Diversity in Intrinsic Strengths of the Human Complement System: Serum C4 Protein Concentrations Correlate with<i>C4</i>Gene Size and Polygenic Variations, Hemolytic Activities, and Body Mass Index

Yang, Yan; Chung, Erwin K.; Zhou, Bi; Blanchong, Carol A.; Yu, Chack‐Yung; Füst, George; Kovács, Margit; Vatay, Ágnes; Szalai, Csaba; Karádi, István; Varga, Lilian

doi:10.4049/jimmunol.171.5.2734

Cited by 112 publications

(121 citation statements)

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“…Dosage of C4A and C4B genes influences the corresponding serum protein concentrations and hemolytic activities. 3 C4A primarily takes part in removing immune complexes, whereas C4B takes part in the defense against intruders. 4 Lower levels of C4A confer higher susceptibility to autoimmune disorders, 5 and lower levels of C4B have been associated with increased prevalence of cardiovascular disease.…”

Section: Introductionmentioning

confidence: 99%

“…9 Population studies regarding RCCX structural variations are traditionally carried out using Southern blot techniques, generally directed at the total number of long and short C4 genes in the haplotypes, length of the most telomeric RCCX module of each chromosome and total C4A and C4B copy numbers in the genome. 2,3,10,11 However, no systematic study describing precise localization of C4A and C4B genes has yet been published, nor has the exact order of long and short C4 genes in RCCX structures containing more than two modules ever been determined. Thus, detailed characterization of RCCX structural variants occurring in the healthy Caucasian population became our goal.…”

Section: Introductionmentioning

confidence: 99%

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Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes

et al. 2012

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The human RCCX is a common multiallelic copy number variation locus whose number of segments varies between one and four in a chromosome. The monomodular form normally comprises four functional genes, but in duplicated RCCX segments generally only the gene-encoding complement component C4 produces a protein. C4 genes can code either for a C4A or a C4B isotype protein and exhibit dichotomous size variation. Distinct RCCX variants show association with numerous diseases; however, identification of the basis of these associations is often challenging, not least because the RCCX is localized in the major histocompatibility complex (MHC) region, a genomic area characterized by exceedingly long-range linkage disequilibrium. Here we present a detailed analysis on RCCX variants and their relationship with so-called 'ancestral' or 'conserved extended' MHC haplotypes in healthy Caucasians. In addition to former investigations, precise order and size of all C4A and C4B genes were determined even in trimodular RCCX structures. Considering C4 copy numbers, length, isotype specificity and CYP21A2 copy numbers, we have identified 15 distinct RCCX variants and described the RCCX structures involved in 29 repeatedly occurring MHC haplotypes. The findings should become a useful tool for future RCCX-and MHC-related disease association studies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes

et al. 2012

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“…Results from another study suggest that the complement system is also involved in the pathogenesis of a variety of liver disorders, including liver injury and repair, fibrosis, viral hepatitis, alcoholic liver disease, and liver ischemia/reperfusion injury (24). The fourth component of the complement system, C4, plays a vital role in mounting a proper immune response against infection (35). Chronic hepatitis C virus (HCV) infection is a leading cause of progressive liver disease.…”

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confidence: 99%

Transcriptional Repression of C4 Complement by Hepatitis C Virus Proteins

Banerjee

Mazumdar

Meyer

et al. 2011

J Virol

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The fourth component of human complement (C4) plays an important role in innate immune function. C4 activity has been observed to be significantly lower in patients with chronic hepatitis C virus (HCV) infections, although the mechanism remains unknown. In this study, we have examined the mechanisms of C4 regulation by HCV. Liver biopsy specimens from patients with chronic HCV infections displayed significantly lower C4 mRNA levels than liver tissue samples from patients with unrelated liver disease. Further, C4 mRNA levels of the two isoforms (C4A and C4B) were significantly reduced in hepatocytes transfected with RNA from HCV genotype 1a or 2a. Subsequently, a significant C4 regulatory role of HCV core or NS5A upon C4 promoter activity was observed. HCV core or NS5A transgenic mice displayed a reduction in C4 mRNA. Gamma interferon (IFN-␥)-induced C4 promoter activation was also impaired in the presence of HCV proteins. We further demonstrated that HCV core reduced the expression of upstream stimulating factor 1 (USF-1), a transcription factor important for basal C4 expression. On the other hand, the expression of interferon regulatory factor 1 (IRF-1), which is important for IFN-␥-induced C4 expression, was inhibited by hepatocytes expressing HCV NS5A. These results underscore the roles of HCV proteins in innate immune regulation in establishing a chronic infection.The complement system is a set of biochemical pathways that helps to clear pathogens from an organism as part of the innate and acquired immunity programs. Activation of the complement system triggers a wide range of cellular responses ranging from apoptosis to opsonization (27). The complement system plays a critical role in the pathogenesis of a variety of chronic human diseases. Viruses have been shown to attenuate complement activation. Recently, the nonstructural protein (NS1) from flaviviruses (dengue fever virus, West Nile virus, and yellow fever virus) has been reported to attenuate complement activation by interacting with several complement components (1,8). Results from another study suggest that the complement system is also involved in the pathogenesis of a variety of liver disorders, including liver injury and repair, fibrosis, viral hepatitis, alcoholic liver disease, and liver ischemia/reperfusion injury (24). The fourth component of the complement system, C4, plays a vital role in mounting a proper immune response against infection (35). Chronic hepatitis C virus (HCV) infection is a leading cause of progressive liver disease. The mechanisms responsible for HCV persistence are not well understood, although the interactions between HCV and host cells appear to play an important role. Dumestre-Perard et al. (11) reported in a study of a large cohort that in patients with chronic HCV infections, the blood level of specific complement components is depleted, and C4 activity is significantly lower. A decrease in specific C4 activity was reported among relapsers compared with sustained responders, before and during therapy, suggesting it...

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“…In humans, people with a short C4B gene have higher C4 serum protein levels and higher C4 hemolytic activity than those with a long C4A gene, which contains an endogenous retrovirus HERV-K (C4) in intron 9 (Yang et al, 2003). In H-2 k mice, the insertion of the B2 sequence into intron 13 results in low C4 expression in serum (Pattanakitsakul et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of a novel splice variant of the complement component 4 (C4A) gene in mastitis-infected dairy cattle

Yang¹,

Huang²,

Ju³

et al. 2012

Genet. Mol. Res.

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ABSTRACT. The complement system helps in the direct lysis of invading pathogens and modulates phagocytic, humoral and cellular immune responses. Complement 4 is a critical component in complement activity and protection against many bacterial pathogens because it is essential to classical and lectin activation pathways. We used reverse transcription and PCR to investigate alternative splicing and expression of the complement component 4 (C4A) gene in Chinese Holstein cattle. The PCR products were cloned and sequenced. A novel splice variant involving intron 10 was identified, which we named C4A-AS. To examine how C4A gene activity is affected by bovine mastitis, six Chinese Holstein cattle were divided into healthy (nonmastitic) and Staphylococcus aureus-induced mastitic groups. Realtime quantitative PCR (qRT-PCR) revealed that the C4A-complete and C4A-AS transcripts are expressed at significantly different levels in healthy cows, while there were no significant differences in the mastitic group (P = 0.257). Expression of C4A-AS increased significantly when mastitis developed. We also examined the expression of C4A-complete and C4A-AS in several tissues (liver, heart, spleen, lung, kidney, tongue, and muscle). The two transcripts were expressed in all of these tissues but there were no significant differences in expression between healthy and mastitic cows. We therefore conclude that the C4A-complete transcript is the main transcript under normal physiological conditions, while C4A-AS is augmented when mastitis develops.

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Diversity in Intrinsic Strengths of the Human Complement System: Serum C4 Protein Concentrations Correlate withC4Gene Size and Polygenic Variations, Hemolytic Activities, and Body Mass Index

Cited by 112 publications

References 64 publications

Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes

Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes

Transcriptional Repression of C4 Complement by Hepatitis C Virus Proteins

Increased expression of a novel splice variant of the complement component 4 (C4A) gene in mastitis-infected dairy cattle

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