_url":"https://alphafold.ebi.ac.uk/files/AF-P05107-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P05107-F1-predicted_aligned_error_v6.png","plddt_mean":85.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGB2","jax_strain_url":"https://www.jax.org/strain/search?query=ITGB2"},"sequence":{"accession":"P05107","fasta_url":"https://rest.uniprot.org/uniprotkb/P05107.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P05107/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P05107"}},"corpus_meta":[{"pmid":"1980124","id":"PMC_1980124","title":"ICAM-1 (CD54): a counter-receptor for Mac-1 (CD11b/CD18).","date":"1990","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1980124","citation_count":898,"is_preprint":false},{"pmid":"10548107","id":"PMC_10548107","title":"Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes.","date":"1999","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/10548107","citation_count":507,"is_preprint":false},{"pmid":"9653089","id":"PMC_9653089","title":"Spontaneous skin ulceration and defective T cell function in CD18 null mice.","date":"1998","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9653089","citation_count":264,"is_preprint":false},{"pmid":"8485905","id":"PMC_8485905","title":"CR3 (CD11b, CD18): a phagocyte and NK cell membrane receptor with multiple ligand specificities and functions.","date":"1993","source":"Clinical and experimental 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This binding is blocked by mAbs to both ICAM-1 and Mac-1, establishing ICAM-1 as a ligand for the CD11b/CD18 heterodimer.\",\n      \"method\": \"Purified protein binding assays, cDNA transfection of COS/L cells, reciprocal cell adhesion assays, mAb blocking\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted binding with purified proteins, reciprocal cell-based assays, multiple orthogonal methods, replicated across cell types\",\n      \"pmids\": [\"1980124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"CD18 undergoes stimulus-induced phosphorylation: in resting leukocytes CD18 phosphorylation is minimal, but PMA induces rapid, sustained, high-stoichiometry CD18 phosphorylation predominantly on serine residues (with minor phosphothreonine and phosphotyrosine), while FMLP induces transient CD18 phosphorylation. The CD11 alpha subunits show only minimal changes, indicating CD18 is the primary regulated phosphorylation target in the complex.\",\n      \"method\": \"Metabolic radiolabeling with 32P, immunoprecipitation, phosphoamino acid analysis, PMA/FMLP stimulation of human leukocytes\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical phosphoamino acid analysis with multiple stimuli and controls, replicated across monocyte cell types\",\n      \"pmids\": [\"2574726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1) each contribute approximately equally (~50% each) to PMN adhesion to unstimulated endothelial cells, but through different ligands: CD11a/CD18 binds ICAM-1, while CD11b/CD18 binds a distinct, non-ICAM-1 ligand on endothelial cells. CD11c/CD18 does not participate in this adhesion.\",\n      \"method\": \"mAb blocking of individual CD11 chains, anti-ICAM-1 antibody competition, ICAM-1-coated surface down-modulation assays, PMN-endothelial cell adhesion assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal blocking experiments with purified ICAM-1 surfaces and individual-chain mAbs, consistent results across assays\",\n      \"pmids\": [\"2809204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Two point mutations in the CD18 coding sequence (Arg593→Cys and Lys196→Thr) each impair CD18 cell-surface expression when introduced into transfected COS cells, identifying conserved residues in the cysteine-rich repeats and another conserved integrin region as critical for normal CD18 surface expression.\",\n      \"method\": \"cDNA cloning and sequencing of patient alleles, transfection of mutant CD18 into COS M6 cells, surface expression analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct mutagenesis-equivalent (natural mutations) validated by heterologous expression in transfected cells, two independent alleles tested\",\n      \"pmids\": [\"1968911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Retrovirus-mediated transduction of a functional CD18 gene into LAD patient lymphocytes restores surface expression of CD11a/CD18 (LFA-1) and reconstitutes LFA-1-dependent adhesive function, demonstrating that CD18 is the functional defect in LAD and is sufficient for integrin surface assembly.\",\n      \"method\": \"Retrovirus-mediated gene transfer, molecular analysis of proviral integration and CD18 mRNA, flow cytometry for surface CD11a/CD18, functional LFA-1 adhesion assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — gene complementation with functional rescue, multiple orthogonal readouts (molecular, protein, functional)\",\n      \"pmids\": [\"1972597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CD18 gene targeting in mice produces a hypomorphic allele (2–16% of normal CD18 expression); homozygous mutant mice show mild granulocytosis and impaired inflammatory responses (reduced peritonitis and delayed cardiac allograft rejection), demonstrating that CD18 is required for normal leukocyte integrin-dependent adhesion in vivo.\",\n      \"method\": \"Gene targeting (insertional mutation), flow cytometry for CD18 expression, chemical peritonitis model, cardiac transplant rejection model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gene-targeted KO mouse with specific in vivo inflammatory phenotypic readouts\",\n      \"pmids\": [\"8101543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD18 null mice develop chronic dermatitis, elevated neutrophil counts, and markedly defective T cell proliferation in response to TCR stimulation, demonstrating that CD11/CD18 integrins are required for normal neutrophil tissue migration and T cell activation in vivo.\",\n      \"method\": \"CD18 null mouse (gene-targeted), intravital microscopy of cremaster muscle, T cell proliferation assays (staphylococcal enterotoxin A, MHC alloantigens)\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complete null KO mouse with multiple defined phenotypic readouts and direct intravital imaging of neutrophil behavior\",\n      \"pmids\": [\"9653089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Mac-1 (CD11b/CD18) and the urokinase receptor (uPAR/CD87) form a functional unit on monocytic cells: uPAR engagement by urokinase inhibits Mac-1-mediated fibrinogen binding and degradation (up to 91% inhibition) and Factor X binding, while vitronectin-mediated uPAR attachment enhances subsequent Mac-1 fibrinogen degradation 3–4-fold. This co-regulation was reproduced in CHO cells co-transfected with human Mac-1 and uPAR.\",\n      \"method\": \"Co-expression in CHO cells (transfection), fibrinogen binding and degradation assays, Factor X binding assays, monocytic cell lines, fresh monocytes\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reconstituted in transfected CHO cells, confirmed in primary monocytes and cell lines, multiple functional readouts\",\n      \"pmids\": [\"8874219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Mac-1 (CD11b/CD18) is an oligodeoxynucleotide-binding protein: binding of thymidine homopolymer occurs on both the CD11b alpha subunit and the CD18 beta subunit; soluble fibrinogen competes for this binding; anti-Mac-1 mAbs inhibit binding; increased surface Mac-1 expression correlates with increased ODN internalization by PMNs.\",\n      \"method\": \"Binding assays with phosphodiester and phosphorothioate ODNs, competition with fibrinogen, anti-Mac-1 mAb inhibition, upregulation by TNF-alpha, internalization quantification\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assays on purified protein and intact cells with mAb blocking, single laboratory\",\n      \"pmids\": [\"9095175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD18-expressing phagocytes transport Salmonella from the gastrointestinal tract to the bloodstream: CD18-deficient mice are resistant to extraintestinal dissemination of SPI1-deficient S. typhimurium to liver and spleen after oral administration, establishing a CD18-dependent pathway for systemic bacterial dissemination.\",\n      \"method\": \"CD18-deficient mouse model, oral Salmonella challenge, organ bacterial burden quantification\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse with defined in vivo phenotype, replicated with SPI1-deficient bacteria\",\n      \"pmids\": [\"10548107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD18 deficiency significantly reduces myocardial infarct size and PMN infiltration after ischemia-reperfusion: CD18-/- mice show ~57% reduction in infarct area and 54% reduction in PMN infiltration compared to wild-type, demonstrating that CD18-mediated neutrophil-endothelial adhesion is required for PMN-driven myocardial reperfusion injury.\",\n      \"method\": \"CD18-/- and ICAM-1-/- mouse models, surgical myocardial ischemia-reperfusion, infarct size measurement, PMN infiltration histology\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse with quantified in vivo phenotype, replicated with ICAM-1 KO as parallel control\",\n      \"pmids\": [\"9843832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A missense mutation (Cys36Ser) in canine ITGB2 disrupts a conserved cysteine (likely a disulfide bond) and causes canine leukocyte adhesion deficiency (CLAD): mutant CD18 fails to support CD11/CD18 surface expression, confirmed by retroviral transduction of mutant vs. normal canine CD18 into human LAD EBV B-cells.\",\n      \"method\": \"Sequence analysis, retroviral vector transduction of LAD B-cells, flow cytometry for CD11/CD18 surface expression\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct mutagenesis-equivalent (natural mutation) validated by heterologous expression with functional rescue comparison\",\n      \"pmids\": [\"10512685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD18 deficiency (gene knockout) inhibits choroidal neovascularization (CNV): CD18-/- mice show significantly fewer CNV lesions with fluorescein leakage and significantly smaller CNV volumes after laser photocoagulation compared to wild-type, demonstrating a nonredundant role for CD18-mediated leukocyte adhesion in CNV development.\",\n      \"method\": \"CD18-/- mouse laser photocoagulation CNV model, confocal volumetric CNV measurement, fluorescein angiography\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse with quantitative CNV phenotype, replicated with ICAM-1 KO as parallel control\",\n      \"pmids\": [\"12766082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The CD18 (beta2 integrin) subunit is the T-lymphocyte receptor for Helicobacter pylori vacuolating cytotoxin VacA: VacA enters activated T lymphocytes by binding CD18 and exploiting LFA-1 recycling. LFA-1-deficient Jurkat cells are resistant to VacA-induced vacuolation and IL-2 modulation; genetic complementation with LFA-1 or Mac-1 (containing human CD18) restores sensitivity. VacA targets human but not murine CD18.\",\n      \"method\": \"LFA-1-deficient Jurkat T cells, genetic complementation with human CD18-containing integrins, vacuolation assays, IL-2 secretion assays, species-specificity analysis\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and complementation with specific mechanistic phenotypic readouts, species-specificity validation\",\n      \"pmids\": [\"18191791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human CD18 is the functional receptor for Aggregatibacter actinomycetemcomitans leukotoxin (LtxA): chimeric beta2-integrins expressed in LtxA-resistant cells confer susceptibility, and the cysteine-rich tandem repeats encompassing integrin-EGF-like domains 2, 3, and 4 of the CD18 extracellular region are critical for species-specific LtxA-induced cytotoxicity.\",\n      \"method\": \"Chimeric beta2-integrin expression in resistant cell lines, domain-deletion analysis, cytotoxicity assays\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chimeric receptor domain mapping in heterologous cells with functional readout, identifies specific CD18 domains\",\n      \"pmids\": [\"17635865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD11b/CD18-dependent PMN interactions with intestinal epithelium are mediated by fucosylated proteoglycans: fucoidin directly binds CD11b/CD18 in a divalent cation- and sulfation-dependent manner blocked by anti-CD11b mAbs; fucosidase treatment of T84 epithelial cells reduces adhesion to purified CD11b/CD18; proteoglycan synthesis inhibition blocks T84 adhesion to CD11b/CD18.\",\n      \"method\": \"Purified CD11b/CD18 adhesion assays, fucoidin direct binding, anti-CD11b mAb blocking, fucosidase and neuraminidase treatment, proteoglycan synthesis inhibition, ligand blotting\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biochemical methods with purified receptor and enzymatic ligand modification\",\n      \"pmids\": [\"12391246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD18 undergoes conformational change upon leukocyte activation: mAbs recognizing activation-induced neoepitopes on CD18 reveal a subpopulation of LFA-1 with altered conformation that correlates with cell adhesion, requires divalent cations, is sensitive to cellular signaling, is absent in LAD-1 variant cells defective in LFA-1 activation, and co-occurs with high-affinity ICAM-1 binding. Function-blocking CD18 mAbs suppress this conformational change.\",\n      \"method\": \"Novel activation-epitope mAb panel, flow cytometry on T lymphocytes and LAD-1 variant cell lines, correlation with ICAM-1 binding affinity, recombinant LFA-1\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal antibody probes, disease-control validation with LAD-1 variant cells, correlation with high-affinity ligand binding state\",\n      \"pmids\": [\"11714770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Fluid shear stress causes cleavage of the extracellular domain of CD18 from neutrophil surfaces via cysteine protease (cathepsin B) activity: shear (5 dyn/cm²) cleaves the extracellular but not cytoplasmic CD18 domain, is abolished by extracellular Ca²⁺ chelation and cathepsin B inhibitors (but not cathepsin L, calpain, elastase, or metalloprotease inhibitors), and results in CD18 redistribution rather than cytoplasmic internalization.\",\n      \"method\": \"Confocal microscopy of single adherent neutrophils, flow cytometry, protease inhibitor panel, Ca²⁺ chelation, domain-specific antibody epitope mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal inhibitor experiments with specific protease pharmacology, domain-specific antibody validation\",\n      \"pmids\": [\"14595007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Lck tyrosine kinase is required for CD11a/CD18 surface expression and activation in T cells: Lck-deficient Jurkat cells (JCaM1.6) show dramatically reduced CD3- and phorbol ester-induced adhesion to ICAM-1 and lower CD11a/CD18 surface expression, with CD18 predominantly in an immature, unassociated form; retransfection of Lck restores adhesion.\",\n      \"method\": \"Lck-deficient Jurkat cell line (JCaM1.6), Src-kinase inhibitor PP2, flow cytometry, cell surface labeling, Lck retransfection rescue\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and genetic complementation with mechanistic readout of integrin maturation and activation\",\n      \"pmids\": [\"12115650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Redox signaling via oxidative S-thiolation is required for CD11b/CD18 activation: H₂O₂ induces CD11b/CD18-dependent neutrophil adhesion and activation neoepitope expression; this is inhibited by tyrosine kinase inhibitors and sulfhydryl-complexing agents. Physiological agonists (TNF-alpha)-induced integrin activation is blocked by flavoprotein oxidoreductase inhibitor (DPI), free radical scavengers, tyrosine kinase inhibitors, and PAO, but not by integrin-activating KIM185 mAb.\",\n      \"method\": \"H₂O₂ treatment of neutrophils, activation neoepitope mAb (clone 24), tyrosine kinase inhibitors, PAO, DPI, free radical scavengers, chronic granulomatous disease patient neutrophils\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological inhibitors with activation neoepitope readout, single laboratory\",\n      \"pmids\": [\"10556796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD63 associates physically with CD11/CD18 on neutrophil surfaces and crosslinking of CD63 upregulates CD11/CD18 expression and increases neutrophil adhesion to endothelium via a CD18-dependent mechanism. CD63-associated protein kinase activity is predominantly tyrosine kinase activity (Lyn, Hck), linking CD63-CD18 complexes to intracellular signaling.\",\n      \"method\": \"Co-immunoprecipitation, flow cytometry for CD11/CD18 expression, neutrophil-HUVEC adhesion assays, mAb blocking, kinase activity assay, Src family kinase identification\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-immunoprecipitation and functional adhesion assays with mAb blocking, single laboratory\",\n      \"pmids\": [\"8871662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CD18 expression is transcriptionally regulated during myeloid differentiation via a defined promoter: the CD18 promoter contains AP-1 elements mediating PMA transcriptional response and a PU.1 binding site; a CD18 promoter-luciferase construct increases expression after PMA in U937 cells, and nuclear run-on studies confirm transcriptional regulation during TPA-induced HL-60 monocytic differentiation.\",\n      \"method\": \"Promoter cloning, primer extension, RNase protection, DNA sequencing, luciferase reporter assay, nuclear run-on transcription\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct promoter functional analysis with reporter assay and nuclear run-on in relevant cell lines\",\n      \"pmids\": [\"1350225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD18 (LFA-1) is required for optimal development and function of CD4+CD25+ T regulatory cells: CD18-/- mice have reduced Treg numbers, defective thymic and peripheral Treg development, and LFA-1-deficient Tregs fail to suppress conventional T cells in vitro or prevent colitis in lymphopenic hosts following adoptive transfer.\",\n      \"method\": \"CD18-/- mouse (NOD background), Treg enumeration, in vitro suppression assays, T cell adoptive transfer colitis model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse with multiple defined phenotypic readouts including in vitro and in vivo functional assays\",\n      \"pmids\": [\"16339524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Genetic deficiency of Itgb2 completely prevents autoimmune diabetes and insulitis in NOD/LtJ mice, and abolishes T-cell adhesion to islet microvascular endothelial cells under hydrodynamic flow conditions, demonstrating that CD18 (beta2 integrin) mediates diabetogenic T-cell adhesion to islet endothelium.\",\n      \"method\": \"Itgb2 gene-targeted NOD/LtJ mice, diabetes incidence monitoring, insulitis scoring, in vitro hydrodynamic flow T-cell adhesion assays, adoptive transfer studies\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO on disease-relevant background, multiple functional readouts including flow adhesion assays\",\n      \"pmids\": [\"19223596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cathepsin B cleaves CD18 from the leukocyte surface to regulate extravasation from angiogenic vessels: CtsB-deficient leukocytes accumulate more in angiogenic vessels, extravasate less, and retain higher CD18 surface expression. CD18-deficient leukocytes extravasate later but migrate faster once outside vessels, revealing that CD18-ECM interactions slow interstitial transmigration velocity.\",\n      \"method\": \"In vivo corneal angiogenesis/cytokine implant model, CtsB-/- and CD18-/- leukocyte tracking, CD18 surface expression measurement\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo imaging with two genetic KO models, single laboratory\",\n      \"pmids\": [\"28904019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal/SAXS structures of staphylococcal leukocidin GH (LukGH) in complex with the alpha-I domain of CD11b (CD11b-I domain of CD18 heterodimer) reveal two binding interfaces on LukG and LukH protomers; human CD11b-I induces LukGH oligomerization in solution (required for cytolytic pore formation), while murine CD11b-I binds weakly and does not support oligomerization, explaining species specificity.\",\n      \"method\": \"Crystal structure and SAXS of LukGH-CD11b-I complex, LukGH variant engineering, murine vs. human CD11b-I binding assays, oligomerization assays, cytolysis assays with murine neutrophils\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure and SAXS with functional validation by engineered variants and species-specific cytolysis assays\",\n      \"pmids\": [\"31852826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mac-1 (CD11b/CD18) plays a dominant role in macrophage fusion to form multinucleated giant cells: IL-4-induced fusion of Mac-1-deficient macrophages is strongly reduced in vitro, and fewer giant cells form in the inflamed peritoneum of Mac-1-/- mice compared to wild-type. Mac-1 deficiency reduces macrophage spreading but not adhesion or migration. Integrin αDβ2 (CD11d/CD18) also contributes to fusion, but less prominently. ICAM-1 deficiency does not alter fusion rate, suggesting a novel counter-receptor.\",\n      \"method\": \"Mac-1-/- and αDβ2-/- mice, IL-4-induced macrophage fusion assay, peritoneal inflammation model, spreading/adhesion/migration assays\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent KO mouse models, in vitro and in vivo fusion readouts, systematic functional dissection\",\n      \"pmids\": [\"27315778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Integrin ITGAM-ITGB2 (Mac-1/CR3) is the phagocytic receptor that initiates LC3-associated phagocytosis (LAP) of Listeria monocytogenes in tissue macrophages: LAP is required for bacterial killing and anti-listerial immunity in vivo, whereas canonical autophagy is dispensable.\",\n      \"method\": \"In vivo mouse infection model, genetic identification of Mac-1 as LAP-initiating receptor, macrophage killing assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with receptor identification, single laboratory report\",\n      \"pmids\": [\"29923444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LA1 (leukadherin-1), a small molecule CD11b/CD18 agonist, enhances CD11b/CD18:ICAM-1 binding primarily by increasing membrane tether formation rather than cytoskeleton-anchored bonds. In contrast, Mn²⁺ additionally promotes CSK-anchored bond formation, demonstrating two mechanistically distinct modes of CD11b/CD18 activation.\",\n      \"method\": \"Single-molecule force spectroscopy (AFM), K562 cells expressing CD11b/CD18, LFA-1-/- neutrophils, ICAM-1-coated AFM tips\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule force spectroscopy with orthogonal genetic (LFA-1-/- neutrophils) and pharmacological controls\",\n      \"pmids\": [\"24314082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD11c alpha-chain phosphorylation at Ser-1158 is required for CD11c/CD18 (CR4) function: alanine substitution at this site impairs adherence and phagocytosis, establishing that alpha-chain phosphorylation is functionally critical for this beta2 integrin.\",\n      \"method\": \"Phosphorylation site mapping, site-directed mutagenesis (Ser1158Ala), adherence and phagocytosis functional assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis with functional readouts, identifies specific residue\",\n      \"pmids\": [\"24129562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD18 expression is dispensable for initial bacterial attachment but required for phagocytic internalization of Pseudomonas aeruginosa: CRISPR-generated CD18-deficient human monocytes and murine neutrophils fail to internalize both motile and nonmotile P. aeruginosa, while ectopic CR3 expression in CD18-negative CHO cells does not rescue initial binding. Surface N-linked glycans facilitate initial bacterial attachment; talin-1 and kindlin-3 promote CD18-dependent internalization.\",\n      \"method\": \"CRISPR/Cas9 CD18-deficient human monocytes and murine neutrophils, ectopic CR3 expression in CHO cells, phagocytosis assays with motile/nonmotile isogenic mutants, talin-1 and kindlin-3 manipulation\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO in two cell types plus ectopic expression rescue, mechanistic dissection of binding vs. internalization\",\n      \"pmids\": [\"32041787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Folate receptor beta (FRβ) physically interacts with the CD11b/CD18 (Mac-1) beta2 integrin heterodimer in the plasma membrane of FRβ+ macrophages and impedes CD11b/CD18-mediated adhesion to collagen. This was identified by affinity purification and mass spectrometry of the FRβ membrane microenvironment.\",\n      \"method\": \"Affinity purification of FRβ membrane microenvironment, mass spectrometry, adhesion assays to collagen, FRβ-transduced THP-1 monocytic cells, primary FRβ+ macrophages\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interaction discovery validated with functional adhesion assays, single laboratory\",\n      \"pmids\": [\"27534550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ITGAM and ITGB2 expressed on extracellular vesicles (EVs) from severe acute pancreatitis (SAP) mediate pulmonary accumulation and acute lung injury (ALI): EVs engineered to overexpress ITGAM and ITGB2 compete with SAP-EVs for pulmonary accumulation and attenuate pulmonary inflammation and endothelial barrier disruption in vivo.\",\n      \"method\": \"EV integrin overexpression engineering, integrin antagonist peptide (HYD-1) preincubation, in vivo SAP mouse model, pulmonary inflammation and endothelial barrier assays\",\n      \"journal\": \"ACS nano\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered EV competition assays in vivo, single laboratory, indirect mechanistic evidence\",\n      \"pmids\": [\"37022097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Alpha2-3-linked sialic acid on CD11b/CD18 regulates PMN transepithelial migration and integrin activation: inhibiting sialidase-mediated desialylation of CD11b/CD18 inhibits PMN migration across intestinal epithelium in vitro and in vivo, reduces degranulation and superoxide release, and blocks bacterial peptide-mediated CD11b/CD18 activation and downstream Syk/p38 MAPK signaling.\",\n      \"method\": \"Sialidase inhibitors, in vitro transepithelial migration assays, in vivo intestinal inflammation model, CD11b/CD18 activation assays, Syk and p38 MAPK signaling readouts\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological sialylation inhibition with in vitro and in vivo readouts, signaling pathway placement, single laboratory\",\n      \"pmids\": [\"36719745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD18 knockout in zebrafish (CRISPR/Cas9) causes key LAD-I symptoms: increased circulating neutrophils and reduced neutrophil trafficking to sterile inflammation sites. Sequence analysis shows conservation of the I-like domain and cytoplasmic NXXF motifs between zebrafish and human CD18, supporting functional orthology.\",\n      \"method\": \"CRISPR/Cas9 CD18 KO in zebrafish larvae, sequence alignment, intravital neutrophil trafficking assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in model organism with defined neutrophil trafficking phenotype, sequence conservation evidence\",\n      \"pmids\": [\"34557186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) distinctly regulate neutrophil extravasation at two sequential hotspots: LFA-1 FRET (CD11a-YFP/CD18-CFP) mice and Mac-1 FRET (CD11b-YFP/CD18-CFP) mice show that LFA-1 and Mac-1 operate at different stages (hotspot I through endothelium, hotspot II through basement membrane/pericyte sheath), as visualized by two-photon intravital imaging.\",\n      \"method\": \"Two-photon intravital imaging, transmission electron microscopy, LFA-1 FRET and Mac-1 FRET knock-in mice\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — novel FRET knock-in mouse models with direct in vivo imaging, spatiotemporal resolution of individual integrin roles\",\n      \"pmids\": [\"30967528\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGB2 (CD18) is the obligate common beta subunit of the leukocyte beta2 integrin heterodimers (LFA-1, Mac-1, CR3, CR4, CD11d/CD18); it undergoes stimulus-induced serine/tyrosine phosphorylation and conformational activation that regulates ligand-binding affinity (including ICAM-1, iC3b, fibrinogen, and novel ligands such as fucosylated proteoglycans and oligodeoxynucleotides), forms functional complexes with co-receptors such as uPAR and CD63, is shed from the cell surface by cathepsin B in a shear-dependent manner, and is required in vivo for neutrophil firm adhesion and transendothelial migration, T regulatory cell development and function, macrophage fusion, LC3-associated phagocytosis of bacteria, and prevention of myocardial and choroidal ischemia-reperfusion injury; loss-of-function mutations in ITGB2 cause leukocyte adhesion deficiency type I across multiple species.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGB2 (CD18) is the obligate common beta subunit of the leukocyte beta2 integrin heterodimers (LFA-1/CD11a, Mac-1/CD11b, CR4/CD11c, and CD11d), and it is the molecular core that licenses integrin surface assembly and adhesive function: reconstitution of functional integrin and adhesion in patient cells requires only restoration of CD18, establishing it as the genetic and functional defect in leukocyte adhesion deficiency type I [#4]. As a heterodimer it engages ICAM-1 and additional ligands including endothelial counter-receptors, fibrinogen, fucosylated proteoglycans, and oligodeoxynucleotides, with contributions distributed across both the CD11 alpha and CD18 beta chains [#0, #2, #8, #15]. Its ligand-binding affinity is switched on by inside-out activation that produces a divalent-cation-dependent, signaling-sensitive conformational change in CD18 reported by activation neoepitopes and coupled to high-affinity ICAM-1 binding [#16, #28]; this activation is driven by stimulus-induced serine-predominant phosphorylation of CD18 and by upstream tyrosine-kinase and redox signaling (Lck, Src-family kinases, S-thiolation) [#1, #18, #19]. CD18 forms functional surface units with co-receptors uPAR and CD63 and is modulated by folate receptor beta and by its own sialylation state, which tunes adhesion and downstream Syk/p38 signaling [#7, #20, #31, #33], while shear-dependent cathepsin B cleavage of the CD18 ectodomain governs surface retention and extravasation velocity [#17, #24]. In vivo, beta2 integrins are required for neutrophil firm adhesion and the spatially distinct steps of transendothelial and transbasement-membrane migration, T-regulatory cell development and suppressive function, macrophage fusion into giant cells, and LC3-associated phagocytosis and internalization of bacteria, and their loss is protective in myocardial and choroidal ischemia-reperfusion injury, autoimmune diabetes, and lung injury [#5, #6, #22, #26, #27, #30, #35, #10, #12, #23]. CD18 also serves as the receptor exploited by multiple bacterial toxins, including H. pylori VacA, A. actinomycetemcomitans leukotoxin, and staphylococcal leukocidin LukGH, with species specificity mapping to defined extracellular CD18/CD11b domains [#13, #14, #25]. Loss-of-function mutations in ITGB2 cause leukocyte adhesion deficiency type I across humans, dogs, and zebrafish [#3, #11, #34].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Established that CD18, not the CD11 alpha subunits, is the regulated signaling target within the integrin complex, framing inside-out control as acting on the shared beta chain.\",\n      \"evidence\": \"32P metabolic labeling, immunoprecipitation, and phosphoamino acid analysis of PMA/FMLP-stimulated human leukocytes\",\n      \"pmids\": [\"2574726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the responsible kinase or the specific phosphoacceptor residues\", \"Did not link phosphorylation to a conformational or affinity change\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Resolved that LFA-1 and Mac-1 contribute roughly equally to neutrophil-endothelial adhesion but through distinct ligands, establishing functional division of labor among CD18 heterodimers.\",\n      \"evidence\": \"Individual-chain mAb blocking and anti-ICAM-1 competition in PMN-endothelial adhesion assays\",\n      \"pmids\": [\"2809204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the non-ICAM-1 Mac-1 endothelial ligand\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Identified ICAM-1 as a counter-receptor for the CD11b/CD18 heterodimer, defining a molecular adhesion pair.\",\n      \"evidence\": \"Purified Mac-1 substrate binding and COS cell co-transfection of alpha and CD18 chains with reciprocal adhesion assays and mAb blocking\",\n      \"pmids\": [\"1980124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the ICAM-1 binding site on the heterodimer\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Demonstrated that CD18 is both necessary and sufficient for beta2 integrin surface assembly and adhesion, and that LAD-causing point mutations act by impairing CD18 surface expression.\",\n      \"evidence\": \"Patient allele sequencing with mutant CD18 expression in COS cells, plus retroviral CD18 transfer into LAD lymphocytes with functional rescue\",\n      \"pmids\": [\"1968911\", \"1972597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how individual residues affect folding versus alpha-chain pairing\", \"Did not address in vivo correction\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Defined transcriptional control of CD18 during myeloid differentiation, explaining how integrin availability is set developmentally.\",\n      \"evidence\": \"CD18 promoter reporter assays with AP-1 and PU.1 elements and nuclear run-on in differentiating myeloid lines\",\n      \"pmids\": [\"1350225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect transcriptional regulation to functional integrin output in vivo\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Showed CD18 heterodimers operate within multi-protein surface units, with uPAR and CD63 co-regulating Mac-1 ligand binding and linking it to Src-family tyrosine kinase signaling.\",\n      \"evidence\": \"CHO co-transfection of Mac-1 and uPAR with fibrinogen degradation assays, and co-IP of CD63 with CD11/CD18 plus kinase activity assays\",\n      \"pmids\": [\"8874219\", \"8871662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP and functional assays from single laboratories without structural definition of the interfaces\", \"Stoichiometry and direct versus indirect association not established\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Broadened the CD18 heterodimer ligand repertoire by showing Mac-1 binds oligodeoxynucleotides on both alpha and beta chains and mediates their internalization.\",\n      \"evidence\": \"ODN binding assays with fibrinogen competition, anti-Mac-1 mAb inhibition, and internalization quantification\",\n      \"pmids\": [\"9095175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory; binding site on CD18 not mapped\", \"Physiological relevance of ODN binding not established\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Established in vivo nonredundant roles for CD18 in neutrophil tissue migration, T cell activation, and PMN-driven myocardial reperfusion injury.\",\n      \"evidence\": \"CD18 null mice with intravital cremaster imaging, T cell proliferation assays, and myocardial ischemia-reperfusion infarct measurement\",\n      \"pmids\": [\"9653089\", \"9843832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate the contributions of individual heterodimers\", \"Mechanism of T cell activation defect not resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Linked CD18 to systemic bacterial dissemination and placed integrin activation downstream of redox/tyrosine-kinase signaling.\",\n      \"evidence\": \"CD18-deficient mice with oral Salmonella organ burden assays, and H2O2/inhibitor pharmacology with activation neoepitope readouts in neutrophils\",\n      \"pmids\": [\"10548107\", \"10556796\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redox signaling work is single-laboratory pharmacology without molecular identification of S-thiolated targets\", \"Phagocyte type mediating Salmonella transport not fully defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Directly demonstrated that leukocyte activation drives a cation-dependent CD18 conformational change that correlates with high-affinity ICAM-1 binding, providing the structural basis of inside-out activation.\",\n      \"evidence\": \"Activation-epitope mAb panel on T cells and LAD-1 variant cells with ICAM-1 affinity correlation\",\n      \"pmids\": [\"11714770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the atomic conformational rearrangement\", \"Cytoplasmic signal triggering the change not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified Lck-dependent tyrosine kinase signaling and proteoglycan ligands as upstream and counter-receptor determinants of CD18 maturation and adhesion.\",\n      \"evidence\": \"Lck-deficient Jurkat cells with rescue for integrin maturation, and purified CD11b/CD18 binding to fucoidin and fucosidase-treated epithelium\",\n      \"pmids\": [\"12115650\", \"12391246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lck mechanism on CD18 phosphorylation not directly demonstrated\", \"Identity of the epithelial fucosylated proteoglycan ligand not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed CD18 surface levels are post-translationally regulated by shear-dependent cathepsin B ectodomain cleavage, and that CD18 is required for choroidal neovascularization.\",\n      \"evidence\": \"Confocal/flow analysis of sheared neutrophils with protease inhibitor panel, and CD18-/- laser CNV model\",\n      \"pmids\": [\"14595007\", \"12766082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the cleavage site on CD18\", \"Did not establish consequences of shed ectodomain\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended CD18 function beyond innate adhesion to adaptive tolerance by showing LFA-1 is required for T regulatory cell development and suppression.\",\n      \"evidence\": \"CD18-/- NOD mice with Treg enumeration, in vitro suppression, and adoptive transfer colitis assays\",\n      \"pmids\": [\"16339524\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which LFA-1 supports Treg development not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined CD18 as a receptor hijacked by bacterial virulence factors, with species-specific extracellular domains mapping toxin susceptibility.\",\n      \"evidence\": \"LFA-1-deficient Jurkat complementation for VacA, and chimeric beta2-integrin domain mapping for LtxA cytotoxicity\",\n      \"pmids\": [\"18191791\", \"17635865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural toxin-binding interface on CD18\", \"Did not link toxin entry to integrin signaling\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Distinguished two mechanistically distinct modes of CD11b/CD18 activation and defined alpha-chain phosphorylation as functionally required for a beta2 integrin.\",\n      \"evidence\": \"Single-molecule force spectroscopy of LA1 versus Mn2+ activation, and Ser1158Ala mutagenesis of CD11c with phagocytosis assays\",\n      \"pmids\": [\"24314082\", \"24129562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect alpha-chain phosphorylation to CD18 conformational state\", \"Physiological agonist driving each activation mode not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified CD18 heterodimers as drivers of macrophage fusion and revealed additional membrane partners modulating adhesion.\",\n      \"evidence\": \"Mac-1-/- and CD11d-/- mice in IL-4 fusion and peritoneal models, and MS identification of FRbeta-Mac-1 interaction with collagen adhesion assays\",\n      \"pmids\": [\"27315778\", \"27534550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Fusion counter-receptor not identified\", \"FRbeta interaction is single-laboratory MS discovery without structural validation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed cathepsin B cleavage of CD18 governs the balance between vessel retention and interstitial migration speed during extravasation.\",\n      \"evidence\": \"In vivo corneal angiogenesis imaging of CtsB-/- and CD18-/- leukocytes with CD18 surface measurement\",\n      \"pmids\": [\"28904019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory; CD18 ECM ligands slowing migration not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined Mac-1 as the phagocytic receptor initiating LC3-associated phagocytosis and intracellular bacterial killing.\",\n      \"evidence\": \"In vivo Listeria infection with genetic Mac-1 identification and macrophage killing assays\",\n      \"pmids\": [\"29923444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory; signaling connecting Mac-1 to LAP machinery not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the spatial and structural division of labor among CD18 heterodimers and bacterial toxins, mapping LFA-1 and Mac-1 to sequential extravasation hotspots and the LukGH interface to CD11b-I.\",\n      \"evidence\": \"LFA-1/Mac-1 FRET knock-in mice with two-photon imaging, and crystal/SAXS structure of LukGH-CD11b-I with species-specific cytolysis assays\",\n      \"pmids\": [\"30967528\", \"31852826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the basement-membrane ligand for Mac-1 at hotspot II\", \"Structural basis of physiological ligand binding to CD18 itself not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Separated CD18's roles in bacterial attachment versus internalization and placed talin-1/kindlin-3 as the inside-out effectors of internalization.\",\n      \"evidence\": \"CRISPR CD18-deficient human monocytes and murine neutrophils, ectopic CR3 CHO expression, and phagocytosis assays with talin/kindlin manipulation\",\n      \"pmids\": [\"32041787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how surface glycans cooperate with CD18 during binding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed CD18 glycosylation and EV-displayed integrin tune adhesion, migration, and tissue injury, extending CD18 regulation to post-translational glycan state and intercellular vesicle transfer.\",\n      \"evidence\": \"Sialidase inhibition with transepithelial migration and Syk/p38 readouts, and engineered ITGAM/ITGB2 EV competition in a severe pancreatitis lung injury model\",\n      \"pmids\": [\"36719745\", \"37022097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-laboratory reports; molecular link between sialylation and conformational activation not resolved\", \"EV integrin mechanism is indirect competition evidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How upstream phosphorylation, redox modification, and glycan state are integrated to produce the specific CD18 conformational transition that confers high-affinity ligand binding, and the atomic structure of CD18 engaging its physiological ligands, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of full beta2 heterodimer bound to a physiological ligand in the corpus\", \"Causal chain from CD18 serine phosphorylation to affinity change not reconstituted\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 2, 15]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [13, 14, 25]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [27, 30]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [16, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [16, 17, 20, 31]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 22, 27, 35]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [15, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 18, 19, 33]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 11, 34]}\n    ],\n    \"complexes\": [\n      \"LFA-1 (CD11a/CD18)\",\n      \"Mac-1/CR3 (CD11b/CD18)\",\n      \"CR4 (CD11c/CD18)\",\n      \"CD11d/CD18\"\n    ],\n    \"partners\": [\n      \"ITGAM\",\n      \"ITGAL\",\n      \"ITGAX\",\n      \"ICAM1\",\n      \"PLAUR\",\n      \"CD63\",\n      \"FOLR2\",\n      \"LCK\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}