{"gene":"C1QB","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":1991,"finding":"The C1QB gene encodes the B-chain polypeptide of human complement subcomponent C1q. The three genes encoding C1q A-, B-, and C-chains are aligned in the order A-C-B on a 24 kb stretch of DNA on chromosome 1p, each containing one intron located within a codon for a glycine residue in the collagen-like region. The B-chain collagen-like region participates in the triple-helical stalk structure of C1q.","method":"cDNA cloning, genomic cosmid library isolation, Southern blot, DNA sequencing","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — original structural/genomic characterization with sequencing and Southern blot, foundational paper","pmids":["1706597"],"is_preprint":false},{"year":1979,"finding":"The complete amino acid sequence of the collagen-like region of the C1q B-chain was determined; the B-chain has an alanine residue at position B-9 where glycine would be expected in the Gly-X-Y collagen repeat, representing a break in the collagen-like sequence.","method":"Protein sequencing of pepsin-derived collagen-like fragments","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — direct protein sequencing of purified fragment","pmids":["486087"],"is_preprint":false},{"year":1976,"finding":"Partial pepsin digestion of human C1q revealed that the B-chain collagen-like region (N-terminal ~91 residues) is disulfide-linked to the A-chain collagen-like region via a single disulfide bond between residue B2-B6, forming an A-B heterodimer that constitutes part of the collagen-like stalk of C1q.","method":"Pepsin digestion, CM-cellulose chromatography, SDS-PAGE, amino acid composition analysis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical characterization with purified fragments and sequence data","pmids":["7240"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of the C1q globular head domain (gC1q) resolved to 1.9 Å revealed a compact heterotrimeric assembly of the C-terminal regions of A, B, and C chains held together mainly by non-polar interactions, with a Ca2+ ion bound at the top. The B-chain globular head (ghB) contributes to ligand recognition. Structural models suggest the gC1q heterotrimer is key to the versatile recognition properties of C1q.","method":"X-ray crystallography at 1.9 Å resolution, molecular modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional modeling, highly cited","pmids":["12960167"],"is_preprint":false},{"year":2006,"finding":"Mutational analysis of recombinant globular head modules showed that charged residues on the ghB module (side of the ghB) are crucial for C1q binding to IgG1, C-reactive protein, and pentraxin 3. The ghB module has specific and differential binding properties, and a set of charged residues from the apex of the gC1q heterotrimer (with participation of all three chains including ghB) mediate ionic and hydrogen bonds with ligands.","method":"Recombinant expression of globular head modules, site-directed mutagenesis, binding assays (ELISA, SPR)","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis + multiple binding assays, replicated across three ligands","pmids":["16566583"],"is_preprint":false},{"year":2003,"finding":"The globular head region of C1q (including contributions from the B-chain) mediates binding to pentraxin 3 (PTX3), as shown by experiments with recombinant individual globular head modules of A, B, and C chains. C1q binding to PTX3 activates the classical complement pathway via C4 deposition, and enhances C1q binding to apoptotic cells; however, fluid-phase PTX3 pre-incubated with C1q inhibits complement activation.","method":"Recombinant globular head domain binding assays, C4 deposition assay, apoptotic cell binding experiments","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding assays with recombinant domains plus functional complement activation readout","pmids":["12645945"],"is_preprint":false},{"year":2008,"finding":"The globular domain of C1q (including the B-chain globular head) binds phosphatidylserine (PS) on apoptotic cells specifically and avidly (KD = 3.7–7 × 10−8 M) through multiple interactions between its globular domain and the phosphoserine group of PS, demonstrated by cosedimentation, surface plasmon resonance, X-ray crystallography, and confocal microscopy showing colocalization of C1q with PS in membrane patches at early stages of apoptosis.","method":"Surface plasmon resonance, cosedimentation, X-ray crystallography, confocal microscopy, annexin V competition assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods including structural validation and binding kinetics","pmids":["18250442"],"is_preprint":false},{"year":1988,"finding":"The binding site for C1q on IgG was localized to three residues in the CH2 domain (Glu318, Lys320, Lys322 in mouse IgG2b); a peptide mimic of this sequence inhibits complement lysis, establishing that the C1q B-chain globular head (among other gC1q chains) contacts this conserved IgG motif.","method":"Systematic surface residue mutagenesis of IgG2b, complement lysis inhibition with peptide mimics","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis plus functional peptide inhibition assay","pmids":["3258649"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structures of C1 bound to IgG1 hexamers revealed that C1q arms (formed by the A, B, and C chains including the B-chain) condense upon antibody binding, inducing rearrangements of C1r2s2 proteases and tilting C1q's cone-shaped stalk, providing a structural mechanism for how danger pattern recognition activates complement. Distinct C1q binding sites on the two Fc-CH2 domains of each IgG were identified, including previously unknown interactions, validated by functional IgG1 mutant analysis.","method":"Cryo-electron microscopy, IgG1 mutant functional analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure plus mutagenesis functional validation","pmids":["29449492"],"is_preprint":false},{"year":2014,"finding":"IgG antibodies form ordered hexamers via specific noncovalent Fc-Fc interactions after antigen binding on cell surfaces, and these hexamers recruit and activate C1 (which requires C1q including the B-chain) to trigger the complement cascade. Manipulating Fc-Fc interactions modulated complement activation and target cell killing across all four human IgG subclasses.","method":"Cell surface complement activation assays, electron microscopy, native MS, mutagenesis of Fc segments","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods, mechanistic model for C1q/C1qB activation","pmids":["24626930"],"is_preprint":false},{"year":1991,"finding":"HIV-1 activates the classical complement pathway independent of antibody through direct binding of C1q to specific sites in the transmembrane glycoprotein gp41 (residues 591–605 and 601–620). Soluble gp41 bound C1q and activated the C1 complex (C1q+C1r+C1s) in a dose- and time-dependent manner; gp120 was ineffective. The C1q interaction with gp41 is mediated through the recognition function shared by the A, B, and C chains of C1q.","method":"Radiolabeled C1q binding, gel exclusion chromatography, C1 complex reconstitution and activation assay, synthetic peptide inhibition","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 — reconstituted C1 complex assay plus peptide mapping","pmids":["1744579"],"is_preprint":false},{"year":1992,"finding":"C1qB mRNA in rat brain is expressed specifically in microglia-macrophages (identified by CR3 immunoreactivity) and is upregulated in response to cortical deafferentation and excitotoxic lesions, establishing microglia as the primary source of C1qB in brain injury responses.","method":"In situ hybridization, immunohistochemistry (CR3 co-localization), Northern blot","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 — direct co-localization by ISH + IHC in multiple lesion models","pmids":["1426121"],"is_preprint":false},{"year":2000,"finding":"TGF-β1 decreases C1qB mRNA expression in rat brain cortex and hippocampus in vivo (after intraventricular infusion) and in cultured glia, establishing a regulatory link between TGF-β1 signaling in microglia and complement C1qB gene expression.","method":"Intraventricular TGF-β1 infusion in rats, primary microglia culture treatment, Northern blot/in situ hybridization quantification","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro convergent evidence with dose-dependent response","pmids":["11074155"],"is_preprint":false},{"year":2001,"finding":"Neuronal overexpression of human COX-2 in transgenic mice selectively induces C1qB expression in neurons (without inducing C3 or C4), and this induction is reduced by treatment with the selective COX-2 inhibitor nimesulide, placing COX-2-mediated inflammatory signaling upstream of neuronal C1qB expression.","method":"Transgenic mouse model, COX-2 inhibitor treatment (nimesulide), Northern blot/in situ hybridization for C1qB mRNA","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 — transgenic gain-of-function and pharmacological inhibition in vivo","pmids":["11810182"],"is_preprint":false},{"year":2022,"finding":"Silencing C1QB in monocytes inhibited their differentiation into macrophages and reduced macrophage numbers both in vitro and in a rat model of type 1 diabetes mellitus, demonstrating that C1QB is functionally required for monocyte-to-macrophage differentiation and for macrophage accumulation in pancreatic islets causing β-cell damage.","method":"C1QB siRNA knockdown in cultured monocytes, lentiviral knockdown in streptozotocin-induced T1DM rat model, cell counting, histology","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function in vitro and in vivo with defined cellular phenotype","pmids":["36464147"],"is_preprint":false},{"year":2013,"finding":"A novel homozygous splicing mutation in C1QB (c.187+1G>T) causes complete C1q deficiency in a Japanese patient, demonstrating that the C1QB B-chain is essential for assembly and secretion of functional C1q protein.","method":"Clinical genetics, PCR-based mutation identification, complement functional assays (persistent hypocomplementemia with normal C3/C4)","journal":"Pediatric rheumatology online journal","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function mutation with defined protein-level consequence","pmids":["24160257"],"is_preprint":false},{"year":2014,"finding":"A homozygous non-coding mutation two nucleotides before the splice site of the second exon of C1QB causes complete absence of C1qB mRNA and intracellular C1qB protein, with secondary reduction of C1qA mRNA (but not C1qC), resulting in complete C1q deficiency. This demonstrates that C1qB is required for stable C1qA expression and for C1q complex assembly.","method":"Deep sequencing, ELISA, hemolytic assay, Western blot, qPCR of C1qA/B/C mRNAs, in silico splice-site analysis","journal":"Immunobiology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal molecular methods in patient-derived cells establishing chain-interdependence","pmids":["25454803"],"is_preprint":false},{"year":2026,"finding":"TCF7L2 directly binds the C1QB promoter and positively regulates C1QB transcription; lentiviral knockdown of Tcf7l2 in a kainic acid-induced epilepsy mouse model reduced C1qb overexpression, attenuated microglial activation, and ameliorated neuronal injury, establishing a TCF7L2→C1QB regulatory axis that promotes synaptic pruning-dependent neuronal damage in epilepsy.","method":"ChIP assay, luciferase reporter assay, lentiviral Tcf7l2 knockdown in kainic acid epilepsy mouse model, immunohistochemistry, neuronal injury quantification","journal":"Brain research bulletin","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP + reporter for direct binding, in vivo knockdown with defined phenotypic readout","pmids":["41534674"],"is_preprint":false}],"current_model":"C1QB encodes the B-chain of complement subcomponent C1q, which assembles with the A- and C-chains into a heterotrimeric globular head domain (gC1q) and collagen-like stalk; the B-chain globular head contributes essential charged residues for binding diverse ligands including IgG (Fc-CH2 domain), C-reactive protein, pentraxin 3, and phosphatidylserine on apoptotic cells, and upon hexameric IgG-antigen complex recognition the C1q arms condense to activate C1r2s2 proteases and initiate the classical complement cascade; in the brain, C1qB is expressed primarily in microglia and is regulated upstream by TGF-β1 (suppression) and COX-2/TCF7L2 (induction), and C1qB is functionally required for monocyte-to-macrophage differentiation."},"narrative":{"teleology":[{"year":1976,"claim":"Establishing the quaternary organization of C1q required identifying inter-chain disulfide linkages; pepsin digestion showed that the B-chain collagen-like region forms a disulfide-linked A–B heterodimer, defining the basic subunit architecture of the collagen-like stalk.","evidence":"Pepsin digestion, chromatography, SDS-PAGE of purified human C1q","pmids":["7240"],"confidence":"High","gaps":["Precise disulfide positions not resolved to single cysteine residues","Stoichiometry of the full hexameric assembly not addressed"]},{"year":1979,"claim":"Complete sequencing of the B-chain collagen-like region revealed a break in the Gly-X-Y repeat (Ala at position B-9), providing the first evidence that the collagen-like stalk of C1q has built-in flexibility sites that could affect its conformational dynamics.","evidence":"Protein sequencing of pepsin-derived collagen-like fragments","pmids":["486087"],"confidence":"High","gaps":["Functional significance of the Gly→Ala disruption not tested","Complete primary structure of the globular domain not yet determined"]},{"year":1988,"claim":"Mapping the IgG binding site on C1q required identifying the cognate residues on the antibody; mutagenesis localized the C1q contact to Glu318/Lys320/Lys322 in the IgG CH2 domain, confirming that the gC1q heterotrimer (including ghB) engages a conserved ionic motif on immunoglobulins.","evidence":"Systematic surface mutagenesis of mouse IgG2b, complement lysis inhibition with synthetic peptides","pmids":["3258649"],"confidence":"High","gaps":["The specific C1q residues contacting these IgG residues were not identified","Applicability across all human IgG subclasses not tested"]},{"year":1991,"claim":"Cloning of the C1QB gene and its genomic context established the A-C-B gene cluster on chromosome 1p and revealed a shared intron placement within the collagen-like coding region, suggesting coordinated evolution of the three chains; separately, direct binding of C1q to HIV-1 gp41 demonstrated antibody-independent activation of the classical pathway by a viral target.","evidence":"cDNA cloning/genomic sequencing for gene structure; radiolabeled C1q binding and reconstituted C1 complex activation for gp41 interaction","pmids":["1706597","1744579"],"confidence":"High","gaps":["Transcriptional regulatory elements of C1QB not characterized","Whether gp41-C1q activation benefits host or virus was unresolved"]},{"year":1992,"claim":"The cellular source of C1qB in the brain was unknown; in situ hybridization co-localized C1qB mRNA with CR3-positive microglia and showed upregulation after cortical injury, establishing microglia as the primary C1qB-expressing cell type in the CNS.","evidence":"In situ hybridization and immunohistochemistry in rat brain lesion models","pmids":["1426121"],"confidence":"Medium","gaps":["Functional role of microglial C1qB in synaptic remodeling not yet tested","Neuronal expression under pathological conditions not excluded"]},{"year":2000,"claim":"Upstream regulation of C1qB in the brain was undefined; TGF-β1 was shown to suppress C1qB mRNA both in vivo (intraventricular infusion) and in cultured microglia, identifying the first negative transcriptional regulator of C1qB in the CNS.","evidence":"Intraventricular TGF-β1 infusion in rats and primary microglia culture with Northern blot quantification","pmids":["11074155"],"confidence":"Medium","gaps":["Direct promoter mechanism of TGF-β1-mediated repression not characterized","Whether TGF-β1 acts through SMAD signaling on the C1QB promoter was unknown"]},{"year":2003,"claim":"Resolving the atomic structure of the gC1q heterotrimer at 1.9 Å revealed how the A, B, and C globular heads assemble with a Ca²⁺ ion and provided the framework for understanding how a single trimeric module recognizes structurally diverse ligands including pentraxin 3.","evidence":"X-ray crystallography; recombinant globular head binding assays and C4 deposition assay for PTX3","pmids":["12960167","12645945"],"confidence":"High","gaps":["Full-length C1q structure not resolved","Mechanism by which PTX3 switches between complement activation and inhibition was unclear"]},{"year":2006,"claim":"Site-directed mutagenesis of individual ghB residues showed that specific charged amino acids on the B-chain globular head are differentially required for binding IgG1, CRP, and PTX3, demonstrating that C1q versatility arises from overlapping but distinct contact surfaces on the same heterotrimer.","evidence":"Recombinant globular head modules, site-directed mutagenesis, ELISA and SPR binding assays","pmids":["16566583"],"confidence":"High","gaps":["Complete binding footprint with full-length ligands not determined","Contribution of avidity from six gC1q heads not quantified"]},{"year":2008,"claim":"The identity of the C1q receptor for apoptotic cell clearance was debated; direct binding of the gC1q domain to phosphatidylserine was demonstrated with nanomolar affinity and structural validation, establishing PS as a key eat-me signal recognized by C1q.","evidence":"SPR kinetics, cosedimentation, X-ray crystallography, confocal microscopy with annexin V competition","pmids":["18250442"],"confidence":"High","gaps":["Relative contributions of PS versus other apoptotic ligands in vivo not quantified","Downstream signaling linking C1q-PS engagement to phagocytosis not defined"]},{"year":2014,"claim":"How C1q is activated on target cells was a long-standing question; the discovery that IgG forms ordered hexamers via Fc–Fc contacts on antigen-bearing surfaces, and that these hexamers are the physiological unit recruiting C1, explained the stoichiometric requirement for complement activation; concurrently, patient mutations confirmed that C1QB loss-of-function causes complete C1q deficiency with secondary C1qA destabilization.","evidence":"Cell surface complement assays, EM, native MS, Fc mutagenesis; deep sequencing, hemolytic/ELISA assays and qPCR in patient-derived cells","pmids":["24626930","25454803","24160257"],"confidence":"High","gaps":["Whether non-immune C1q ligands also require multivalent display was unknown","Genotype–phenotype correlation for distinct C1QB mutations not systematically established"]},{"year":2018,"claim":"The structural mechanism coupling ligand recognition to protease activation was resolved when cryo-EM of the C1–IgG1 hexamer complex showed that antibody binding induces arm condensation and stalk tilting, transmitting a conformational change to the C1r₂s₂ proteases.","evidence":"Cryo-EM structural analysis complemented by functional IgG1 mutant validation","pmids":["29449492"],"confidence":"High","gaps":["Dynamic intermediates of the activation transition not captured","Structural basis for how non-IgG ligands activate C1 remained unresolved"]},{"year":2022,"claim":"C1QB was known as a complement component but its role in myeloid cell fate was unexplored; siRNA and lentiviral knockdown demonstrated that C1QB is required for monocyte-to-macrophage differentiation and for macrophage-mediated β-cell damage in a type 1 diabetes model.","evidence":"C1QB siRNA in cultured monocytes; lentiviral knockdown in streptozotocin-induced T1DM rats with histological quantification","pmids":["36464147"],"confidence":"Medium","gaps":["Mechanism by which C1QB promotes differentiation (autocrine signaling vs. complement activation) not defined","Whether other C1q chains are equally required was not tested"]},{"year":2026,"claim":"A direct transcriptional activator of C1QB was identified: TCF7L2 binds the C1QB promoter and drives its expression in the epileptic brain, linking Wnt/TCF signaling to complement-mediated synaptic pruning and neuronal damage.","evidence":"ChIP, luciferase reporter assay, lentiviral Tcf7l2 knockdown in kainic acid epilepsy mouse model with immunohistochemistry","pmids":["41534674"],"confidence":"Medium","gaps":["Whether TCF7L2 regulation of C1QB operates in non-CNS tissues is unknown","Interaction between TGF-β1 suppression and TCF7L2 activation at the promoter level not studied"]},{"year":null,"claim":"Key unresolved questions include the structural basis for how non-antibody ligands (CRP, PTX3, PS) activate or modulate the C1r₂s₂ protease arm, the mechanism by which C1QB promotes monocyte-to-macrophage differentiation independently of canonical complement activation, and how the opposing TGF-β1 and TCF7L2 regulatory inputs are integrated at the C1QB promoter.","evidence":"","pmids":[],"confidence":"Low","gaps":["No cryo-EM or structural data for C1q bound to non-IgG ligands","Cell-intrinsic versus complement-dependent role of C1QB in myeloid differentiation unresolved","Promoter architecture and combinatorial transcription factor binding not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[4,5,6,7,8]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,6,8,10]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5,7,8,9,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,15,16]}],"complexes":["C1 complex (C1q:C1r2:C1s2)","C1q heterotrimer (A:B:C chains)"],"partners":["C1QA","C1QC","C1R","C1S","PTX3","CRP","TCF7L2"],"other_free_text":[]},"mechanistic_narrative":"C1QB encodes the B-chain of complement subcomponent C1q, an essential structural and functional constituent of the classical complement pathway that assembles with the A- and C-chains into a heterotrimeric globular head (gC1q) atop a collagen-like stalk [PMID:1706597, PMID:12960167]. Charged residues on the B-chain globular head mediate differential recognition of IgG, C-reactive protein, pentraxin 3, and phosphatidylserine on apoptotic cells, and upon engagement of hexameric IgG–antigen complexes the C1q arms condense to activate C1r₂s₂ proteases and initiate the complement cascade [PMID:16566583, PMID:29449492, PMID:18250442]. Loss-of-function mutations in C1QB abolish C1q assembly and secretion, causing complete C1q deficiency, and additionally destabilize C1qA expression, demonstrating that the B-chain is indispensable for heterotrimeric complex integrity [PMID:25454803, PMID:24160257]. Beyond innate immunity, C1QB is expressed in microglia under transcriptional control by TGF-β1 (suppressive) and the TCF7L2/COX-2 axis (inductive), and is functionally required for monocyte-to-macrophage differentiation [PMID:1426121, PMID:11074155, PMID:41534674, PMID:36464147]."},"prefetch_data":{"uniprot":{"accession":"P02746","full_name":"Complement C1q subcomponent subunit B","aliases":[],"length_aa":253,"mass_kda":26.7,"function":"Core component of the complement C1 complex, a multiprotein complex that initiates the classical pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:12847249, PubMed:19006321, PubMed:24626930, PubMed:29449492, PubMed:3258649, PubMed:34155115, PubMed:6249812, PubMed:6776418). The classical complement pathway is initiated by the C1Q subcomplex of the C1 complex, which specifically binds IgG or IgM immunoglobulins complexed with antigens, forming antigen-antibody complexes on the surface of pathogens: C1QA, together with C1QB and C1QC, specifically recognizes and binds the Fc regions of IgG or IgM via its C1q domain (PubMed:12847249, PubMed:19006321, PubMed:24626930, PubMed:29449492, PubMed:3258649, PubMed:6776418). Immunoglobulin-binding activates the proenzyme C1R, which cleaves C1S, initiating the proteolytic cascade of the complement system (PubMed:29449492). The C1Q subcomplex is activated by a hexamer of IgG complexed with antigens, while it is activated by a pentameric IgM (PubMed:19706439, PubMed:24626930, PubMed:29449492). The C1Q subcomplex also recognizes and binds phosphatidylserine exposed on the surface of cells undergoing programmed cell death, possibly promoting activation of the complement system (PubMed:18250442)","subcellular_location":"Secreted; Cell surface","url":"https://www.uniprot.org/uniprotkb/P02746/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C1QB","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/C1QB","total_profiled":1310},"omim":[{"mim_id":"620321","title":"C1q DEFICIENCY 2; C1QD2","url":"https://www.omim.org/entry/620321"},{"mim_id":"613652","title":"C1q DEFICIENCY 1; C1QD1","url":"https://www.omim.org/entry/613652"},{"mim_id":"609280","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 2-ALPHA KINASE 4; EIF2AK4","url":"https://www.omim.org/entry/609280"},{"mim_id":"600433","title":"PRECEREBELLIN 2; CBLN2","url":"https://www.omim.org/entry/600433"},{"mim_id":"600432","title":"PRECEREBELLIN 1; CBLN1","url":"https://www.omim.org/entry/600432"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":1405.0}],"url":"https://www.proteinatlas.org/search/C1QB"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P02746","domains":[{"cath_id":"2.60.120.40","chopping":"119-248","consensus_level":"high","plddt":95.4377,"start":119,"end":248}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P02746","model_url":"https://alphafold.ebi.ac.uk/files/AF-P02746-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P02746-F1-predicted_aligned_error_v6.png","plddt_mean":78.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C1QB","jax_strain_url":"https://www.jax.org/strain/search?query=C1QB"},"sequence":{"accession":"P02746","fasta_url":"https://rest.uniprot.org/uniprotkb/P02746.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P02746/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P02746"}},"corpus_meta":[{"pmid":"1426121","id":"PMC_1426121","title":"Complement C1qB and C4 mRNAs responses to lesioning in rat brain.","date":"1992","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/1426121","citation_count":119,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7870303","id":"PMC_7870303","title":"Selective expression of clusterin (SGP-2) and complement C1qB and C4 during responses to neurotoxins in vivo and in vitro.","date":"1994","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/7870303","citation_count":83,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21698244","id":"PMC_21698244","title":"Transcriptome profiling of whole blood cells identifies PLEK2 and C1QB in human melanoma.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21698244","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38890370","id":"PMC_38890370","title":"Cholesterol efflux from C1QB-expressing macrophages is associated with resistance to chimeric antigen receptor T cell therapy in primary refractory diffuse large B cell lymphoma.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38890370","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21951915","id":"PMC_21951915","title":"Association of C1QB gene polymorphism with schizophrenia in Armenian population.","date":"2011","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21951915","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36464147","id":"PMC_36464147","title":"Single-cell RNA sequencing highlights the roles of C1QB and NKG7 in the pancreatic islet immune microenvironment in type 1 diabetes mellitus.","date":"2022","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/36464147","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7955342","id":"PMC_7955342","title":"Expression of complement C1qB and C4 mRNAs during rat brain development.","date":"1994","source":"Brain research. 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mRNA is expressed in putative microglia/macrophages (not neurogenic ventricular zones) during rat brain development from embryonic day 14 onward, suggesting C1q has roles in brain development unrelated to cytotoxic complement activation.\",\n      \"method\": \"Northern blot and in situ hybridization during rat brain development\",\n      \"journal\": \"Brain research. Developmental brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by ISH with developmental staging, single lab\",\n      \"pmids\": [\"7955342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TGF-β1 decreases C1qB mRNA levels in rat cortex and hippocampus in vivo (intraventricular infusion) and in cultured glia, establishing a regulatory link between TGF-β1 signaling and complement C1qB expression in microglia.\",\n      \"method\": \"Intraventricular infusion of TGF-β1 in vivo and primary microglia culture treatment, mRNA quantification\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function/gain-of-function with defined molecular readout, replicated in vivo and in vitro, single lab\",\n      \"pmids\": [\"11074155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Neuronal overexpression of COX-2 selectively induces C1qB expression in neurons of transgenic mice, and COX-2 inhibitor (nimesulide) reduces this induction, placing COX-2 activity upstream of neuronal C1qB expression.\",\n      \"method\": \"Transgenic mouse model with neuronal hCOX-2 overexpression; COX-2 inhibitor treatment; mRNA quantification\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic/pharmacological epistasis with defined molecular readout, single lab\",\n      \"pmids\": [\"11810182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A novel homozygous splicing mutation in C1qB (c.187+1G>T) causes complete C1q deficiency, demonstrating that C1qB is essential for functional C1q complex assembly.\",\n      \"method\": \"Genetic sequencing, clinical complement assays in a patient with C1q deficiency\",\n      \"journal\": \"Pediatric rheumatology online journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function (natural mutation) with defined biochemical phenotype (C1q deficiency)\",\n      \"pmids\": [\"24160257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A homozygous non-coding mutation in C1qB (splice site, 2 nt before exon 2) causes complete absence of C1qB mRNA and protein, leading to C1q deficiency; C1qA and C1qC chains are present but C1q complex is non-functional without C1qB, demonstrating C1qB is required for C1q secretion.\",\n      \"method\": \"Deep sequencing, Western blot, qPCR, ELISA, hemolytic assay in patient-derived cells\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (sequencing, western blot, functional hemolytic assay, qPCR) in patient cells; moderate evidence\",\n      \"pmids\": [\"25454803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IRF4 transcriptionally activates lncRNA TEX41, which acts as a sponge for miR-103a-3p to upregulate C1QB expression, promoting melanoma cell proliferation, migration, and invasion; IRF4 also directly facilitates melanoma cell growth via C1QB upregulation.\",\n      \"method\": \"Luciferase reporter assay, RNA pulldown, functional knockdown/overexpression assays in melanoma cells\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanistic assays (luciferase, pulldown, rescue experiments) in a single lab\",\n      \"pmids\": [\"34915882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Silencing C1QB in monocytes inhibits their differentiation into macrophages, reducing macrophage numbers; in a rat T1DM model, C1QB knockdown reduced macrophage infiltration in pancreatic islets and alleviated β-cell damage, establishing C1QB as a regulator of monocyte-to-macrophage differentiation.\",\n      \"method\": \"siRNA-mediated knockdown in cultured monocytes and lymphocytes; in vivo knockdown in rat T1DM model; cell counting and functional assays\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular phenotype replicated in vitro and in vivo, single lab\",\n      \"pmids\": [\"36464147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"C1QB-expressing M2 macrophages mediate cholesterol efflux that induces an immunosuppressive/exhausted state in CD8+ T cells, inhibiting CAR-T cell cytotoxicity; interactions via LGALS9-HAVCR2, CD86-CTLA4, and NECTIN2-TIGIT pathways are enhanced during disease progression.\",\n      \"method\": \"Single-cell RNA sequencing of patient samples; correlation of C1QB+ macrophage proportion with CAR-T resistance; in vitro cholesterol efflux and CD8+ T cell exhaustion assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — scRNA-seq with in vitro functional validation of cholesterol efflux mechanism, single lab\",\n      \"pmids\": [\"38890370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TCF7L2 directly binds the C1QB promoter and positively regulates C1QB expression; lentivirus-mediated knockdown of Tcf7l2 in a kainic acid epilepsy mouse model reduced C1qb overexpression, attenuated microglial activation, and ameliorated neuronal injury, establishing a TCF7L2→C1QB→synaptic pruning/neuronal injury axis in epilepsy.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, lentivirus-mediated knockdown in kainic acid mouse epilepsy model, immunohistochemistry\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP + luciferase reporter (direct transcriptional mechanism) + in vivo rescue with defined phenotypic readout\",\n      \"pmids\": [\"41534674\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C1QB encodes the B-chain of the complement C1q complex, which is required for C1q assembly and secretion (loss of C1qB abolishes functional C1q); it is expressed predominantly in microglia/macrophages in the brain, where its transcription is positively regulated by COX-2 activity and the TCF7L2 transcription factor (via direct promoter binding), negatively regulated by TGF-β1 signaling, and post-transcriptionally regulated by the IRF4–TEX41–miR-103a-3p axis; functionally, C1QB promotes monocyte-to-macrophage differentiation, participates in complement-mediated synaptic pruning associated with neuronal injury, and in the tumor microenvironment, C1QB-expressing macrophages drive CD8+ T cell exhaustion through cholesterol efflux.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"The C1QB gene encodes the B-chain polypeptide of human complement subcomponent C1q. The three genes encoding C1q A-, B-, and C-chains are aligned in the order A-C-B on a 24 kb stretch of DNA on chromosome 1p, each containing one intron located within a codon for a glycine residue in the collagen-like region. The B-chain collagen-like region participates in the triple-helical stalk structure of C1q.\",\n      \"method\": \"cDNA cloning, genomic cosmid library isolation, Southern blot, DNA sequencing\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original structural/genomic characterization with sequencing and Southern blot, foundational paper\",\n      \"pmids\": [\"1706597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1979,\n      \"finding\": \"The complete amino acid sequence of the collagen-like region of the C1q B-chain was determined; the B-chain has an alanine residue at position B-9 where glycine would be expected in the Gly-X-Y collagen repeat, representing a break in the collagen-like sequence.\",\n      \"method\": \"Protein sequencing of pepsin-derived collagen-like fragments\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct protein sequencing of purified fragment\",\n      \"pmids\": [\"486087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1976,\n      \"finding\": \"Partial pepsin digestion of human C1q revealed that the B-chain collagen-like region (N-terminal ~91 residues) is disulfide-linked to the A-chain collagen-like region via a single disulfide bond between residue B2-B6, forming an A-B heterodimer that constitutes part of the collagen-like stalk of C1q.\",\n      \"method\": \"Pepsin digestion, CM-cellulose chromatography, SDS-PAGE, amino acid composition analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical characterization with purified fragments and sequence data\",\n      \"pmids\": [\"7240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of the C1q globular head domain (gC1q) resolved to 1.9 Å revealed a compact heterotrimeric assembly of the C-terminal regions of A, B, and C chains held together mainly by non-polar interactions, with a Ca2+ ion bound at the top. The B-chain globular head (ghB) contributes to ligand recognition. Structural models suggest the gC1q heterotrimer is key to the versatile recognition properties of C1q.\",\n      \"method\": \"X-ray crystallography at 1.9 Å resolution, molecular modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional modeling, highly cited\",\n      \"pmids\": [\"12960167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mutational analysis of recombinant globular head modules showed that charged residues on the ghB module (side of the ghB) are crucial for C1q binding to IgG1, C-reactive protein, and pentraxin 3. The ghB module has specific and differential binding properties, and a set of charged residues from the apex of the gC1q heterotrimer (with participation of all three chains including ghB) mediate ionic and hydrogen bonds with ligands.\",\n      \"method\": \"Recombinant expression of globular head modules, site-directed mutagenesis, binding assays (ELISA, SPR)\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis + multiple binding assays, replicated across three ligands\",\n      \"pmids\": [\"16566583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The globular head region of C1q (including contributions from the B-chain) mediates binding to pentraxin 3 (PTX3), as shown by experiments with recombinant individual globular head modules of A, B, and C chains. C1q binding to PTX3 activates the classical complement pathway via C4 deposition, and enhances C1q binding to apoptotic cells; however, fluid-phase PTX3 pre-incubated with C1q inhibits complement activation.\",\n      \"method\": \"Recombinant globular head domain binding assays, C4 deposition assay, apoptotic cell binding experiments\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays with recombinant domains plus functional complement activation readout\",\n      \"pmids\": [\"12645945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The globular domain of C1q (including the B-chain globular head) binds phosphatidylserine (PS) on apoptotic cells specifically and avidly (KD = 3.7–7 × 10−8 M) through multiple interactions between its globular domain and the phosphoserine group of PS, demonstrated by cosedimentation, surface plasmon resonance, X-ray crystallography, and confocal microscopy showing colocalization of C1q with PS in membrane patches at early stages of apoptosis.\",\n      \"method\": \"Surface plasmon resonance, cosedimentation, X-ray crystallography, confocal microscopy, annexin V competition assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods including structural validation and binding kinetics\",\n      \"pmids\": [\"18250442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"The binding site for C1q on IgG was localized to three residues in the CH2 domain (Glu318, Lys320, Lys322 in mouse IgG2b); a peptide mimic of this sequence inhibits complement lysis, establishing that the C1q B-chain globular head (among other gC1q chains) contacts this conserved IgG motif.\",\n      \"method\": \"Systematic surface residue mutagenesis of IgG2b, complement lysis inhibition with peptide mimics\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis plus functional peptide inhibition assay\",\n      \"pmids\": [\"3258649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structures of C1 bound to IgG1 hexamers revealed that C1q arms (formed by the A, B, and C chains including the B-chain) condense upon antibody binding, inducing rearrangements of C1r2s2 proteases and tilting C1q's cone-shaped stalk, providing a structural mechanism for how danger pattern recognition activates complement. Distinct C1q binding sites on the two Fc-CH2 domains of each IgG were identified, including previously unknown interactions, validated by functional IgG1 mutant analysis.\",\n      \"method\": \"Cryo-electron microscopy, IgG1 mutant functional analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure plus mutagenesis functional validation\",\n      \"pmids\": [\"29449492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IgG antibodies form ordered hexamers via specific noncovalent Fc-Fc interactions after antigen binding on cell surfaces, and these hexamers recruit and activate C1 (which requires C1q including the B-chain) to trigger the complement cascade. Manipulating Fc-Fc interactions modulated complement activation and target cell killing across all four human IgG subclasses.\",\n      \"method\": \"Cell surface complement activation assays, electron microscopy, native MS, mutagenesis of Fc segments\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods, mechanistic model for C1q/C1qB activation\",\n      \"pmids\": [\"24626930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"HIV-1 activates the classical complement pathway independent of antibody through direct binding of C1q to specific sites in the transmembrane glycoprotein gp41 (residues 591–605 and 601–620). Soluble gp41 bound C1q and activated the C1 complex (C1q+C1r+C1s) in a dose- and time-dependent manner; gp120 was ineffective. The C1q interaction with gp41 is mediated through the recognition function shared by the A, B, and C chains of C1q.\",\n      \"method\": \"Radiolabeled C1q binding, gel exclusion chromatography, C1 complex reconstitution and activation assay, synthetic peptide inhibition\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstituted C1 complex assay plus peptide mapping\",\n      \"pmids\": [\"1744579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"C1qB mRNA in rat brain is expressed specifically in microglia-macrophages (identified by CR3 immunoreactivity) and is upregulated in response to cortical deafferentation and excitotoxic lesions, establishing microglia as the primary source of C1qB in brain injury responses.\",\n      \"method\": \"In situ hybridization, immunohistochemistry (CR3 co-localization), Northern blot\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct co-localization by ISH + IHC in multiple lesion models\",\n      \"pmids\": [\"1426121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TGF-β1 decreases C1qB mRNA expression in rat brain cortex and hippocampus in vivo (after intraventricular infusion) and in cultured glia, establishing a regulatory link between TGF-β1 signaling in microglia and complement C1qB gene expression.\",\n      \"method\": \"Intraventricular TGF-β1 infusion in rats, primary microglia culture treatment, Northern blot/in situ hybridization quantification\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro convergent evidence with dose-dependent response\",\n      \"pmids\": [\"11074155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Neuronal overexpression of human COX-2 in transgenic mice selectively induces C1qB expression in neurons (without inducing C3 or C4), and this induction is reduced by treatment with the selective COX-2 inhibitor nimesulide, placing COX-2-mediated inflammatory signaling upstream of neuronal C1qB expression.\",\n      \"method\": \"Transgenic mouse model, COX-2 inhibitor treatment (nimesulide), Northern blot/in situ hybridization for C1qB mRNA\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic gain-of-function and pharmacological inhibition in vivo\",\n      \"pmids\": [\"11810182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Silencing C1QB in monocytes inhibited their differentiation into macrophages and reduced macrophage numbers both in vitro and in a rat model of type 1 diabetes mellitus, demonstrating that C1QB is functionally required for monocyte-to-macrophage differentiation and for macrophage accumulation in pancreatic islets causing β-cell damage.\",\n      \"method\": \"C1QB siRNA knockdown in cultured monocytes, lentiviral knockdown in streptozotocin-induced T1DM rat model, cell counting, histology\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in vitro and in vivo with defined cellular phenotype\",\n      \"pmids\": [\"36464147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A novel homozygous splicing mutation in C1QB (c.187+1G>T) causes complete C1q deficiency in a Japanese patient, demonstrating that the C1QB B-chain is essential for assembly and secretion of functional C1q protein.\",\n      \"method\": \"Clinical genetics, PCR-based mutation identification, complement functional assays (persistent hypocomplementemia with normal C3/C4)\",\n      \"journal\": \"Pediatric rheumatology online journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function mutation with defined protein-level consequence\",\n      \"pmids\": [\"24160257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A homozygous non-coding mutation two nucleotides before the splice site of the second exon of C1QB causes complete absence of C1qB mRNA and intracellular C1qB protein, with secondary reduction of C1qA mRNA (but not C1qC), resulting in complete C1q deficiency. This demonstrates that C1qB is required for stable C1qA expression and for C1q complex assembly.\",\n      \"method\": \"Deep sequencing, ELISA, hemolytic assay, Western blot, qPCR of C1qA/B/C mRNAs, in silico splice-site analysis\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal molecular methods in patient-derived cells establishing chain-interdependence\",\n      \"pmids\": [\"25454803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TCF7L2 directly binds the C1QB promoter and positively regulates C1QB transcription; lentiviral knockdown of Tcf7l2 in a kainic acid-induced epilepsy mouse model reduced C1qb overexpression, attenuated microglial activation, and ameliorated neuronal injury, establishing a TCF7L2→C1QB regulatory axis that promotes synaptic pruning-dependent neuronal damage in epilepsy.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, lentiviral Tcf7l2 knockdown in kainic acid epilepsy mouse model, immunohistochemistry, neuronal injury quantification\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + reporter for direct binding, in vivo knockdown with defined phenotypic readout\",\n      \"pmids\": [\"41534674\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C1QB encodes the B-chain of complement subcomponent C1q, which assembles with the A- and C-chains into a heterotrimeric globular head domain (gC1q) and collagen-like stalk; the B-chain globular head contributes essential charged residues for binding diverse ligands including IgG (Fc-CH2 domain), C-reactive protein, pentraxin 3, and phosphatidylserine on apoptotic cells, and upon hexameric IgG-antigen complex recognition the C1q arms condense to activate C1r2s2 proteases and initiate the classical complement cascade; in the brain, C1qB is expressed primarily in microglia and is regulated upstream by TGF-β1 (suppression) and COX-2/TCF7L2 (induction), and C1qB is functionally required for monocyte-to-macrophage differentiation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"C1QB encodes the B-chain of the complement C1q heterotrimer and is essential for C1q complex assembly and secretion, as loss-of-function mutations in C1QB abolish functional C1q despite preserved expression of C1qA and C1qC chains [PMID:25454803, PMID:24160257]. In the brain, C1QB is expressed predominantly by microglia/macrophages from embryonic development onward, where its transcription is positively regulated by COX-2 activity and TCF7L2 (which binds the C1QB promoter directly) and negatively regulated by TGF-β1, and it participates in complement-mediated synaptic pruning linked to neuronal injury in epilepsy models [PMID:1426121, PMID:11810182, PMID:41534674, PMID:11074155]. Beyond its classical complement role, C1QB promotes monocyte-to-macrophage differentiation, and in the tumor microenvironment C1QB-expressing macrophages drive CD8+ T-cell exhaustion through cholesterol efflux, contributing to immunotherapy resistance [PMID:36464147, PMID:38890370]. Homozygous loss-of-function mutations in C1QB cause hereditary C1q deficiency, a condition associated with susceptibility to systemic lupus erythematosus-like disease [PMID:25454803, PMID:24160257].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Identifying the cellular source of C1qB in the brain resolved whether neurons, astrocytes, or microglia produce complement components locally, establishing microglia/macrophages as the principal C1qB-expressing cells after cortical injury.\",\n      \"evidence\": \"In situ hybridization combined with CR3 immunoreactivity colocalization in lesioned rat striatum\",\n      \"pmids\": [\"1426121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single injury model (cortical deafferentation); generalizability to other CNS insults not tested\", \"No functional consequence of microglial C1qB demonstrated\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstrating C1qB expression during embryonic brain development (E14 onward) in microglia/macrophages established that C1q has developmental roles beyond cytotoxic complement activation.\",\n      \"evidence\": \"Northern blot and in situ hybridization across rat embryonic and postnatal brain stages\",\n      \"pmids\": [\"7955342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Developmental function inferred but not tested by loss-of-function\", \"No protein-level confirmation\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showing that TGF-β1 suppresses C1qB mRNA both in vivo and in cultured glia established a negative regulatory pathway for complement expression in the CNS, suggesting anti-inflammatory cytokines limit local complement activation.\",\n      \"evidence\": \"Intraventricular TGF-β1 infusion in rats and primary microglia culture treatment with mRNA quantification\",\n      \"pmids\": [\"11074155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of TGF-β1-mediated repression (direct promoter effect vs. indirect) not defined\", \"Protein-level confirmation of C1qB reduction not shown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrating that neuronal COX-2 overexpression induces C1qB and that a COX-2 inhibitor reverses this induction placed prostaglandin signaling upstream of C1qB transcription, linking neuroinflammatory prostaglandin pathways to complement activation.\",\n      \"evidence\": \"Transgenic mice overexpressing hCOX-2 in neurons; pharmacological inhibition with nimesulide; mRNA quantification\",\n      \"pmids\": [\"11810182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific prostaglandin species and downstream transcription factor mediating the effect not identified\", \"Observed in neurons of transgenic mice, not confirmed in microglia or human cells\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that a homozygous splice-site mutation abolishing C1qB expression leads to complete C1q deficiency — despite preserved C1qA/C1qC — established that C1qB is indispensable for C1q heterotrimeric complex assembly and secretion.\",\n      \"evidence\": \"Deep sequencing, Western blot, qPCR, ELISA, and hemolytic complement assay in patient-derived cells\",\n      \"pmids\": [\"25454803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether C1qA/C1qC are degraded intracellularly or secreted as non-functional monomers not fully resolved\", \"Structural basis for why all three chains are required for assembly not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Elucidating the IRF4→TEX41→miR-103a-3p axis as a post-transcriptional regulator of C1QB expression in melanoma revealed a non-immune, tumor-cell-intrinsic role for C1QB in promoting proliferation and invasion.\",\n      \"evidence\": \"Luciferase reporter assays, RNA pulldown, knockdown/overexpression rescue experiments in melanoma cell lines\",\n      \"pmids\": [\"34915882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which C1QB protein promotes melanoma cell proliferation (complement-dependent vs. independent) not defined\", \"Findings limited to melanoma cell lines; in vivo validation lacking\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that C1QB silencing blocks monocyte-to-macrophage differentiation and reduces macrophage infiltration in diabetic pancreatic islets established C1QB as a functional regulator of myeloid cell fate beyond its structural role in complement.\",\n      \"evidence\": \"siRNA knockdown in cultured monocytes; in vivo knockdown in a rat T1DM model with cell counting and functional assays\",\n      \"pmids\": [\"36464147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking C1QB to differentiation signaling not identified\", \"Whether effect is C1q-complex-dependent or C1qB-chain-autonomous not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying C1QB-expressing M2 macrophages as drivers of CD8+ T-cell exhaustion via cholesterol efflux connected C1QB to immune evasion in the tumor microenvironment and explained a mechanism of CAR-T cell resistance.\",\n      \"evidence\": \"Single-cell RNA-seq of patient samples; in vitro cholesterol efflux and T-cell exhaustion assays; correlation with CAR-T resistance\",\n      \"pmids\": [\"38890370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether C1QB directly mediates cholesterol efflux or is a marker of the macrophage subset responsible is unclear\", \"Causal link between C1QB itself and the LGALS9–HAVCR2/CD86–CTLA4/NECTIN2–TIGIT checkpoint pathways not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrating that TCF7L2 directly binds the C1QB promoter and that its knockdown reduces C1qB overexpression, microglial activation, and neuronal injury in epilepsy established a transcription-factor-level control node for complement-mediated synaptic pruning in disease.\",\n      \"evidence\": \"ChIP and luciferase reporter assay for direct promoter binding; lentivirus-mediated Tcf7l2 knockdown in kainic acid mouse epilepsy model with immunohistochemistry\",\n      \"pmids\": [\"41534674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TCF7L2 regulation of C1QB generalizes beyond epilepsy to other neurodegenerative conditions not tested\", \"Downstream synaptic targets of C1q-mediated pruning not molecularly defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether C1QB's roles in macrophage differentiation and tumor immune evasion depend on the assembled C1q complex or represent chain-autonomous functions, and the structural basis for obligate heterotrimerization of C1q chains is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution studies distinguishing C1qB chain-autonomous vs. C1q-complex-dependent signaling\", \"No structural model of how C1qB loss prevents C1q assembly\", \"Mechanism linking C1QB to monocyte differentiation signaling uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5, 8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 9]}\n    ],\n    \"complexes\": [\"C1q complex\"],\n    \"partners\": [\"C1QA\", \"C1QC\", \"TCF7L2\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"C1QB encodes the B-chain of complement subcomponent C1q, an essential structural and functional constituent of the classical complement pathway that assembles with the A- and C-chains into a heterotrimeric globular head (gC1q) atop a collagen-like stalk [PMID:1706597, PMID:12960167]. Charged residues on the B-chain globular head mediate differential recognition of IgG, C-reactive protein, pentraxin 3, and phosphatidylserine on apoptotic cells, and upon engagement of hexameric IgG–antigen complexes the C1q arms condense to activate C1r₂s₂ proteases and initiate the complement cascade [PMID:16566583, PMID:29449492, PMID:18250442]. Loss-of-function mutations in C1QB abolish C1q assembly and secretion, causing complete C1q deficiency, and additionally destabilize C1qA expression, demonstrating that the B-chain is indispensable for heterotrimeric complex integrity [PMID:25454803, PMID:24160257]. Beyond innate immunity, C1QB is expressed in microglia under transcriptional control by TGF-β1 (suppressive) and the TCF7L2/COX-2 axis (inductive), and is functionally required for monocyte-to-macrophage differentiation [PMID:1426121, PMID:11074155, PMID:41534674, PMID:36464147].\",\n  \"teleology\": [\n    {\n      \"year\": 1976,\n      \"claim\": \"Establishing the quaternary organization of C1q required identifying inter-chain disulfide linkages; pepsin digestion showed that the B-chain collagen-like region forms a disulfide-linked A–B heterodimer, defining the basic subunit architecture of the collagen-like stalk.\",\n      \"evidence\": \"Pepsin digestion, chromatography, SDS-PAGE of purified human C1q\",\n      \"pmids\": [\"7240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise disulfide positions not resolved to single cysteine residues\", \"Stoichiometry of the full hexameric assembly not addressed\"]\n    },\n    {\n      \"year\": 1979,\n      \"claim\": \"Complete sequencing of the B-chain collagen-like region revealed a break in the Gly-X-Y repeat (Ala at position B-9), providing the first evidence that the collagen-like stalk of C1q has built-in flexibility sites that could affect its conformational dynamics.\",\n      \"evidence\": \"Protein sequencing of pepsin-derived collagen-like fragments\",\n      \"pmids\": [\"486087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of the Gly→Ala disruption not tested\", \"Complete primary structure of the globular domain not yet determined\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Mapping the IgG binding site on C1q required identifying the cognate residues on the antibody; mutagenesis localized the C1q contact to Glu318/Lys320/Lys322 in the IgG CH2 domain, confirming that the gC1q heterotrimer (including ghB) engages a conserved ionic motif on immunoglobulins.\",\n      \"evidence\": \"Systematic surface mutagenesis of mouse IgG2b, complement lysis inhibition with synthetic peptides\",\n      \"pmids\": [\"3258649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The specific C1q residues contacting these IgG residues were not identified\", \"Applicability across all human IgG subclasses not tested\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Cloning of the C1QB gene and its genomic context established the A-C-B gene cluster on chromosome 1p and revealed a shared intron placement within the collagen-like coding region, suggesting coordinated evolution of the three chains; separately, direct binding of C1q to HIV-1 gp41 demonstrated antibody-independent activation of the classical pathway by a viral target.\",\n      \"evidence\": \"cDNA cloning/genomic sequencing for gene structure; radiolabeled C1q binding and reconstituted C1 complex activation for gp41 interaction\",\n      \"pmids\": [\"1706597\", \"1744579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional regulatory elements of C1QB not characterized\", \"Whether gp41-C1q activation benefits host or virus was unresolved\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"The cellular source of C1qB in the brain was unknown; in situ hybridization co-localized C1qB mRNA with CR3-positive microglia and showed upregulation after cortical injury, establishing microglia as the primary C1qB-expressing cell type in the CNS.\",\n      \"evidence\": \"In situ hybridization and immunohistochemistry in rat brain lesion models\",\n      \"pmids\": [\"1426121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of microglial C1qB in synaptic remodeling not yet tested\", \"Neuronal expression under pathological conditions not excluded\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Upstream regulation of C1qB in the brain was undefined; TGF-β1 was shown to suppress C1qB mRNA both in vivo (intraventricular infusion) and in cultured microglia, identifying the first negative transcriptional regulator of C1qB in the CNS.\",\n      \"evidence\": \"Intraventricular TGF-β1 infusion in rats and primary microglia culture with Northern blot quantification\",\n      \"pmids\": [\"11074155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter mechanism of TGF-β1-mediated repression not characterized\", \"Whether TGF-β1 acts through SMAD signaling on the C1QB promoter was unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolving the atomic structure of the gC1q heterotrimer at 1.9 Å revealed how the A, B, and C globular heads assemble with a Ca²⁺ ion and provided the framework for understanding how a single trimeric module recognizes structurally diverse ligands including pentraxin 3.\",\n      \"evidence\": \"X-ray crystallography; recombinant globular head binding assays and C4 deposition assay for PTX3\",\n      \"pmids\": [\"12960167\", \"12645945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length C1q structure not resolved\", \"Mechanism by which PTX3 switches between complement activation and inhibition was unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Site-directed mutagenesis of individual ghB residues showed that specific charged amino acids on the B-chain globular head are differentially required for binding IgG1, CRP, and PTX3, demonstrating that C1q versatility arises from overlapping but distinct contact surfaces on the same heterotrimer.\",\n      \"evidence\": \"Recombinant globular head modules, site-directed mutagenesis, ELISA and SPR binding assays\",\n      \"pmids\": [\"16566583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Complete binding footprint with full-length ligands not determined\", \"Contribution of avidity from six gC1q heads not quantified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The identity of the C1q receptor for apoptotic cell clearance was debated; direct binding of the gC1q domain to phosphatidylserine was demonstrated with nanomolar affinity and structural validation, establishing PS as a key eat-me signal recognized by C1q.\",\n      \"evidence\": \"SPR kinetics, cosedimentation, X-ray crystallography, confocal microscopy with annexin V competition\",\n      \"pmids\": [\"18250442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of PS versus other apoptotic ligands in vivo not quantified\", \"Downstream signaling linking C1q-PS engagement to phagocytosis not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"How C1q is activated on target cells was a long-standing question; the discovery that IgG forms ordered hexamers via Fc–Fc contacts on antigen-bearing surfaces, and that these hexamers are the physiological unit recruiting C1, explained the stoichiometric requirement for complement activation; concurrently, patient mutations confirmed that C1QB loss-of-function causes complete C1q deficiency with secondary C1qA destabilization.\",\n      \"evidence\": \"Cell surface complement assays, EM, native MS, Fc mutagenesis; deep sequencing, hemolytic/ELISA assays and qPCR in patient-derived cells\",\n      \"pmids\": [\"24626930\", \"25454803\", \"24160257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether non-immune C1q ligands also require multivalent display was unknown\", \"Genotype–phenotype correlation for distinct C1QB mutations not systematically established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The structural mechanism coupling ligand recognition to protease activation was resolved when cryo-EM of the C1–IgG1 hexamer complex showed that antibody binding induces arm condensation and stalk tilting, transmitting a conformational change to the C1r₂s₂ proteases.\",\n      \"evidence\": \"Cryo-EM structural analysis complemented by functional IgG1 mutant validation\",\n      \"pmids\": [\"29449492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamic intermediates of the activation transition not captured\", \"Structural basis for how non-IgG ligands activate C1 remained unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"C1QB was known as a complement component but its role in myeloid cell fate was unexplored; siRNA and lentiviral knockdown demonstrated that C1QB is required for monocyte-to-macrophage differentiation and for macrophage-mediated β-cell damage in a type 1 diabetes model.\",\n      \"evidence\": \"C1QB siRNA in cultured monocytes; lentiviral knockdown in streptozotocin-induced T1DM rats with histological quantification\",\n      \"pmids\": [\"36464147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which C1QB promotes differentiation (autocrine signaling vs. complement activation) not defined\", \"Whether other C1q chains are equally required was not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A direct transcriptional activator of C1QB was identified: TCF7L2 binds the C1QB promoter and drives its expression in the epileptic brain, linking Wnt/TCF signaling to complement-mediated synaptic pruning and neuronal damage.\",\n      \"evidence\": \"ChIP, luciferase reporter assay, lentiviral Tcf7l2 knockdown in kainic acid epilepsy mouse model with immunohistochemistry\",\n      \"pmids\": [\"41534674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TCF7L2 regulation of C1QB operates in non-CNS tissues is unknown\", \"Interaction between TGF-β1 suppression and TCF7L2 activation at the promoter level not studied\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for how non-antibody ligands (CRP, PTX3, PS) activate or modulate the C1r₂s₂ protease arm, the mechanism by which C1QB promotes monocyte-to-macrophage differentiation independently of canonical complement activation, and how the opposing TGF-β1 and TCF7L2 regulatory inputs are integrated at the C1QB promoter.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No cryo-EM or structural data for C1q bound to non-IgG ligands\", \"Cell-intrinsic versus complement-dependent role of C1QB in myeloid differentiation unresolved\", \"Promoter architecture and combinatorial transcription factor binding not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [4, 5, 6, 7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 6, 8, 10]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5, 7, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 15, 16]}\n    ],\n    \"complexes\": [\n      \"C1 complex (C1q:C1r2:C1s2)\",\n      \"C1q heterotrimer (A:B:C chains)\"\n    ],\n    \"partners\": [\n      \"C1QA\",\n      \"C1QC\",\n      \"C1R\",\n      \"C1S\",\n      \"PTX3\",\n      \"CRP\",\n      \"TCF7L2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}