complement c4


Summary: A glycoprotein that is important in the activation of CLASSICAL COMPLEMENT PATHWAY. C4 is cleaved by the activated COMPLEMENT C1S into COMPLEMENT C4A and COMPLEMENT C4B.

Top Publications

  1. Wu Y, Hauptmann G, Viguier M, Yu C. Molecular basis of complete complement C4 deficiency in two North-African families with systemic lupus erythematosus. Genes Immun. 2009;10:433-45 pubmed publisher
    Complete deficiency of complement C4 is among the strongest genetic risk factors for human systemic lupus erythematosus (SLE)...
  2. Grossmayer G, Munoz L, Weber C, Franz S, Voll R, Kern P, et al. IgG autoantibodies bound to surfaces of necrotic cells and complement C4 comprise the phagocytosis promoting activity for necrotic cells of systemic lupus erythaematosus sera. Ann Rheum Dis. 2008;67:1626-32 pubmed publisher
    ..Complement is required for this process and autoantibodies binding to the surfaces of necrotic cells additionally promote their phagocytosis. ..
  3. Sawai S, Umemura H, Mori M, Satoh M, Hayakawa S, Kodera Y, et al. Serum levels of complement C4 fragments correlate with disease activity in multiple sclerosis: proteomic analysis. J Neuroimmunol. 2010;218:112-5 pubmed publisher
    ..Tandem mass spectrometry analysis revealed that the peptide was a fragment of complement C4 (NGFKSHALQLNNRQI). This fragment peptide could be a possible marker of disease activity...
  4. Saxena K, Kitzmiller K, Wu Y, Zhou B, Esack N, Hiremath L, et al. Great genotypic and phenotypic diversities associated with copy-number variations of complement C4 and RP-C4-CYP21-TNX (RCCX) modules: a comparison of Asian-Indian and European American populations. Mol Immunol. 2009;46:1289-303 pubmed publisher
    ..The high copy-numbers of C4 and the high frequency of RCCX recombinants offer important insights to the prevalence of autoimmune and genetic diseases. ..
  5. Lin T, Zhou W, Farrar C, Hargreaves R, Sheerin N, Sacks S. Deficiency of C4 from donor or recipient mouse fails to prevent renal allograft rejection. Am J Pathol. 2006;168:1241-8 pubmed
  6. Savage D, Semple R, Clatworthy M, Lyons P, Morgan B, Cochran E, et al. Complement abnormalities in acquired lipodystrophy revisited. J Clin Endocrinol Metab. 2009;94:10-6 pubmed publisher
    ..Patients and Research Design: Three unrelated patients with acquired lipodystrophy and low complement C4 levels are described...
  7. Takahashi M, Iwaki D, Kanno K, Ishida Y, Xiong J, Matsushita M, et al. Mannose-binding lectin (MBL)-associated serine protease (MASP)-1 contributes to activation of the lectin complement pathway. J Immunol. 2008;180:6132-8 pubmed
    ..From these results, we propose that MASP-1 contributes to the activation of the lectin pathway, probably through the activation of MASP-2. ..
  8. Seppanen M, Lokki M, Notkola I, Mattila K, Valtonen V, Nieminen A, et al. Complement and c4 null alleles in severe chronic adult periodontitis. Scand J Immunol. 2007;65:176-81 pubmed
    ..4, 95% confidence interval 1.1-5.5, P = 0.032). Changes in complement levels may reflect chronic, recurring inflammation. C4 gene deficiencies are associated with predisposition to chronic periodontitis. ..
  9. Finke D, Randers K, Hoerster R, Hennig H, Zawatzky R, Marion T, et al. Elevated levels of endogenous apoptotic DNA and IFN-alpha in complement C4-deficient mice: implications for induction of systemic lupus erythematosus. Eur J Immunol. 2007;37:1702-9 pubmed
    ..Here, we demonstrate that in lupus-susceptible, complement C4-deficient mice the lack of complement results in elevated intravascular levels of apoptotic DNA...

More Information


  1. Shields K, Stolz D, Watkins S, Ahearn J. Complement proteins C3 and C4 bind to collagen and elastin in the vascular wall: a potential role in vascular stiffness and atherosclerosis. Clin Transl Sci. 2011;4:146-52 pubmed publisher
  2. Boteva L, Wu Y, Cortes Hernández J, Martin J, Vyse T, Fernando M. Determination of the loss of function complement C4 exon 29 CT insertion using a novel paralog-specific assay in healthy UK and Spanish populations. PLoS ONE. 2011;6:e22128 pubmed publisher
    ..Therefore it is important to note that, as with C4 gene CNV, disease-association due to this variant will be missed by current SNP-based genome-wide association strategies. ..
  3. Hunnangkul S, Nitsch D, Rhodes B, Chadha S, Roberton C, Pessôa Lopes P, et al. Familial clustering of non-nuclear autoantibodies and C3 and C4 complement components in systemic lupus erythematosus. Arthritis Rheum. 2008;58:1116-24 pubmed publisher
    ..Anti-C1q antibodies accelerate C3 and C4 depletion in patients with SLE but have no effect in the absence of disease. ..
  4. Fernando M, Boteva L, Morris D, Zhou B, Wu Y, Lokki M, et al. Assessment of complement C4 gene copy number using the paralog ratio test. Hum Mutat. 2010;31:866-74 pubmed publisher
    The complement C4 locus is in the class III region of the MHC, and exhibits copy number variation. Complement C4 null alleles have shown association with a number of diseases including systemic lupus erythematosus (SLE)...
  5. Yang Y, Chung E, Wu Y, Savelli S, Nagaraja H, Zhou B, et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Am. Am J Hum Genet. 2007;80:1037-54 pubmed
    ..This work demonstrates how gene CNV and its related polymorphisms are associated with the susceptibility to a human complex disease. ..
  6. Schwaeble W, Lynch N, Clark J, Marber M, Samani N, Ali Y, et al. Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury. Proc Natl Acad Sci U S A. 2011;108:7523-8 pubmed publisher
    ..The therapeutic effects of MASP-2 inhibition in this experimental model suggest the utility of anti-MASP-2 antibody therapy in reperfusion injury and other lectin pathway-mediated disorders. ..
  7. Uehara S, Handa H, Gotoh K, Tomita H, Sennshuu M. Plasma concentrations of growth arrest-specific protein 6 and protein S in patients with acute pancreatitis. J Gastroenterol Hepatol. 2009;24:1567-73 pubmed publisher
    ..Plasma concentrations of Gas6 and PS correlate with disease severity. High concentrations of Gas6 reflect microcirculatory abnormalities, and phagocytosis of dying cells in sepsis associated with severe AP. ..
  8. Munthe Fog L, Hummelshøj T, Honore C, Madsen H, Permin H, Garred P. Immunodeficiency associated with FCN3 mutation and ficolin-3 deficiency. N Engl J Med. 2009;360:2637-44 pubmed publisher
    ..01). We describe a patient with recurrent infections who was homozygous for this mutation, who had undetectable serum levels of ficolin-3, and who had a deficiency in ficolin-3-dependent complement activation. ..
  9. Iwaki D, Kanno K, Takahashi M, Endo Y, Lynch N, Schwaeble W, et al. Small mannose-binding lectin-associated protein plays a regulatory role in the lectin complement pathway. J Immunol. 2006;177:8626-32 pubmed
    ..Therefore, MASP-2 is essential for the activation of C4 and sMAP plays a regulatory role in the activation of the lectin pathway. ..
  10. Wu Y, Yang Y, Chung E, Zhou B, Kitzmiller K, Savelli S, et al. Phenotypes, genotypes and disease susceptibility associated with gene copy number variations: complement C4 CNVs in European American healthy subjects and those with systemic lupus erythematosus. Cytogenet Genome Res. 2008;123:131-41 pubmed publisher
    ..In this review we describe the phenotypic and genotypic diversities of complement C4 created by copy number variations of RCCX modules (RP-C4-CYP21-TNX) and size dichotomy of C4 genes...
  11. Li J, Szalai A, Hollingshead S, Nahm M, Briles D. Antibody to the type 3 capsule facilitates immune adherence of pneumococci to erythrocytes and augments their transfer to macrophages. Infect Immun. 2009;77:464-71 pubmed publisher
  12. Wenderfer S, Soimo K, Wetsel R, Braun M. Analysis of C4 and the C4 binding protein in the MRL/lpr mouse. Arthritis Res Ther. 2007;9:R114 pubmed
    ..Given that immune complex renal injury in the MRL/lpr mouse is independent of Fc receptors as well as the major negative regulator of the classical pathway, new mechanisms for immune-complex-mediated renal injury need to be considered...
  13. Peake P, Shen Y, Walther A, Charlesworth J. Adiponectin binds C1q and activates the classical pathway of complement. Biochem Biophys Res Commun. 2008;367:560-5 pubmed publisher
    ..It may therefore play an important role in innate immunity and autoimmune phenomena. ..
  14. Thiel S, Vorup Jensen T, Stover C, Schwaeble W, Laursen S, Poulsen K, et al. A second serine protease associated with mannan-binding lectin that activates complement. Nature. 1997;386:506-10 pubmed
    ..Thus complement activation through MBL, like the classical pathway, involves two serine proteases and may antedate the development of the specific immune system of vertebrates. ..
  15. Man X, Luo H, Li X, Yao Y, Mao C, Zhang Y. Polymerase chain reaction based C4AQ0 and C4BQ0 genotyping: association with systemic lupus erythematosus in southwest Han Chinese. Ann Rheum Dis. 2003;62:71-3 pubmed
    To investigate the association of complement C4 null genes (C4Q0, including C4AQ0 and C4BQ0) and C2 gene with systemic lupus erythematosus (SLE) in southwest Han Chinese; 136 patients with SLE and 174 matched controls were genotyped...
  16. Chen Z, Koralov S, Kelsoe G. Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. J Exp Med. 2000;192:1339-52 pubmed
    ..Clearance of circulating ICs is impaired in preautoimmune C4(-)(/)-, but not Cr2(-)(/)-, mice. C4 deficiency causes spontaneous, lupus-like autoimmunity through a mechanism that is independent of CR1/CR2. ..
  17. Boos L, Szalai A, Barnum S. Murine complement C4 is not required for experimental autoimmune encephalomyelitis. Glia. 2005;49:158-60 pubmed
    ..These results support the conclusion that the contribution of murine complement to the pathogenesis of demyelinating disease is realized via the alternative pathway. ..
  18. Blanchong C, Chung E, Rupert K, Yang Y, Yang Z, Zhou B, et al. Genetic, structural and functional diversities of human complement components C4A and C4B and their mouse homologues, Slp and C4. Int Immunopharmacol. 2001;1:365-92 pubmed
    ..Monomodular, bimodular and trimodular RCCX structures with 1, 2 and 3 complement C4 genes have frequencies of 17%, 69% and 14%, respectively...
  19. Kuraya M, Ming Z, Liu X, Matsushita M, Fujita T. Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation. Immunobiology. 2005;209:689-97 pubmed
    ..Thus, L-ficolin and H-ficolin as well as MBL participate in the clearance of apoptotic cells through complement activation. ..
  20. Herzenberg A, Gill J, Djurdjev O, Magil A. C4d deposition in acute rejection: an independent long-term prognostic factor. J Am Soc Nephrol. 2002;13:234-41 pubmed
    ..Peritubular C4d deposition is a significant predictor of graft survival rates and is independent of histologic rejection type and a variety of clinical prognostic factors. ..
  21. Rupert K, Moulds J, Yang Y, Arnett F, Warren R, Reveille J, et al. The molecular basis of complete complement C4A and C4B deficiencies in a systemic lupus erythematosus patient with homozygous C4A and C4B mutant genes. J Immunol. 2002;169:1570-8 pubmed
    ..Hence, complete C4 deficiency is one of the most penetrant genetic risk factors for human systemic lupus erythematosus. ..
  22. Taylor P, Pickering M, Kosco Vilbois M, Walport M, Botto M, Gordon S, et al. The follicular dendritic cell restricted epitope, FDC-M2, is complement C4; localization of immune complexes in mouse tissues. Eur J Immunol. 2002;32:1888-96 pubmed
    ..These results demonstrate that mAb209, in addition to its role as an FDC marker, is a valuable reagent for the analysis of complement deposition in vivo. ..
  23. Vorup Jensen T, Petersen S, Hansen A, Poulsen K, Schwaeble W, Sim R, et al. Distinct pathways of mannan-binding lectin (MBL)- and C1-complex autoactivation revealed by reconstitution of MBL with recombinant MBL-associated serine protease-2. J Immunol. 2000;165:2093-100 pubmed
    ..The results suggest that the catalytic activities of MASP-2 split between the two proteases of the C1 complex during the course of vertebrate complement evolution. ..
  24. Schneider P, Witzel Schlömp K, Rittner C, Zhang L. The endogenous retroviral insertion in the human complement C4 gene modulates the expression of homologous genes by antisense inhibition. Immunogenetics. 2001;53:1-9 pubmed
    ..These results support the hypothesis of a genomic antisense strategy mediated by the HERV-K(C4) insertion as a possible defense mechanism against exogenous retroviral infections. ..
  25. Einav S, Pozdnyakova O, Ma M, Carroll M. Complement C4 is protective for lupus disease independent of C3. J Immunol. 2002;168:1036-41 pubmed
    ..Thus, complement C4 provides an important protective role against the development of SLE.
  26. Regele H, Böhmig G, Habicht A, Gollowitzer D, Schillinger M, Rockenschaub S, et al. Capillary deposition of complement split product C4d in renal allografts is associated with basement membrane injury in peritubular and glomerular capillaries: a contribution of humoral immunity to chronic allograft rejection. J Am Soc Nephrol. 2002;13:2371-80 pubmed
  27. Yu C, Whitacre C. Sex, MHC and complement C4 in autoimmune diseases. Trends Immunol. 2004;25:694-9 pubmed
    ..Recent data suggest that quantitative and qualitative diversities of the MHC-linked complement C4 among different ethnic groups can be important in the susceptibility and disease severity of SLE.
  28. Vorup Jensen T, Jensenius J, Thiel S. MASP-2, the C3 convertase generating protease of the MBLectin complement activating pathway. Immunobiology. 1998;199:348-57 pubmed
    ..Phylogenetic analysis indicates that MASP-2 is closer to C1r and C1s than is MASP-1, but no particular association between MASP-2 and the C4 cleaving enzyme, C1s, can be deduced from sequence comparison. ..
  29. Karim Y, Griffiths H, Deacock S. Normal complement C4 values do not exclude hereditary angioedema. J Clin Pathol. 2004;57:213-4 pubmed
    This report describes a patient with hereditary angioedema (HAE) in whom complement C4 values were consistently normal...
  30. Walker D, Kim S, McGeer P. Expression of complement C4 and C9 genes by human astrocytes. Brain Res. 1998;809:31-8 pubmed
    ..Two key proteins in the complement pathway are the complement C4 and C9 proteins...
  31. Lynch N, Roscher S, Hartung T, Morath S, Matsushita M, Maennel D, et al. L-ficolin specifically binds to lipoteichoic acid, a cell wall constituent of Gram-positive bacteria, and activates the lectin pathway of complement. J Immunol. 2004;172:1198-202 pubmed
    ..None of the LTA preparations bound MBL, H-ficolin, or the classical pathway recognition molecule, C1q. ..
  32. Prodeus A, Goerg S, Shen L, Pozdnyakova O, Chu L, Alicot E, et al. A critical role for complement in maintenance of self-tolerance. Immunity. 1998;9:721-31 pubmed
    ..These findings suggest a novel role for the complement system in B cell tolerance and provide insight into the genetic association of complement deficiency with susceptibility to systemic lupus erythematosus. ..
  33. Bijl M, Reefman E, Horst G, Limburg P, Kallenberg C. Reduced uptake of apoptotic cells by macrophages in systemic lupus erythematosus: correlates with decreased serum levels of complement. Ann Rheum Dis. 2006;65:57-63 pubmed
    ..Reduced uptake of apoptotic cells by MDM from patients with SLE is not an intrinsic defect but is serum dependent and associated with decreased levels of C1q, C4, and C3. ..
  34. Boshra H, Gelman A, Sunyer J. Structural and functional characterization of complement C4 and C1s-like molecules in teleost fish: insights into the evolution of classical and alternative pathways. J Immunol. 2004;173:349-59 pubmed
    ..These data suggest that functional diversification between the two pathways must have occurred shortly after the gene duplication that gave rise to the earliest classical pathway molecules...
  35. Dodds A, Smith S, Levine R, Willis A. Isolation and initial characterisation of complement components C3 and C4 of the nurse shark and the channel catfish. Dev Comp Immunol. 1998;22:207-16 pubmed
    ..We have confirmed that the activity/protein previously designated C2n is the nurse shark analogue of mammalian C4. This is the first report of structural evidence for C4 in both the bony and cartilaginous fish. ..
  36. Lokki M, Circolo A, Ahokas P, Rupert K, Yu C, Colten H. Deficiency of human complement protein C4 due to identical frameshift mutations in the C4A and C4B genes. J Immunol. 1999;162:3687-93 pubmed
    ..Among the possible genetic mechanisms that produce identical mutations is both genes, the most likely is a mutation in C4A followed by a gene conversion to generate the mutated C4B allele. ..
  37. Yu C, Chung E, Yang Y, Blanchong C, Jacobsen N, Saxena K, et al. Dancing with complement C4 and the RP-C4-CYP21-TNX (RCCX) modules of the major histocompatibility complex. Prog Nucleic Acid Res Mol Biol. 2003;75:217-92 pubmed
    ..Furthermore, the influence of the endogenous retrovirus HERV-K(C4) on C4 gene expression and the dispersal of HERV-K(C4) family members in the human genome are discussed. ..
  38. Seppanen M, Lokki M, Timonen T, Lappalainen M, Jarva H, Jarvinen A, et al. Complement C4 deficiency and HLA homozygosity in patients with frequent intraoral herpes simplex virus type 1 infections. Clin Infect Dis. 2001;33:1604-7 pubmed
  39. Schneider P, Witzel Schlömp K, Steinhauer C, Stradmann Bellinghausen B, Rittner C. Rapid detection of the ERV-K(C4) retroviral insertion reveals further structural polymorphism of the complement C4 genes in old world primates. Exp Clin Immunogenet. 2001;18:130-4 pubmed
    ..Based on these findings we propose that the primigenial retroviral integration occurred prior to the radiation of old world primate species, and that both the long and the short forms of the C4 gene have existed side by side since then. ..
  40. Suankratay C, Mold C, Zhang Y, Lint T, Gewurz H. Mechanism of complement-dependent haemolysis via the lectin pathway: role of the complement regulatory proteins. Clin Exp Immunol. 1999;117:442-8 pubmed
    ..Thus, the lectin pathway of humans is particularly susceptible to the regulatory effects of C4bp and factor H, due at least in part to MBL enhancement of C4bp binding to C4b and factor H binding to C3b. ..
  41. Dodds A, Law S. The phylogeny and evolution of the thioester bond-containing proteins C3, C4 and alpha 2-macroglobulin. Immunol Rev. 1998;166:15-26 pubmed
    ..An important development in the C3 molecule has been the acquisition of a catalytic His residue which greatly increases the rate of reaction of the thioester with hydroxyl groups and with water. ..
  42. Frederiksen P, Thiel S, Larsen C, Jensenius J. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol. 2005;62:462-73 pubmed
    ..We developed a monoclonal rat anti-human-M/L-ficolin antibody and verified by flow cytometric analysis the presence of ficolin on the surface of peripheral blood monocytes. ..
  43. Dumestre perard C, Ponard D, Drouet C, Leroy V, Zarski J, Dutertre N, et al. Complement C4 monitoring in the follow-up of chronic hepatitis C treatment. Clin Exp Immunol. 2002;127:131-6 pubmed
    ..Specific C4 monitoring appears to be a valuable tool for the follow-up of chronic hepatitis C treatment, together with the other conventional investigations. ..
  44. Dragon Durey M, Rougier N, Clauvel J, Caillat Zucman S, Remy P, Guillevin L, et al. Lack of evidence of a specific role for C4A gene deficiency in determining disease susceptibility among C4-deficient patients with systemic lupus erythematosus (SLE). Clin Exp Immunol. 2001;123:133-9 pubmed
    ..Our results argue against a specific role for C4A gene deficiency in determining disease susceptibility among patients with SLE that are C4-deficient. ..
  45. Ochsenbein A, Pinschewer D, Odermatt B, Carroll M, Hengartner H, Zinkernagel R. Protective T cell-independent antiviral antibody responses are dependent on complement. J Exp Med. 1999;190:1165-74 pubmed
    ..Absence of the early neutralizing antibody responses, together with the reduced efficiency of neutralizing IgM in C3(-/-) mice, led to a drastically enhanced susceptibility to disease after infection with VSV. ..
  46. Bultink I, Hamann D, Seelen M, Hart M, Dijkmans B, Daha M, et al. Deficiency of functional mannose-binding lectin is not associated with infections in patients with systemic lupus erythematosus. Arthritis Res Ther. 2006;8:R183 pubmed
    ..In conclusion, SLE patients frequently suffer from infections, but deficiency of functional MBL does not confer additional risk. ..
  47. Tang Y, Li P, Kondo M, Ji H, Kou Y, Ou B. Effect of a mangosteen dietary supplement on human immune function: a randomized, double-blind, placebo-controlled trial. J Med Food. 2009;12:755-63 pubmed publisher
    ..001). The results indicated that the intake of an antioxidant-rich product significantly enhanced immune responses and improved the subject's self-appraisal on his or her overall health status...
  48. Helal I, Goucha R, Hamida F, Elyounsi F, Maiz H, Kheder A. Renal AA amyloidosis in a patient with hereditary complete complement C4 deficiency. Saudi J Kidney Dis Transpl. 2011;22:1008-11 pubmed
    ..Furthermore, in clinical practice, the nephrotic syndrome occurring in a patient with hereditary complete complement C4 deficiency should lead to the suspicion of renal AA amyloidosis.
  49. Sivaram G, Tiwari S, Bardia A, Manoj G, Santhosh B, Saikant R, et al. Association of genetic variants of mannan-binding (MBL) lectin-2 gene, MBL levels and function in ulcerative colitis and Crohn's disease. Innate Immun. 2011;17:526-31 pubmed publisher
    ..In conclusion, single nucleotide polymorphism in the MBL-2 gene is an important risk factor significantly affecting MBL levels and function in the development of ulcerative colitis among Indians. ..
  50. Granell M, Urbano Ispizua A, Suarez B, Rovira M, Fernandez Aviles F, Martinez C, et al. Mannan-binding lectin pathway deficiencies and invasive fungal infections following allogeneic stem cell transplantation. Exp Hematol. 2006;34:1435-41 pubmed
    ..8, p = 0.02) retained independent prognostic value. These results show for the first time that polymorphisms responsible for not only MBL but also MASP-2 deficiency are independent predictive factors for IFI after allo-SCT. ..
  51. Geelen J, van den Dries K, Roos A, van de Kar N, de Kat Angelino C, Klasen I, et al. A missense mutation in factor I (IF) predisposes to atypical haemolytic uraemic syndrome. Pediatr Nephrol. 2007;22:371-5 pubmed
    ..One additional transplant was lost due to arterial thrombosis of the renal artery. This report confirms the gloomy outcome of renal transplants in patients with an IF deficiency. New therapies should be evaluated in these patients...
  52. Shitrit D, Ollech J, Ollech A, Peled N, Amital A, Fox B, et al. Diagnostic value of complement components in pleural fluid: report of 135 cases. Respir Med. 2008;102:1631-5 pubmed publisher
    ..Complement should be included in the assessment of pleural effusion when traditional diagnostic methods fail. ..