{"gene":"C1QB","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":1992,"finding":"C1qB mRNA in lesioned rat striatum was colocalized to cells immunoreactive for CR3, identifying microglia-macrophages as the cellular source of C1qB expression in the brain following cortical deafferentation.","method":"In situ hybridization combined with immunoreactivity for CR3 (complement receptor on microglia-macrophages)","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct colocalization by two orthogonal methods (ISH + immunohistochemistry), single lab, establishes cell-type identity of C1qB expression","pmids":["1426121"],"is_preprint":false},{"year":1994,"finding":"C1qB mRNA is expressed in microglia/macrophages (not in neurogenic ventricular or sub-ventricular zones) during rat brain development from embryonic day 14 onward, and its widespread distribution does not correlate anatomically with apoptotic profiles, arguing against a role for C1q in programmed cell death during brain development.","method":"Northern blot and in situ hybridization during rat brain development","journal":"Brain research. Developmental brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (northern blot + ISH) in a single lab establishing cell-type localization and a negative functional finding","pmids":["7955342"],"is_preprint":false},{"year":1994,"finding":"Elevations of C1qB mRNA after kainate-induced neuronal injury in vivo were blocked by barbiturates that prevented seizures and neurodegeneration, and a subpopulation of cultured hippocampal neurons that survived glutamate toxicity in vitro also showed parallel elevations of C1qB mRNA, placing C1qB induction downstream of excitotoxic neuronal injury.","method":"In vivo kainate lesion model with barbiturate blockade; primary hippocampal neuronal cultures treated with glutamate","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis in vivo plus in vitro model, single lab, two orthogonal experimental contexts","pmids":["7870303"],"is_preprint":false},{"year":2000,"finding":"TGF-β1 decreases C1qB mRNA levels in rat cortex, hippocampus, and cultured glia, establishing TGF-β1 as a negative regulator of C1qB expression in microglia; microglia were identified as the main cell type containing TGF-β1 and its receptors after entorhinal cortex lesion by immunocytochemistry combined with in situ hybridization.","method":"Intraventricular infusion of TGF-β1 in vivo; primary microglia cultures; immunocytochemistry combined with in situ hybridization; entorhinal cortex lesion model","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro experiments, multiple methods (ISH, immunocytochemistry, primary cultures), single lab","pmids":["11074155"],"is_preprint":false},{"year":2001,"finding":"Neuronal overexpression of human COX-2 in transgenic mice selectively induced endogenous C1qB expression in neurons, and treatment with the COX-2 inhibitor nimesulide reduced this hCOX-2-mediated induction of hippocampal C1qB mRNA, placing COX-2 activity upstream of C1qB gene expression in neurons.","method":"Transgenic mouse model (neuronal hCOX-2 overexpression); COX-2 inhibitor treatment; mRNA quantification","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic overexpression plus pharmacological inhibition in vivo, single lab, two orthogonal approaches","pmids":["11810182"],"is_preprint":false},{"year":2013,"finding":"A novel homozygous splicing mutation in C1qB (c.187+1G>T) was identified in a Japanese girl with complete C1q deficiency, demonstrating that loss-of-function mutations in C1qB are sufficient to abolish C1q activity and cause immunodeficiency/SLE-like disease.","method":"Genetic sequencing (identification of homozygous splice-site mutation); clinical complement assays","journal":"Pediatric rheumatology online journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single case report with mutation identification but no in vitro functional reconstitution of splicing defect","pmids":["24160257"],"is_preprint":false},{"year":2014,"finding":"A novel homozygous non-coding mutation in C1qB (two nucleotides before the splice site of exon 2) caused complete absence of C1qB mRNA and intracellular C1qB protein, reduced C1qA mRNA, and total loss of C1q production, demonstrating that C1qB is required for assembly and secretion of the complete C1q complex.","method":"Deep sequencing; ELISA and hemolytic assay for C1q; western blot of C1q chains in cell lysates; qPCR of C1qA, C1qB, and C1qC mRNA; in silico splice-site analysis","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (deep sequencing, western blot, ELISA, qPCR) in a single patient/lab establishing mechanistic link between C1qB loss and C1q assembly failure","pmids":["25454803"],"is_preprint":false},{"year":2022,"finding":"Silencing C1qB in cultured monocytes inhibited their differentiation into macrophages and reduced macrophage numbers; in a kainic acid-induced rat model of type 1 diabetes, C1qB knockdown reduced macrophage numbers in pancreatic islets and alleviated β-cell damage, placing C1qB as a functional regulator of monocyte-to-macrophage differentiation.","method":"C1qB siRNA silencing in cultured monocytes/lymphocytes; in vivo lentiviral knockdown in a rat T1DM model; cell counting and histological assessment of β-cell damage","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in vitro and in vivo with defined cellular phenotype, single lab, two experimental contexts","pmids":["36464147"],"is_preprint":false},{"year":2026,"finding":"TCF7L2 directly binds the C1qB promoter and positively regulates C1qB expression; lentiviral knockdown of Tcf7l2 in a kainic acid-induced epilepsy mouse model reversed C1qb overexpression, attenuated microglial activation, and ameliorated neuronal injury, establishing a TCF7L2→C1qB regulatory axis that drives synaptic pruning-dependent neuronal damage in epilepsy.","method":"Chromatin immunoprecipitation (ChIP); luciferase reporter assay; lentivirus-mediated Tcf7l2 knockdown in a kainic acid epilepsy mouse model; assessment of microglial activation and neuronal injury","journal":"Brain research bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase assays establish direct promoter binding (Tier 1 elements), combined with in vivo epistasis; single lab","pmids":["41534674"],"is_preprint":false},{"year":2025,"finding":"Single-nucleus RNA sequencing of human hippocampus revealed that C1QA/B/C genes are exclusively expressed in microglia (not in other brain cell types), and C1QB expression is upregulated in Alzheimer's disease microglia compared to non-demented controls, with female microglia showing higher baseline C1QA/B/C expression than male microglia.","method":"Single-nucleus RNA sequencing (snRNA-seq) of 398,097 nuclei from 48 human hippocampal samples; integrated atlas analysis","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — large-scale transcriptomic atlas, no direct functional validation of C1QB protein activity; preprint, single study","pmids":[],"is_preprint":true}],"current_model":"C1QB encodes the B-chain of the C1q complement subcomponent and is expressed exclusively in microglia/macrophages in the brain; it is required for C1q complex assembly and secretion (loss of C1qB abolishes C1q production), its transcription is positively regulated by TCF7L2 (via direct promoter binding) and by COX-2 activity, and negatively regulated by TGF-β1; functionally, C1qB promotes monocyte-to-macrophage differentiation and, when overexpressed in epilepsy or neurodegeneration, drives microglial activation and synaptic pruning-dependent neuronal injury."},"narrative":{"mechanistic_narrative":"C1QB encodes the B-chain of the C1q complement subcomponent and is expressed by microglia/macrophages, identified as the cellular source of brain C1qB expression following injury [PMID:1426121, PMID:7955342]. C1qB is required for assembly and secretion of the complete C1q complex: a homozygous non-coding mutation abolishing C1qB mRNA and intracellular protein also reduced C1qA mRNA and produced total loss of C1q production [PMID:25454803]. Its transcription is dynamically controlled — induced downstream of excitotoxic neuronal injury [PMID:7870303] and by neuronal COX-2 activity [PMID:11810182], positively regulated by direct TCF7L2 binding to the C1qB promoter [PMID:41534674], and negatively regulated by TGF-β1 in microglia [PMID:11074155]. Functionally, C1qB promotes monocyte-to-macrophage differentiation, with knockdown reducing macrophage numbers and alleviating tissue damage in a diabetes model [PMID:36464147], and a TCF7L2→C1qB axis drives microglial activation and synaptic pruning-dependent neuronal injury in epilepsy [PMID:41534674]. Loss-of-function C1qB mutations cause complete C1q deficiency with immunodeficiency/SLE-like disease [PMID:25454803].","teleology":[{"year":1992,"claim":"Established which brain cell type produces C1qB, a prerequisite for interpreting its role in CNS injury and inflammation.","evidence":"In situ hybridization with CR3 immunoreactivity in lesioned rat striatum","pmids":["1426121"],"confidence":"Medium","gaps":["Does not address C1qB function or whether secreted C1q is assembled locally","Single injury model in one species"]},{"year":1994,"claim":"Defined the developmental expression pattern of C1qB and argued against a role in programmed cell death, narrowing its candidate functions during brain development.","evidence":"Northern blot and in situ hybridization across rat brain development","pmids":["7955342"],"confidence":"Medium","gaps":["Negative correlation does not exclude injury-specific roles","No loss-of-function test"]},{"year":1994,"claim":"Placed C1qB induction causally downstream of excitotoxic neuronal injury, linking its expression to neurodegenerative signaling rather than constitutive baseline.","evidence":"Kainate lesion with barbiturate blockade in vivo plus glutamate-treated hippocampal cultures","pmids":["7870303"],"confidence":"Medium","gaps":["Upstream inducing signal not molecularly identified","Whether C1qB induction is protective or injurious unresolved"]},{"year":2000,"claim":"Identified TGF-β1 as a negative regulator of microglial C1qB expression, defining a cytokine input controlling C1qB transcription.","evidence":"Intraventricular TGF-β1 infusion in vivo and primary microglia cultures with ISH/immunocytochemistry","pmids":["11074155"],"confidence":"Medium","gaps":["Direct vs indirect transcriptional mechanism not resolved","No promoter-level evidence"]},{"year":2001,"claim":"Positioned COX-2 activity upstream of C1qB expression, connecting prostaglandin signaling to complement induction in neurons.","evidence":"Neuronal hCOX-2 transgenic mice with COX-2 inhibitor treatment and mRNA quantification","pmids":["11810182"],"confidence":"Medium","gaps":["Mechanistic intermediary between COX-2 and C1qB transcription unknown","Neuronal C1qB expression here contrasts with microglial source"]},{"year":2013,"claim":"Demonstrated that C1qB loss-of-function mutations cause complete C1q deficiency and SLE-like disease, establishing clinical consequence of C1qB loss.","evidence":"Genetic sequencing and clinical complement assays in a patient with complete C1q deficiency","pmids":["24160257"],"confidence":"Low","gaps":["No in vitro functional reconstitution of the splicing defect","Single case report"]},{"year":2014,"claim":"Showed that C1qB is mechanistically required for assembly and secretion of the entire C1q complex, not merely a passive subunit.","evidence":"Deep sequencing, western blot, ELISA, hemolytic assay and qPCR of C1q chains in a patient","pmids":["25454803"],"confidence":"Medium","gaps":["Single patient","Structural basis of assembly dependence not defined"]},{"year":2022,"claim":"Assigned C1qB a functional role in promoting monocyte-to-macrophage differentiation with disease relevance beyond the CNS.","evidence":"siRNA silencing in cultured monocytes and lentiviral knockdown in a rat T1DM model with histological assessment","pmids":["36464147"],"confidence":"Medium","gaps":["Molecular pathway linking C1qB to differentiation unknown","Single lab and model"]},{"year":2026,"claim":"Established a direct TCF7L2→C1qB transcriptional axis driving microglial activation and synaptic pruning-dependent neuronal injury in epilepsy.","evidence":"ChIP and luciferase reporter assays plus lentiviral Tcf7l2 knockdown in a kainic acid epilepsy mouse model","pmids":["41534674"],"confidence":"Medium","gaps":["Whether C1q-mediated pruning is the sole effector mechanism not isolated","Other promoter regulators not surveyed"]},{"year":2025,"claim":"Provided single-cell resolution confirming microglia-exclusive C1QB expression and upregulation in Alzheimer's disease with sex differences.","evidence":"Single-nucleus RNA sequencing of human hippocampus (preprint)","pmids":[],"confidence":"Low","gaps":["No functional validation of C1qB protein activity","Preprint, single study","Causal role in AD not tested"]},{"year":null,"claim":"How C1q produced by C1qB-expressing microglia mechanistically executes synaptic pruning and whether this is protective or pathogenic across disease contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of how C1qB drives C1q assembly","Effector pathway from C1q deposition to neuronal injury not isolated","Reconciliation of neuronal vs microglial C1qB expression unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,7]}],"complexes":["C1q complex"],"partners":["C1QA","C1QC","TCF7L2"],"other_free_text":[]}},"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},{"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},{"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},{"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":35,"is_preprint":false},{"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":27,"is_preprint":false},{"pmid":"7955342","id":"PMC_7955342","title":"Expression of complement C1qB and C4 mRNAs during rat brain development.","date":"1994","source":"Brain research. Developmental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/7955342","citation_count":26,"is_preprint":false},{"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},{"pmid":"11074155","id":"PMC_11074155","title":"Transforming growth factor-beta1 induces transforming growth factor-beta1 and transforming growth factor-beta receptor messenger RNAs and reduces complement C1qB messenger RNA in rat brain microglia.","date":"2000","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/11074155","citation_count":24,"is_preprint":false},{"pmid":"11810182","id":"PMC_11810182","title":"Induction of the complement component C1qB in brain of transgenic mice with neuronal overexpression of human cyclooxygenase-2.","date":"2001","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/11810182","citation_count":24,"is_preprint":false},{"pmid":"29331040","id":"PMC_29331040","title":"Jun, Gal, Cd74, and C1qb as potential indicator for neuropathic pain.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29331040","citation_count":21,"is_preprint":false},{"pmid":"24160257","id":"PMC_24160257","title":"The identification of a novel splicing mutation in C1qB in a Japanese family with C1q deficiency: a case report.","date":"2013","source":"Pediatric rheumatology online journal","url":"https://pubmed.ncbi.nlm.nih.gov/24160257","citation_count":17,"is_preprint":false},{"pmid":"25454803","id":"PMC_25454803","title":"Identification of a novel non-coding mutation in C1qB in a Dutch child with C1q deficiency associated with recurrent infections.","date":"2014","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/25454803","citation_count":14,"is_preprint":false},{"pmid":"34915882","id":"PMC_34915882","title":"IRF4-activated TEX41 promotes the malignant behaviors of melanoma cells by targeting miR-103a-3p/C1QB axis.","date":"2021","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34915882","citation_count":11,"is_preprint":false},{"pmid":"38447782","id":"PMC_38447782","title":"Identification of the C1qDC gene family in grass carp (Ctenopharyngodon idellus) and the response of C1qA, C1qB, and C1qC to GCRV infection in vivo and in vitro.","date":"2024","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38447782","citation_count":3,"is_preprint":false},{"pmid":"39109334","id":"PMC_39109334","title":"Causal relationship between complement C1QB and colorectal cancer: a drug target Mendelian randomization study.","date":"2024","source":"Frontiers in 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hippocampus","date":"2025-05-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.06.652374","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14679,"output_tokens":2573,"usd":0.041316,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9721,"output_tokens":2715,"usd":0.05824,"stage2_stop_reason":"end_turn"},"total_usd":0.099556,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"C1qB mRNA in lesioned rat striatum was colocalized to cells immunoreactive for CR3, identifying microglia-macrophages as the cellular source of C1qB expression in the brain following cortical deafferentation.\",\n      \"method\": \"In situ hybridization combined with immunoreactivity for CR3 (complement receptor on microglia-macrophages)\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct colocalization by two orthogonal methods (ISH + immunohistochemistry), single lab, establishes cell-type identity of C1qB expression\",\n      \"pmids\": [\"1426121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"C1qB mRNA is expressed in microglia/macrophages (not in neurogenic ventricular or sub-ventricular zones) during rat brain development from embryonic day 14 onward, and its widespread distribution does not correlate anatomically with apoptotic profiles, arguing against a role for C1q in programmed cell death during brain development.\",\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 / Moderate — two orthogonal methods (northern blot + ISH) in a single lab establishing cell-type localization and a negative functional finding\",\n      \"pmids\": [\"7955342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Elevations of C1qB mRNA after kainate-induced neuronal injury in vivo were blocked by barbiturates that prevented seizures and neurodegeneration, and a subpopulation of cultured hippocampal neurons that survived glutamate toxicity in vitro also showed parallel elevations of C1qB mRNA, placing C1qB induction downstream of excitotoxic neuronal injury.\",\n      \"method\": \"In vivo kainate lesion model with barbiturate blockade; primary hippocampal neuronal cultures treated with glutamate\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis in vivo plus in vitro model, single lab, two orthogonal experimental contexts\",\n      \"pmids\": [\"7870303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TGF-β1 decreases C1qB mRNA levels in rat cortex, hippocampus, and cultured glia, establishing TGF-β1 as a negative regulator of C1qB expression in microglia; microglia were identified as the main cell type containing TGF-β1 and its receptors after entorhinal cortex lesion by immunocytochemistry combined with in situ hybridization.\",\n      \"method\": \"Intraventricular infusion of TGF-β1 in vivo; primary microglia cultures; immunocytochemistry combined with in situ hybridization; entorhinal cortex lesion model\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro experiments, multiple methods (ISH, immunocytochemistry, primary cultures), single lab\",\n      \"pmids\": [\"11074155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Neuronal overexpression of human COX-2 in transgenic mice selectively induced endogenous C1qB expression in neurons, and treatment with the COX-2 inhibitor nimesulide reduced this hCOX-2-mediated induction of hippocampal C1qB mRNA, placing COX-2 activity upstream of C1qB gene expression in neurons.\",\n      \"method\": \"Transgenic mouse model (neuronal hCOX-2 overexpression); COX-2 inhibitor treatment; mRNA quantification\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic overexpression plus pharmacological inhibition in vivo, single lab, two orthogonal approaches\",\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) was identified in a Japanese girl with complete C1q deficiency, demonstrating that loss-of-function mutations in C1qB are sufficient to abolish C1q activity and cause immunodeficiency/SLE-like disease.\",\n      \"method\": \"Genetic sequencing (identification of homozygous splice-site mutation); clinical complement assays\",\n      \"journal\": \"Pediatric rheumatology online journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single case report with mutation identification but no in vitro functional reconstitution of splicing defect\",\n      \"pmids\": [\"24160257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A novel homozygous non-coding mutation in C1qB (two nucleotides before the splice site of exon 2) caused complete absence of C1qB mRNA and intracellular C1qB protein, reduced C1qA mRNA, and total loss of C1q production, demonstrating that C1qB is required for assembly and secretion of the complete C1q complex.\",\n      \"method\": \"Deep sequencing; ELISA and hemolytic assay for C1q; western blot of C1q chains in cell lysates; qPCR of C1qA, C1qB, and C1qC mRNA; in silico splice-site analysis\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (deep sequencing, western blot, ELISA, qPCR) in a single patient/lab establishing mechanistic link between C1qB loss and C1q assembly failure\",\n      \"pmids\": [\"25454803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Silencing C1qB in cultured monocytes inhibited their differentiation into macrophages and reduced macrophage numbers; in a kainic acid-induced rat model of type 1 diabetes, C1qB knockdown reduced macrophage numbers in pancreatic islets and alleviated β-cell damage, placing C1qB as a functional regulator of monocyte-to-macrophage differentiation.\",\n      \"method\": \"C1qB siRNA silencing in cultured monocytes/lymphocytes; in vivo lentiviral knockdown in a rat T1DM model; cell counting and histological assessment of β-cell damage\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in vitro and in vivo with defined cellular phenotype, single lab, two experimental contexts\",\n      \"pmids\": [\"36464147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TCF7L2 directly binds the C1qB promoter and positively regulates C1qB expression; lentiviral knockdown of Tcf7l2 in a kainic acid-induced epilepsy mouse model reversed C1qb overexpression, attenuated microglial activation, and ameliorated neuronal injury, establishing a TCF7L2→C1qB regulatory axis that drives synaptic pruning-dependent neuronal damage in epilepsy.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP); luciferase reporter assay; lentivirus-mediated Tcf7l2 knockdown in a kainic acid epilepsy mouse model; assessment of microglial activation and neuronal injury\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase assays establish direct promoter binding (Tier 1 elements), combined with in vivo epistasis; single lab\",\n      \"pmids\": [\"41534674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Single-nucleus RNA sequencing of human hippocampus revealed that C1QA/B/C genes are exclusively expressed in microglia (not in other brain cell types), and C1QB expression is upregulated in Alzheimer's disease microglia compared to non-demented controls, with female microglia showing higher baseline C1QA/B/C expression than male microglia.\",\n      \"method\": \"Single-nucleus RNA sequencing (snRNA-seq) of 398,097 nuclei from 48 human hippocampal samples; integrated atlas analysis\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — large-scale transcriptomic atlas, no direct functional validation of C1QB protein activity; preprint, single study\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"C1QB encodes the B-chain of the C1q complement subcomponent and is expressed exclusively in microglia/macrophages in the brain; it is required for C1q complex assembly and secretion (loss of C1qB abolishes C1q production), its transcription is positively regulated by TCF7L2 (via direct promoter binding) and by COX-2 activity, and negatively regulated by TGF-β1; functionally, C1qB promotes monocyte-to-macrophage differentiation and, when overexpressed in epilepsy or neurodegeneration, drives microglial activation and synaptic pruning-dependent neuronal injury.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C1QB encodes the B-chain of the C1q complement subcomponent and is expressed by microglia/macrophages, identified as the cellular source of brain C1qB expression following injury [#0, #1, #9]. C1qB is required for assembly and secretion of the complete C1q complex: a homozygous non-coding mutation abolishing C1qB mRNA and intracellular protein also reduced C1qA mRNA and produced total loss of C1q production [#6]. Its transcription is dynamically controlled — induced downstream of excitotoxic neuronal injury [#2] and by neuronal COX-2 activity [#4], positively regulated by direct TCF7L2 binding to the C1qB promoter [#8], and negatively regulated by TGF-\\u03b21 in microglia [#3]. Functionally, C1qB promotes monocyte-to-macrophage differentiation, with knockdown reducing macrophage numbers and alleviating tissue damage in a diabetes model [#7], and a TCF7L2\\u2192C1qB axis drives microglial activation and synaptic pruning-dependent neuronal injury in epilepsy [#8]. Loss-of-function C1qB mutations cause complete C1q deficiency with immunodeficiency/SLE-like disease [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established which brain cell type produces C1qB, a prerequisite for interpreting its role in CNS injury and inflammation.\",\n      \"evidence\": \"In situ hybridization with CR3 immunoreactivity in lesioned rat striatum\",\n      \"pmids\": [\"1426121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address C1qB function or whether secreted C1q is assembled locally\", \"Single injury model in one species\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Defined the developmental expression pattern of C1qB and argued against a role in programmed cell death, narrowing its candidate functions during brain development.\",\n      \"evidence\": \"Northern blot and in situ hybridization across rat brain development\",\n      \"pmids\": [\"7955342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative correlation does not exclude injury-specific roles\", \"No loss-of-function test\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Placed C1qB induction causally downstream of excitotoxic neuronal injury, linking its expression to neurodegenerative signaling rather than constitutive baseline.\",\n      \"evidence\": \"Kainate lesion with barbiturate blockade in vivo plus glutamate-treated hippocampal cultures\",\n      \"pmids\": [\"7870303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream inducing signal not molecularly identified\", \"Whether C1qB induction is protective or injurious unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified TGF-\\u03b21 as a negative regulator of microglial C1qB expression, defining a cytokine input controlling C1qB transcription.\",\n      \"evidence\": \"Intraventricular TGF-\\u03b21 infusion in vivo and primary microglia cultures with ISH/immunocytochemistry\",\n      \"pmids\": [\"11074155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect transcriptional mechanism not resolved\", \"No promoter-level evidence\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Positioned COX-2 activity upstream of C1qB expression, connecting prostaglandin signaling to complement induction in neurons.\",\n      \"evidence\": \"Neuronal hCOX-2 transgenic mice with COX-2 inhibitor treatment and mRNA quantification\",\n      \"pmids\": [\"11810182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic intermediary between COX-2 and C1qB transcription unknown\", \"Neuronal C1qB expression here contrasts with microglial source\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that C1qB loss-of-function mutations cause complete C1q deficiency and SLE-like disease, establishing clinical consequence of C1qB loss.\",\n      \"evidence\": \"Genetic sequencing and clinical complement assays in a patient with complete C1q deficiency\",\n      \"pmids\": [\"24160257\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vitro functional reconstitution of the splicing defect\", \"Single case report\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed that C1qB is mechanistically required for assembly and secretion of the entire C1q complex, not merely a passive subunit.\",\n      \"evidence\": \"Deep sequencing, western blot, ELISA, hemolytic assay and qPCR of C1q chains in a patient\",\n      \"pmids\": [\"25454803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient\", \"Structural basis of assembly dependence not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Assigned C1qB a functional role in promoting monocyte-to-macrophage differentiation with disease relevance beyond the CNS.\",\n      \"evidence\": \"siRNA silencing in cultured monocytes and lentiviral knockdown in a rat T1DM model with histological assessment\",\n      \"pmids\": [\"36464147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway linking C1qB to differentiation unknown\", \"Single lab and model\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a direct TCF7L2\\u2192C1qB transcriptional axis driving microglial activation and synaptic pruning-dependent neuronal injury in epilepsy.\",\n      \"evidence\": \"ChIP and luciferase reporter assays plus lentiviral Tcf7l2 knockdown in a kainic acid epilepsy mouse model\",\n      \"pmids\": [\"41534674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether C1q-mediated pruning is the sole effector mechanism not isolated\", \"Other promoter regulators not surveyed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided single-cell resolution confirming microglia-exclusive C1QB expression and upregulation in Alzheimer's disease with sex differences.\",\n      \"evidence\": \"Single-nucleus RNA sequencing of human hippocampus (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional validation of C1qB protein activity\", \"Preprint, single study\", \"Causal role in AD not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How C1q produced by C1qB-expressing microglia mechanistically executes synaptic pruning and whether this is protective or pathogenic across disease contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of how C1qB drives C1q assembly\", \"Effector pathway from C1q deposition to neuronal injury not isolated\", \"Reconciliation of neuronal vs microglial C1qB expression unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\"C1q complex\"],\n    \"partners\": [\"C1QA\", \"C1QC\", \"TCF7L2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}