CR1 AND FCYRIIA/IIIA DEFECTS IN THE PATHOGENESIS OF SLE

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The long-term goal of this research is to define the environmental and genetic influences that lead to the development of SLE and to disease manifestation. Because the classic lesion in SLE is immune complex (IC) driven tissue inflammation, we believe that these influences are, in part, defects in IC clearance receptors, namely erythrocyte type on complement receptor (E-CR1). Studies indicate that specific defects in CR1 occur in SLE. It is not known if these defects are genetic in nature or are acquired during disease, or whether these defects can affect or predict disease severity. In support of genetic defects, we have recently identified 7 CR1 mutations, 6 which appear to segregate with SLE or normals, and one which may be associated with low E-CR1 levels. Three mutations appear to affect ligand binding. The goal of this proposal is determine the extent that these mutations affect CR1 function, and to establish if these mutations, with or without combinations of dysfunctional FcgammaRIIa/FcgammaRIIIa variants, are associated with SLE. This study will also seek to determine if acquired E-CR1 defects preclude SLE relapse or are associated with disease manifestation. Accordingly, the aims of this project are to: 1) Characterize E-CR1 phenotypes at study entry in a large cohort of normals and SLE patients, 2) Map the seven known mutation for CR1 in the normals and SLE patients to determine relative frequencies, 3) Express and characterize the CR1 patients variants, 4) Map two known FcgammaR variants known to be associated with SLE, and 5) Assess changes in E-CR1 in SLE patients during periods of relapse and remission. E-CR1 will be characterized in 144 SLE patients and 144 normals. Leukocyte cDNA for specific regions of CR1, FcgammaRIIa, and FcgammaRIIIa will be amplified, and the frequency of known mutations will be identified to determine if any polymorphic variant or combination of variants are associated with SLE. The CR1 polymorphisms will be expressed in truncated CR1 constructs to determine the affects on specific functional domains, and this data will be compared to the E-CR1 characterization to assess mutation effects in the intact CR1 molecule. Finally, E-CR1 will be characterized in 50 SLE patients at bi-monthly intervals to determine if E-CR1 defects preclude, and thus predict, SLE relapse, or are associated with specific disease manifestations. The results of the proposed studies should clarify the roles that both genetic and acquired defects in CR1 play in the onset and disease manifestation of SLE.