Genetic variants of CR1& FcgammaR in human SLE nephritis

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The long-term goals of this research are to define the various factors that lead to nephritis in SLE. We postulate that, because SLE nephritis is driven by IC deposition, factors that decrease safe IC clearance. In this proposal, we hypothesize that SLE patients with genetic defects in IC clearance receptors (erythrocyte type one complement receptor (E-CR1), FcgammaRIIa, and FcgammaRIIIa) are prone to develop nephritis. Furthermore, we hypothesize that acquired E-CR1 defects that are known to occur in SLE predict and/or influence SLE nephritis relapse. To test these hypotheses, the aims of this proposal are to 1) Characterize E-CR1 phenotypes at study entry in 500 SLE patients, half of whom have renal involvement, and 250 normals, 2) Determine the frequencies of eight CR1 mutations in these study populations which appear to be associated with SLE nephritis and/or are affect CR1 function or presentation, 3) Express and characterize and characterize the CR1 variants in truncated, single-domain CR1 constructs, 4) Map two FcgammaR variants which affect FcgammaR function and which have been implicated as playing a role in SLE nephritis, and 5) Assess serial changes in E-CR1 levels and function in 100 frequently relapsing SLE patients, half of whom have renal involvement, during a 5 year period of relapse and remission. The characterization of the CR1 and FcgammaRIIa/FcgammaRIIIa variants will reveal if specific polymorphisms are associated with SLE nephritis. Exploratory statistical analyses will be done on various combinations of polymorphisms as a first step in identifying if any combinations provide a stronger or unique association with SLE nephritis or SLE in general. For CR1, expression studies in truncated, single- domain CR1 constructs will identify any functional consequence associated with each mutation. Comparing the expression data with E- CR1 characterization collected at study entry will clarify how any difference at a single functional domain is revealed in the intact CR1 molecule containing multiple functional domains. The E-CR1 data will also serve as a baseline for the longitudinal study assessing the serial changes between E-CR1 and SLE relapse, both renal and non-renal. Thus, the longitudinal study will define whether acquired E-CR1 defects predict and/or influence SLE relapse severity or frequency. In summary, these studies should identify the extent that defects in IC clearance proteins contribute to SLE nephritis, SLE in general, and to the frequency and severity of SLE relapse.