Variations of Complement in Immunity and Diseases

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DESCRIPTION (provided by applicant): 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.