{"gene":"ITGAD","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2000,"finding":"CD11d gene transcription is activated by transcription factors Sp1 and Sp3 binding to the -63 to -40 region of the promoter; deletion of this Sp-binding site significantly reduced CD11d promoter activity, and overexpression of Sp1 or Sp3 activated the promoter even in the presence of phorbol ester, while antisense knockdown of either factor decreased CD11d promoter activity.","method":"DNase I footprint analysis, EMSA, transfection of reporter constructs, antisense oligonucleotides, in vivo genomic footprinting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (footprinting, EMSA, reporter assay, antisense KD, in vivo genomic footprinting) in a single rigorous study","pmids":["10722744"],"is_preprint":false},{"year":2004,"finding":"TIEG1 (TGF-β-inducible early gene-1) binds the -61 to -45 region of the CD11d promoter, competing with Sp1 and Sp3, and confers myeloid-specific activation of CD11d expression; TIEG1 occupancy of the promoter increases upon myeloid differentiation, and siRNA knockdown of TIEG1 reduces CD11d expression.","method":"Yeast one-hybrid screen, GST pulldown/EMSA, transfection overexpression/siRNA, chromatin immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — yeast one-hybrid, in vitro binding, ChIP, and siRNA in the same study with multiple orthogonal methods","pmids":["15087465"],"is_preprint":false},{"year":2004,"finding":"GKLFa (a longer isoform of gut-enriched Krüppel-like factor 4) binds the -61 to -44 region of the CD11d promoter (overlapping Sp1 and TIEG1 sites) and represses CD11d expression in myeloid cells; GKLFa physically associates with HDAC1 and HDAC2, which are bound to the CD11d promoter and released upon phorbol ester stimulation, indicating HDAC-mediated repression.","method":"Yeast one-hybrid screen, GST pulldown, transfection, siRNA, chromatin immunoprecipitation, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (yeast one-hybrid, in vitro binding, ChIP, siRNA, co-IP) in a single rigorous study","pmids":["15561714"],"is_preprint":false},{"year":2004,"finding":"CD11d deficiency in mice results in altered T cell phenotype (reduced CD3 and CD28 expression, decreased CD4/CD8 ratio, reduced CD4+ thymocytes) and reduced T cell proliferative response to staphylococcal enterotoxins; the defect resides in T cells rather than APCs. CD11b and CD11d were co-expressed on a subset of early fetal thymocytes, and transient thymocyte expression of both is nonredundantly required for normal thymocyte and T cell development.","method":"Knockout mouse analysis, mixing experiments, flow cytometry, superantigen stimulation assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cellular phenotype, mixing experiments to locate defect, flow cytometry; single lab","pmids":["15210787"],"is_preprint":false},{"year":2008,"finding":"Integrin αDβ2 (CD11d/CD18) modulates macrophage migration in a density-dependent manner: low surface density of αDβ2 cooperates with β1/β3 integrins to support cell migration, whereas high surface density (induced by PMA upregulation or forced overexpression) increases cell adhesiveness and inhibits migration; anti-αD blocking antibody restores β1/β3-driven migration and increases inflammatory macrophage numbers recovered from inflamed peritoneum in vivo.","method":"Recombinant HEK293 cell lines expressing different densities of αDβ2, IC-21 macrophage migration assays, anti-αD antibody blockade, in vivo peritoneal inflammation model","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell systems (recombinant + natural), in vitro migration assays corroborated by in vivo model, mechanistic conclusion replicated across systems","pmids":["18621369"],"is_preprint":false},{"year":2009,"finding":"CD11d surface expression requires heterodimerization with CD18: CD11d-YFP is retained intracellularly in the trans-Golgi network (TGN) of heterologous cells lacking CD18, but co-expression of CD18-mRFP relieves this retention and allows surface expression of the CD11d/CD18 heterodimer. Domain-swapping experiments identified the extracellular domain of CD11d as required and sufficient for intracellular retention in heterologous cells, while the transmembrane and C-terminus are required for proper heterodimerization and plasma membrane localization.","method":"Fluorescent protein fusions (YFP/mRFP), flow cytometry, confocal microscopy, domain-swapping experiments with CD25","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-cell imaging, flow cytometry, and domain-swap mutagenesis in the same study; mechanistic conclusion well-supported by multiple orthogonal approaches","pmids":["19571252"],"is_preprint":false},{"year":2011,"finding":"CD11d/CD18 on macrophages promotes macrophage retention at vascular inflammatory sites: CD11d-deficient macrophages show improved three-dimensional migration in fibrin matrix and faster resolution of peritoneal inflammation; adoptive transfer experiments showed similar recruitment of CD11d-/- monocytes from circulation but reduced accumulation in atherosclerotic aortas compared to wild-type, demonstrating CD11d arrests macrophages at lesion sites rather than affecting initial recruitment.","method":"CD11d-/-/ApoE-/- double-knockout mouse atherosclerosis model, adoptive transfer of fluorescently labeled monocytes, 3D fibrin matrix migration assay, peritoneal inflammation model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO atherosclerosis model, adoptive transfer experiments, in vitro migration assay; multiple orthogonal approaches in one study","pmids":["28500072"],"is_preprint":false},{"year":2016,"finding":"Integrin αDβ2 (CD11d/CD18) participates in macrophage fusion leading to multinucleated giant cell (MGC) formation during peritoneal inflammation: αDβ2-deficient macrophages showed significantly reduced IL-4-induced fusion compared to wild-type, though to a lesser extent than Mac-1 (CD11b/CD18). Deficiency of ICAM-1 (a counter-receptor for both Mac-1 and αDβ2) did not alter fusion rate, suggesting αDβ2 uses a different, unidentified counter-receptor for fusion.","method":"αDβ2-knockout mouse peritoneal macrophage IL-4-induced fusion assay, in vivo peritoneal inflammation model, adhesion/spreading/migration assays","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse macrophage functional assay, both in vitro and in vivo; single lab","pmids":["27315778"],"is_preprint":false},{"year":2014,"finding":"αDβ2 (CD11d/CD18) delivers outside-in signals in human monocytes: engagement of αDβ2 induces cell spreading and upregulates mRNAs encoding inflammatory chemokines and cytokines, leading to secretion of their protein products.","method":"Freshly isolated human monocytes, outside-in signaling assays, gene expression screening with validation, ELISA for cytokine/chemokine secretion","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional signaling experiments with primary human monocytes, gene expression + protein secretion validation; single lab","pmids":["25415295"],"is_preprint":false},{"year":2011,"finding":"CD11d/CD18 on neutrophils mediates co-stimulation of IFN-γ production by NK cells through interaction with ICAM-3 on neutrophils; ICAM-3/CD11d-CD18 cross-talk was identified as the molecular mechanism of neutrophil-NK cell interaction.","method":"Blocking antibody experiments with primary human neutrophils and NK cells, cytokine measurement","journal":"Haematologica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, antibody blocking approach; interaction inferred rather than directly reconstituted","pmids":["21712539"],"is_preprint":false},{"year":2016,"finding":"Integrin αDβ2 (CD11d/CD18) mediates leukocyte accumulation and alveolar-capillary barrier disruption in malaria-associated ARDS: αDβ2-deficient (αD-/-) mice infected with Plasmodium berghei showed reduced alveolar inflammation, reduced vascular and interstitial monocyte/macrophage accumulation, improved alveolar-capillary barrier function, and decreased key pro-inflammatory cytokines in lung tissue.","method":"αD-/- knockout mouse model, P. berghei infection, Evans blue dye vascular permeability assay, ELISA, immunohistochemistry, bronchoalveolar lavage analysis, respiratory function measurement","journal":"Malaria journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with multiple biochemical and functional readouts; single lab","pmids":["27473068"],"is_preprint":false},{"year":2018,"finding":"αDβ2 (CD11d/CD18) deficiency impairs leukocyte accumulation in response to Salmonella Typhimurium peritoneal infection, impairs pathogen clearance in vivo, reduces bacterial elimination by cultured peritoneal macrophages, and enhances pyroptosis in infected animals.","method":"αD-/- knockout mouse infection model, peritoneal macrophage bacterial killing assay, cytokine measurement, pyroptosis markers","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with in vivo infection and in vitro macrophage killing assays; single lab","pmids":["29881383"],"is_preprint":false},{"year":2021,"finding":"Integrin αDβ2 on neutrophils (not only macrophages) mediates a defense mechanism during sepsis/endotoxemia: αD-knockout mice show dramatically increased mortality in CLP sepsis and LPS endotoxemia, associated with reduced monocyte-derived macrophages and increased neutrophils in lungs. αD-deficient neutrophils demonstrate increased necrosis/pyroptosis; injection of WT neutrophils (not WT monocytes alone) into αD-/- mice markedly increased macrophage migration to lungs and dramatically improved survival, revealing a neutrophil-dependent pathway for αDβ2-mediated macrophage lung accumulation and efferocytosis.","method":"αD-/- KO mouse CLP sepsis and LPS endotoxemia models, adoptive transfer of fluorescently labeled WT and αD-/- monocytes and neutrophils, lung histology, survival analysis","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo models, adoptive transfer rescue experiments with WT neutrophils, mechanistic dissection of neutrophil-macrophage interplay; multiple orthogonal approaches","pmids":["33438263"],"is_preprint":false},{"year":2022,"finding":"LINC02190 lncRNA binds to the ITGAD (CD11d) mRNA promoter (specifically the 150-250 bp region) and suppresses ITGAD expression; overexpression of LINC02190 reduces ITGAD expression and decreases adhesion of Ishikawa and JAR cells, while LINC02190 knockdown increases ITGAD expression and cell adhesion rate.","method":"Endometrial tissue lncRNA/mRNA profiling, reporter assay for LINC02190 cis-element mapping, overexpression/knockdown of LINC02190 in Ishikawa cells, immunofluorescence, adhesion assay","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — promoter reporter assay, gain-of-function/loss-of-function, adhesion assay; single lab but multiple approaches","pmids":["35038314"],"is_preprint":false},{"year":2007,"finding":"CD11d deficiency does NOT protect against experimental autoimmune encephalomyelitis (EAE): CD11d-/- and wild-type C57BL/6 mice showed identical clinical course and histopathology, with no differences in leukocyte subset infiltration into the CNS or T cell cytokine production.","method":"CD11d-/- KO mouse EAE model (MOG35-55 peptide immunization), clinical scoring, histopathology, flow cytometry, cytokine measurement","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse disease model with histopathological and immunological readouts; single lab; negative result mechanistically informative","pmids":["17254640"],"is_preprint":false},{"year":2024,"finding":"A humanized anti-CD11d-2 antibody binds both active and inactive CD11d/CD18 conformations on human monocytes and neutrophils without inducing inflammatory cell signaling. CD11d/CD18 surface expression analysis revealed a mismatch between total and surface-level CD11d and CD18 expression not altered by CK2 inhibition.","method":"Flow cytometry on primary human leukocytes and THP-1 cells, western blotting, biochemical signaling assays, rat SCI model","journal":"Antibody therapeutics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily antibody characterization, limited mechanistic depth on conformational binding","pmids":["39839909"],"is_preprint":false}],"current_model":"ITGAD (CD11d) encodes the αD subunit of the leukocyte β2 integrin αDβ2 (CD11d/CD18), which heterodimerizes with CD18 in the trans-Golgi network (requiring its extracellular domain for proper trafficking) and is expressed predominantly on myeloid cells (monocytes, macrophages, neutrophils) as well as NK cells, B cells, and γδ T cells; transcription is activated by Sp1/Sp3 and TIEG1 binding the core promoter and repressed by GKLFa recruiting HDAC1/2; at low surface density αDβ2 cooperates with β1/β3 integrins to support cell migration, whereas its upregulation at inflammatory sites markedly increases adhesiveness, arrests macrophages (promoting chronic inflammation and atherosclerosis), supports macrophage fusion into multinucleated giant cells, and enables outside-in signaling that drives inflammatory chemokine/cytokine production; on neutrophils, αDβ2 mediates a neutrophil-dependent pathway for macrophage lung recruitment and efferocytosis that is protective in sepsis/endotoxemia."},"narrative":{"mechanistic_narrative":"ITGAD (CD11d) encodes the αD subunit of the leukocyte β2 integrin αDβ2 (CD11d/CD18), an adhesion receptor that tunes myeloid cell positioning and inflammatory output at sites of tissue injury and infection [PMID:18621369, PMID:28500072]. Surface display of CD11d requires obligate heterodimerization with CD18: the CD11d extracellular domain otherwise drives intracellular retention in the trans-Golgi network, while co-expression of CD18 relieves retention and permits plasma-membrane localization [PMID:19571252]. Functionally, αDβ2 acts in a surface-density-dependent manner—at low density it cooperates with β1/β3 integrins to support migration, whereas high density increases adhesiveness and arrests macrophages, promoting their retention at vascular lesions and atherosclerotic plaques rather than altering initial recruitment [PMID:18621369, PMID:28500072]. αDβ2 also supports IL-4-induced macrophage fusion into multinucleated giant cells [PMID:27315778] and delivers outside-in signals in human monocytes that drive cell spreading and secretion of inflammatory chemokines and cytokines [PMID:25415295]. In vivo, αDβ2 governs leukocyte accumulation across diverse inflammatory and infectious settings—mediating barrier disruption in malaria-associated lung injury [PMID:27473068] and pathogen clearance in Salmonella infection [PMID:29881383]—and on neutrophils it directs a protective, neutrophil-dependent pathway for macrophage lung recruitment and efferocytosis during sepsis and endotoxemia [PMID:33438263]. Transcription of CD11d is set by competition at a shared promoter element: Sp1/Sp3 and the myeloid factor TIEG1 activate, while the KLF4 isoform GKLFa recruits HDAC1/2 to repress expression [PMID:10722744, PMID:15087465, PMID:15561714].","teleology":[{"year":2000,"claim":"Established the basal transcriptional control of CD11d by identifying the core promoter element required for its activity.","evidence":"DNase I footprinting, EMSA, reporter transfection, antisense knockdown and in vivo genomic footprinting of the CD11d promoter","pmids":["10722744"],"confidence":"High","gaps":["Did not address myeloid-specific or inducible regulation","Did not connect promoter activity to cell-type expression patterns"]},{"year":2004,"claim":"Resolved how CD11d transcription is set by competing factors at one promoter element—TIEG1 confers myeloid-specific activation while GKLFa recruits HDACs to repress.","evidence":"Yeast one-hybrid, GST pulldown/EMSA, ChIP, co-IP and siRNA targeting the -61/-44 CD11d promoter region","pmids":["15087465","15561714"],"confidence":"High","gaps":["Upstream signals controlling the activator/repressor switch not fully defined","Did not establish how differentiation triggers HDAC release"]},{"year":2004,"claim":"Tested whether CD11d has a developmental role beyond inflammation, showing a non-redundant T-cell-intrinsic requirement in thymocyte development.","evidence":"CD11d knockout mouse analysis with mixing experiments, flow cytometry and superantigen stimulation","pmids":["15210787"],"confidence":"Medium","gaps":["Molecular ligand/mechanism in thymocytes not identified","Single lab, not independently replicated"]},{"year":2009,"claim":"Defined the biosynthetic requirement for surface expression, showing CD18 heterodimerization rescues TGN retention driven by the CD11d extracellular domain.","evidence":"YFP/mRFP fusions, confocal microscopy, flow cytometry and CD25 domain-swap mutagenesis in heterologous cells","pmids":["19571252"],"confidence":"High","gaps":["Retention machinery in the TGN not identified","Conducted in heterologous cells rather than native myeloid cells"]},{"year":2008,"claim":"Reconciled migration versus adhesion by showing αDβ2 function is surface-density-dependent.","evidence":"Recombinant HEK293 lines at graded αDβ2 density, macrophage migration assays, anti-αD blockade and an in vivo peritoneal inflammation model","pmids":["18621369"],"confidence":"High","gaps":["Counter-receptors driving the adhesion-dominant state not fully defined","Signaling effectors linking density to motility not mapped"]},{"year":2011,"claim":"Distinguished recruitment from retention, demonstrating αDβ2 arrests macrophages at atherosclerotic lesions rather than affecting their initial entry.","evidence":"CD11d-/-/ApoE-/- atherosclerosis model, adoptive transfer of labeled monocytes, 3D fibrin migration and peritoneal inflammation assays","pmids":["28500072"],"confidence":"High","gaps":["Lesion ligand mediating arrest not identified","Relative contribution versus other β2 integrins in vivo unresolved"]},{"year":2011,"claim":"Probed a non-macrophage role, implicating neutrophil CD11d/CD18–ICAM-3 cross-talk in co-stimulating NK-cell IFN-γ production.","evidence":"Blocking-antibody experiments with primary human neutrophils and NK cells plus cytokine measurement","pmids":["21712539"],"confidence":"Low","gaps":["Interaction inferred from antibody blockade, not directly reconstituted","No reciprocal or genetic validation of the ICAM-3 partnership"]},{"year":2014,"claim":"Showed αDβ2 is not merely adhesive but signaling-competent, driving inflammatory gene expression via outside-in signals.","evidence":"Outside-in engagement of αDβ2 on primary human monocytes with gene expression screening and ELISA validation","pmids":["25415295"],"confidence":"Medium","gaps":["Downstream signaling intermediates not delineated","Single lab"]},{"year":2016,"claim":"Extended αDβ2 function to macrophage multinucleation and to lung pathology, establishing roles in giant-cell formation and malaria-associated ARDS.","evidence":"αDβ2-knockout IL-4 macrophage fusion assays and a P. berghei lung-injury model with permeability, cytokine and histology readouts","pmids":["27315778","27473068"],"confidence":"Medium","gaps":["Counter-receptor for fusion remains unidentified (ICAM-1-independent)","Single labs for each model"]},{"year":2018,"claim":"Demonstrated a protective host-defense role, with αDβ2 required for leukocyte accumulation and pathogen clearance in Salmonella infection.","evidence":"αD-/- mouse peritoneal infection model, macrophage bacterial-killing assay and pyroptosis readouts","pmids":["29881383"],"confidence":"Medium","gaps":["Mechanism linking αDβ2 to bacterial killing not defined","Single lab"]},{"year":2021,"claim":"Revealed a neutrophil-dependent axis, showing αDβ2 on neutrophils drives macrophage lung accumulation and efferocytosis that is protective in sepsis.","evidence":"αD-/- CLP and LPS endotoxemia models with adoptive-transfer rescue using WT neutrophils versus monocytes and survival analysis","pmids":["33438263"],"confidence":"High","gaps":["Molecular signal by which neutrophils recruit macrophages unresolved","Ligand/counter-receptor for neutrophil αDβ2 not identified"]},{"year":2022,"claim":"Added a post-transcriptional layer of regulation, with the lncRNA LINC02190 suppressing ITGAD expression and cell adhesion.","evidence":"Reporter cis-element mapping plus LINC02190 overexpression/knockdown with adhesion assays in Ishikawa/JAR cells","pmids":["35038314"],"confidence":"Medium","gaps":["Mechanism of LINC02190 action at the ITGAD locus not detailed","Relevance to myeloid αDβ2 biology untested"]},{"year":2024,"claim":"Characterized a conformation-independent anti-CD11d antibody and noted a total-versus-surface CD11d/CD18 expression mismatch unaltered by CK2 inhibition.","evidence":"Flow cytometry/western blot on primary human leukocytes and THP-1 cells with biochemical signaling assays and a rat SCI model","pmids":["39839909"],"confidence":"Low","gaps":["Mechanism of surface-expression mismatch not resolved","Limited mechanistic depth; primarily antibody characterization"]},{"year":null,"claim":"The physiological counter-receptors and downstream signaling effectors that distinguish αDβ2-mediated arrest, fusion, and protective recruitment remain unidentified.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined ligand for macrophage arrest at lesions or for fusion","Outside-in signaling intermediates unmapped","Mechanism of neutrophil-to-macrophage relay in sepsis unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[4,6,13]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,12,11]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[4,6,7]}],"complexes":["αDβ2 integrin (CD11d/CD18)"],"partners":["ITGB2","ICAM3","SP1","SP3","TIEG1","KLF4","HDAC1","HDAC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13349","full_name":"Integrin alpha-D","aliases":["ADB2","CD11 antigen-like family member D","Leukointegrin alpha D"],"length_aa":1161,"mass_kda":126.8,"function":"Integrin alpha-D/beta-2 is a receptor for ICAM3 and VCAM1 (PubMed:10438935, PubMed:8777714, PubMed:9841932). May play a role in the atherosclerotic process such as clearing lipoproteins from plaques and in phagocytosis of blood-borne pathogens, particulate matter, and senescent erythrocytes from the blood (Probable)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q13349/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGAD","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITGAD","total_profiled":1310},"omim":[{"mim_id":"602453","title":"INTEGRIN, ALPHA-D; ITGAD","url":"https://www.omim.org/entry/602453"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":19.4}],"url":"https://www.proteinatlas.org/search/ITGAD"},"hgnc":{"alias_symbol":["CD11d","ADB2"],"prev_symbol":[]},"alphafold":{"accession":"Q13349","domains":[{"cath_id":"2.130.10.130","chopping":"21-140_349-615","consensus_level":"medium","plddt":91.0534,"start":21,"end":615},{"cath_id":"3.40.50.410","chopping":"150-162_183-325","consensus_level":"high","plddt":92.7664,"start":150,"end":325},{"cath_id":"2.60.40.1460","chopping":"618-763","consensus_level":"high","plddt":83.8435,"start":618,"end":763},{"cath_id":"2.60.40.1510","chopping":"779-919","consensus_level":"high","plddt":84.1485,"start":779,"end":919},{"cath_id":"2.60.40.1530","chopping":"924-1095","consensus_level":"high","plddt":87.1245,"start":924,"end":1095}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13349","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13349-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13349-F1-predicted_aligned_error_v6.png","plddt_mean":85.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGAD","jax_strain_url":"https://www.jax.org/strain/search?query=ITGAD"},"sequence":{"accession":"Q13349","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13349.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13349/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13349"}},"corpus_meta":[{"pmid":"15102919","id":"PMC_15102919","title":"Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function.","date":"2004","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15102919","citation_count":271,"is_preprint":false},{"pmid":"16966440","id":"PMC_16966440","title":"Canine hemophagocytic histiocytic sarcoma: a proliferative disorder of CD11d+ macrophages.","date":"2006","source":"Veterinary pathology","url":"https://pubmed.ncbi.nlm.nih.gov/16966440","citation_count":112,"is_preprint":false},{"pmid":"15465595","id":"PMC_15465595","title":"A monoclonal antibody to CD11d reduces the inflammatory infiltrate into the injured spinal cord: a potential neuroprotective treatment.","date":"2004","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/15465595","citation_count":103,"is_preprint":false},{"pmid":"22676851","id":"PMC_22676851","title":"A CD11d monoclonal antibody treatment reduces tissue injury and improves neurological outcome after fluid percussion brain injury in rats.","date":"2012","source":"Journal of neurotrauma","url":"https://pubmed.ncbi.nlm.nih.gov/22676851","citation_count":71,"is_preprint":false},{"pmid":"15992367","id":"PMC_15992367","title":"Anti-CD11d antibody treatment reduces free radical formation and cell death in the injured spinal cord of rats.","date":"2005","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15992367","citation_count":69,"is_preprint":false},{"pmid":"15210787","id":"PMC_15210787","title":"Deficiency of CD11b or CD11d results in reduced staphylococcal enterotoxin-induced T cell response and T cell phenotypic changes.","date":"2004","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15210787","citation_count":68,"is_preprint":false},{"pmid":"15659600","id":"PMC_15659600","title":"Anti-CD11d integrin antibody treatment restores normal serotonergic projections to the dorsal, intermediate, and ventral horns of the injured spinal cord.","date":"2005","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15659600","citation_count":68,"is_preprint":false},{"pmid":"28500072","id":"PMC_28500072","title":"The Upregulation of Integrin αDβ2 (CD11d/CD18) on Inflammatory Macrophages Promotes Macrophage Retention in Vascular Lesions and Development of Atherosclerosis.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/28500072","citation_count":63,"is_preprint":false},{"pmid":"15312174","id":"PMC_15312174","title":"An anti-CD11d integrin antibody reduces cyclooxygenase-2 expression and protein and DNA oxidation after spinal cord injury in rats.","date":"2004","source":"Journal of 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Essential role of Sp1 and Sp3.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10722744","citation_count":38,"is_preprint":false},{"pmid":"25415295","id":"PMC_25415295","title":"Integrin αDβ2 (CD11d/CD18) is expressed by human circulating and tissue myeloid leukocytes and mediates inflammatory signaling.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25415295","citation_count":36,"is_preprint":false},{"pmid":"15561714","id":"PMC_15561714","title":"The leukocyte integrin gene CD11d is repressed by gut-enriched Kruppel-like factor 4 in myeloid cells.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15561714","citation_count":33,"is_preprint":false},{"pmid":"15087465","id":"PMC_15087465","title":"The zinc finger transcription factor transforming growth factor beta-inducible early gene-1 confers myeloid-specific activation of the leukocyte integrin CD11d promoter.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15087465","citation_count":33,"is_preprint":false},{"pmid":"21508205","id":"PMC_21508205","title":"Inflammatory phenotyping identifies CD11d as a gene markedly induced in white adipose tissue in obese rodents and women.","date":"2011","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/21508205","citation_count":32,"is_preprint":false},{"pmid":"34858434","id":"PMC_34858434","title":"β2 Integrin CD11d/CD18: From Expression to an Emerging Role in Staged Leukocyte Migration.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34858434","citation_count":28,"is_preprint":false},{"pmid":"15890340","id":"PMC_15890340","title":"Comparison of effects of methylprednisolone and anti-CD11d antibody treatments on autonomic dysreflexia after spinal cord injury.","date":"2005","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15890340","citation_count":25,"is_preprint":false},{"pmid":"12429998","id":"PMC_12429998","title":"Expression of the myeloid-specific leukocyte integrin gene CD11d during macrophage foam cell differentiation and exposure to lipoproteins.","date":"2002","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12429998","citation_count":20,"is_preprint":false},{"pmid":"27473068","id":"PMC_27473068","title":"Integrin αDβ2 (CD11d/CD18) mediates experimental malaria-associated acute respiratory distress syndrome (MA-ARDS).","date":"2016","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/27473068","citation_count":19,"is_preprint":false},{"pmid":"21712539","id":"PMC_21712539","title":"On the potential involvement of CD11d in co-stimulating the production of interferon-γ by natural killer cells upon interaction with neutrophils via intercellular adhesion molecule-3.","date":"2011","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/21712539","citation_count":16,"is_preprint":false},{"pmid":"27881604","id":"PMC_27881604","title":"CD11d β2 integrin expression on human NK, B, and γδ T cells.","date":"2016","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/27881604","citation_count":13,"is_preprint":false},{"pmid":"33438263","id":"PMC_33438263","title":"Frontline Science: The expression of integrin αD β2 (CD11d/CD18) on neutrophils orchestrates the defense mechanism against endotoxemia and sepsis.","date":"2021","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/33438263","citation_count":13,"is_preprint":false},{"pmid":"29881383","id":"PMC_29881383","title":"Integrin αDβ2 (CD11d/CD18) Modulates Leukocyte Accumulation, Pathogen Clearance, and Pyroptosis in Experimental Salmonella Typhimurium Infection.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29881383","citation_count":11,"is_preprint":false},{"pmid":"35038314","id":"PMC_35038314","title":"LINC02190 inhibits the embryo-endometrial attachment by decreasing ITGAD expression.","date":"2022","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/35038314","citation_count":9,"is_preprint":false},{"pmid":"32534212","id":"PMC_32534212","title":"CD11d is a novel antigen on chicken leukocytes.","date":"2020","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/32534212","citation_count":8,"is_preprint":false},{"pmid":"19571252","id":"PMC_19571252","title":"The extracellular domain of CD11d regulates its cell surface expression.","date":"2009","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/19571252","citation_count":6,"is_preprint":false},{"pmid":"17254640","id":"PMC_17254640","title":"Disruption of the beta2-integrin CD11d (alphaDbeta2) gene fails to protect against experimental autoimmune encephalomyelitis.","date":"2007","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/17254640","citation_count":5,"is_preprint":false},{"pmid":"39839909","id":"PMC_39839909","title":"Humanized anti-CD11d monoclonal antibodies suitable for basic research and therapeutic applications.","date":"2024","source":"Antibody therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/39839909","citation_count":0,"is_preprint":false},{"pmid":"41760944","id":"PMC_41760944","title":"CD11d+ NK cell-derived exosomal HSPB1 suppresses angiogenesis in adenomyosis.","date":"2026","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/41760944","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19865,"output_tokens":4440,"usd":0.063098,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12656,"output_tokens":4048,"usd":0.08224,"stage2_stop_reason":"end_turn"},"total_usd":0.145338,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"CD11d gene transcription is activated by transcription factors Sp1 and Sp3 binding to the -63 to -40 region of the promoter; deletion of this Sp-binding site significantly reduced CD11d promoter activity, and overexpression of Sp1 or Sp3 activated the promoter even in the presence of phorbol ester, while antisense knockdown of either factor decreased CD11d promoter activity.\",\n      \"method\": \"DNase I footprint analysis, EMSA, transfection of reporter constructs, antisense oligonucleotides, in vivo genomic footprinting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (footprinting, EMSA, reporter assay, antisense KD, in vivo genomic footprinting) in a single rigorous study\",\n      \"pmids\": [\"10722744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TIEG1 (TGF-β-inducible early gene-1) binds the -61 to -45 region of the CD11d promoter, competing with Sp1 and Sp3, and confers myeloid-specific activation of CD11d expression; TIEG1 occupancy of the promoter increases upon myeloid differentiation, and siRNA knockdown of TIEG1 reduces CD11d expression.\",\n      \"method\": \"Yeast one-hybrid screen, GST pulldown/EMSA, transfection overexpression/siRNA, chromatin immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — yeast one-hybrid, in vitro binding, ChIP, and siRNA in the same study with multiple orthogonal methods\",\n      \"pmids\": [\"15087465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"GKLFa (a longer isoform of gut-enriched Krüppel-like factor 4) binds the -61 to -44 region of the CD11d promoter (overlapping Sp1 and TIEG1 sites) and represses CD11d expression in myeloid cells; GKLFa physically associates with HDAC1 and HDAC2, which are bound to the CD11d promoter and released upon phorbol ester stimulation, indicating HDAC-mediated repression.\",\n      \"method\": \"Yeast one-hybrid screen, GST pulldown, transfection, siRNA, chromatin immunoprecipitation, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (yeast one-hybrid, in vitro binding, ChIP, siRNA, co-IP) in a single rigorous study\",\n      \"pmids\": [\"15561714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD11d deficiency in mice results in altered T cell phenotype (reduced CD3 and CD28 expression, decreased CD4/CD8 ratio, reduced CD4+ thymocytes) and reduced T cell proliferative response to staphylococcal enterotoxins; the defect resides in T cells rather than APCs. CD11b and CD11d were co-expressed on a subset of early fetal thymocytes, and transient thymocyte expression of both is nonredundantly required for normal thymocyte and T cell development.\",\n      \"method\": \"Knockout mouse analysis, mixing experiments, flow cytometry, superantigen stimulation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cellular phenotype, mixing experiments to locate defect, flow cytometry; single lab\",\n      \"pmids\": [\"15210787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Integrin αDβ2 (CD11d/CD18) modulates macrophage migration in a density-dependent manner: low surface density of αDβ2 cooperates with β1/β3 integrins to support cell migration, whereas high surface density (induced by PMA upregulation or forced overexpression) increases cell adhesiveness and inhibits migration; anti-αD blocking antibody restores β1/β3-driven migration and increases inflammatory macrophage numbers recovered from inflamed peritoneum in vivo.\",\n      \"method\": \"Recombinant HEK293 cell lines expressing different densities of αDβ2, IC-21 macrophage migration assays, anti-αD antibody blockade, in vivo peritoneal inflammation model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell systems (recombinant + natural), in vitro migration assays corroborated by in vivo model, mechanistic conclusion replicated across systems\",\n      \"pmids\": [\"18621369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD11d surface expression requires heterodimerization with CD18: CD11d-YFP is retained intracellularly in the trans-Golgi network (TGN) of heterologous cells lacking CD18, but co-expression of CD18-mRFP relieves this retention and allows surface expression of the CD11d/CD18 heterodimer. Domain-swapping experiments identified the extracellular domain of CD11d as required and sufficient for intracellular retention in heterologous cells, while the transmembrane and C-terminus are required for proper heterodimerization and plasma membrane localization.\",\n      \"method\": \"Fluorescent protein fusions (YFP/mRFP), flow cytometry, confocal microscopy, domain-swapping experiments with CD25\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-cell imaging, flow cytometry, and domain-swap mutagenesis in the same study; mechanistic conclusion well-supported by multiple orthogonal approaches\",\n      \"pmids\": [\"19571252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD11d/CD18 on macrophages promotes macrophage retention at vascular inflammatory sites: CD11d-deficient macrophages show improved three-dimensional migration in fibrin matrix and faster resolution of peritoneal inflammation; adoptive transfer experiments showed similar recruitment of CD11d-/- monocytes from circulation but reduced accumulation in atherosclerotic aortas compared to wild-type, demonstrating CD11d arrests macrophages at lesion sites rather than affecting initial recruitment.\",\n      \"method\": \"CD11d-/-/ApoE-/- double-knockout mouse atherosclerosis model, adoptive transfer of fluorescently labeled monocytes, 3D fibrin matrix migration assay, peritoneal inflammation model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO atherosclerosis model, adoptive transfer experiments, in vitro migration assay; multiple orthogonal approaches in one study\",\n      \"pmids\": [\"28500072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Integrin αDβ2 (CD11d/CD18) participates in macrophage fusion leading to multinucleated giant cell (MGC) formation during peritoneal inflammation: αDβ2-deficient macrophages showed significantly reduced IL-4-induced fusion compared to wild-type, though to a lesser extent than Mac-1 (CD11b/CD18). Deficiency of ICAM-1 (a counter-receptor for both Mac-1 and αDβ2) did not alter fusion rate, suggesting αDβ2 uses a different, unidentified counter-receptor for fusion.\",\n      \"method\": \"αDβ2-knockout mouse peritoneal macrophage IL-4-induced fusion assay, in vivo peritoneal inflammation model, adhesion/spreading/migration assays\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse macrophage functional assay, both in vitro and in vivo; single lab\",\n      \"pmids\": [\"27315778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"αDβ2 (CD11d/CD18) delivers outside-in signals in human monocytes: engagement of αDβ2 induces cell spreading and upregulates mRNAs encoding inflammatory chemokines and cytokines, leading to secretion of their protein products.\",\n      \"method\": \"Freshly isolated human monocytes, outside-in signaling assays, gene expression screening with validation, ELISA for cytokine/chemokine secretion\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional signaling experiments with primary human monocytes, gene expression + protein secretion validation; single lab\",\n      \"pmids\": [\"25415295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD11d/CD18 on neutrophils mediates co-stimulation of IFN-γ production by NK cells through interaction with ICAM-3 on neutrophils; ICAM-3/CD11d-CD18 cross-talk was identified as the molecular mechanism of neutrophil-NK cell interaction.\",\n      \"method\": \"Blocking antibody experiments with primary human neutrophils and NK cells, cytokine measurement\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, antibody blocking approach; interaction inferred rather than directly reconstituted\",\n      \"pmids\": [\"21712539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Integrin αDβ2 (CD11d/CD18) mediates leukocyte accumulation and alveolar-capillary barrier disruption in malaria-associated ARDS: αDβ2-deficient (αD-/-) mice infected with Plasmodium berghei showed reduced alveolar inflammation, reduced vascular and interstitial monocyte/macrophage accumulation, improved alveolar-capillary barrier function, and decreased key pro-inflammatory cytokines in lung tissue.\",\n      \"method\": \"αD-/- knockout mouse model, P. berghei infection, Evans blue dye vascular permeability assay, ELISA, immunohistochemistry, bronchoalveolar lavage analysis, respiratory function measurement\",\n      \"journal\": \"Malaria journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with multiple biochemical and functional readouts; single lab\",\n      \"pmids\": [\"27473068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"αDβ2 (CD11d/CD18) deficiency impairs leukocyte accumulation in response to Salmonella Typhimurium peritoneal infection, impairs pathogen clearance in vivo, reduces bacterial elimination by cultured peritoneal macrophages, and enhances pyroptosis in infected animals.\",\n      \"method\": \"αD-/- knockout mouse infection model, peritoneal macrophage bacterial killing assay, cytokine measurement, pyroptosis markers\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with in vivo infection and in vitro macrophage killing assays; single lab\",\n      \"pmids\": [\"29881383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Integrin αDβ2 on neutrophils (not only macrophages) mediates a defense mechanism during sepsis/endotoxemia: αD-knockout mice show dramatically increased mortality in CLP sepsis and LPS endotoxemia, associated with reduced monocyte-derived macrophages and increased neutrophils in lungs. αD-deficient neutrophils demonstrate increased necrosis/pyroptosis; injection of WT neutrophils (not WT monocytes alone) into αD-/- mice markedly increased macrophage migration to lungs and dramatically improved survival, revealing a neutrophil-dependent pathway for αDβ2-mediated macrophage lung accumulation and efferocytosis.\",\n      \"method\": \"αD-/- KO mouse CLP sepsis and LPS endotoxemia models, adoptive transfer of fluorescently labeled WT and αD-/- monocytes and neutrophils, lung histology, survival analysis\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo models, adoptive transfer rescue experiments with WT neutrophils, mechanistic dissection of neutrophil-macrophage interplay; multiple orthogonal approaches\",\n      \"pmids\": [\"33438263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LINC02190 lncRNA binds to the ITGAD (CD11d) mRNA promoter (specifically the 150-250 bp region) and suppresses ITGAD expression; overexpression of LINC02190 reduces ITGAD expression and decreases adhesion of Ishikawa and JAR cells, while LINC02190 knockdown increases ITGAD expression and cell adhesion rate.\",\n      \"method\": \"Endometrial tissue lncRNA/mRNA profiling, reporter assay for LINC02190 cis-element mapping, overexpression/knockdown of LINC02190 in Ishikawa cells, immunofluorescence, adhesion assay\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — promoter reporter assay, gain-of-function/loss-of-function, adhesion assay; single lab but multiple approaches\",\n      \"pmids\": [\"35038314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD11d deficiency does NOT protect against experimental autoimmune encephalomyelitis (EAE): CD11d-/- and wild-type C57BL/6 mice showed identical clinical course and histopathology, with no differences in leukocyte subset infiltration into the CNS or T cell cytokine production.\",\n      \"method\": \"CD11d-/- KO mouse EAE model (MOG35-55 peptide immunization), clinical scoring, histopathology, flow cytometry, cytokine measurement\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse disease model with histopathological and immunological readouts; single lab; negative result mechanistically informative\",\n      \"pmids\": [\"17254640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A humanized anti-CD11d-2 antibody binds both active and inactive CD11d/CD18 conformations on human monocytes and neutrophils without inducing inflammatory cell signaling. CD11d/CD18 surface expression analysis revealed a mismatch between total and surface-level CD11d and CD18 expression not altered by CK2 inhibition.\",\n      \"method\": \"Flow cytometry on primary human leukocytes and THP-1 cells, western blotting, biochemical signaling assays, rat SCI model\",\n      \"journal\": \"Antibody therapeutics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily antibody characterization, limited mechanistic depth on conformational binding\",\n      \"pmids\": [\"39839909\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGAD (CD11d) encodes the αD subunit of the leukocyte β2 integrin αDβ2 (CD11d/CD18), which heterodimerizes with CD18 in the trans-Golgi network (requiring its extracellular domain for proper trafficking) and is expressed predominantly on myeloid cells (monocytes, macrophages, neutrophils) as well as NK cells, B cells, and γδ T cells; transcription is activated by Sp1/Sp3 and TIEG1 binding the core promoter and repressed by GKLFa recruiting HDAC1/2; at low surface density αDβ2 cooperates with β1/β3 integrins to support cell migration, whereas its upregulation at inflammatory sites markedly increases adhesiveness, arrests macrophages (promoting chronic inflammation and atherosclerosis), supports macrophage fusion into multinucleated giant cells, and enables outside-in signaling that drives inflammatory chemokine/cytokine production; on neutrophils, αDβ2 mediates a neutrophil-dependent pathway for macrophage lung recruitment and efferocytosis that is protective in sepsis/endotoxemia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGAD (CD11d) encodes the \\u03b1D subunit of the leukocyte \\u03b22 integrin \\u03b1D\\u03b22 (CD11d/CD18), an adhesion receptor that tunes myeloid cell positioning and inflammatory output at sites of tissue injury and infection [#4, #6]. Surface display of CD11d requires obligate heterodimerization with CD18: the CD11d extracellular domain otherwise drives intracellular retention in the trans-Golgi network, while co-expression of CD18 relieves retention and permits plasma-membrane localization [#5]. Functionally, \\u03b1D\\u03b22 acts in a surface-density-dependent manner\\u2014at low density it cooperates with \\u03b21/\\u03b23 integrins to support migration, whereas high density increases adhesiveness and arrests macrophages, promoting their retention at vascular lesions and atherosclerotic plaques rather than altering initial recruitment [#4, #6]. \\u03b1D\\u03b22 also supports IL-4-induced macrophage fusion into multinucleated giant cells [#7] and delivers outside-in signals in human monocytes that drive cell spreading and secretion of inflammatory chemokines and cytokines [#8]. In vivo, \\u03b1D\\u03b22 governs leukocyte accumulation across diverse inflammatory and infectious settings\\u2014mediating barrier disruption in malaria-associated lung injury [#10] and pathogen clearance in Salmonella infection [#11]\\u2014and on neutrophils it directs a protective, neutrophil-dependent pathway for macrophage lung recruitment and efferocytosis during sepsis and endotoxemia [#12]. Transcription of CD11d is set by competition at a shared promoter element: Sp1/Sp3 and the myeloid factor TIEG1 activate, while the KLF4 isoform GKLFa recruits HDAC1/2 to repress expression [#0, #1, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the basal transcriptional control of CD11d by identifying the core promoter element required for its activity.\",\n      \"evidence\": \"DNase I footprinting, EMSA, reporter transfection, antisense knockdown and in vivo genomic footprinting of the CD11d promoter\",\n      \"pmids\": [\"10722744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address myeloid-specific or inducible regulation\", \"Did not connect promoter activity to cell-type expression patterns\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved how CD11d transcription is set by competing factors at one promoter element\\u2014TIEG1 confers myeloid-specific activation while GKLFa recruits HDACs to repress.\",\n      \"evidence\": \"Yeast one-hybrid, GST pulldown/EMSA, ChIP, co-IP and siRNA targeting the -61/-44 CD11d promoter region\",\n      \"pmids\": [\"15087465\", \"15561714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling the activator/repressor switch not fully defined\", \"Did not establish how differentiation triggers HDAC release\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Tested whether CD11d has a developmental role beyond inflammation, showing a non-redundant T-cell-intrinsic requirement in thymocyte development.\",\n      \"evidence\": \"CD11d knockout mouse analysis with mixing experiments, flow cytometry and superantigen stimulation\",\n      \"pmids\": [\"15210787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular ligand/mechanism in thymocytes not identified\", \"Single lab, not independently replicated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the biosynthetic requirement for surface expression, showing CD18 heterodimerization rescues TGN retention driven by the CD11d extracellular domain.\",\n      \"evidence\": \"YFP/mRFP fusions, confocal microscopy, flow cytometry and CD25 domain-swap mutagenesis in heterologous cells\",\n      \"pmids\": [\"19571252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Retention machinery in the TGN not identified\", \"Conducted in heterologous cells rather than native myeloid cells\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Reconciled migration versus adhesion by showing \\u03b1D\\u03b22 function is surface-density-dependent.\",\n      \"evidence\": \"Recombinant HEK293 lines at graded \\u03b1D\\u03b22 density, macrophage migration assays, anti-\\u03b1D blockade and an in vivo peritoneal inflammation model\",\n      \"pmids\": [\"18621369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Counter-receptors driving the adhesion-dominant state not fully defined\", \"Signaling effectors linking density to motility not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Distinguished recruitment from retention, demonstrating \\u03b1D\\u03b22 arrests macrophages at atherosclerotic lesions rather than affecting their initial entry.\",\n      \"evidence\": \"CD11d-/-/ApoE-/- atherosclerosis model, adoptive transfer of labeled monocytes, 3D fibrin migration and peritoneal inflammation assays\",\n      \"pmids\": [\"28500072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lesion ligand mediating arrest not identified\", \"Relative contribution versus other \\u03b22 integrins in vivo unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Probed a non-macrophage role, implicating neutrophil CD11d/CD18\\u2013ICAM-3 cross-talk in co-stimulating NK-cell IFN-\\u03b3 production.\",\n      \"evidence\": \"Blocking-antibody experiments with primary human neutrophils and NK cells plus cytokine measurement\",\n      \"pmids\": [\"21712539\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Interaction inferred from antibody blockade, not directly reconstituted\", \"No reciprocal or genetic validation of the ICAM-3 partnership\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed \\u03b1D\\u03b22 is not merely adhesive but signaling-competent, driving inflammatory gene expression via outside-in signals.\",\n      \"evidence\": \"Outside-in engagement of \\u03b1D\\u03b22 on primary human monocytes with gene expression screening and ELISA validation\",\n      \"pmids\": [\"25415295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling intermediates not delineated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended \\u03b1D\\u03b22 function to macrophage multinucleation and to lung pathology, establishing roles in giant-cell formation and malaria-associated ARDS.\",\n      \"evidence\": \"\\u03b1D\\u03b22-knockout IL-4 macrophage fusion assays and a P. berghei lung-injury model with permeability, cytokine and histology readouts\",\n      \"pmids\": [\"27315778\", \"27473068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Counter-receptor for fusion remains unidentified (ICAM-1-independent)\", \"Single labs for each model\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a protective host-defense role, with \\u03b1D\\u03b22 required for leukocyte accumulation and pathogen clearance in Salmonella infection.\",\n      \"evidence\": \"\\u03b1D-/- mouse peritoneal infection model, macrophage bacterial-killing assay and pyroptosis readouts\",\n      \"pmids\": [\"29881383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking \\u03b1D\\u03b22 to bacterial killing not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a neutrophil-dependent axis, showing \\u03b1D\\u03b22 on neutrophils drives macrophage lung accumulation and efferocytosis that is protective in sepsis.\",\n      \"evidence\": \"\\u03b1D-/- CLP and LPS endotoxemia models with adoptive-transfer rescue using WT neutrophils versus monocytes and survival analysis\",\n      \"pmids\": [\"33438263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signal by which neutrophils recruit macrophages unresolved\", \"Ligand/counter-receptor for neutrophil \\u03b1D\\u03b22 not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Added a post-transcriptional layer of regulation, with the lncRNA LINC02190 suppressing ITGAD expression and cell adhesion.\",\n      \"evidence\": \"Reporter cis-element mapping plus LINC02190 overexpression/knockdown with adhesion assays in Ishikawa/JAR cells\",\n      \"pmids\": [\"35038314\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of LINC02190 action at the ITGAD locus not detailed\", \"Relevance to myeloid \\u03b1D\\u03b22 biology untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Characterized a conformation-independent anti-CD11d antibody and noted a total-versus-surface CD11d/CD18 expression mismatch unaltered by CK2 inhibition.\",\n      \"evidence\": \"Flow cytometry/western blot on primary human leukocytes and THP-1 cells with biochemical signaling assays and a rat SCI model\",\n      \"pmids\": [\"39839909\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanism of surface-expression mismatch not resolved\", \"Limited mechanistic depth; primarily antibody characterization\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physiological counter-receptors and downstream signaling effectors that distinguish \\u03b1D\\u03b22-mediated arrest, fusion, and protective recruitment remain unidentified.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined ligand for macrophage arrest at lesions or for fusion\", \"Outside-in signaling intermediates unmapped\", \"Mechanism of neutrophil-to-macrophage relay in sepsis unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [4, 6, 13]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 12, 11]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [4, 6, 7]}\n    ],\n    \"complexes\": [\"\\u03b1D\\u03b22 integrin (CD11d/CD18)\"],\n    \"partners\": [\"ITGB2\", \"ICAM3\", \"SP1\", \"SP3\", \"TIEG1\", \"KLF4\", \"HDAC1\", \"HDAC2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}