Affinage

C4A

Complement C4-A · UniProt P0C0L4

Length
1744 aa
Mass
192.8 kDa
Annotated
2026-06-09
100 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C4A is one of two isotypes of the complement component C4, a central effector of the classical and lectin pathways whose alpha-chain thioester is exposed and made reactive by C1s cleavage of mature, fully processed three-chain C4 (PMID:6321593, PMID:3264881). C1s cleavage also liberates the small C4a fragment, a 77-residue cationic peptide originally placed in the anaphylatoxin family by sequence homology to C3a and C5a (PMID:6167582); however, C4a has no identified receptor of its own and does not signal through C3aR or C5aR, so earlier reports of anaphylatoxin-like activity reflected C3a/C5a contamination (PMID:25659340, PMID:9476119). The functional identity of C4A resides in the covalent-binding chemistry of the resulting C4b fragment: the isotypic residue D1106 directs C4A toward amide-bond formation with protein/immune-complex antigens, whereas H1106 in C4B favors transacylation to ester bonds with carbohydrate antigens (PMID:11367523). This chemistry makes C4A markedly more efficient than C4B at binding immunoglobulin and immune complexes, inhibiting immune precipitation, and enhancing CR1-mediated immune-complex handling on erythrocytes (PMID:3264881, PMID:3180739, PMID:2138067). C4 deposition is also directly antimicrobial, blocking adenovirus capsid disassembly and endosomal escape independently of downstream C2/C3 (PMID:30926239). Beyond the liver, C4 is produced locally by splenic macrophages—sufficient to restore humoral immunity in C4-deficient mice—and by CNS astrocytes (PMID:12421924, PMID:9795119). In vivo, isotype-specific mouse models establish that C4A's superior self-antigen clearance promotes follicular exclusion of autoreactive B cells and protection against lupus-like autoimmunity (PMID:33147456), while excess C4A drives microglial engulfment of synapses and synaptic loss (PMID:33353966). Consistent with this, C4A null alleles condition poor C4 activation and predispose to SLE (PMID:2029208), and complete C4 deficiency arises from frameshift null mutations in C4A and C4B (PMID:12133986).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1981 High

    Establishing the primary structure of C4a defined it as a member of the anaphylatoxin family and located the C1s cleavage site that releases it from the C4 alpha-chain.

    Evidence Protein purification, fragmentation, and direct amino acid sequencing of serum-derived C4a

    PMID:6167582

    Open questions at the time
    • Sequence homology to C3a/C5a did not establish a functional receptor or activity for C4a
    • Did not address isotypic differences between C4A and C4B
  2. 1984 High

    Cloning and genomic mapping placed C4A and C4B at separate, tandemly arranged loci in the HLA Class III region and provided isotype-specific sequence probes, the genetic basis for distinguishing the two genes.

    Evidence cDNA sequencing, restriction mapping, and cosmid genomic cloning with isotype-specific oligonucleotides

    PMID:6149580

    Open questions at the time
    • Did not assign the functional consequence of class-specific sequence differences
    • Copy-number variation at the locus not resolved
  3. 1984 High

    Demonstrating that only fully processed three-chain C4 is cleaved by C1s and hemolytically active defined a maturation requirement that gates complement activation.

    Evidence Hemolytic and C1s cleavage assays on HepG2-secreted C4 processing intermediates and pro-C4

    PMID:6321593

    Open questions at the time
    • Did not identify the protease(s) responsible for chain processing
    • No isotype comparison of processing
  4. 1985 Medium

    Localizing the C4A/C4B size difference to amino-acid sequence (not glycosylation) and showing differential hydralazine binding pointed to a chemical difference in the thioester region between isotypes.

    Evidence Glycan composition analysis of purified C4 chains; covalent hydralazine binding compared across isotypes

    PMID:2981921 PMID:3873356

    Open questions at the time
    • The specific residues responsible were not yet identified
    • Hydralazine result was an indirect probe of thioester chemistry
  5. 1988 High

    Reconstituted binding assays established that C4A (C4A3) binds immunoglobulin and immune complexes far more efficiently than C4B, preferentially through amide bonds, defining the molecular basis of C4A's immune-complex specialization.

    Evidence Fluid-phase covalent binding and immune-precipitation inhibition assays with purified C4 variants and C1s

    PMID:3180739 PMID:3264881

    Open questions at the time
    • Mechanism was demonstrated in vitro; physiological relevance for clearance not yet shown
    • Residues governing amide vs ester preference not identified
  6. 1990 High

    Showing C4A is markedly superior at enhancing immune-complex binding to CR1 on erythrocytes identified the dominant functional distinction relevant to immune-complex clearance, and comparative species data placed the C4A/C4B dichotomy in evolutionary context.

    Evidence CR1 binding and immunoprecipitation assays with purified isotypes; comparative C4 binding specificity across mammals

    PMID:2138067 PMID:2302180 PMID:2650988

    Open questions at the time
    • In vivo clearance kinetics not measured
    • Receptor-level structural basis of CR1 enhancement not defined
  7. 1991 Medium

    Linking C4A null alleles to reduced C4 activation (lower C4d) provided a mechanistic rationale for the C4A-SLE association via impaired immune-complex clearance.

    Evidence C4 phenotyping and C4d split-product quantitation in SLE patients stratified by null-allele status

    PMID:2029208

    Open questions at the time
    • Association is correlative within a patient cohort
    • Causality and copy-number confounding not resolved
  8. 1998 Medium

    Identifying constitutive, cytokine-modulated C4 expression in human astrocytes established a CNS-intrinsic source of C4 beyond the liver.

    Evidence RT-PCR, ELISA, immunocytochemistry, and immunoblot on IFN-γ/IL-1β-treated primary human astrocytes

    PMID:9795119

    Open questions at the time
    • Single lab; did not distinguish C4A vs C4B expression
    • Functional role of astrocyte-derived C4 not tested
  9. 2001 High

    Site-directed mutagenesis pinpointed residue 1106 (D in C4A, H in C4B) as the determinant directing amide- versus ester-bond formation, providing the chemical mechanism behind the two isotypes' divergent target specificities.

    Evidence Mutagenesis of isotypic residues in the C4d region with bond-type binding assays

    PMID:11367523

    Open questions at the time
    • No structural model of the transacylation transition state
    • Contribution of residues 1101/1102/1105 quantified only as modulators
  10. 2002 High

    A bone-marrow reconstitution rescue showed that locally synthesized, macrophage-derived C4 in the spleen is sufficient for humoral immunity, decoupling effector function from hepatic C4.

    Evidence Bone-marrow reconstitution of C4−/− mice with immunization/infection challenge, in situ hybridization, immunofluorescence, and cell-sorted RT-PCR

    PMID:12421924

    Open questions at the time
    • Did not separate C4A and C4B contributions
    • Murine C4 isotype does not directly model human C4A
  11. 2002 High

    Complete sequencing of a C4-deficient patient defined the molecular basis of C4A and C4B null alleles as distinct frameshift mutations producing absent protein and blood-group antigens.

    Evidence Full exonic sequencing of C4A and C4B, multiplex PCR, protein quantitation, and blood-group antigen typing

    PMID:12133986

    Open questions at the time
    • Single patient; allele spectrum not generalized
    • Did not address common copy-number null variation
  12. 2015 Medium

    Reassessment of C4a established that, despite its anaphylatoxin classification, it has no receptor and prior activities were contamination artifacts, redirecting the field to C4b-mediated effector functions.

    Evidence Literature review supported by calcium-mobilization assays in C3aR-expressing cells using carefully prepared C4a

    PMID:25659340 PMID:9476119

    Open questions at the time
    • A bona fide C4a receptor, if any, remains unidentified
    • Negative finding; cannot exclude low-affinity or context-specific signaling
  13. 2019 High

    Demonstrating that C4b deposition blocks adenovirus capsid disassembly and endosomal escape independently of C2/C3 revealed a direct, downstream-component-independent antiviral function of C4.

    Evidence C4-deficient mouse infection, reconstitution, endosomal-escape assays, and C2/C3-deficient controls

    PMID:30926239

    Open questions at the time
    • C4A vs C4B efficacy not distinguished
    • Generality across other viruses not established
  14. 2020 High

    Isotype-specific in vivo models established the divergent disease-relevant roles of human C4A: superior self-antigen clearance drives follicular exclusion of autoreactive B cells (lupus protection), while excess C4A promotes microglial synapse engulfment and synaptic loss.

    Evidence Gene-edited mice expressing human C4A or C4B in lupus (564Igi) and neural synaptic-refinement/overexpression paradigms with flow cytometry, engulfment, density, and behavioral readouts

    PMID:33147456 PMID:33353966

    Open questions at the time
    • Molecular tags/receptors mediating synaptic C4A targeting not identified
    • Direct evidence in human schizophrenia/SLE tissue not provided by these models

Open questions

Synthesis pass · forward-looking unresolved questions
  • How C4A target selectivity translates into tissue-specific outcomes—the molecular signals marking synapses versus self-antigens for C4A-amide deposition and the receptors that read out that deposition—remains unresolved.
  • No identified molecular determinant of synapse-versus-immune-complex targeting
  • No structural model of the C4A thioester transacylation reaction
  • Human disease causality inferred from mouse isotype models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-168256 Immune System 4
Partners
C1SCR1

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1981 Human C4a anaphylatoxin is a 77-residue cationic polypeptide (Mr ~9000) generated by C1s cleavage of the C4 alpha-chain between positions 77 and 78. Primary structure determination revealed ~30% homology with C3a and ~36% with C5a, placing C4a in the anaphylatoxin family derived from a common genetic origin. Protein purification from activated serum, cyanogen bromide fragmentation, chymotryptic digestion, amino acid sequence analysis The Journal of biological chemistry High 6167582
1984 C4A and C4B are encoded by at least two separate loci in the HLA Class III region on chromosome 6, and nucleotide sequence analysis of full-length C4A cDNA and partial C4B cDNA identified class-specific sequence differences, enabling synthesis of isotype-specific oligonucleotide probes. Three C4 loci (~16 kb each, spaced by ~10 kb) were aligned 30 kb from the factor B gene in overlapping cosmid genomic fragments. cDNA cloning, complete nucleotide sequencing, restriction mapping, hybridization with C4A/C4B-specific synthetic oligonucleotides, cosmid library genomic cloning Philosophical transactions of the Royal Society of London. Series B, Biological sciences High 6149580
1984 Processing of C4 to its three-chain (beta-alpha-gamma) structure is required for efficient activation by C1s. Incompletely processed two-chain C4 forms (beta-alpha+gamma and beta+alpha-gamma) and the extracellular precursor pro-C4 are resistant to C1s cleavage and hemolytically inactive relative to the mature three-chain C4. Hemolytic activity assays, solid-phase competitive radioimmunoassay, C1s cleavage experiments on HepG2-secreted C4 forms, autolysis assays Journal of immunology High 6321593
1985 The alpha- and beta-chains of human C4 are glycosylated (the gamma-chain is not). The alpha-chain bears three complex fucosylated biantennary oligosaccharides and is sulfated in its alpha-4 fragment; the beta-chain bears a single high-mannose oligosaccharide. The ~2000 Mr difference between C4A and C4B alpha-chains localizes to the alpha-2 fragment and is not due to carbohydrate, indicating the difference resides in amino acid sequence. Biochemical fractionation of purified plasma C4 and HepG2-secreted C4; carbohydrate composition analysis; localization of oligosaccharide modifications to individual chain fragments Journal of immunology High 2981921
1985 Hydralazine binds covalently to C4, becoming attached to the polypeptide chain containing the active-site thioester; C4A gene product binds hydralazine more efficiently than C4B, suggesting the thioester chemistry differs between the two isotypes. Covalent binding assay with radiolabeled hydralazine; SDS-PAGE analysis of C4A vs C4B after hydralazine treatment FEBS letters Medium 3873356
1988 C4b binds covalently to IgG heavy chains in the fluid phase (in the absence of preformed immune precipitates), primarily via amide bonds for C4A3 and via both amide and acyl ester bonds for C4B1. C4A3 binds 3–4 times more IgG than C4B1 across a range of concentrations, and also shows higher binding efficiency for IgM, IgA, IgG2a, F(ab')2, and BSA. Fluid-phase binding assay with purified C4 variants and C1s; SDS-PAGE to identify chain of attachment; comparison of amide vs. ester linkage chemistry Molecular immunology High 3264881
1988 C4A3 is more effective than C4B1 at inhibiting the rate of immune precipitate formation in both serum and serum-free reaction mixtures containing C1 and C4. Covalent deposition of C4b on immune complexes is the essential mechanistic step underlying inhibition of immune precipitation. Immune precipitation inhibition assay in serum and reconstituted serum-free system; rate measurements with purified C4A3 vs C4B1 Complement (Basel, Switzerland) Medium 3180739
1989 The two C4 isotypes C4A and C4B differ in covalent binding specificity: C4B is more efficient in hemolytic assays (binding to carbohydrate antigens via ester bonds), whereas C4A binds preferentially to immune complexes (via amide bonds with protein antigens). The two isotypes differ more than fivefold in hemolysis-to-immune-complex-processing assays. Hemolytic assays and immune complex processing assays comparing purified C4A and C4B isotypes Complement and inflammation Medium 2650988
1990 C4A is markedly more effective than C4B at enhancing binding of immune complexes to complement receptor CR1 on red blood cells, with the difference being the major functional distinction between the two isotypes in immune complex handling. This was demonstrated with both preformed and nascent immune complexes at equivalence and antibody excess. CR1 binding assay with red blood cells; inhibition of immunoprecipitation assay; comparison of purified C4A vs C4B with preformed and nascent immune complexes Clinical and experimental immunology High 2138067
1990 Mammalian C4 binding specificity is evolutionarily variable: chimpanzee and rhesus monkey produce two C4 types with C4A-like and C4B-like reactivities (similar to humans), while rat, guinea pig, whale, rabbit, dog, and pig express C4 with only a single C4B-like specificity. Sheep and cattle express both C4A-like and C4B-like proteins, suggesting a duplicated locus. C4 purification from multiple mammalian species; binding specificity assays The Biochemical journal Medium 2302180
2001 Site-directed mutagenesis of the C4d region revealed that residue D1106 in C4A is responsible for effective amide bond formation with protein/immune complex antigens, whereas H1106 in C4B catalyzes transacylation of the thioester carbonyl to form ester bonds with carbohydrate antigens. Four isotypic residues at positions 1101, 1102, 1105, and 1106 modulate the covalent binding affinities of the thioester carbonyl group. Site-directed mutagenesis of C4A and C4B at isotypic residues; binding assays to determine bond type (amide vs. ester) International immunopharmacology High 11367523
2002 Macrophage-derived C4 produced locally in the spleen is sufficient to restore humoral immunity in C4-deficient mice. Bone marrow-derived macrophages (CD11b+, CD11c−) were identified as the cellular source of C4 synthesis within the spleen, with C4 mRNA identified by in situ hybridization and C4 protein deposits detected in germinal center areas by immunofluorescence. Bone marrow reconstitution of C4−/− mice; immunization with NP5-KLH and HSV-1 infection; in situ hybridization for C4 mRNA; immunofluorescence for C4 protein; cell-sorting with RT-PCR Journal of immunology High 12421924
2002 Complete C4 deficiency in a patient was caused by two distinct frameshift mutations: a 2-bp insertion in exon 29 (codon 1213) of the C4A gene causing premature termination, and a single C nucleotide deletion in exon 13 (codon 522) of the C4B gene causing frame-shift and premature termination. The patient expressed no Rodgers (C4A) or Chido (C4B) blood group antigens and had no detectable C4A or C4B protein. PCR amplification and complete sequencing of all 41 exons of C4A and C4B; multiplex PCR for mutation detection; immunochemical protein quantitation; blood group antigen testing Journal of immunology High 12133986
1998 Primary human astrocytes constitutively express complement C4 mRNA and protein; expression is enhanced by interferon-gamma and inhibited by interleukin-1β. C4 immunoreactivity was localized to GFAP-positive astrocytes when protein secretion was blocked, identifying astrocytes as an extrahepatic CNS source of C4. RT-PCR, ELISA, immunocytochemistry, and immunoblot on primary human astrocytes treated with IFN-γ or IL-1β Brain research Medium 9795119
2015 C4a does not function as an anaphylatoxin; it does not signal through C3a or C5a receptors and has no identified receptor of its own. Prior reports of C4a biological activity were attributable to contamination of C4a preparations with physiologically relevant levels of C3a and/or C5a. Review of experimental literature; calcium mobilization assays (PMID 9476119) showing C4a up to 3.3 µM has no effect on C3aR-expressing cells or human neutrophils Journal of innate immunity Medium 25659340
1997 C4a does not interact with the C3a receptor (C3aR): concentrations up to 3.3 µM of C4a purified by in vitro cleavage of purified C4 had no effect on calcium mobilization in human neutrophils or in RBL-2H3 cells stably expressing cloned human or mouse C3aR. This demonstrates C4a receptor is distinct from C3aR. Calcium mobilization assay in RBL-2H3 cells expressing cloned human or mouse C3aR; C4a prepared by in vitro cleavage of purified C4 to avoid C5a contamination Immunopharmacology Medium 9476119
2019 C4 inhibits human adenovirus infection through a C4-dependent but C2/C3-independent mechanism: antibody-mediated classical pathway activation causes rapid C4 activation and deposition of cleaved C4b onto the viral capsid, which inhibits capsid disassembly and prevents endosomal escape. C4-deficient mice exhibit heightened viral burdens. This antiviral function requires C1q antibody engagement but is independent of downstream complement components. C4-deficient mouse infection model; neutralization assays with purified C4 components; genetic complementation; endosomal escape assays; C2/C3-deficient controls Cell host & microbe High 30926239
2020 Human C4A binds synapses more efficiently than C4B and rescues visual system synaptic refinement deficits in C4 knockout mice, while C4B does not. Overexpression of C4A (but not C4B) in mice reduces cortical synapse density, increases microglial engulfment of synapses, and alters behavior. C4 knockout mice have normal numbers of cortical synapses, indicating complement is not required for normal developmental synaptic pruning. Transgenic mouse model expressing human C4A or C4B; visual system synaptic refinement assay; cortical synapse density quantification; microglial engulfment assay; behavioral testing; C4 KO comparison Nature neuroscience High 33353966
2020 Human C4A is more protective than C4B against humoral autoimmunity in lupus-prone mice: C4A-expressing 564Igi mice develop fewer germinal centers, fewer autoreactive B cells, fewer autoantibodies, and fewer memory B cells than C4B-expressing mice. The mechanism involves higher C4A efficiency at inducing self-antigen clearance, which promotes follicular exclusion of autoreactive B cells. Gene-edited mouse strains expressing human C4A or C4B crossed with 564Igi lupus strain; flow cytometry for GC, autoreactive B cells, memory B cells; ELISA for autoantibodies; follicular exclusion assays Cell reports High 33147456
1991 Possession of C4A null alleles (C4A Q0) is associated with reduced C4 activation as measured by lower C4d split product concentrations, independent of total C4 concentration. This suggests that C4A null alleles predispose to SLE by conditioning poor C4 activation and thereby impairing immune complex clearance via the classical complement pathway. C4 phenotyping; measurement of C4 concentration and C4d (activation product) by quantitative assay in SLE patients stratified by C4 null allele status Annals of the rheumatic diseases Medium 2029208
2014 Complement anaphylatoxin C4a inhibits C5a-induced neointima formation and macrophage-driven inflammatory responses (TNF-α, IL-6, MCP-1) by suppressing Ca2+-dependent ERK activation in macrophages. C4a does not directly inhibit VSMC migration, proliferation, or VCAM-1 expression; its inhibitory effect on VSMCs is mediated indirectly via conditioned medium from C4a-pretreated macrophages. Wire-induced arterial injury mouse model; in vitro macrophage treatment with C4a/C5a; conditioned medium transfer experiments; Ca2+ influx and ERK phosphorylation assays; VSMC migration and proliferation assays Molecular medicine reports Medium 24789665

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice. Nature neuroscience 263 33353966
2002 C4-dicarboxylate carriers and sensors in bacteria. Biochimica et biophysica acta 213 11803016
2013 International Union of Basic and Clinical Pharmacology. [corrected]. LXXXVII. Complement peptide C5a, C4a, and C3a receptors. Pharmacological reviews 195 23383423
2000 Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in caucasians. The load of RCCX genetic diversity on major histocompatibility complex-associated disease. The Journal of experimental medicine 155 10859342
2001 Genetic, structural and functional diversities of human complement components C4A and C4B and their mouse homologues, Slp and C4. International immunopharmacology 134 11367523
1987 Deletion of C4A genes in patients with systemic lupus erythematosus. Arthritis and rheumatism 114 3499152
1989 Analysis of C4-dicarboxylate transport genes in Rhizobium meliloti. Molecular microbiology 110 2546011
2021 Complement C4, Infections, and Autoimmune Diseases. Frontiers in immunology 103 34335607
2014 Optimal translational termination requires C4 lysyl hydroxylation of eRF1. Molecular cell 94 24486019
1983 Complement allotyping in SLE: association with C4A null. Australian and New Zealand journal of medicine 85 6606418
2003 Evolution of C4 phosphoenolpyruvate carboxylase. Archives of biochemistry and biophysics 84 12781769
2011 Functional evolution of C(4) pyruvate, orthophosphate dikinase. Journal of experimental botany 81 21414960
1984 Structure and organization of the C4 genes. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 74 6149580
1984 Human C4 haplotypes with duplicated C4A or C4B. American journal of human genetics 69 6607672
2014 Deconstructing Kranz anatomy to understand C4 evolution. Journal of experimental botany 68 24799561
1989 C4A gene deletion and HLA associations in black Americans with systemic lupus erythematosus. Immunogenetics 65 2568334
2002 Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex. American journal of human genetics 63 12226794
2019 Complement C4 Prevents Viral Infection through Capsid Inactivation. Cell host & microbe 61 30926239
2011 Stabilization of C4a-hydroperoxyflavin in a two-component flavin-dependent monooxygenase is achieved through interactions at flavin N5 and C4a atoms. The Journal of biological chemistry 60 21680741
1981 Complete primary structure of human C4a anaphylatoxin. The Journal of biological chemistry 56 6167582
2006 Real-time PCR quantification of human complement C4A and C4B genes. BMC genetics 55 16403222
2004 Structural analysis and tissue localization of human C4.4A: a protein homologue of the urokinase receptor. The Biochemical journal 55 15012588
1993 Clinical expression of systemic lupus erythematosus in patients with C4A deficiency. Medicine 55 8341140
2009 Crystallographic, spectroscopic, and computational analysis of a flavin C4a-oxygen adduct in choline oxidase. Biochemistry 54 19133805
2002 C4A deficiency and nonresponse to hepatitis B vaccination. Journal of hepatology 52 12175635
2003 Leukotriene C(4) synthase. Prostaglandins, leukotrienes, and essential fatty acids 47 12895593
1990 Differences between C4A and C4B in the handling of immune complexes: the enhancement of CR1 binding is more important than the inhibition of immunoprecipitation. Clinical and experimental immunology 47 2138067
2003 Dancing with complement C4 and the RP-C4-CYP21-TNX (RCCX) modules of the major histocompatibility complex. Progress in nucleic acid research and molecular biology 46 14604014
2015 C4a: An Anaphylatoxin in Name Only. Journal of innate immunity 45 25659340
2000 Biological activities of recombinant chicken leptin C4S analog compared with unmodified leptins. American journal of physiology. Endocrinology and metabolism 45 10893330
2016 Walking the C4 pathway: past, present, and future. Journal of experimental botany 44 27059273
2013 A recombinant begomovirus resulting from exchange of the C4 gene. The Journal of general virology 44 23720217
2002 The molecular basis of complete complement C4A and C4B deficiencies in a systemic lupus erythematosus patient with homozygous C4A and C4B mutant genes. Journal of immunology (Baltimore, Md. : 1950) 43 12133986
1990 The c4 repressors of bacteriophages P1 and P7 are antisense RNAs. Cell 43 1696181
2002 Transport of leukotriene C4 and structurally related conjugates. Vitamins and hormones 42 11898391
2002 Maize C4 and non-C4 NADP-dependent malic enzymes are encoded by distinct genes derived from a plastid-localized ancestor. Plant molecular biology 42 12374297
2002 C4 mechanisms in aquatic angiosperms: comparisons with terrestrial C4 systems. Functional plant biology : FPB 41 32689483
1990 C4 nomenclature statement (1990). Complement and inflammation 41 2088664
1981 Genetic analysis of C4 deficiency. The Journal of clinical investigation 41 7451653
2015 Gene copy-number variations (CNVs) of complement C4 and C4A deficiency in genetic risk and pathogenesis of juvenile dermatomyositis. Annals of the rheumatic diseases 40 26493816
2006 Immunoglobulins and complement factor C4 in adult rhinosinusitis. Clinical and experimental immunology 40 16879240
2017 Complement C4A and C4B Gene Copy Number Study in Alzheimer's Disease Patients. Current Alzheimer research 39 27758680
2002 Macrophage-derived complement component C4 can restore humoral immunity in C4-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 39 12421924
2016 Glycine decarboxylase in C3, C4 and C3-C4 intermediate species. Current opinion in plant biology 36 27038285
2005 Ly6 family member C4.4A binds laminins 1 and 5, associates with galectin-3 and supports cell migration. International journal of cancer 36 15729693
1985 Oligosaccharide structure of human C4. Journal of immunology (Baltimore, Md. : 1950) 36 2981921
1998 Expression of complement C4 and C9 genes by human astrocytes. Brain research 35 9795119
1990 The complement component C4 of mammals. The Biochemical journal 35 2302180
2008 Altered expression of the urokinase receptor homologue, C4.4A, in invasive areas of human esophageal squamous cell carcinoma. International journal of cancer 34 17849475
2003 Leukotriene C4 synthase polymorphisms and responsiveness to leukotriene antagonists in asthma. British journal of clinical pharmacology 34 12968987
2017 Low copy numbers of complement C4 and homozygous deficiency of C4A may predispose to severe disease and earlier disease onset in patients with systemic lupus erythematosus. Lupus 33 29050534
2007 C4.4A as a candidate marker in the diagnosis of colorectal cancer. British journal of cancer 33 17912244
2016 Finding the genes to build C4 rice. Current opinion in plant biology 32 27055266
2021 C4 Bacterial Volatiles Improve Plant Health. Pathogens (Basel, Switzerland) 29 34072921
2016 Low C4, C4A and C4B gene copy numbers are stronger risk factors for juvenile-onset than for adult-onset systemic lupus erythematosus. Rheumatology (Oxford, England) 29 26800705
1991 DR3 and nonDR3 associated complement component C4A deficiency in systemic lupus erythematosus. Clinical immunology and immunopathology 29 2044237
1988 The fluid-phase binding of human C4 and its genetic variants, C4A3 and C4B1, to immunoglobulins. Molecular immunology 29 3264881
2017 Association between C4, C4A, and C4B copy number variations and susceptibility to autoimmune diseases: a meta-analysis. Scientific reports 28 28205620
2020 Erythritol: Another C4 Platform Chemical in Biomass Refinery. ACS omega 27 32095676
2005 Human complement components C4A and C4B genetic diversities: complex genotypes and phenotypes. Current protocols in immunology 27 18432942
1985 Hydralazine binds covalently to complement component C4. Different reactivity of C4A and C4B gene products. FEBS letters 26 3873356
2012 C4.4A is associated with tumor budding and epithelial-mesenchymal transition of colorectal cancer. Cancer science 25 22404718
1989 Two isotypes of human C4, C4A and C4B have different structure and function. Complement and inflammation 25 2650988
2012 Copy number analysis of complement C4A, C4B and C4A silencing mutation by real-time quantitative polymerase chain reaction. PloS one 24 22737222
2004 Untranslated regions from C4 amaranth AhRbcS1 mRNAs confer translational enhancement and preferential bundle sheath cell expression in transgenic C4 Flaveria bidentis. Plant physiology 24 15489276
2022 Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability. European archives of psychiatry and clinical neuroscience 23 35532796
1999 The biochemical, molecular, and genomic aspects of leukotriene C4 synthase. Proceedings of the Association of American Physicians 23 10591082
1990 C4 reference typing report. Complement and inflammation 23 1708323
1988 C4-mediated inhibition of immune precipitation and differences in inhibitory action of genetic variants, C4A3 and C4B1. Complement (Basel, Switzerland) 23 3180739
2017 Characterization and Stability of Trypanosoma cruzi 24-C4 (Tc24-C4), a Candidate Antigen for a Therapeutic Vaccine Against Chagas Disease. Journal of pharmaceutical sciences 22 29274820
2020 Complement C4A Regulates Autoreactive B Cells in Murine Lupus. Cell reports 21 33147456
1992 Neonatal lupus erythematosus syndrome: analysis of C4 allotypes and C4 genes in 18 families. Medicine 21 1545698
2022 Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies. Annals of the rheumatic diseases 20 36171069
2021 Genetically Predicted Brain C4A Expression Is Associated With TSPO and Hippocampal Morphology. Biological psychiatry 19 34456009
2016 Evolution of carbonic anhydrase in C4 plants. Current opinion in plant biology 19 27016649
2015 Toward understanding the molecular mechanism of a geminivirus C4 protein. Plant signaling & behavior 19 26492168
1986 Conservation of sequences adjacent to the telomeric C4A2 repeats of ciliate macronuclear ribosomal RNA gene molecules. Nucleic acids research 19 3092184
2011 Expression of C4.4A, a structural uPAR homolog, reflects squamous epithelial differentiation in the adult mouse and during embryogenesis. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 18 21339181
1991 Influence of C4 null alleles on C4 activation in systemic lupus erythematosus. Annals of the rheumatic diseases 18 2029208
2018 Geminivirus C4: Interplaying with Receptor-like Kinases. Trends in plant science 17 30279072
2011 Expression of C4.4A in precursor lesions of pulmonary adenocarcinoma and squamous cell carcinoma. International journal of cancer 17 21792890
2009 Genetic deficiency of complement isoforms C4A or C4B predicts improved survival of metastatic renal cell carcinoma. The Journal of urology 17 19150565
1991 The genomic structure of two ancestral haplotypes carrying C4A duplications. Immunogenetics 17 1680806
2021 Adjuvant properties of IFN-γ and GM-CSF in the scFv6.C4 DNA vaccine against CEA-expressing tumors. Gene therapy 16 34108629
2014 Complement anaphylatoxin C4a inhibits C5a-induced neointima formation following arterial injury. Molecular medicine reports 16 24789665
1997 DNA synthesis arrest at C4'-modified deoxyribose residues. Biochemistry 16 9047336
1997 Evidence that the receptor for C4a is distinct from the C3a receptor. Immunopharmacology 16 9476119
1984 Functional studies on the secreted form of human C4 (C4s), two incompletely processed two-subunit C4 molecules (beta - alpha + gamma and beta + alpha - gamma), and pro-C4. Journal of immunology (Baltimore, Md. : 1950) 16 6321593
2023 Unifying and versatile features of flavin-dependent monooxygenases: Diverse catalysis by a common C4a-(hydro)peroxyflavin. The Journal of biological chemistry 15 37918809
2007 Analysis of C4 and the C4 binding protein in the MRL/lpr mouse. Arthritis research & therapy 15 17971229
1992 Effects of C4 null alleles and homoduplications on quantitative expression of C4A and C4B. Clinical and experimental immunology 15 1563101
2023 Gene duplications facilitate C4-CAM compatibility in common purslane. Plant physiology 14 37587696
2018 Clinical features of patients with homozygous complement C4A or C4B deficiency. PloS one 14 29928053
2012 C4A deficiency in children and adolescents with recurrent respiratory infections. Human immunology 14 22406254
2012 Leukotriene c4 synthase: upcoming drug target for inflammation. Current drug targets 14 22420309
2019 Impact of C4, C4A and C4B gene copy number variation in the susceptibility, phenotype and progression of systemic lupus erythematosus. Advances in rheumatology (London, England) 12 31387635
2007 CEBPbeta, JunD and c-Jun contribute to the transcriptional activation of the metastasis-associated C4.4A gene. International journal of cancer 12 17278103
1992 Quantitation of the human component C4: definition of C4 Q0 alleles and C4A duplications. Vox sanguinis 12 1519366
2022 Using breeding and quantitative genetics to understand the C4 pathway. Journal of experimental botany 11 34747993
2017 Walking the C4 pathway: past, present, and future. Journal of experimental botany 11 28110279

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