Complement receptor 2 (CR2/CD21) is the strongest candidate gene for lupus susceptibility in the Slelc lupus susceptibility interval of the NZM2410 mouse model of lupus, based on structural and functional alterations in its protein products. In humans, CR2 is located in a syntenic genetic interval that is also linked and associated with lupus susceptibility. A polymorphism in the proximal promoter of human CR2 alters its transcriptional activity, potentially contributing to the decreased B cell expression of CR2 that has been previously described in patients with systemic lupus erythematosus (SLE). We hypothesize that alterations in CR2 expression, whether by genetic or acquired means, reflect disease activity in human SLE, and that tracking CR2 expression and/or identifying polymorphisms that alter its function can assist in the management and treatment of patients with SLE.
Our specific aims are to determine whether B cell CR2 levels in lupus patients are correlated with disease activity, to determine the mechanism by which CR2 levels are decreased in lupus patients, and to determine whether a specific CR2 allele affects the correlation of CR2 levels with disease activity. Adults with active SLE, inactive SLE, rheumatoid arthritis, or no autoimmune disease (15 each group) will be evaluated every 3 months for 1 year, with interim evaluation for lupus flares. At each visit, history and physical exam will be performed, disease activity assessed, and 60 milliliters of peripheral blood obtained. Peripheral blood mononuclear cells will be isolated for preparation of genomic DNA for genotyping, for flow cytometric analyses of B cell expression of CR2 on B cell subsets, and for purification of B cells from which mRNA will be prepared for quantitative reverse transcriptase PCR. Additional blood will be obtained for measurement of serologic parameters of disease activity. Urinalysis will be performed and urine collected for measurement of protein and creatinine. CR2 levels will be correlated with disease activity, and the mechanisms underlying decreased levels will be defined. These studies will reveal the value of monitoring CR2 levels as a biomarker for lupus disease activity, which would assist in diagnosis and treatment of lupus and improve the evaluation of new therapies tested in clinical trials. In addition, they will advance our understanding of the role of CR2 in the pathogenesis of SLE and provide insight into the mechanisms that contribute to the development of this disease. ? ? ?
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