The overall goal of this research proposal is the exploration of functional consequences of specific immunogenetic and molecular DNA markers of disease which may be related to the pathogenesis of certain glomerulonephritides. Humoral factors such as complement (C) participate in many forms of immune mediated diseases; previous studies from this laboratory and other have identified specific alleles of the highly polymorphic C4A, C4B, BF and HLA loci of the 6th human chromosome which are statistically more common in certain glomerulonephritides - such as lupus erythematosus, Henoch-Schonlein purpura, IgA nephropathy and the nephrotic syndrome of childhood.
Our specific aims are to further study the isolated DNA from selected patients with these diseases using available complement (C4 and C3) cDNA probes and endonuclease digestions followed by Southern transfer to nitrocellulose and hybridization with labelled (32P) probes. Gene deletions, restriction fragment polymorphism (RFLP) and other molecular abberations (such as gene conversion) will be sought using standard methods. Functional studies of specific alleles (which may be related to pathogenesis of disease) will be studied. Specifically, the activity of different C4 and C3 alleles to mediate attachment to the C3b/C4b (CR1) red cell receptor will be evaluated; circulating antibody which may interfere with the normal CR1 activity and which may be related to specific DNA abnormalities or to specific C alleles will be sought. The C3 nephritic factor - an autoantibody to activated C3 and factor B may be such an antibody. The recognition that the C4A allele is deleted from the """"""""immune related"""""""" haplotype HLA-A1, B8, DR3, C4AQO, C4B1, BFS has lead us to investigate diseases associated with C4A and C4B null alleles but not necessarily with this entire """"""""extended haplotype"""""""". Preliminary studies support the conclusion that deletions of C4 genes may be associated with certain glomerulonephritides. Clarification of the association between C gene abberations and glomerulonephritis may reveal important pathogenic mechanisms which may permit more specific therapy.
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