Genomes and Genes
Summary: The large fragment formed when COMPLEMENT C4 is cleaved by COMPLEMENT C1S. The membrane-bound C4b binds COMPLEMENT C2A, a SERINE PROTEASE, to form C4b2a (CLASSICAL PATHWAY C3 CONVERTASE) and subsequent C4b2a3b (CLASSICAL PATHWAY C5 CONVERTASE).
- Mroz A, Lewandowski Z, Cieciura T, Matłosz B, Pazik J, Kwiatkowski A, et al. C4d complement split product in diagnosis of immunological activity of chronic allograft nephropathy. Transplant Proc. 2006;38:97-100 pubmed..C4d peritubular capillary expression did not differentiate patients after immunosuppression enhancement, but it predisposed to progression of chronic morphological findings during 1-year observation. ..
- Blasko B, Kolka R, Thorbjornsdottir P, Sigurdarson S, Sigurdsson G, Ronai Z, et al. Low complement C4B gene copy number predicts short-term mortality after acute myocardial infarction. Int Immunol. 2008;20:31-7 pubmed..This observation indicates that low C4B copy number is a strong risk factor for short-term mortality after AMI in smoking Icelandic patients, whereas LTA 252 G allele is not a risk factor in Caucasian population. ..
- Loupy A, Suberbielle Boissel C, Hill G, Lefaucheur C, Anglicheau D, Zuber J, et al. Outcome of subclinical antibody-mediated rejection in kidney transplant recipients with preformed donor-specific antibodies. Am J Transplant. 2009;9:2561-70 pubmed publisher..C4d-negative SAMR patients displayed an intermediate course between the no-SAMR group and the C4d+ SAMR group. Screening biopsies may be useful to recognize patients more likely to develop SAMR. ..
- Jarva H, Ram S, Vogel U, Blom A, Meri S. Binding of the complement inhibitor C4bp to serogroup B Neisseria meningitidis. J Immunol. 2005;174:6299-307 pubmed..PorA-expressing strains were also more resistant to C lysis than PorA-negative strains in a serum bactericidal assay. Binding of C4bp thus helps Neisseria meningitidis to escape CP complement activation...
- Ittiprasert W, Kantachuvesiri S, Pavasuthipaisit K, Verasertniyom O, Chaomthum L, Totemchokchyakarn K, et al. Complete deficiencies of complement C4A and C4B including 2-bp insertion in codon 1213 are genetic risk factors of systemic lupus erythematosus in Thai populations. J Autoimmun. 2005;25:77-84 pubmed..We suggested that the different racial and genetic backgrounds could alter the thresholds for requirement of C4A or C4B protein levels in immune tolerance and regulation. ..
- Fotheringham J, Angel C, McKane W. Transplant glomerulopathy: morphology, associations and mechanism. Nephron Clin Pract. 2009;113:c1-7; discussion c7 pubmed publisher..Proposed treatments include augmentation of background immunosuppression, and trials of monoclonal therapies targeted at CD20-positive B cells are underway. ..
- Ramu P, Tanskanen R, Holmberg M, L hteenm ki K, Korhonen T, Meri S. The surface protease PgtE of Salmonella enterica affects complement activity by proteolytically cleaving C3b, C4b and C5. FEBS Lett. 2007;581:1716-20 pubmed publisher..enterica proteolytically cleaves C3b, C4b and C5 and that the expression of PgtE enhances bacterial resistance to human serum. Degradation of C3b was further enhanced by PgtE-mediated plasminogen activation...
- Mougey R. A review of the Chido/Rodgers blood group. Immunohematology. 2010;26:30-8 pubmed..The recognition of the extreme polymorphism of the C4 gene and the gene complex RCCX should lead to more insights in the understanding of disease risk and potential treatment. ..
- Kavanagh D, Richards A, Noris M, Hauhart R, Liszewski M, Karpman D, et al. Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome. Mol Immunol. 2008;45:95-105 pubmed..The excessive complement activation for a given degree of damage may result in generation of a procoagulant state and aHUS. ..
- Roversi P, Johnson S, Caesar J, McLean F, Leath K, Tsiftsoglou S, et al. Structural basis for complement factor I control and its disease-associated sequence polymorphisms. Proc Natl Acad Sci U S A. 2011;108:12839-44 pubmed publisher..In addition to explaining how circulating fI is limited to cleaving only C3b/C4b, our model explains the molecular basis of disease-associated polymorphisms in fI and its cofactors. ..
- Kainulainen L, Peltola V, Seppanen M, Viander M, He Q, Lokki M, et al. C4A deficiency in children and adolescents with recurrent respiratory infections. Hum Immunol. 2012;73:498-501 pubmed publisher..C4 gene testing should be added to the list of investigations when the cause for recurrent acute otitis media, maxillary sinusitis, or pneumonia in children and young adults is sought. ..
- Colvin R. Antibody-mediated renal allograft rejection: diagnosis and pathogenesis. J Am Soc Nephrol. 2007;18:1046-56 pubmed..Clinical trials will be needed to ascertain the optimal treatment for the newly appreciated conditions chronic humoral rejection and accommodation. ..
- Szilagyi A, Blasko B, Szilassy D, Fust G, Sasvari Szekely M, Ronai Z. Real-time PCR quantification of human complement C4A and C4B genes. BMC Genet. 2006;7:1 pubmed..This report describes a novel real-time PCR method for single-step quantification of C4A and C4B genes. The developed technique could facilitate studies investigating disease association of different C4 isotypes. ..
- Puah S, Lian L, Chew C, Chua K, Tan S. A study of association of the complement C4 mutations with systemic lupus erythematosus in the Malaysian population. Lupus. 2007;16:750-4 pubmed..Overall, our results do not demonstrate a significant association to these known C4 mutations identified by previous studies, in the Malaysian scenario. ..
- Mayilyan K, Dodds A, Boyajyan A, Soghoyan A, Sim R. Complement C4B protein in schizophrenia. World J Biol Psychiatry. 2008;9:225-30 pubmed..Previous reports suggest abnormalities in the complement C4B isotype in schizophrenia and other mental disorders...
- Al Aly Z, Yalamanchili P, Cortese C, Salinas Madrigal L, Bastani B. C4d peritubular capillary staining in chronic allograft nephropathy and transplant glomerulopathy: an uncommon finding. Transpl Int. 2005;18:800-5 pubmed..None of the TGP biopsies showed peritubular C4d staining. C4d staining of the peritubular capillaries appears to be rare in patients with pure CAN with and without TGP features. ..
- Akalin E, Dinavahi R, Dikman S, de Boccardo G, Friedlander R, Schroppel B, et al. Transplant glomerulopathy may occur in the absence of donor-specific antibody and C4d staining. Clin J Am Soc Nephrol. 2007;2:1261-7 pubmed..These results suggest that a substantial number of patients with TGP did not have positive C4d staining or DSA, indicating that a non-alloantibody-mediated process may be involved in the development of TGP in some patients. ..
- Odell D, Maciulis A, Cutler A, Warren L, McMahon W, Coon H, et al. Confirmation of the association of the C4B null allelle in autism. Hum Immunol. 2005;66:140-5 pubmed..1 that lacks a C4B gene and has 2 C4A genes was also observed. The results of this study suggest that the human leukocyte antigen class III C4BQ0 significantly increases the risk for autism. ..
- Poduval R, Kadambi P, Josephson M, Cohn R, Harland R, Javaid B, et al. Implications of immunohistochemical detection of C4d along peritubular capillaries in late acute renal allograft rejection. Transplantation. 2005;79:228-35 pubmed..Late acute humoral rejection may be associated with interstitial hemorrhage and plasma cells and contributes significantly to graft loss. ..
- Böhmig G, Bartel G, Wahrmann M. Antibodies, isotypes and complement in allograft rejection. Curr Opin Organ Transplant. 2008;13:411-8 pubmed publisher..Considering the pivotal role of complement, technologies that uncover the complement-fixing ability of alloantibodies may be of particular interest for the selective detection of deleterious sensitization. ..
- Gaston R, Cecka J, Kasiske B, Fieberg A, Leduc R, Cosio F, et al. Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure. Transplantation. 2010;90:68-74 pubmed publisher..Evidence of antibody-mediated injury (DSA or C4d) is common (57%) in patients with new onset late kidney allograft dysfunction. The risk of subsequent graft failure is significantly worse in the presence of C4d+ staining. ..
- Cohen D, Koopmans M, Kremer Hovinga I, Berger S, Roos van Groningen M, Steup Beekman G, et al. Potential for glomerular C4d as an indicator of thrombotic microangiopathy in lupus nephritis. Arthritis Rheum. 2008;58:2460-9 pubmed publisher..Immunodetection of glomerular C4d deposition in renal biopsy samples could be a convenient method of identifying patients at risk of thrombotic microangiopathy. ..
- Wouters D, van Schouwenburg P, van der Horst A, de Boer M, Schooneman D, Kuijpers T, et al. High-throughput analysis of the C4 polymorphism by a combination of MLPA and isotype-specific ELISA's. Mol Immunol. 2009;46:592-600 pubmed publisher..In conclusion, the combination of MLPA and ELISA is very suitable to study the geno- and phenotype of complement C4 in large patient groups...
- Sis B, Halloran P. Endothelial transcripts uncover a previously unknown phenotype: C4d-negative antibody-mediated rejection. Curr Opin Organ Transplant. 2010;15:42-8 pubmed publisher..C4d staining, although very useful, is insensitive for detecting ABMR. Measuring endothelial gene expression in biopsies from kidneys with alloantibody is a sensitive and specific method to diagnose ABMR and predict graft outcomes. ..
- Haas M. C4d-negative antibody-mediated rejection in renal allografts: evidence for its existence and effect on graft survival. Clin Nephrol. 2011;75:271-8 pubmed
- Boteva L, Wu Y, Cortes HernÃ¡ndez 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. ..
- Wennerström A, Pietinalho A, Vauhkonen H, Lahtela L, Palikhe A, Hedman J, et al. HLA-DRB1 allele frequencies and C4 copy number variation in Finnish sarcoidosis patients and associations with disease prognosis. Hum Immunol. 2012;73:93-100 pubmed publisher..Thus, accurate categorization of disease phenotype and HLA-DRB1 sequencing offer a basis for disease course estimation of sarcoidosis. ..
- Takeda A, Otsuka Y, Horike K, Inaguma D, Hiramitsu T, Yamamoto T, et al. Significance of C4d deposition in antibody-mediated rejection. Clin Transplant. 2012;26 Suppl 24:43-8 pubmed publisher..C4d positivity could not come to a specific marker of ABMR diagnosing based on clinically and ordinary morphological findings. ..
- Liszewski M, Leung M, Hauhart R, Buller R, Bertram P, Wang X, et al. Structure and regulatory profile of the monkeypox inhibitor of complement: comparison to homologs in vaccinia and variola and evidence for dimer formation. J Immunol. 2006;176:3725-34 pubmed..Furthermore, targeting and neutralizing these complement regulatory active sites via mAbs is a therapeutic approach that may enhance protection against smallpox...
- Nordstrom T, Blom A, Forsgren A, Riesbeck K. The emerging pathogen Moraxella catarrhalis interacts with complement inhibitor C4b binding protein through ubiquitous surface proteins A1 and A2. J Immunol. 2004;173:4598-606 pubmed..catarrhalis retained its cofactor activity as determined by analysis of C4b degradation. Taken together, M. catarrhalis interferes with the classical complement activation pathway by binding C4BP to UspA1 and UspA2. ..
- Li S, Liu Z, Zen C, Wang Q, Wang Y, Li L. Peritubular capillary C4d deposition in lupus nephritis different from antibody-mediated renal rejection. Lupus. 2007;16:875-80 pubmed
- Feucht H. Complement C4d in graft capillaries -- the missing link in the recognition of humoral alloreactivity. Am J Transplant. 2003;3:646-52 pubmed..Presensitization, however, will remain a potential threat to allografts. ..
- Chung E, Yang Y, Rupert K, Jones K, Rennebohm R, Blanchong C, et al. Determining the one, two, three, or four long and short loci of human complement C4 in a major histocompatibility complex haplotype encoding C4A or C4B proteins. Am J Hum Genet. 2002;71:810-22 pubmed..Applications of these vigorously tested techniques may clarify the roles that human C4A and C4B gene-dosage variations play in infectious and autoimmune diseases. ..
- Iwata K, Seya T, Yanagi Y, Pesando J, Johnson P, Okabe M, et al. Diversity of sites for measles virus binding and for inactivation of complement C3b and C4b on membrane cofactor protein CD46. J Biol Chem. 1995;270:15148-52 pubmed..The functional domains of MCP for the three natural ligands C3b, C4b, and MV, therefore, map to different, although partly overlapping, SCR domains. ..
- Villoutreix B, Härdig Y, Wallqvist A, Covell D, Garcia de Frutos P, Dahlback B. Structural investigation of C4b-binding protein by molecular modeling: localization of putative binding sites. Proteins. 1998;31:391-405 pubmed..An understanding of these intermolecular interactions should contribute to the rational design of potential therapeutic agents aiming at interfering specifically some of these protein-protein interactions. ..
- 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. ..
- Blom A, Rytkonen A, Vasquez P, Lindahl G, Dahlback B, Jonsson A. A novel interaction between type IV pili of Neisseria gonorrhoeae and the human complement regulator C4B-binding protein. J Immunol. 2001;166:6764-70 pubmed..Accordingly, high concentrations of C4BP were required to inhibit binding of N. gonorrhoeae to Chang conjunctiva cells, and no inhibition of binding was observed with cervical epithelial cells. ..
- Adams E, Brown M, Nunge M, Krych M, Atkinson J. Contribution of the repeating domains of membrane cofactor protein (CD46) of the complement system to ligand binding and cofactor activity. J Immunol. 1991;147:3005-11 pubmed..The data also suggest the presence of distinguishable iC3 and C4b binding sites and provide evidence that iC3 binding is not always sufficient for cofactor activity. ..
- Yu C, Belt K, Giles C, Campbell R, Porter R. Structural basis of the polymorphism of human complement components C4A and C4B: gene size, reactivity and antigenicity. EMBO J. 1986;5:2873-81 pubmed..Our structural data on the C4A and C4B polymorphism pattern suggests a gene conversion-like mechanism is operating in mixing the generally discrete serological phenotypes between C4A and C4B. ..
- Dahlback B, Smith C, Muller Eberhard H. Visualization of human C4b-binding protein and its complexes with vitamin K-dependent protein S and complement protein C4b. Proc Natl Acad Sci U S A. 1983;80:3461-5 pubmed..C4b imaged as an irregular, relatively compact molecule. It was found to interact with the peripheral ends of the elongated subunits, suggesting seven C4b-binding sites per molecule of C4bp. ..
- Blom A, Webb J, Villoutreix B, Dahlback B. A cluster of positively charged amino acids in the C4BP alpha-chain is crucial for C4b binding and factor I cofactor function. J Biol Chem. 1999;274:19237-45 pubmed..In conclusion, we identify a cluster of amino acids that is part of a C4b binding site involved in the regulation of the complement system. ..
- Mauiyyedi S, Pelle P, Saidman S, Collins A, Pascual M, Tolkoff Rubin N, et al. Chronic humoral rejection: identification of antibody-mediated chronic renal allograft rejection by C4d deposits in peritubular capillaries. J Am Soc Nephrol. 2001;12:574-82 pubmed..C4d can be used to separate this group of CR from the nonspecific category of chronic allograft nephropathy and may have the potential to guide successful therapeutic intervention. ..
- 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..An undesirable accompanying byproduct of this phenomenon is the inherent deleterious recombinations among the RCCX constituents leading to autoimmune and genetic disorders. ..
- 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..Racial differences seem to be relevant in susceptibility to SLE ..
- Blom A, Kask L, Dahlback B. Structural requirements for the complement regulatory activities of C4BP. J Biol Chem. 2001;276:27136-44 pubmed..The results presented here elucidate the structural requirements of individual CCPs of C4BP, as well as their spatial arrangements within and between subunits for expression of full functional activity. ..
- Franciotta D, Cuccia M, Dondi E, Piccolo G, Cosi V. Polymorphic markers in MHC class II/III region: a study on Italian patients with myasthenia gravis. J Neurol Sci. 2001;190:11-6 pubmed..g. TNF-B*1 and C4A*Q0, might contribute to pathogenetically significant abnormalities in immune responses in a subset of female MG patients. The combined effect of other intervening genes cannot be excluded. ..
- 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. ..
- Nickeleit V, Zeiler M, Gudat F, Thiel G, Mihatsch M. Detection of the complement degradation product C4d in renal allografts: diagnostic and therapeutic implications. J Am Soc Nephrol. 2002;13:242-51 pubmed..In addition, we show that a subgroup of C4d-positive cases may not require any immediate therapeutic intervention. The presence of C4d is clinically relevant and should be reported in the histologic diagnosis. ..
- 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
- Klickstein L, Wong W, Smith J, Weis J, Wilson J, Fearon D. Human C3b/C4b receptor (CR1). Demonstration of long homologous repeating domains that are composed of the short consensus repeats characteristics of C3/C4 binding proteins. J Exp Med. 1987;165:1095-112 pubmed..The COOH-terminal cytoplasmic domain of 43 residues contains a six-amino-acid sequence that is homologous to the sequence in the epidermal growth factor receptor that is phosphorylated by protein kinase C. ..
- Yang Y, Chung E, Zhou B, Blanchong C, Yu C, Fust G, et al. Diversity in intrinsic strengths of the human complement system: serum C4 protein concentrations correlate with C4 gene size and polygenic variations, hemolytic activities, and body mass index. J Immunol. 2003;171:2734-45 pubmed..Thus, the polygenic and gene size variations of C4A and C4B contribute to the quantitative traits of C4 with a wide range of serum protein levels and hemolytic activities, and consequently the power of the innate defense system. ..