{"gene":"MBL2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1998,"finding":"MBL2-encoded mannose-binding lectin (MBL) binds to oligosaccharides on microbial surfaces in a calcium-dependent manner through multiple C-type lectin domains, and upon surface binding activates a pro-serine protease complex (MASP-1 and MASP-2) leading to cleavage of complement components C4 and C2, initiating the lectin pathway of complement activation.","method":"In vitro functional assays, biochemical characterization of MBL-MASP complexes","journal":"Immunobiology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical reconstitution of MBL-MASP complex activity, replicated across multiple independent laboratories over many years","pmids":["9777416"],"is_preprint":false},{"year":2002,"finding":"MASP-2, when complexed with MBL, cleaves complement C4 and C2 to form C3 convertase (C4b2a), directly activating the complement cascade. MASP-1 can cleave C3 directly but this activity is very slow and may not be biologically significant; additionally, MASP-1 cleaves fibrinogen (releasing fibrinopeptide B) and activates plasma transglutaminase (Factor XIII).","method":"In vitro enzymatic assays with purified recombinant and native MASP-1 and MASP-2 proteins","journal":"Immunobiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins, replicated across multiple labs","pmids":["12396008"],"is_preprint":false},{"year":2000,"finding":"The MBL complex (comprising MBL, MASP-1, MASP-2, and MAp19) is inhibited by C1-inhibitor, which associates with the complex. Alpha-2-macroglobulin (alpha2M) was found to associate with the MBL complex but did not inhibit complement activation via this pathway. At physiological ionic strength, MASP-1, MASP-2, MAp19, and associated inhibitors dissociate from MBL, whereas high ionic strength (1 M NaCl) stabilizes the complex.","method":"Complement activation assay specific for the MBL pathway; protein association studies with MBL complex from serum","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complement activation assay combined with protein association studies, single lab with multiple orthogonal methods","pmids":["11257302"],"is_preprint":false},{"year":2003,"finding":"MBL is a collectin assembled from polypeptide subunits each containing a collagen-like domain followed by a C-type lectin domain; polypeptides trimerize to form subunits that associate into higher-order oligomers (typically 12-18 polypeptides). Mutations in the collagen-like region (at codons 52, 54, or 57 in exon 1) disrupt triple helix formation, preventing assembly of functional higher-order oligomers and reducing serum MBL. MBL is the only collectin that activates complement, doing so through MASP-2 which activates C4 and C2, analogously to the C1q pathway.","method":"Biochemical characterization, structural analysis, serum MBL quantitation with known genotypes","journal":"Biochemical Society transactions","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — structural and biochemical characterization replicated across multiple independent laboratories","pmids":["12887296"],"is_preprint":false},{"year":2003,"finding":"MBL forms two molecular forms in serum: a high-molecular-mass form and a lower-molecular-mass form. The high-molecular form (present in wild-type A/A homozygotes) binds mannan and associates with MASP-1/3, while the low-molecular form (present in homozygous codon-54 mutants, B/B) lacks these functional capabilities. Thus, MBL deficiency-associated mutations produce circulating oligomeric MBL with impaired functional activity rather than complete absence of protein.","method":"Gel filtration of sera from individuals of known MBL2 genotype; ELISA for MBL; functional binding assays to mannan and MASP-1/3","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gel filtration combined with functional ELISA binding assays, single lab, multiple orthogonal methods","pmids":["14515259"],"is_preprint":false},{"year":2005,"finding":"MBL binds to HIV-1 via high-mannose glycans on gp120; this binding activates complement on gp120 and opsonizes HIV. MBL was shown to block the interaction between HIV and DC-SIGN. Direct neutralization of HIV produced in T cell lines was observed, though neutralization of primary isolates was low; drugs altering carbohydrate processing enhanced neutralization of primary isolates by MBL.","method":"Binding assays, complement activation assays on gp120, neutralization assays, DC-SIGN competition assays","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays including binding, complement activation, and neutralization, replicated across studies","pmids":["15488604"],"is_preprint":false},{"year":2005,"finding":"Human MBL2 gene is transcribed from two alternative promoters (promoter 0 and promoter 1); promoter 0 produces transcripts with an additional 5' untranslated exon (exon 0). Low-level extra-hepatic mbl2 mRNA expression occurs predominantly in small intestine and testis tissue, dominated by promoter 1 transcripts. Alternative acceptor splice sites within exon 1 generate additional transcript variants.","method":"RT-PCR, quantitative PCR, RNA analysis from multiple human tissues; promoter-specific analysis","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mRNA analysis from multiple tissues with quantitative PCR and promoter-specific approaches, single lab","pmids":["16112196"],"is_preprint":false},{"year":2006,"finding":"MBL, under conditions enhancing phagocytosis, modulates cytokine production in human peripheral blood mononuclear cells: it suppresses LPS-induced proinflammatory cytokines IL-1alpha and IL-1beta, and increases secretion of IL-10, IL-1 receptor antagonist, monocyte chemoattractant protein-1, and IL-6, at both mRNA and protein levels.","method":"Treatment of human PBMCs with MBL under phagocytosis-enhancing conditions; measurement of cytokine mRNA and protein","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay in primary human cells measuring both mRNA and protein cytokine levels, single lab with orthogonal methods","pmids":["16617157"],"is_preprint":false},{"year":2006,"finding":"MBL binds to human umbilical vein endothelial cells (HUVEC) in a dose-dependent, calcium-independent manner involving its collagenous domains. MBL and C1q compete for binding to a shared receptor on endothelial cells; pre-incubation with MBL inhibits subsequent C1q binding and vice versa. LPS activation of HUVEC increases both C1q and MBL binding. MBL stimulation of HUVEC did not detectably increase cytokine production.","method":"Flow cytometry binding assays on HUVEC; cross-competition experiments with digoxygenin-labeled MBL and C1q","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and competition assays on primary human endothelial cells, single lab with multiple orthogonal methods","pmids":["16911830"],"is_preprint":false},{"year":2006,"finding":"The MBL-MASP and C1 complexes share a common assembly mechanism: C1r/C1s and MASPs associate with their partner recognition proteins (C1q and MBL/ficolins, respectively) through a common mechanism involving their N-terminal CUB1-EGF region; however, the C1s-C1r-C1r-C1s tetramer and the (MASP)2 dimers use distinct strategies to associate with their partner proteins.","method":"Structural and functional studies, 3D structural investigations","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural analysis with functional validation, single review summarizing structural findings from primary studies","pmids":["17544813"],"is_preprint":false},{"year":2007,"finding":"MASP-2 is the primary complement-activating protease in the MBL complex, cleaving C4 and C2 to form C3 convertase. In MASP-1/MASP-3-deficient mice, C3 deposition on mannan and zymosan surfaces was reduced, indicating MASP-1/3 also contribute to lectin pathway complement activation. MASP-1/3-deficient mice showed increased susceptibility to influenza virus.","method":"MASP-deficient knockout mouse models; C3 deposition assay on mannan/zymosan surfaces; viral infection challenge","journal":"Advances in experimental medicine and biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout models with defined functional readouts (C3 deposition and viral susceptibility), replicated across MASP-1 and MASP-2 knockouts","pmids":["17892207"],"is_preprint":false},{"year":2005,"finding":"In a population of 152 healthy individuals, MASP-1 and MASP-2 activities were each correlated with MBL concentration. However, when normalized to MBL concentration, MASP-1 activity was inversely correlated with MASP-2 activity. This finding is consistent with separate, distinct populations of MBL-MASP-1 complexes and MBL-MASP-2 complexes in serum, without fixed MBL-(MASP-1)-(MASP-2) stoichiometry.","method":"ELISA for MBL; amidolytic assay for MASP-1 activity; C4 fixation assay for MASP-2 activity on mannan-bound MBL from 152 sera","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent functional activity assays on MBL complexes from a large serum population, single lab","pmids":["16102832"],"is_preprint":false},{"year":2010,"finding":"MAP-1 (MBL/ficolin associated protein-1, derived from the MASP1 gene via differential splicing) circulates in serum primarily in complex with Ficolin-3, and to a lesser degree with Ficolin-2 and MBL. MAP-1 is a glycosylated serum protein (~45 kDa, reduced to ~40 kDa after N-glycosidase F treatment).","method":"Recombinant MAP-1 expression; quantitative ELISA; density gradient ultracentrifugation; N-glycosidase F treatment","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical characterization with multiple orthogonal methods (ELISA, ultracentrifugation, enzymatic deglycosylation), single lab","pmids":["21035894"],"is_preprint":false},{"year":2014,"finding":"MAP-1 forms heterocomplexes with MASP-1 and MASP-3 in a calcium-dependent manner, as detected in both recombinant protein experiments and native human serum/plasma. MASP-1 and MASP-3 also form heterocomplexes with each other. Free circulating MAP-1/MASP heterocomplexes exist in blood independently of lectin pathway recognition molecules.","method":"ELISA, size-exclusion chromatography, immunoblotting using recombinant proteins and serum/plasma; depletion of recognition molecules from ficolin-3-deficient serum","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ELISA, SEC, immunoblot) in both recombinant and native serum contexts, single lab","pmids":["24683193"],"is_preprint":false},{"year":2022,"finding":"The helminth parasite Fasciola hepatica evades MBL-mediated complement killing through two mechanisms: (1) MBL does not bind to the surface of live newly excysted juveniles (NEJ) despite mannosylated surface proteins; (2) recombinant serine protease inhibitors secreted by NEJ (rFhSrp1 and rFhSrp2) selectively inhibit native and recombinant MASPs, preventing C3b and C4b deposition on NEJ. Immunofluorescence confirmed absence of MBL, C3b, C4b, and MAC on NEJ surface incubated in normal human serum.","method":"Binding assays with purified MBL; recombinant serpin inhibition assays with native and recombinant MASPs; immunofluorescence microscopy; C3b/C4b deposition assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstitution with purified/recombinant components combined with multiple orthogonal functional assays and immunofluorescence, single rigorous study","pmids":["35007288"],"is_preprint":false},{"year":2010,"finding":"In MBL gene-knockout mice (lacking both MBL-A and MBL-C), susceptibility to experimental systemic aspergillosis was not greater than wild-type mice; at lower inocula, MBL-KO mice were actually less susceptible to lethal infection, suggesting MBL may play a deleterious (rather than protective) role in systemic aspergillosis.","method":"MBL-A and MBL-C double knockout mouse model; intravenous challenge with Aspergillus fumigatus conidia at multiple doses; survival monitoring","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout model with dose-response infection challenge, single lab; notable as negative/paradoxical finding","pmids":["20064561"],"is_preprint":false},{"year":2003,"finding":"Recombinant MBL produced in a transfected human cell line shows the same biological activity (complement activation and opsonization) and essentially identical mass spectrometry profile as plasma-derived MBL, confirming that oligomeric assembly and post-translational modifications are preserved in recombinant production.","method":"Recombinant expression in human cell line; functional complement activation assay; mass spectrometry comparison to plasma-derived MBL","journal":"Biochemical Society transactions","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — functional reconstitution with MS validation, single lab","pmids":["12887299"],"is_preprint":false}],"current_model":"MBL2 encodes mannose-binding lectin (MBL), a calcium-dependent C-type lectin collectin that oligomerizes into higher-order structures via its collagen-like domain; upon binding to mannose/oligosaccharide arrays on pathogen surfaces through its lectin domains, MBL activates the lectin complement pathway by recruiting and activating MASP-2 (which cleaves C4 and C2 to form C3 convertase) and MASP-1/3 (which contribute to C3 deposition); exon-1 mutations at codons 52, 54, or 57 disrupt the collagen-like triple helix, preventing functional higher-order oligomer assembly and abolishing complement-activating activity; MBL also modulates cytokine responses in monocytes, binds endothelial cells via its collagenous domain competing with C1q, and circulates in distinct MBL-MASP-1 and MBL-MASP-2 sub-complexes whose activity is controlled by C1-inhibitor and by MAP-1 (which competes with MASPs for MBL binding and forms inhibitory heterocomplexes with MASP-1 and MASP-3)."},"narrative":{"mechanistic_narrative":"MBL2 encodes mannose-binding lectin (MBL), a calcium-dependent C-type lectin collectin that recognizes oligosaccharide arrays on microbial surfaces and initiates the lectin pathway of complement activation [PMID:9777416]. Each polypeptide pairs a collagen-like domain with a C-type lectin domain; polypeptides trimerize and assemble into higher-order oligomers (typically 12–18 chains), and MBL is the only collectin able to activate complement [PMID:12887296]. Surface binding triggers associated MBL-associated serine proteases: MASP-2 is the principal complement-activating protease, cleaving C4 and C2 to generate the C3 convertase (C4b2a), while MASP-1/3 contribute additionally to C3 deposition [PMID:12396008, PMID:17892207]. Functional studies of human sera and the MBL complex indicate that MBL circulates as distinct MBL–MASP-1 and MBL–MASP-2 subpopulations rather than a fixed stoichiometric complex, and that complex assembly and activity are regulated by C1-inhibitor and by the MASP1-derived splice product MAP-1, which forms inhibitory heterocomplexes with MASP-1 and MASP-3 [PMID:11257302, PMID:16102832, PMID:24683193]. Common exon-1 mutations at codons 52, 54, or 57 disrupt the collagen-like triple helix and prevent assembly of functional higher-order oligomers, producing low-molecular-mass circulating MBL with impaired mannan binding and complement-activating activity rather than complete protein absence [PMID:12887296, PMID:14515259]. Beyond complement, MBL binds endothelial cells through its collagenous domain in competition with C1q [PMID:16911830], and modulates monocyte cytokine responses by suppressing LPS-induced IL-1 and enhancing IL-10, IL-1Ra, and IL-6 [PMID:16617157]. MBL recognizes pathogen glycans including HIV-1 gp120 high-mannose glycans, opsonizing the virus and blocking DC-SIGN interaction [PMID:15488604], though its role in infection is context-dependent, with both protective and deleterious outcomes observed in animal models [PMID:17892207, PMID:20064561].","teleology":[{"year":1998,"claim":"Established that MBL is a pattern-recognition molecule whose surface binding triggers a protease cascade, defining the lectin pathway of complement as a distinct innate immune activation route.","evidence":"In vitro functional assays of MBL-MASP complex activity on microbial oligosaccharides","pmids":["9777416"],"confidence":"High","gaps":["Did not resolve which MASP is the primary activating protease","Stoichiometry of MBL-MASP complexes not defined"]},{"year":2002,"claim":"Resolved the division of labor among MASPs, showing MASP-2 is the C4/C2-cleaving convertase-forming enzyme while MASP-1 has slow C3 and extra-complement (fibrinogen, FXIII) activities.","evidence":"In vitro enzymatic assays with purified recombinant and native MASP-1 and MASP-2","pmids":["12396008"],"confidence":"High","gaps":["Physiological significance of MASP-1 C3 cleavage unresolved","Quantitative contribution of MASP-1 to lectin pathway in vivo not addressed"]},{"year":2003,"claim":"Connected genotype to molecular phenotype, demonstrating that exon-1 codon 52/54/57 mutations disrupt the collagen-like triple helix, preventing functional oligomer assembly and explaining MBL deficiency.","evidence":"Biochemical/structural characterization and serum MBL quantitation across known MBL2 genotypes","pmids":["12887296","14515259"],"confidence":"High","gaps":["Quantitative threshold of oligomer size needed for complement activation not defined","How residual low-mass MBL behaves in tissue not addressed"]},{"year":2003,"claim":"Confirmed that recombinant MBL faithfully reproduces native oligomeric assembly, modifications, and complement-activating function, enabling reagent-grade study and therapeutic production.","evidence":"Recombinant expression in human cell line with functional assay and mass spectrometry comparison to plasma MBL","pmids":["12887299"],"confidence":"Medium","gaps":["Single-lab MS comparison","Long-term stability and in vivo behavior of recombinant MBL not assessed"]},{"year":2005,"claim":"Provided serum-level evidence that MBL-MASP-1 and MBL-MASP-2 exist as separate complex populations rather than a fixed ternary complex, reframing how lectin pathway activity is apportioned.","evidence":"ELISA and activity assays (amidolytic for MASP-1, C4 fixation for MASP-2) across 152 sera","pmids":["16102832"],"confidence":"Medium","gaps":["Correlative population data, not direct structural separation of complexes","Determinants of complex preference unknown"]},{"year":2005,"claim":"Demonstrated MBL recognition of HIV-1 gp120 high-mannose glycans, defining an antiviral opsonic and DC-SIGN-blocking role and linking glycan processing to neutralization potency.","evidence":"Binding, complement activation, neutralization, and DC-SIGN competition assays on gp120","pmids":["15488604"],"confidence":"Medium","gaps":["Weak neutralization of primary isolates","In vivo antiviral relevance not established"]},{"year":2006,"claim":"Extended MBL function beyond complement by showing it reprograms monocyte cytokine output, dampening proinflammatory IL-1 while boosting anti-inflammatory and chemotactic mediators.","evidence":"Treatment of human PBMCs under phagocytosis-enhancing conditions with cytokine mRNA and protein readouts","pmids":["16617157"],"confidence":"Medium","gaps":["Receptor mediating cytokine modulation not identified","Single-lab primary cell study"]},{"year":2006,"claim":"Identified a complement-independent endothelial interaction in which MBL binds via its collagenous domain and competes with C1q for a shared receptor, suggesting non-canonical surface roles.","evidence":"Flow cytometry binding and cross-competition assays on HUVEC with labeled MBL and C1q","pmids":["16911830"],"confidence":"Medium","gaps":["Shared receptor molecular identity unknown","Functional consequence of endothelial binding not defined"]},{"year":2006,"claim":"Clarified the structural basis of recognition-protein/protease assembly, showing MASPs and C1r/C1s use a common CUB1-EGF region but distinct dimer strategies to engage MBL versus C1q.","evidence":"Structural and 3D functional studies summarized across primary work","pmids":["17544813"],"confidence":"Medium","gaps":["Review-level synthesis rather than single primary structure","Atomic detail of MBL-MASP contact not fully resolved here"]},{"year":2007,"claim":"Genetically dissected MASP contributions in vivo, confirming MASP-2 as the primary activator while showing MASP-1/3 promote C3 deposition and antiviral defense.","evidence":"MASP-deficient knockout mice with C3 deposition assays and influenza challenge","pmids":["17892207"],"confidence":"High","gaps":["Mechanism of MASP-1/3 contribution to C3 deposition not fully resolved","Mouse-to-human extrapolation"]},{"year":2010,"claim":"Revealed regulatory architecture of the lectin pathway by characterizing MAP-1, a MASP1 splice product that circulates with recognition molecules and forms calcium-dependent inhibitory heterocomplexes with MASP-1 and MASP-3.","evidence":"Recombinant expression, ELISA, ultracentrifugation, SEC, immunoblot in serum/plasma and recognition-molecule-depleted serum","pmids":["21035894","24683193"],"confidence":"Medium","gaps":["Quantitative inhibitory potency of MAP-1 in vivo not established","Single-lab characterization"]},{"year":2010,"claim":"Challenged a purely protective view of MBL by showing it can be deleterious, with MBL-knockout mice no more (and sometimes less) susceptible to systemic aspergillosis.","evidence":"MBL-A/MBL-C double knockout mice with dose-response Aspergillus challenge and survival monitoring","pmids":["20064561"],"confidence":"Medium","gaps":["Mechanism of the deleterious effect not defined","Pathogen- and route-specific generalizability unclear"]},{"year":2022,"claim":"Demonstrated active pathogen evasion of MBL-mediated complement, with Fasciola hepatica both escaping MBL surface binding and secreting serpins that inhibit MASPs to block C3b/C4b deposition.","evidence":"Purified MBL binding assays, recombinant serpin MASP-inhibition assays, immunofluorescence, and deposition assays in human serum","pmids":["35007288"],"confidence":"High","gaps":["Whether these mechanisms operate across other parasites unknown","Structural basis of serpin-MASP inhibition not defined"]},{"year":null,"claim":"The receptor(s) mediating MBL's complement-independent endothelial binding and monocyte cytokine modulation remain molecularly unidentified, and the in vivo determinants partitioning MBL into distinct MASP subcomplexes are unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Shared MBL/C1q endothelial receptor not cloned","Signaling pathway for cytokine modulation undefined","Regulation of MBL-MASP-1 vs MBL-MASP-2 complex formation unknown"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,4,11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,10]}],"complexes":["MBL-MASP lectin pathway complex"],"partners":["MASP1","MASP2","C4","C2","C1QA","MAP-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P11226","full_name":"Mannose-binding protein C","aliases":["Collectin-1","MBP1","Mannan-binding protein","Mannose-binding lectin"],"length_aa":248,"mass_kda":26.1,"function":"Calcium-dependent lectin, which acts as a pattern recognition receptor that initiates the lectin 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:14515269, PubMed:22966085, PubMed:7634089, PubMed:9087411). Specifically recognizes and binds the mannose moiety of carbohydrates on the pathogen surface, activating the MASP1 serine protease and initiating the proteolytic cascade of the lectin complement pathway (PubMed:22966085, PubMed:2573758, PubMed:6643429, PubMed:8082295, PubMed:9087411). Upon SARS coronavirus-2/SARS-CoV-2 infection, activates the complement lectin pathway which leads to the inhibition SARS-CoV-2 infection and a reduction of the induced inflammatory response (PubMed:35102342). May bind DNA (PubMed:15145932)","subcellular_location":"Secreted; Cell surface","url":"https://www.uniprot.org/uniprotkb/P11226/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MBL2","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/MBL2","total_profiled":1310},"omim":[{"mim_id":"614372","title":"MANNOSE-BINDING LECTIN DEFICIENCY; MBLD","url":"https://www.omim.org/entry/614372"},{"mim_id":"613860","title":"FICOLIN 3 DEFICIENCY","url":"https://www.omim.org/entry/613860"},{"mim_id":"613791","title":"MASP2 DEFICIENCY","url":"https://www.omim.org/entry/613791"},{"mim_id":"610424","title":"HEPATITIS B VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/610424"},{"mim_id":"607948","title":"MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/607948"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"liver","ntpm":262.8}],"url":"https://www.proteinatlas.org/search/MBL2"},"hgnc":{"alias_symbol":["COLEC1","MBP-C","MBP1","MBP"],"prev_symbol":["MBL"]},"alphafold":{"accession":"P11226","domains":[{"cath_id":"3.10.100.10","chopping":"134-248","consensus_level":"high","plddt":97.8844,"start":134,"end":248}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P11226","model_url":"https://alphafold.ebi.ac.uk/files/AF-P11226-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P11226-F1-predicted_aligned_error_v6.png","plddt_mean":81.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MBL2","jax_strain_url":"https://www.jax.org/strain/search?query=MBL2"},"sequence":{"accession":"P11226","fasta_url":"https://rest.uniprot.org/uniprotkb/P11226.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P11226/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P11226"}},"corpus_meta":[{"pmid":"8372350","id":"PMC_8372350","title":"A role for the transcription factors Mbp1 and Swi4 in progression from G1 to S phase.","date":"1993","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/8372350","citation_count":341,"is_preprint":false},{"pmid":"27782323","id":"PMC_27782323","title":"A journey through the lectin pathway of complement-MBL and beyond.","date":"2016","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/27782323","citation_count":333,"is_preprint":false},{"pmid":"12047967","id":"PMC_12047967","title":"MBL genotype and risk of invasive pneumococcal disease: a case-control study.","date":"2002","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/12047967","citation_count":237,"is_preprint":false},{"pmid":"20090778","id":"PMC_20090778","title":"Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management.","date":"2010","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/20090778","citation_count":171,"is_preprint":false},{"pmid":"9777416","id":"PMC_9777416","title":"Mannose-binding lectin (MBL) in health and disease.","date":"1998","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/9777416","citation_count":140,"is_preprint":false},{"pmid":"16617157","id":"PMC_16617157","title":"C1q and MBL, components of the innate immune system, influence monocyte cytokine expression.","date":"2006","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/16617157","citation_count":126,"is_preprint":false},{"pmid":"19501910","id":"PMC_19501910","title":"MBL2, FCN1, FCN2 and FCN3-The genes behind the initiation of the lectin pathway of complement.","date":"2009","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19501910","citation_count":122,"is_preprint":false},{"pmid":"12396008","id":"PMC_12396008","title":"The biological functions of MBL-associated serine proteases (MASPs).","date":"2002","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/12396008","citation_count":118,"is_preprint":false},{"pmid":"11257302","id":"PMC_11257302","title":"Control of the classical and the MBL pathway of complement activation.","date":"2000","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11257302","citation_count":109,"is_preprint":false},{"pmid":"15488604","id":"PMC_15488604","title":"Mannose binding lectin (MBL) and HIV.","date":"2005","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15488604","citation_count":105,"is_preprint":false},{"pmid":"9343412","id":"PMC_9343412","title":"Xbp1, a stress-induced transcriptional repressor of the Saccharomyces cerevisiae Swi4/Mbp1 family.","date":"1997","source":"Molecular and cellular 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activity.","date":"1997","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9074493","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51169,"output_tokens":4609,"usd":0.111321,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12461,"output_tokens":3995,"usd":0.08109,"stage2_stop_reason":"end_turn"},"total_usd":0.192411,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"MBL2-encoded mannose-binding lectin (MBL) binds to oligosaccharides on microbial surfaces in a calcium-dependent manner through multiple C-type lectin domains, and upon surface binding activates a pro-serine protease complex (MASP-1 and MASP-2) leading to cleavage of complement components C4 and C2, initiating the lectin pathway of complement activation.\",\n      \"method\": \"In vitro functional assays, biochemical characterization of MBL-MASP complexes\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical reconstitution of MBL-MASP complex activity, replicated across multiple independent laboratories over many years\",\n      \"pmids\": [\"9777416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MASP-2, when complexed with MBL, cleaves complement C4 and C2 to form C3 convertase (C4b2a), directly activating the complement cascade. MASP-1 can cleave C3 directly but this activity is very slow and may not be biologically significant; additionally, MASP-1 cleaves fibrinogen (releasing fibrinopeptide B) and activates plasma transglutaminase (Factor XIII).\",\n      \"method\": \"In vitro enzymatic assays with purified recombinant and native MASP-1 and MASP-2 proteins\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins, replicated across multiple labs\",\n      \"pmids\": [\"12396008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The MBL complex (comprising MBL, MASP-1, MASP-2, and MAp19) is inhibited by C1-inhibitor, which associates with the complex. Alpha-2-macroglobulin (alpha2M) was found to associate with the MBL complex but did not inhibit complement activation via this pathway. At physiological ionic strength, MASP-1, MASP-2, MAp19, and associated inhibitors dissociate from MBL, whereas high ionic strength (1 M NaCl) stabilizes the complex.\",\n      \"method\": \"Complement activation assay specific for the MBL pathway; protein association studies with MBL complex from serum\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complement activation assay combined with protein association studies, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"11257302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MBL is a collectin assembled from polypeptide subunits each containing a collagen-like domain followed by a C-type lectin domain; polypeptides trimerize to form subunits that associate into higher-order oligomers (typically 12-18 polypeptides). Mutations in the collagen-like region (at codons 52, 54, or 57 in exon 1) disrupt triple helix formation, preventing assembly of functional higher-order oligomers and reducing serum MBL. MBL is the only collectin that activates complement, doing so through MASP-2 which activates C4 and C2, analogously to the C1q pathway.\",\n      \"method\": \"Biochemical characterization, structural analysis, serum MBL quantitation with known genotypes\",\n      \"journal\": \"Biochemical Society transactions\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — structural and biochemical characterization replicated across multiple independent laboratories\",\n      \"pmids\": [\"12887296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MBL forms two molecular forms in serum: a high-molecular-mass form and a lower-molecular-mass form. The high-molecular form (present in wild-type A/A homozygotes) binds mannan and associates with MASP-1/3, while the low-molecular form (present in homozygous codon-54 mutants, B/B) lacks these functional capabilities. Thus, MBL deficiency-associated mutations produce circulating oligomeric MBL with impaired functional activity rather than complete absence of protein.\",\n      \"method\": \"Gel filtration of sera from individuals of known MBL2 genotype; ELISA for MBL; functional binding assays to mannan and MASP-1/3\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gel filtration combined with functional ELISA binding assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"14515259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MBL binds to HIV-1 via high-mannose glycans on gp120; this binding activates complement on gp120 and opsonizes HIV. MBL was shown to block the interaction between HIV and DC-SIGN. Direct neutralization of HIV produced in T cell lines was observed, though neutralization of primary isolates was low; drugs altering carbohydrate processing enhanced neutralization of primary isolates by MBL.\",\n      \"method\": \"Binding assays, complement activation assays on gp120, neutralization assays, DC-SIGN competition assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays including binding, complement activation, and neutralization, replicated across studies\",\n      \"pmids\": [\"15488604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human MBL2 gene is transcribed from two alternative promoters (promoter 0 and promoter 1); promoter 0 produces transcripts with an additional 5' untranslated exon (exon 0). Low-level extra-hepatic mbl2 mRNA expression occurs predominantly in small intestine and testis tissue, dominated by promoter 1 transcripts. Alternative acceptor splice sites within exon 1 generate additional transcript variants.\",\n      \"method\": \"RT-PCR, quantitative PCR, RNA analysis from multiple human tissues; promoter-specific analysis\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mRNA analysis from multiple tissues with quantitative PCR and promoter-specific approaches, single lab\",\n      \"pmids\": [\"16112196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MBL, under conditions enhancing phagocytosis, modulates cytokine production in human peripheral blood mononuclear cells: it suppresses LPS-induced proinflammatory cytokines IL-1alpha and IL-1beta, and increases secretion of IL-10, IL-1 receptor antagonist, monocyte chemoattractant protein-1, and IL-6, at both mRNA and protein levels.\",\n      \"method\": \"Treatment of human PBMCs with MBL under phagocytosis-enhancing conditions; measurement of cytokine mRNA and protein\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay in primary human cells measuring both mRNA and protein cytokine levels, single lab with orthogonal methods\",\n      \"pmids\": [\"16617157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MBL binds to human umbilical vein endothelial cells (HUVEC) in a dose-dependent, calcium-independent manner involving its collagenous domains. MBL and C1q compete for binding to a shared receptor on endothelial cells; pre-incubation with MBL inhibits subsequent C1q binding and vice versa. LPS activation of HUVEC increases both C1q and MBL binding. MBL stimulation of HUVEC did not detectably increase cytokine production.\",\n      \"method\": \"Flow cytometry binding assays on HUVEC; cross-competition experiments with digoxygenin-labeled MBL and C1q\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and competition assays on primary human endothelial cells, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16911830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The MBL-MASP and C1 complexes share a common assembly mechanism: C1r/C1s and MASPs associate with their partner recognition proteins (C1q and MBL/ficolins, respectively) through a common mechanism involving their N-terminal CUB1-EGF region; however, the C1s-C1r-C1r-C1s tetramer and the (MASP)2 dimers use distinct strategies to associate with their partner proteins.\",\n      \"method\": \"Structural and functional studies, 3D structural investigations\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural analysis with functional validation, single review summarizing structural findings from primary studies\",\n      \"pmids\": [\"17544813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MASP-2 is the primary complement-activating protease in the MBL complex, cleaving C4 and C2 to form C3 convertase. In MASP-1/MASP-3-deficient mice, C3 deposition on mannan and zymosan surfaces was reduced, indicating MASP-1/3 also contribute to lectin pathway complement activation. MASP-1/3-deficient mice showed increased susceptibility to influenza virus.\",\n      \"method\": \"MASP-deficient knockout mouse models; C3 deposition assay on mannan/zymosan surfaces; viral infection challenge\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout models with defined functional readouts (C3 deposition and viral susceptibility), replicated across MASP-1 and MASP-2 knockouts\",\n      \"pmids\": [\"17892207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In a population of 152 healthy individuals, MASP-1 and MASP-2 activities were each correlated with MBL concentration. However, when normalized to MBL concentration, MASP-1 activity was inversely correlated with MASP-2 activity. This finding is consistent with separate, distinct populations of MBL-MASP-1 complexes and MBL-MASP-2 complexes in serum, without fixed MBL-(MASP-1)-(MASP-2) stoichiometry.\",\n      \"method\": \"ELISA for MBL; amidolytic assay for MASP-1 activity; C4 fixation assay for MASP-2 activity on mannan-bound MBL from 152 sera\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent functional activity assays on MBL complexes from a large serum population, single lab\",\n      \"pmids\": [\"16102832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MAP-1 (MBL/ficolin associated protein-1, derived from the MASP1 gene via differential splicing) circulates in serum primarily in complex with Ficolin-3, and to a lesser degree with Ficolin-2 and MBL. MAP-1 is a glycosylated serum protein (~45 kDa, reduced to ~40 kDa after N-glycosidase F treatment).\",\n      \"method\": \"Recombinant MAP-1 expression; quantitative ELISA; density gradient ultracentrifugation; N-glycosidase F treatment\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical characterization with multiple orthogonal methods (ELISA, ultracentrifugation, enzymatic deglycosylation), single lab\",\n      \"pmids\": [\"21035894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAP-1 forms heterocomplexes with MASP-1 and MASP-3 in a calcium-dependent manner, as detected in both recombinant protein experiments and native human serum/plasma. MASP-1 and MASP-3 also form heterocomplexes with each other. Free circulating MAP-1/MASP heterocomplexes exist in blood independently of lectin pathway recognition molecules.\",\n      \"method\": \"ELISA, size-exclusion chromatography, immunoblotting using recombinant proteins and serum/plasma; depletion of recognition molecules from ficolin-3-deficient serum\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ELISA, SEC, immunoblot) in both recombinant and native serum contexts, single lab\",\n      \"pmids\": [\"24683193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The helminth parasite Fasciola hepatica evades MBL-mediated complement killing through two mechanisms: (1) MBL does not bind to the surface of live newly excysted juveniles (NEJ) despite mannosylated surface proteins; (2) recombinant serine protease inhibitors secreted by NEJ (rFhSrp1 and rFhSrp2) selectively inhibit native and recombinant MASPs, preventing C3b and C4b deposition on NEJ. Immunofluorescence confirmed absence of MBL, C3b, C4b, and MAC on NEJ surface incubated in normal human serum.\",\n      \"method\": \"Binding assays with purified MBL; recombinant serpin inhibition assays with native and recombinant MASPs; immunofluorescence microscopy; C3b/C4b deposition assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstitution with purified/recombinant components combined with multiple orthogonal functional assays and immunofluorescence, single rigorous study\",\n      \"pmids\": [\"35007288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In MBL gene-knockout mice (lacking both MBL-A and MBL-C), susceptibility to experimental systemic aspergillosis was not greater than wild-type mice; at lower inocula, MBL-KO mice were actually less susceptible to lethal infection, suggesting MBL may play a deleterious (rather than protective) role in systemic aspergillosis.\",\n      \"method\": \"MBL-A and MBL-C double knockout mouse model; intravenous challenge with Aspergillus fumigatus conidia at multiple doses; survival monitoring\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout model with dose-response infection challenge, single lab; notable as negative/paradoxical finding\",\n      \"pmids\": [\"20064561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Recombinant MBL produced in a transfected human cell line shows the same biological activity (complement activation and opsonization) and essentially identical mass spectrometry profile as plasma-derived MBL, confirming that oligomeric assembly and post-translational modifications are preserved in recombinant production.\",\n      \"method\": \"Recombinant expression in human cell line; functional complement activation assay; mass spectrometry comparison to plasma-derived MBL\",\n      \"journal\": \"Biochemical Society transactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional reconstitution with MS validation, single lab\",\n      \"pmids\": [\"12887299\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MBL2 encodes mannose-binding lectin (MBL), a calcium-dependent C-type lectin collectin that oligomerizes into higher-order structures via its collagen-like domain; upon binding to mannose/oligosaccharide arrays on pathogen surfaces through its lectin domains, MBL activates the lectin complement pathway by recruiting and activating MASP-2 (which cleaves C4 and C2 to form C3 convertase) and MASP-1/3 (which contribute to C3 deposition); exon-1 mutations at codons 52, 54, or 57 disrupt the collagen-like triple helix, preventing functional higher-order oligomer assembly and abolishing complement-activating activity; MBL also modulates cytokine responses in monocytes, binds endothelial cells via its collagenous domain competing with C1q, and circulates in distinct MBL-MASP-1 and MBL-MASP-2 sub-complexes whose activity is controlled by C1-inhibitor and by MAP-1 (which competes with MASPs for MBL binding and forms inhibitory heterocomplexes with MASP-1 and MASP-3).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MBL2 encodes mannose-binding lectin (MBL), a calcium-dependent C-type lectin collectin that recognizes oligosaccharide arrays on microbial surfaces and initiates the lectin pathway of complement activation [#0]. Each polypeptide pairs a collagen-like domain with a C-type lectin domain; polypeptides trimerize and assemble into higher-order oligomers (typically 12–18 chains), and MBL is the only collectin able to activate complement [#3]. Surface binding triggers associated MBL-associated serine proteases: MASP-2 is the principal complement-activating protease, cleaving C4 and C2 to generate the C3 convertase (C4b2a), while MASP-1/3 contribute additionally to C3 deposition [#1, #10]. Functional studies of human sera and the MBL complex indicate that MBL circulates as distinct MBL–MASP-1 and MBL–MASP-2 subpopulations rather than a fixed stoichiometric complex, and that complex assembly and activity are regulated by C1-inhibitor and by the MASP1-derived splice product MAP-1, which forms inhibitory heterocomplexes with MASP-1 and MASP-3 [#2, #11, #13]. Common exon-1 mutations at codons 52, 54, or 57 disrupt the collagen-like triple helix and prevent assembly of functional higher-order oligomers, producing low-molecular-mass circulating MBL with impaired mannan binding and complement-activating activity rather than complete protein absence [#3, #4]. Beyond complement, MBL binds endothelial cells through its collagenous domain in competition with C1q [#8], and modulates monocyte cytokine responses by suppressing LPS-induced IL-1 and enhancing IL-10, IL-1Ra, and IL-6 [#7]. MBL recognizes pathogen glycans including HIV-1 gp120 high-mannose glycans, opsonizing the virus and blocking DC-SIGN interaction [#5], though its role in infection is context-dependent, with both protective and deleterious outcomes observed in animal models [#10, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that MBL is a pattern-recognition molecule whose surface binding triggers a protease cascade, defining the lectin pathway of complement as a distinct innate immune activation route.\",\n      \"evidence\": \"In vitro functional assays of MBL-MASP complex activity on microbial oligosaccharides\",\n      \"pmids\": [\"9777416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which MASP is the primary activating protease\", \"Stoichiometry of MBL-MASP complexes not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved the division of labor among MASPs, showing MASP-2 is the C4/C2-cleaving convertase-forming enzyme while MASP-1 has slow C3 and extra-complement (fibrinogen, FXIII) activities.\",\n      \"evidence\": \"In vitro enzymatic assays with purified recombinant and native MASP-1 and MASP-2\",\n      \"pmids\": [\"12396008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological significance of MASP-1 C3 cleavage unresolved\", \"Quantitative contribution of MASP-1 to lectin pathway in vivo not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected genotype to molecular phenotype, demonstrating that exon-1 codon 52/54/57 mutations disrupt the collagen-like triple helix, preventing functional oligomer assembly and explaining MBL deficiency.\",\n      \"evidence\": \"Biochemical/structural characterization and serum MBL quantitation across known MBL2 genotypes\",\n      \"pmids\": [\"12887296\", \"14515259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative threshold of oligomer size needed for complement activation not defined\", \"How residual low-mass MBL behaves in tissue not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Confirmed that recombinant MBL faithfully reproduces native oligomeric assembly, modifications, and complement-activating function, enabling reagent-grade study and therapeutic production.\",\n      \"evidence\": \"Recombinant expression in human cell line with functional assay and mass spectrometry comparison to plasma MBL\",\n      \"pmids\": [\"12887299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab MS comparison\", \"Long-term stability and in vivo behavior of recombinant MBL not assessed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Provided serum-level evidence that MBL-MASP-1 and MBL-MASP-2 exist as separate complex populations rather than a fixed ternary complex, reframing how lectin pathway activity is apportioned.\",\n      \"evidence\": \"ELISA and activity assays (amidolytic for MASP-1, C4 fixation for MASP-2) across 152 sera\",\n      \"pmids\": [\"16102832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative population data, not direct structural separation of complexes\", \"Determinants of complex preference unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated MBL recognition of HIV-1 gp120 high-mannose glycans, defining an antiviral opsonic and DC-SIGN-blocking role and linking glycan processing to neutralization potency.\",\n      \"evidence\": \"Binding, complement activation, neutralization, and DC-SIGN competition assays on gp120\",\n      \"pmids\": [\"15488604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Weak neutralization of primary isolates\", \"In vivo antiviral relevance not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended MBL function beyond complement by showing it reprograms monocyte cytokine output, dampening proinflammatory IL-1 while boosting anti-inflammatory and chemotactic mediators.\",\n      \"evidence\": \"Treatment of human PBMCs under phagocytosis-enhancing conditions with cytokine mRNA and protein readouts\",\n      \"pmids\": [\"16617157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating cytokine modulation not identified\", \"Single-lab primary cell study\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified a complement-independent endothelial interaction in which MBL binds via its collagenous domain and competes with C1q for a shared receptor, suggesting non-canonical surface roles.\",\n      \"evidence\": \"Flow cytometry binding and cross-competition assays on HUVEC with labeled MBL and C1q\",\n      \"pmids\": [\"16911830\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Shared receptor molecular identity unknown\", \"Functional consequence of endothelial binding not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Clarified the structural basis of recognition-protein/protease assembly, showing MASPs and C1r/C1s use a common CUB1-EGF region but distinct dimer strategies to engage MBL versus C1q.\",\n      \"evidence\": \"Structural and 3D functional studies summarized across primary work\",\n      \"pmids\": [\"17544813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review-level synthesis rather than single primary structure\", \"Atomic detail of MBL-MASP contact not fully resolved here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Genetically dissected MASP contributions in vivo, confirming MASP-2 as the primary activator while showing MASP-1/3 promote C3 deposition and antiviral defense.\",\n      \"evidence\": \"MASP-deficient knockout mice with C3 deposition assays and influenza challenge\",\n      \"pmids\": [\"17892207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of MASP-1/3 contribution to C3 deposition not fully resolved\", \"Mouse-to-human extrapolation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed regulatory architecture of the lectin pathway by characterizing MAP-1, a MASP1 splice product that circulates with recognition molecules and forms calcium-dependent inhibitory heterocomplexes with MASP-1 and MASP-3.\",\n      \"evidence\": \"Recombinant expression, ELISA, ultracentrifugation, SEC, immunoblot in serum/plasma and recognition-molecule-depleted serum\",\n      \"pmids\": [\"21035894\", \"24683193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative inhibitory potency of MAP-1 in vivo not established\", \"Single-lab characterization\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Challenged a purely protective view of MBL by showing it can be deleterious, with MBL-knockout mice no more (and sometimes less) susceptible to systemic aspergillosis.\",\n      \"evidence\": \"MBL-A/MBL-C double knockout mice with dose-response Aspergillus challenge and survival monitoring\",\n      \"pmids\": [\"20064561\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of the deleterious effect not defined\", \"Pathogen- and route-specific generalizability unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated active pathogen evasion of MBL-mediated complement, with Fasciola hepatica both escaping MBL surface binding and secreting serpins that inhibit MASPs to block C3b/C4b deposition.\",\n      \"evidence\": \"Purified MBL binding assays, recombinant serpin MASP-inhibition assays, immunofluorescence, and deposition assays in human serum\",\n      \"pmids\": [\"35007288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these mechanisms operate across other parasites unknown\", \"Structural basis of serpin-MASP inhibition not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor(s) mediating MBL's complement-independent endothelial binding and monocyte cytokine modulation remain molecularly unidentified, and the in vivo determinants partitioning MBL into distinct MASP subcomplexes are unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Shared MBL/C1q endothelial receptor not cloned\", \"Signaling pathway for cytokine modulation undefined\", \"Regulation of MBL-MASP-1 vs MBL-MASP-2 complex formation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0030246\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 4, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 10]}\n    ],\n    \"complexes\": [\n      \"MBL-MASP lectin pathway complex\"\n    ],\n    \"partners\": [\n      \"MASP1\",\n      \"MASP2\",\n      \"C4\",\n      \"C2\",\n      \"C1QA\",\n      \"MAP-1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}