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Gene Review

Hc  -  hemolytic complement

Mus musculus

Synonyms: C5, C5a, Complement C5, He, Hemolytic complement
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Disease relevance of Hc


Psychiatry related information on Hc


High impact information on Hc

  • Fibroblast cells that were transfected with class II genes were compared with fibroblasts supertransfected with the invariant chain gene for their capacity to present the fifth component of complement (C5) to C5-specific class II restricted T cell clones or influenza virus protein to a virus-specific T cell clone [7].
  • Only fibroblasts supertransfected with the invariant chain gene were able to present native antigen, even at very low antigen concentration, whereas both fibroblast types could present cyanogen bromide-fragmented C5 or the virus peptide [7].
  • The peak increase in surface Mo1 coincided with the maximal drop in neutrophil count and with the peak rise in the plasma levels of the complement-activation products C5a desArg and C3a desArg [8].
  • These data suggest that the increased expression of Mo1 on granulocytes in vivo is in part mediated by C5a (and C5a desArg) [8].
  • Injury in lungs of C3-/- mice and C5a levels in bronchoalveolar lavage (BAL) fluids from these mice were greatly reduced in the presence of antithrombin III (ATIII) or hirudin but were not reduced in similarly treated C3+/+ mice [9].

Chemical compound and disease context of Hc


Biological context of Hc

  • Following the inheritance of DNA restriction fragment-length polymorphisms revealed by the probes in recombinant inbred mouse strains allowed the factor H-associated fragments to be mapped to Sas-1 on chromosome 1, and the C5-associated fragments to be mapped to Hc [15].
  • Mice with dual C3 and C5 deficiency had a more exacerbated phenotype that was reversed by combined C3a and C5a reconstitution [16].
  • The proinflammatory mediators C3a and C5a are essential for liver regeneration [16].
  • In contrast, up until now, no specific contribution of C5a and its receptor, C5aR, was recognized in diseases of antibody-dependent type II autoimmunity [17].
  • Taken together, these findings indicate an important linkage of C5a as a component of early activated innate immunity that is required for later elicitation of acquired T cell immunity, probably by facilitating the initial recruitment of T cells into the Ag-challenged local site in CS responses [18].

Anatomical context of Hc

  • Levy et al.5 showed that somatic cell hybrids between C5 deficient (B10.D2/old line) macrophages and either C5 sufficient (B10.D2/new line) mouse kidney or chicken erythroblasts secreted haemolytically active mouse C5 in vitro [19].
  • These data indicate that C3a and C5a, two potent inflammatory mediators of the innate immune response, contribute essentially to the early priming stages of hepatocyte regeneration [16].
  • Although we do not know through which mechanism C5a participates in the development of HN, we propose that the described HN response is related to a local defense mechanism in which TNF and C5a lead to the disruption of capillaries in the direct vicinity of bacteria [3].
  • These data suggest a dual role for C5a in allergic asthma, i.e., protection from the development of maladaptive type 2 immune responses during allergen sensitization at the DC/T cell interface but enhancement of airway inflammation and AHR in an established inflammatory environment [20].
  • Both in patients with AMD and in a recently described mouse model of AMD, early subretinal pigmented epithelium deposition of complement components C3 and C5 occurs, suggesting a contributing role for these inflammatory proteins in the development of AMD [21].

Associations of Hc with chemical compounds

  • A genetic deficiency of the fifth (C5) component of complement1-3, a serum glycoprotein of molecular weight (MW) 220,000 (ref. 4), has been found in 39% of inbred strains of mice3 [19].
  • C3- or C5-deficient mice exhibited high mortality, parenchymal damage, and impaired liver regeneration after partial hepatectomy [16].
  • Tumor necrosis factor/cachectin. Induction of hemorrhagic necrosis in normal tissue requires the fifth component of complement (C5) [3].
  • Mouse complement component C4 is devoid of classical pathway C5 convertase subunit activity [22].
  • Requisite role for complement C5 and the C5a receptor in granulomatous response to mycobacterial glycolipid trehalose 6,6'-dimycolate [23].

Physical interactions of Hc

  • 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 [22].
  • The inhibition of C5a binding to C5a receptor was studied using a radioligand binding assay [24].

Regulatory relationships of Hc


Other interactions of Hc

  • IgG Fc receptors (FcgammaRs, especially FcgammaRIII) and complement (in particular, C5a anaphylatoxin) are critical effectors of the acute inflammatory response to immune complexes (ICs) [30].
  • We have designated the two loci Cfh and C5, respectively [15].
  • The SDP of A and B alleles at the Lr-1 locus was fully concordant with that observed for the Hc locus (controlling the level of the C5 component of complement) [2].
  • Thioglycollate peritonitis in mice lacking C5, 5-lipoxygenase, or p47(phox): complement, leukotrienes, and reactive oxidants in acute inflammation [31].
  • The strain distribution pattern for this polymorphism indicated close linkage of Ass-1 to Hc (the fifth component of complement) on proximal mouse chromosome 2 with a recombination fraction of 0.016 and a 95% confidence interval of 0.003 to 0.054 [32].

Analytical, diagnostic and therapeutic context of Hc


  1. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Hillebrandt, S., Wasmuth, H.E., Weiskirchen, R., Hellerbrand, C., Keppeler, H., Werth, A., Schirin-Sokhan, R., Wilkens, G., Geier, A., Lorenzen, J., Köhl, J., Gressner, A.M., Matern, S., Lammert, F. Nat. Genet. (2005) [Pubmed]
  2. Genetic control of resistance to Listeria monocytogenes: regulation of leukocyte inflammatory responses by the Hc locus. Gervais, F., Stevenson, M., Skamene, E. J. Immunol. (1984) [Pubmed]
  3. Tumor necrosis factor/cachectin. Induction of hemorrhagic necrosis in normal tissue requires the fifth component of complement (C5). Rothstein, J.L., Lint, T.F., Schreiber, H. J. Exp. Med. (1988) [Pubmed]
  4. An unexpected role for the anaphylatoxin C5a receptor in allergic sensitization. Lambrecht, B.N. J. Clin. Invest. (2006) [Pubmed]
  5. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. Girardi, G., Berman, J., Redecha, P., Spruce, L., Thurman, J.M., Kraus, D., Hollmann, T.J., Casali, P., Caroll, M.C., Wetsel, R.A., Lambris, J.D., Holers, V.M., Salmon, J.E. J. Clin. Invest. (2003) [Pubmed]
  6. The role of complement anaphylatoxin C5a in neurodegeneration: implications in Alzheimer's disease. Mukherjee, P., Pasinetti, G.M. J. Neuroimmunol. (2000) [Pubmed]
  7. A role of Ia-associated invariant chains in antigen processing and presentation. Stockinger, B., Pessara, U., Lin, R.H., Habicht, J., Grez, M., Koch, N. Cell (1989) [Pubmed]
  8. Increased expression of an adhesion-promoting surface glycoprotein in the granulocytopenia of hemodialysis. Arnaout, M.A., Hakim, R.M., Todd, R.F., Dana, N., Colten, H.R. N. Engl. J. Med. (1985) [Pubmed]
  9. Generation of C5a in the absence of C3: a new complement activation pathway. Huber-Lang, M., Sarma, J.V., Zetoune, F.S., Rittirsch, D., Neff, T.A., McGuire, S.R., Lambris, J.D., Warner, R.L., Flierl, M.A., Hoesel, L.M., Gebhard, F., Younger, J.G., Drouin, S.M., Wetsel, R.A., Ward, P.A. Nat. Med. (2006) [Pubmed]
  10. Elucidation of the early events contributing to zymosan-induced multiple organ dysfunction syndrome using MIP-1alpha, C3 knockout, and C5-deficient mice. Mahesh, J., Daly, J., Cheadle, W.G., Kotwal, G.J. Shock (1999) [Pubmed]
  11. Development of dextran sulfate sodium-induced colitis is aggravated in mice genetically deficient for complement C5. Deguchi, Y., Andoh, A., Inatomi, O., Araki, Y., Hata, K., Tsujikawa, T., Kitoh, K., Fujiyama, Y. Int. J. Mol. Med. (2005) [Pubmed]
  12. Identification of a potent and orally active non-peptide C5a receptor antagonist. Sumichika, H., Sakata, K., Sato, N., Takeshita, S., Ishibuchi, S., Nakamura, M., Kamahori, T., Ehara, S., Itoh, K., Ohtsuka, T., Ohbora, T., Mishina, T., Komatsu, H., Naka, Y. J. Biol. Chem. (2002) [Pubmed]
  13. A critical role for sphingosine kinase in anaphylatoxin-induced neutropenia, peritonitis, and cytokine production in vivo. Vlasenko, L.P., Melendez, A.J. J. Immunol. (2005) [Pubmed]
  14. Regulation of heme biosynthesis in Escherichia coli. Woodard, S.I., Dailey, H.A. Arch. Biochem. Biophys. (1995) [Pubmed]
  15. Chromosomal location of the genes encoding complement components C5 and factor H in the mouse. D'Eustachio, P., Kristensen, T., Wetsel, R.A., Riblet, R., Taylor, B.A., Tack, B.F. J. Immunol. (1986) [Pubmed]
  16. The proinflammatory mediators C3a and C5a are essential for liver regeneration. Strey, C.W., Markiewski, M., Mastellos, D., Tudoran, R., Spruce, L.A., Greenbaum, L.E., Lambris, J.D. J. Exp. Med. (2003) [Pubmed]
  17. Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice. Kumar, V., Ali, S.R., Konrad, S., Zwirner, J., Verbeek, J.S., Schmidt, R.E., Gessner, J.E. J. Clin. Invest. (2006) [Pubmed]
  18. Early local generation of C5a initiates the elicitation of contact sensitivity by leading to early T cell recruitment. Tsuji, R.F., Kawikova, I., Ramabhadran, R., Akahira-Azuma, M., Taub, D., Hugli, T.E., Gerard, C., Askenase, P.W. J. Immunol. (2000) [Pubmed]
  19. Genetic defect in secretion of complement C5 in mice. Ooi, Y.M., Colten, H.R. Nature (1979) [Pubmed]
  20. A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma. Köhl, J., Baelder, R., Lewkowich, I.P., Pandey, M.K., Hawlisch, H., Wang, L., Best, J., Herman, N.S., Sproles, A.A., Zwirner, J., Whitsett, J.A., Gerard, C., Sfyroera, G., Lambris, J.D., Wills-Karp, M. J. Clin. Invest. (2006) [Pubmed]
  21. Drusen complement components C3a and C5a promote choroidal neovascularization. Nozaki, M., Raisler, B.J., Sakurai, E., Sarma, J.V., Barnum, S.R., Lambris, J.D., Chen, Y., Zhang, K., Ambati, B.K., Baffi, J.Z., Ambati, J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  22. Mouse complement component C4 is devoid of classical pathway C5 convertase subunit activity. Ebanks, R.O., Isenman, D.E. Mol. Immunol. (1996) [Pubmed]
  23. Requisite role for complement C5 and the C5a receptor in granulomatous response to mycobacterial glycolipid trehalose 6,6'-dimycolate. Borders, C.W., Courtney, A., Ronen, K., Pilar Laborde-Lahoz, M., Guidry, T.V., Hwang, S.A., Olsen, M., Hunter, R.L., Hollmann, T.J., Wetsel, R.A., Actor, J.K. Scand. J. Immunol. (2005) [Pubmed]
  24. Pre-neutralization of C5a-mediated effects by the monoclonal antibody 137-26 reacting with the C5a moiety of native C5 without preventing C5 cleavage. Fung, M., Lu, M., Fure, H., Sun, W., Sun, C., Shi, N.Y., Dou, Y., Su, J., Swanson, X., Mollnes, T.E. Clin. Exp. Immunol. (2003) [Pubmed]
  25. Cellular expression of the C5a anaphylatoxin receptor (C5aR): demonstration of C5aR on nonmyeloid cells of the liver and lung. Haviland, D.L., McCoy, R.L., Whitehead, W.T., Akama, H., Molmenti, E.P., Brown, A., Haviland, J.C., Parks, W.C., Perlmutter, D.H., Wetsel, R.A. J. Immunol. (1995) [Pubmed]
  26. NF-kappaB activation is required for C5a-induced interleukin-8 gene expression in mononuclear cells. Hsu, M.H., Wang, M., Browning, D.D., Mukaida, N., Ye, R.D. Blood (1999) [Pubmed]
  27. The differential role of extracellular signal-regulated kinases and p38 mitogen-activated protein kinase in eosinophil functions. Adachi, T., Choudhury, B.K., Stafford, S., Sur, S., Alam, R. J. Immunol. (2000) [Pubmed]
  28. C5a negatively regulates toll-like receptor 4-induced immune responses. Hawlisch, H., Belkaid, Y., Baelder, R., Hildeman, D., Gerard, C., Köhl, J. Immunity (2005) [Pubmed]
  29. C5a-mediated leukotriene B4-amplified neutrophil chemotaxis is essential in tumor immunotherapy facilitated by anti-tumor monoclonal antibody and beta-glucan. Allendorf, D.J., Yan, J., Ross, G.D., Hansen, R.D., Baran, J.T., Subbarao, K., Wang, L., Haribabu, B. J. Immunol. (2005) [Pubmed]
  30. C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs in immune complex-induced lung disease. Shushakova, N., Skokowa, J., Schulman, J., Baumann, U., Zwirner, J., Schmidt, R.E., Gessner, J.E. J. Clin. Invest. (2002) [Pubmed]
  31. Thioglycollate peritonitis in mice lacking C5, 5-lipoxygenase, or p47(phox): complement, leukotrienes, and reactive oxidants in acute inflammation. Segal, B.H., Kuhns, D.B., Ding, L., Gallin, J.I., Holland, S.M. J. Leukoc. Biol. (2002) [Pubmed]
  32. Assignment of the structural gene for argininosuccinate synthetase to proximal mouse chromosome 2. Jackson, M.J., Surh, L.C., O'Brien, W.E., Beaudet, A.L. Genomics (1990) [Pubmed]
  33. A role for complement in antibody-mediated inflammation: C5-deficient DBA/1 mice are resistant to collagen-induced arthritis. Wang, Y., Kristan, J., Hao, L., Lenkoski, C.S., Shen, Y., Matis, L.A. J. Immunol. (2000) [Pubmed]
  34. ApoE(-/-) mice develop atherosclerosis in the absence of complement component C5. Patel, S., Thelander, E.M., Hernandez, M., Montenegro, J., Hassing, H., Burton, C., Mundt, S., Hermanowski-Vosatka, A., Wright, S.D., Chao, Y.S., Detmers, P.A. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  35. The complement component C5 of the common carp (Cyprinus carpio): cDNA cloning of two distinct isotypes that differ in a functional site. Kato, Y., Nakao, M., Mutsuro, J., Zarkadis, I.K., Yano, T. Immunogenetics (2003) [Pubmed]
  36. Studies on the polymorphism of the fifth component of complement in laboratory mice. Lynch, D.M., Kay, P.H. Exp. Clin. Immunogenet. (1995) [Pubmed]
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