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Gene Review

C4b  -  complement component 4B (Chido blood group)

Mus musculus

Synonyms: C4, Complement C4-B, Ss
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Disease relevance of C4b

  • Murine complement C4 is not required for experimental autoimmune encephalomyelitis [1].
  • Factor B(-/-) mice, but not C4(-/-) mice, infected with P. aeruginosa had a mortality rate similar to that of C3(-/-) mice, indicating that in this model the alternative pathway of complement activation is required for the host defense against Pseudomonas infection [2].
  • A new explanation for the association of SLE and complement C4 deficiency would be that in the absence of C4, natural antibodies (IgM type) localize more self-antigen toward the MZ so that the auto-antibody response is increased and autoimmune disease ensues [3].
  • Defects of early complement components (C1, C4 and C2) are associated with the development of systemic lupus erythematosus (SLE) [3].
  • C4-deficient mice demonstrated similar mortality from bacteremia caused by encapsulated S aureus compared with controls, suggesting that in the unimmunized animal the alternative complement pathway contributes more to control of bacteremia caused by encapsulated S aureus than the classical complement pathway or mannan-binding lectin pathway [4].

High impact information on C4b

  • Renal infection occurred less frequently in C3- and C4-deficient mice compared with wild-type mice [5].
  • We found that there are two 21-OH genes in this region, located immediately 3' to the C4 and Slp genes [6].
  • H-2 linked Ss protein is C4 component of complement [7].
  • The complete cDNA sequences of C3 and C4 in mouse and man have given much information on the many posttranslational modifications of these proteins [8].
  • Recombinant Crry/p65 demonstrates cofactor activity for factor I-mediated cleavage of both mouse C3b and C4b [9].

Chemical compound and disease context of C4b


Biological context of C4b

  • To investigate whether K/BxN serum-induced RA involves complement activation and/or the complement receptors (CR) 1 and 2, we analyzed the role of complement C4 and of CR1 and CR2 [12].
  • The lack of protection in C4(-/-) mice suggests that antibody-mediated RA is independent of the classical as well as the lectin complement pathways and the split complement product C4b [12].
  • The targeting of antigen toward the MZ restored adaptive immunity (antibody response and class switch) in C4-deficient animals [3].
  • An impaired removal of apoptotic bodies, a disturbed clearance of IgG immune complexes (ICs) and an insufficient B-cell regulation via complement receptors CD21/CD35 have been discussed as explanations for the induction of autoimmunity; however, a unifying hypothesis for the loss of B-cell tolerance in the absence of C1 or C4 is still lacking [3].
  • The S region of the mouse major histocompatibility complex (MHC) encodes the class III proteins, the second (C2) and fourth (C4) components of complement, and factor B. Previously, the assignment of S-region haplotypes was based on analysis of protein polymorphisms [13].

Anatomical context of C4b

  • We found that deletion of the C4 gene does not significantly change either the time of onset or the severity and tempo of myelin oligodendrocyte-induced EAE compared with controls with a fully intact complement system [1].
  • As such, an inadequate localization of self-antigens might be responsible for the annulment of peripheral B-cell tolerance in the absence of C4 [3].
  • The phenotypic characteristics of human T lymphocytes expressing the C3b/C4b complement receptor type one (CR1, CD35) were investigated using dual-color surface immunofluorescence and cytofluorometric analysis of stained peripheral blood mononuclear cells (PBMC) from normal individuals [14].
  • GBS were effectively killed in vitro by human blood leukocytes in the presence of specific antibody and C4-deficient serum but not C3-deficient serum [15].
  • Now, using quantitatively and qualitatively controlled transfection assays in HepG2 human hepatoma cells and mouse L fibroblasts, we have observed that the C4-Slp promoter is fully effective and unhindered by upstream sequences and that the C4 promoter has a consistent albeit modest superiority [16].

Associations of C4b with chemical compounds

  • The lack of protection in Cr2(-/-) mice suggests that absence of CR1 had no significant affect, considering its role in immune complex clearance, inhibition of C3 and C5 convertase and as receptor for C3b/C4b [12].
  • The recent availability of C2, C4, and factor B cDNA probes prompted a search for restriction fragment length polymorphisms which would serve as additional genetic markers for these loci [13].
  • Mouse complement component C4 is devoid of classical pathway C5 convertase subunit activity [17].
  • C4 binding studies, however, revealed that the observed difference in antibody and C1q binding has no influence on the complement resistance of SK-MEL-170 cells: significantly more C4b was bound to complement-resistant (1565 +/- 92 fg/cell) as compared to susceptible cells (715 +/- 31 fg/cell) [18].
  • As expected the higher affinity monoclonal antibody (Qu) was more effective in binding C1q and causing C1-mediated C4b deposition [19].

Physical interactions of C4b

  • This implies that, in addition to the 455-469 beta-chain segment of human C4, there are other regions of the molecule contributing to C5 binding which are also non-conserved between human and mouse C4 [17].
  • Complement C2 receptor inhibitor trispanning and the beta-chain of C4 share a binding site for complement C2 [20].
  • Under low ionic strength conditions, this mutant was found to be approximately 50 and 75% as active as wild-type IgG1 in the C1q binding and C4b deposition assays, respectively [21].
  • Initiation of the alternative pathway is inhibited by CI already at the stage of cleavage of factor B. CI binds to C4, C4b, C3 and C3b; since the major inhibitory action of CI is lost after washing of cell intermediates, complex formation and, as a consequence, steric hindrance may be responsible for the inhibiting effects of CI [22].
  • These results suggest that Ab 242 recognizes an epitope which is closely related to the C2- and C4bp-binding sites in C4b [23].

Regulatory relationships of C4b

  • Regulation of C4 synthesis in the mouse macrophage is accomplished by mechanisms that are independent of this feedback control but the murine cells also display separate mechanisms for regulation of C4 and factor B-specific mRNA levels [24].

Other interactions of C4b

  • Transmission of antibody-induced arthritis is independent of complement component 4 (C4) and the complement receptors 1 and 2 (CD21/35) [12].
  • Haplotype-specific interactions of non-H-2-linked genetic factors controlling the mouse C4 and Slp protein levels [25].
  • The H-2 S region genes C4 (fourth complement component) and Slp (sex-limited protein) are highly homologous [26].
  • Activation of C4 releases into the fluid phase a fragment of the alpha chain, C4a [27].
  • It also interfered with the binding of C4bp to C4b [23].

Analytical, diagnostic and therapeutic context of C4b

  • We found that C4- or C3-deficient mice were much more sensitive to caecal ligation and puncture than wild-type (WT) controls (100% versus 20% in 24-h mortality, respectively) [28].
  • Southern blot analysis indicated that the aw18 haplotype has a deletion of the C4 gene and a deletion of one of the steroid 21-hydroxylase genes [29].
  • This result was confirmed by an immunodiffusion test that demonstrated the absence of production of the C4 protein in mice of haplotype H-2aw18 [29].
  • The defective opsonization by C3-deficient serum in vitro was corroborated by in vivo studies in which passive immunization of pregnant dams with specific antibodies conferred protection from GBS challenge to normal and C4-deficient pups but not C3-deficient pups [15].
  • In this report, we present the structure of the single C4 and four Slp genes of the B10.W7R S locus and compare the upstream flanking regions by partial sequence analysis and function in transfection assays [30].


  1. Murine complement C4 is not required for experimental autoimmune encephalomyelitis. Boos, L.A., Szalai, A.J., Barnum, S.R. Glia (2005) [Pubmed]
  2. The alternative activation pathway and complement component C3 are critical for a protective immune response against Pseudomonas aeruginosa in a murine model of pneumonia. Mueller-Ortiz, S.L., Drouin, S.M., Wetsel, R.A. Infect. Immun. (2004) [Pubmed]
  3. Antigen localization within the splenic marginal zone restores humoral immune response and IgG class switch in complement C4-deficient mice. Zachrau, B., Finke, D., Kropf, K., Gosink, H.J., Kirchner, H., Goerg, S. Int. Immunol. (2004) [Pubmed]
  4. Role of complement receptors 1 and 2 (CD35 and CD21), C3, C4, and C5 in survival by mice of Staphylococcus aureus bacteremia. Cunnion, K.M., Benjamin, D.K., Hester, C.G., Frank, M.M. J. Lab. Clin. Med. (2004) [Pubmed]
  5. Epithelial secretion of C3 promotes colonization of the upper urinary tract by Escherichia coli. Springall, T., Sheerin, N.S., Abe, K., Holers, V.M., Wan, H., Sacks, S.H. Nat. Med. (2001) [Pubmed]
  6. Two steroid 21-hydroxylase genes are located in the murine S region. White, P.C., Chaplin, D.D., Weis, J.H., Dupont, B., New, M.I., Seidman, J.G. Nature (1984) [Pubmed]
  7. H-2 linked Ss protein is C4 component of complement. Curman, B., Ostberg, L., Sandberg, L., Malmheden-Eriksson, I., Stålenheim, G., Rask, L., Peterson, P.A. Nature (1975) [Pubmed]
  8. The molecular genetics of components of complement. Campbell, R.D., Carroll, M.C., Porter, R.R. Adv. Immunol. (1986) [Pubmed]
  9. Mouse complement regulatory protein Crry/p65 uses the specific mechanisms of both human decay-accelerating factor and membrane cofactor protein. Kim, Y.U., Kinoshita, T., Molina, H., Hourcade, D., Seya, T., Wagner, L.M., Holers, V.M. J. Exp. Med. (1995) [Pubmed]
  10. Vitamin A-enhanced cleft palate susceptibility gene maps between C4 and B144 within the H-2 complex. Tyan, M.L., Tyan, D.B. Proc. Soc. Exp. Biol. Med. (1993) [Pubmed]
  11. Regulation of heme biosynthesis in Escherichia coli. Woodard, S.I., Dailey, H.A. Arch. Biochem. Biophys. (1995) [Pubmed]
  12. Transmission of antibody-induced arthritis is independent of complement component 4 (C4) and the complement receptors 1 and 2 (CD21/35). Solomon, S., Kolb, C., Mohanty, S., Jeisy-Walder, E., Preyer, R., Schöllhorn, V., Illges, H. Eur. J. Immunol. (2002) [Pubmed]
  13. Subdivision of the S region of the mouse major histocompatibility complex by identification of genomic polymorphisms of the class III genes. Sackstein, R., Roos, M.H., Démant, P., Colten, H.R. Immunogenetics (1984) [Pubmed]
  14. Human T lymphocytes expressing the C3b/C4b complement receptor type one (CR1, CD35) belong to Fc gamma receptor-positive CD4-positive T cells. Cohen, J.H., Aubry, J.P., Revillard, J.P., Banchereau, J., Kazatchkine, M.D. Cell. Immunol. (1989) [Pubmed]
  15. Studies of group B streptococcal infection in mice deficient in complement component C3 or C4 demonstrate an essential role for complement in both innate and acquired immunity. Wessels, M.R., Butko, P., Ma, M., Warren, H.B., Lage, A.L., Carroll, M.C. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  16. The androgen-dependent C4-Slp gene is driven by a constitutively competent promoter. Miyagoe, Y., Georgatsou, E., Varin-Blank, N., Meo, T. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  17. Mouse complement component C4 is devoid of classical pathway C5 convertase subunit activity. Ebanks, R.O., Isenman, D.E. Mol. Immunol. (1996) [Pubmed]
  18. Molecular basis of complement resistance of human melanoma cells expressing the C3-cleaving membrane protease p65. Ollert, M.W., Kadlec, J.V., Petrella, E.C., Bredehorst, R., Vogel, C.W. Cancer Res. (1993) [Pubmed]
  19. C1 inhibitor removes the entire C1qr2s2 complex from anti-C1Q monoclonal antibodies with low binding affinities. Chen, C.H., Lam, C.F., Boackle, R.J. Immunology (1998) [Pubmed]
  20. Complement C2 receptor inhibitor trispanning and the beta-chain of C4 share a binding site for complement C2. Inal, J.M., Schifferli, J.A. J. Immunol. (2002) [Pubmed]
  21. Residue at position 331 in the IgG1 and IgG4 CH2 domains contributes to their differential ability to bind and activate complement. Xu, Y., Oomen, R., Klein, M.H. J. Biol. Chem. (1994) [Pubmed]
  22. Isolation and properties of a complement inhibitor from Naja haje venom, distinct from known anticomplementary factors in cobra venom. von Zabern, I., Przyklenk, H., Damerau, B., Zimmermann, B. Scand. J. Immunol. (1981) [Pubmed]
  23. Monoclonal anti-human C4b antibodies: stabilization and inhibition of the classical-pathway C3 convertase. Ichihara, C., Nakamura, T., Nagasawa, S., Koyama, J. Mol. Immunol. (1986) [Pubmed]
  24. Expression of the MHC class III genes. Colten, H.R. Philos. Trans. R. Soc. Lond., B, Biol. Sci. (1984) [Pubmed]
  25. Haplotype-specific interactions of non-H-2-linked genetic factors controlling the mouse C4 and Slp protein levels. Bruisten, S.M., Skamene, E., Demant, P. Genetics (1989) [Pubmed]
  26. Allele-specific occurrence of multiple C4 and Slp mRNAs. Bruisten, S.M., Robins, D.M., Demant, P. Tissue Antigens (1989) [Pubmed]
  27. Evidence of a role for C4 in modulating interstitial inflammation in experimental glomerulonephritis. Welch, T.R., Frenzke, M., Carroll, M.C., Witte, D.P. Clin. Immunol. (2001) [Pubmed]
  28. Impaired mast cell-dependent natural immunity in complement C3-deficient mice. Prodeus, A.P., Zhou, X., Maurer, M., Galli, S.J., Carroll, M.C. Nature (1997) [Pubmed]
  29. Lethal deletion of the complement component C4 and steroid 21-hydroxylase genes in the mouse H-2 class III region, caused by meiotic recombination. Shiroishi, T., Sagai, T., Natsuume-Sakai, S., Moriwaki, K. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  30. Molecular genetics of androgen-dependent and -independent expression of mouse sex-limited protein. Stavenhagen, J., Loreni, F., Hemenway, C., Kalff, M., Robins, D.M. Mol. Cell. Biol. (1987) [Pubmed]
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