The fourth component of complement (C4) is one of the most polymorphic proteins found in humans and has a wide range of serum levels. Two major isotypes exist, i.e., C4A and C4B, which differ functionally and have many polymorphic variants. Complete or partial C4A deficiency has been reported to be a risk factor for systemic lupus erythematosus (SLE) but this conclusion has been based mainly on phenotypic studies or RFLP analysis for the detection of deleted C4A genes. Furthermore, it is generally presumed that there are a (relatively) constant number of genes among different individuals as proposed for the two-locus model in the MHC with one C4A gene, one C4B gene and null alleles in either locus. We have found that there is actually a frequent, dichotomous gene size variation, polygenic and modular duplications of C4A and C4B together with their flanking genes RP1 or RP2, CYP21A or CYP21B, and TNXA or TNXB in humans. We hypothesize that these variations in gene dosages, protein levels and functions of complement component C4A and C4B confer among different human subjects differential intrinsic strengths of immune responses. We further postulate that under- and over-expression of C4 are risk factors for autoimmune diseases and complement-mediated tissue injuries, respectively. Thus, the long-term goals of this study are to elucidate the sophisticated genetic diversities of C4A and C4B in human populations, and to determine their physiological consequences.
The specific aims are: 1) To determine the genetic complexity and protein polymorphisms of human complement components C4A and C4B in Caucasians, Africans, Asians and Hispanics, 2) To investigate the roles of complement C4 gene variation and ligand binding to CR1 in a similar ethnically diverse group of SLE patients, 3) To elucidate the molecular basis of complete complement C4 deficiency in human SLE and kidney disease patients and 4) To develop a non-human primate (macaque) model of complement C4 for studies of polygenic variations, function and disease association. Currently two hypotheses exist for the role of complement in SLE: a) complement is needed to clear apoptotic debris and/or immune complexes (IC), b) complement is needed for the deletion of autoreactive B cells. The information gained from this proposal will help elucidate the role of C4 in autoimmunity, provide a more appropriate animal model for the affect of complement on IC clearance and yield valuable information regarding diagnosis and therapeutic intervention in SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050078-04
Application #
7093009
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Serrate-Sztein, Susana
Project Start
2003-09-15
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$290,988
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
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Saxena, Kapil; Kitzmiller, Kathryn J; Wu, Yee Ling et al. (2009) Great genotypic and phenotypic diversities associated with copy-number variations of complement C4 and RP-C4-CYP21-TNX (RCCX) modules: a comparison of Asian-Indian and European American populations. Mol Immunol 46:1289-303
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Wu, Yee Ling; Savelli, Stephanie L; Yang, Yan et al. (2007) Sensitive and specific real-time polymerase chain reaction assays to accurately determine copy number variations (CNVs) of human complement C4A, C4B, C4-long, C4-short, and RCCX modules: elucidation of C4 CNVs in 50 consanguineous subjects with defined HL J Immunol 179:3012-25
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Kiszel, Petra; Kovacs, Margit; Szalai, Csaba et al. (2007) Frequency of carriers of 8.1 ancestral haplotype and its fragments in two Caucasian populations. Immunol Invest 36:307-19
Yang, Yan; Chung, Erwin K; Wu, Yee Ling et al. (2007) Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European America Am J Hum Genet 80:1037-54

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