The objectives are to define the complete structure of the human receptor for complement fragments C3b/C4b and its functional role in immune and inflammatory reactions. The human C3b/C4b receptor (CR1) is a polymorphic glycoprotein that ranges in size from Mr 160,000 to 250,000 when analyzed by SDS-PAGE and these allelic forms are inherited in an autosomal codominant manner. The receptor is found in soluble form in plasma and on the surface of erythrocytes, neutrophils, monoctyes, lymphocytes and glomerular podocytes. The functional capabilities of CR1 include regulation of the amplification C3 convertase, and the removal of complement coated targets and immune complexes by phagocytic and endocytic reactions. The number of CR1 molecules on erythrocytes is also geneticaly controlled and varies by 10 fold among normal individuals. Inherited as well as acquired deficiencies of CR1 on several cell types have been documented in patients with systemic lupus erythematosus. In order to understand the overall structure and function of human CR1, we propose to 1) Isolate and study the structure of the gene which codes for human CR1, 2) Identify the sites of polymorphisms on the CR1 gene and, 3) Define the functional domains within the CR1 gene. The recent identification of a partial cDNA clone for human CR1 enables us to isolate recombinant genomic clones and identify restriction length polymorphisms in the human CR1 gene. The basis of the structural polymorphisms will be elucidated by isolation and comparisons of the different alleles and the different domains of CR1 will be mapped by studying the functional capacities of deletion mutants after transfection into CR1 recipient cells. The results of these studies will not only facilitiate the understanding of the regulation of CR1 and the basis of its abnormalities in rheumatic diseases, but also provide insight into the evolution of the allelic forms of CR1, and its functional correlates in plasma, factor H and C4 binding protein.
|Vik, D P; Wong, W W (1993) Structure of the gene for the F allele of complement receptor type 1 and sequence of the coding region unique to the S allele. J Immunol 151:6214-24|
|Wong, W W; Farrell, S A (1991) Proposed structure of the F' allotype of human CR1. Loss of a C3b binding site may be associated with altered function. J Immunol 146:656-62|
|Wong, W W; Cahill, J M; Rosen, M D et al. (1989) Structure of the human CR1 gene. Molecular basis of the structural and quantitative polymorphisms and identification of a new CR1-like allele. J Exp Med 169:847-63|