Genomes and Genes
Summary: C5 plays a central role in both the classical and the alternative pathway of COMPLEMENT ACTIVATION. C5 is cleaved by C5 CONVERTASE into COMPLEMENT C5A and COMPLEMENT C5B. The smaller fragment C5a is an ANAPHYLATOXIN and mediator of inflammatory process. The major fragment C5b binds to the membrane initiating the spontaneous assembly of the late complement components, C5-C9, into the MEMBRANE ATTACK COMPLEX.
- Halstead S, Humphreys P, Zitman F, Hamer J, Plomp J, Willison H. C5 inhibitor rEV576 protects against neural injury in an in vitro mouse model of Miller Fisher syndrome. J Peripher Nerv Syst. 2008;13:228-35 pubmed publisher..In this study, we tested whether the complement C5-inhibiting recombinant protein, rEV576, was able to prevent neural injury in a previously developed in vitro ..
- Panoulas V, Smith J, Nightingale P, Kitas G. Association of the TRAF1/C5 locus with increased mortality, particularly from malignancy or sepsis, in patients with rheumatoid arthritis. Arthritis Rheum. 2009;60:39-46 pubmed publisher..If this finding is replicated in future studies, TRAF1/C5 genotyping could identify patients at increased risk of death, particularly death due to malignancy or sepsis. ..
- de Jorge E, Macor P, Paixao Cavalcante D, Rose K, Tedesco F, Cook H, et al. The development of atypical hemolytic uremic syndrome depends on complement C5. J Am Soc Nephrol. 2011;22:137-45 pubmed publisher..To investigate the role of complement C5 activation in this aHUS model, we generated C5-deficient Cfh(-/-).FH?16-20 mice...
- Radovanovic I, Mullick A, Gros P. Genetic control of susceptibility to infection with Candida albicans in mice. PLoS ONE. 2011;6:e18957 pubmed publisher..Our results verify the important effect of C5-deficiency in inbred mouse strains, and further identify two novel loci, Carg3 and Carg4, which regulate resistance to C. albicans infection in a C5-independent manner. ..
- Karp C, Grupe A, Schadt E, Ewart S, Keane Moore M, Cuomo P, et al. Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat Immunol. 2000;1:221-6 pubmed..The role of complement in modulating susceptibility to asthma highlights the importance of immunoregulatory events at the interface of innate and adaptive immunity in disease pathogenesis...
- Zal T, Volkmann A, Stockinger B. Mechanisms of tolerance induction in major histocompatibility complex class II-restricted T cells specific for a blood-borne self-antigen. J Exp Med. 1994;180:2089-99 pubmed..This indicates that endogenous T cell receptor rearrangements possibly leading to the expression of two receptors might be a prerequisite for their survival and export into the periphery. ..
- Grimnes G, Beckman H, Lappegard K, Mollnes T, Skogen V. Recurrent meningococcal sepsis in a presumptive immunocompetent host shown to be complement C5 deficient-a case report. APMIS. 2011;119:479-84 pubmed publisher..This case report emphasizes the need of having complement deficiencies in mind when being introduced to patients with invasive Neisseria-infections. ..
- Wang Y, Kristan J, Hao L, Lenkoski C, Shen Y, Matis L. A role for complement in antibody-mediated inflammation: C5-deficient DBA/1 mice are resistant to collagen-induced arthritis. J Immunol. 2000;164:4340-7 pubmed..Nevertheless, these C5-deficient mice are highly resistant to the induction of CIA. These data provide evidence for an important role of complement in Ab-triggered inflammation and in the pathogenesis of autoimmune arthritis. ..
- Gervais F, Stevenson M, Skamene E. Genetic control of resistance to Listeria monocytogenes: regulation of leukocyte inflammatory responses by the Hc locus. J Immunol. 1984;132:2078-83 pubmed..We conclude that a defect in the phagocyte inflammatory responses caused by C5 deficiency is the major reason for the extreme susceptibility of A mice to Listeria. ..
- Daniel D, Dai G, Singh C, Lindsey D, Smith A, Dhandayuthapani S, et al. The reduced bactericidal function of complement C5-deficient murine macrophages is associated with defects in the synthesis and delivery of reactive oxygen radicals to mycobacterial phagosomes. J Immunol. 2006;177:4688-98 pubmedb>Complement C5-deficient (C5(-/-)) macrophages derived from B.10 congenic mice were found to be defective in killing intracellular Mycobacterium tuberculosis (MTB)...
- Bramham J, Thai C, Soares D, Uhrin D, Ogata R, Barlow P. Functional insights from the structure of the multifunctional C345C domain of C5 of complement. J Biol Chem. 2005;280:10636-45 pubmed..Modeling of homologous domains from complement proteins C3 and C4, which do not participate in membrane attack complex assembly, suggests that this provisionally identified C6/C7-interacting face is indeed specific to C5. ..
- Sinno H, Malhotra M, Lutfy J, Jardin B, Winocour S, Brimo F, et al. Accelerated wound healing with topical application of complement C5. Plast Reconstr Surg. 2012;130:523-9 pubmed publisher..The authors set out to investigate the effects of complement C5, a naturally occurring chemotactic cytokine, on wounds...
- Mullick A, Leon Z, Min oo G, Berghout J, Lo R, Daniels E, et al. Cardiac failure in C5-deficient A/J mice after Candida albicans infection. Infect Immun. 2006;74:4439-51 pubmed
- Pasinetti G, Tocco G, Sakhi S, Musleh W, DeSimoni M, Mascarucci P, et al. Hereditary deficiencies in complement C5 are associated with intensified neurodegenerative responses that implicate new roles for the C-system in neuronal and astrocytic functions. Neurobiol Dis. 1996;3:197-204 pubmed..These pleiotropic associations of C5 deficiency indicate roles for the C-system in neurodegeneration, but also in normal neural functions. ..
- Bradt B, Kolb W, Cooper N. Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide. J Exp Med. 1998;188:431-8 pubmed
- Patsopoulos N, Ioannidis J. Susceptibility variants for rheumatoid arthritis in the TRAF1-C5 and 6q23 loci: a meta-analysis. Ann Rheum Dis. 2010;69:561-6 pubmed publisher..Furthermore, these markers may not be the true causative loci but rather be in linkage disequilibrium with the true ones. ..
- Ooi Y, Colten H. Genetic defect in secretion of complement C5 in mice. Nature. 1979;282:207-8 pubmed..Using similar methods, we now find that C5 deficiency in each of five different mouse strains (AKR, SWR, DBA/2J8 A/HeJ and B10.D2/old line) is due to a failure in secretion of C5 protein and not to a failure in biosynthesis of pro-C5. ..
- Haviland D, Haviland J, Fleischer D, Wetsel R. Structure of the murine fifth complement component (C5) gene. A large, highly interrupted gene with a variant donor splice site and organizational homology with the third and fourth complement component genes. J Biol Chem. 1991;266:11818-25 pubmed..The 5'-flanking region also contained sequences identical with several cis-acting motifs known to bind the liver-specific nuclear protein LF-A1 and the nuclear protein NF-kappa B.(ABSTRACT TRUNCATED AT 250 WORDS) ..
- Mastellos D, Papadimitriou J, Franchini S, Tsonis P, Lambris J. A novel role of complement: mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration. J Immunol. 2001;166:2479-86 pubmed..These results support a novel role for C5 in liver regeneration and strongly implicate the complement system as an important immunoregulatory component of hepatic homeostasis. ..
- Kurreeman F, Rocha D, Houwing Duistermaat J, Vrijmoet S, Teixeira V, Migliorini P, et al. Replication of the tumor necrosis factor receptor-associated factor 1/complement component 5 region as a susceptibility locus for rheumatoid arthritis in a European family-based study. Arthritis Rheum. 2008;58:2670-4 pubmed publisher..Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA. ..
- Deguchi Y, Andoh A, Inatomi O, Araki Y, Hata K, Tsujikawa T, et al. Development of dextran sulfate sodium-induced colitis is aggravated in mice genetically deficient for complement C5. Int J Mol Med. 2005;16:605-8 pubmed..disease (IBD), we evaluated the development of dextran sulfate sodium (DSS)-induced colitis in genetically complement C5-deficient mice. We used DBA2/J mice, which are genetically deficient in complement C5...
- Rhodes J, Wicker L, Urba W. Genetic control of susceptibility to Cryptococcus neoformans in mice. Infect Immun. 1980;29:494-9 pubmed..A 1:1 correspondence was found between C5 deficiency and sensitivity to C. neoformans. Resistance was shown to cosegregate with the presence of hemolytic complement in the F2 and the backcross progenies. ..
- Fredslund F, Laursen N, Roversi P, Jenner L, Oliveira C, Pedersen J, et al. Structure of and influence of a tick complement inhibitor on human complement component 5. Nat Immunol. 2008;9:753-60 pubmed publisher..The structure of C5 may render possible a structure-based approach for the design of new selective complement inhibitors. ..
- Tsuji R, Kawikova I, Ramabhadran R, Akahira Azuma M, Taub D, Hugli T, et al. Early local generation of C5a initiates the elicitation of contact sensitivity by leading to early T cell recruitment. J Immunol. 2000;165:1588-98 pubmedWe have shown previously that an early complement C5-dependent cascade is required to recruit T cells to elicit 24-h contact sensitivity (CS) responses...
- Weerth S, Rus H, Shin M, Raine C. Complement C5 in experimental autoimmune encephalomyelitis (EAE) facilitates remyelination and prevents gliosis. Am J Pathol. 2003;163:1069-80 pubmed..These results in the EAE model indicate that absence of C5 resulted in fiber loss and extensive scarring, whereas presence of C5-favored axonal survival and more efficient remyelination. ..
- Bosmann M, Ward P. Role of C3, C5 and anaphylatoxin receptors in acute lung injury and in sepsis. Adv Exp Med Biol. 2012;946:147-59 pubmed publisher..These observations underscore the diversity of effects of C5a in a variety of inflammatory settings. ..
- Copland D, Hussain K, Baalasubramanian S, Hughes T, Morgan B, Xu H, et al. Systemic and local anti-C5 therapy reduces the disease severity in experimental autoimmune uveoretinitis. Clin Exp Immunol. 2010;159:303-14 pubmed publisher..This presents great therapeutic potential to protect against tissue damage during autoimmune responses in the retina or inflammation-induced degenerative disease. ..
- Nishimoto K, Kochi Y, Ikari K, Yamamoto K, Suzuki A, Shimane K, et al. Association study of TRAF1-C5 polymorphisms with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese. Ann Rheum Dis. 2010;69:368-73 pubmed publisher..Significant positive effect of genotype on the expression of TRAF1 might support the genetic association between TRAF1 and RA. ..
- Garcia C, Weston Davies W, Russo R, Tavares L, Rachid M, Alves Filho J, et al. Complement C5 activation during influenza A infection in mice contributes to neutrophil recruitment and lung injury. PLoS ONE. 2013;8:e64443 pubmed publisher..Taken together, these data suggest that targeting C5 activation with OmCI during IAV infection could be a promising approach to reduce excessive inflammatory reactions associated with the severe forms of IAV infections. ..
- Zal T, Weiss S, Mellor A, Stockinger B. Expression of a second receptor rescues self-specific T cells from thymic deletion and allows activation of autoreactive effector function. Proc Natl Acad Sci U S A. 1996;93:9102-7 pubmed
- Shen Y, Meri S. Yin and Yang: complement activation and regulation in Alzheimer's disease. Prog Neurobiol. 2003;70:463-72 pubmed
- Grant E, Picarella D, Burwell T, Delaney T, Croci A, Avitahl N, et al. Essential role for the C5a receptor in regulating the effector phase of synovial infiltration and joint destruction in experimental arthritis. J Exp Med. 2002;196:1461-71 pubmed..We report that genetic ablation of C5a receptor expression completely protects mice from arthritis. ..
- Liu L, Lioudyno M, Tao R, Eriksson P, Svensson M, Aldskogius H. Hereditary absence of complement C5 in adult mice influences Wallerian degeneration, but not retrograde responses, following injury to peripheral nerve. J Peripher Nerv Syst. 1999;4:123-33 pubmed..These findings elucidate new aspects on the functional role of the complement system in the peripheral nervous system following peripheral nerve injury. ..
- Boor P, Konieczny A, Villa L, Schult A, Bücher E, Rong S, et al. Complement C5 mediates experimental tubulointerstitial fibrosis. J Am Soc Nephrol. 2007;18:1508-15 pubmed..Using a combined genetic and pharmacologic approach, C5, in particular C5a, is identified as a novel profibrotic factor in renal disease and as a potential new therapeutic target. ..
- Rother R, Rollins S, Mojcik C, Brodsky R, Bell L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol. 2007;25:1256-64 pubmed
- Mans B, Ribeiro J. Function, mechanism and evolution of the moubatin-clade of soft tick lipocalins. Insect Biochem Mol Biol. 2008;38:841-52 pubmed publisher..TSGP2 and TSGP3, but not moubatin, binds complement C5, with kinetics that indicates that conformation change occurs during interaction...
- Niculescu T, Weerth S, Niculescu F, Cudrici C, Rus V, Raine C, et al. Effects of complement C5 on apoptosis in experimental autoimmune encephalomyelitis. J Immunol. 2004;172:5702-6 pubmed..Together, these findings are consistent with the role of C5, possibly by forming the membrane attack complex, in limiting OLG apoptosis in EAE, thus promoting remyelination during recovery. ..
- Ashman R, Papadimitriou J, Fulurija A, Drysdale K, Farah C, Naidoo O, et al. Role of complement C5 and T lymphocytes in pathogenesis of disseminated and mucosal candidiasis in susceptible DBA/2 mice. Microb Pathog. 2003;34:103-13 pubmed..anatomical regions of C5-deficient (DBA/2) and C5-sufficient (BALB/c) mice, and to evaluate the importance of complement C5 and T lymphocytes as factors that determine host susceptibility or resistance...
- Soltys J, Kusner L, Young A, Richmonds C, Hatala D, Gong B, et al. Novel complement inhibitor limits severity of experimentally myasthenia gravis. Ann Neurol. 2009;65:67-75 pubmed publisher..Inhibition of complement significantly reduced weakness in two models of EAMG. C5 inhibition could prove to be of significant therapeutic value in human myasthenia gravis. ..
- Huber Lang M, Younkin E, Sarma J, Riedemann N, McGuire S, Lu K, et al. Generation of C5a by phagocytic cells. Am J Pathol. 2002;161:1849-59 pubmed..These data indicate that phagocytic cells, especially lung macrophages, can generate C5a from C5. In the context of the lung, this may represent an important C5a-generating pathway that is independent of the plasma complement system. ..
- Zhou W, Farrar C, Abe K, Pratt J, Marsh J, Wang Y, et al. Predominant role for C5b-9 in renal ischemia/reperfusion injury. J Clin Invest. 2000;105:1363-71 pubmed..The membrane attack complex of complement is a potential target for prevention of I/R injury in this model. ..
- Actor J, Breij E, Wetsel R, Hoffmann H, Hunter R, Jagannath C. A role for complement C5 in organism containment and granulomatous response during murine tuberculosis. Scand J Immunol. 2001;53:464-74 pubmed..To address the molecular basis for this histologic dysfunction, congenic complement C5-sufficient (B10.D2-H2d H2-T18c Hcl/nSnJ) and complement C5-deficient strains (B10...
- Banerjee S, Anderson G, Luthra H, David C. Influence of complement C5 and V beta T cell receptor mutations on susceptibility to collagen-induced arthritis in mice. J Immunol. 1989;142:2237-43 pubmed..These studies show that complement C5 does not play a significant role in CIA susceptibility, and further implicate the V beta TCR mutation in the ..
- Ashman R, Fulurija A, Papadimitriou J. Strain-dependent differences in host response to Candida albicans infection in mice are related to organ susceptibility and infectious load. Infect Immun. 1996;64:1866-9 pubmed..The data suggest that mortality in A/J and DBA/2 mice is related to an unusual susceptibility of the kidneys to colonization by C. albicans and that there may be tissue-specific differences in host protective mechanisms. ..
- Wang Q, Rozelle A, Lepus C, Scanzello C, Song J, Larsen D, et al. Identification of a central role for complement in osteoarthritis. Nat Med. 2011;17:1674-9 pubmed publisher..Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis...
- Johansson A, Sundler M, Kjellen P, Johannesson M, Cook A, Lindqvist A, et al. Genetic control of collagen-induced arthritis in a cross with NOD and C57BL/10 mice is dependent on gene regions encoding complement factor 5 and FcgammaRIIb and is not associated with loci controlling diabetes. Eur J Immunol. 2001;31:1847-56 pubmed..The genetic control of arthritis is unique in comparison to diabetes, since none of these loci have been identified in analysis of diabetes susceptibility. ..
- Marzari R, Sblattero D, Macor P, Fischetti F, Gennaro R, Marks J, et al. The cleavage site of C5 from man and animals as a common target for neutralizing human monoclonal antibodies: in vitro and in vivo studies. Eur J Immunol. 2002;32:2773-82 pubmed..The scFv TS-A12/22 was tested in a rat model of antigen-induced arthritis and proved to be effective in preventing influx of polymorphonuclear cells into the knee joint and C9 deposition on synovial tissue. ..
- Banda N, Kraus D, Vondracek A, Huynh L, Bendele A, Holers V, et al. Mechanisms of effects of complement inhibition in murine collagen-induced arthritis. Arthritis Rheum. 2002;46:3065-75 pubmed..The greater inhibitory effects on CIA of anti-C5 antibody in comparison with Crry-Ig may be attributable primarily to decreased levels of IL-1beta and TNFalpha mRNA in the joints. ..
- Langley R, Wines B, Willoughby N, Basu I, Proft T, Fraser J. The staphylococcal superantigen-like protein 7 binds IgA and complement C5 and inhibits IgA-Fc alpha RI binding and serum killing of bacteria. J Immunol. 2005;174:2926-33 pubmed..SSL7 is a superantigen-like protein secreted from Staphylococcus aureus that blocks IgA-FcR interactions and inhibits complement, leading to increased survival of a sensitive bacterium in blood. ..
- Fischetti F, Durigutto P, Pellis V, Debeus A, Macor P, Bulla R, et al. Thrombus formation induced by antibodies to beta2-glycoprotein I is complement dependent and requires a priming factor. Blood. 2005;106:2340-6 pubmed..In conclusion, our data indicate that antibodies to beta2-glycoprotein I trigger coagulation subsequent to a priming proinflammatory factor and that the terminal C complex is the main mediator of the coagulation process. ..
- Tuite A, Elias M, Picard S, Mullick A, Gros P. Genetic control of susceptibility to Candida albicans in susceptible A/J and resistant C57BL/6J mice. Genes Immun. 2005;6:672-82 pubmed..albicans. ..