Complement proteins are essential in the dissolution of immune complexes (IC). The circulation of pathogenic IC is an etiologic factor for kidney and autoimmune disease. Systemic lupus erythematosus (SLE) is multi-factorial disease with complex genetic trait and diverse clinical manifestations. Lupus nephritis (SLE-N) is a severe form of the disease. Specifically, this proposal seeks to determine the roles of complement component C4, which has an amazing degree of variations in the quantities and qualities of the genes and proteins present in each individual, in the disease etiology of SLE and SLE-N. The quantitative variations include the number of the C4A and C4B genes present that may determine the levels of proteins expressed in patients and in normals. We hypothesize that over-expression of C4 (C4A, C4B or both), under- expression of C4 (C4A or C4B or both), and malfunction of C4A or C4B contribute to the etiological processes of SLE and SLE-N. In other words, the pathogenesis of SLE may be related to the C4 gene dosage (number of C4 genes), C4 gene types (long and short C4 genes), and C4 protein functions (C4A and C4B isotypes and allotypes). Over-expression of C4 may aggravate the disease by directly promoting the local activation of the complement system that causes tissue injuries. Under-expression of malfunction of the CR would lead to impairment in the dissolution of IC. Specific techniques to determine the qualitative and quantitative variations of the RCCX constituents including complement C4A and C4B have been established by our laboratory. Many novel genes have been discovered in the MHC class III region. These breakthroughs allow the following Specific Aims to be addressed: I) To determine the RCCX modular variations in SLE, SLE-N and normals; II) To determine the molecular bases of C4A and C4B deficiencies in SLE-SLE-N and normals; IV) To investigate the molecular genetics of the MHC class III genes in SLE, SLE-N and normals. The study population include 250 individuals with SLE-N, and equal numbers of SLE patients with non- renal involvement, affected family based controls and case matched controls. The results of this proposal will directly influence the philosophy on the treatment (and possibly cure) of SLE and SLE-N. It may have enormous impact on the medicare of the SLE and other rheumatic disease patients.
Showing the most recent 10 out of 68 publications
