Systemic autoimmune disease are a heterogenous and complex group of disorders of unknown etiology,characterized by the production of high titer autoantibodies directed against a variety of self-antigens. Inmany cases, specific autoantibodies are associated with unique phenotypes. Recent studies havedemonstrated that the majority of autoantigens targeted across the spectrum of autoimmune diseases arecleaved efficiently by granzyme B (GrB) during cytotoxic lymphocyte granule-induced cell death, generatingunqiue forms of these molecules not observed during other forms of apoptosis. Taken together with thenumerous observations that cytotoxic lymphocytes are active in several autoimmune phenotypes, includingscleroderma, lupus, polymyositis, and Sjogren's syndrome, these findings suggest that GrB may play a rolein the generation and propagation of rheumatic diseases. It remains unknown whether differences in theexpression and/or function of GrB influence the development or expression of any autoimmune disease.In this pilot proposal, we will address this question in a population of well-characterized andphenotypieally diverse scleroderma patients from the Johns Hopkins Scleroderma Center and controlsmatched for age, sex, and ethnicity from genetic studies ongoing at our institution. Scleroderma patients willinclude those with either the limited or diffuse form of the disease. These patients have been followedlongitudinally and phenotyped thoroughly with respect to the presence or absence of overt (?) vasculardisease, ischemic digital loss, interstitial lung disease, renal crisis, and pulmonary hypertension. DMAsamples on these patients have been saved in the Bioassay Core. In order to define SNP haplotypes in Aim1, we will sequence the entire GrB gene in 25 patients and 25 controls, including 1000 bp from the 5' and 3'UTRs. We will then perform SNP genotyping on 200 scleroderma and 200 control subjects, to define theallelic frequencies for GrB.
In Aim 2, we will test for association between SNPs in the GrB gene and distinctclinical phenotypes and/or serological subsets of scleroderma.
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