Granzyme B Genotypes in Scleroderma

Johns Hopkins University, Baltimore MD

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Abstract

Systemic autoimmune disease are a heterogenous and complex group of disorders of unknown etiology,[unreadable] characterized by the production of high titer autoantibodies directed against a variety of self-antigens. In[unreadable] many cases, specific autoantibodies are associated with unique phenotypes. Recent studies have[unreadable] demonstrated that the majority of autoantigens targeted across the spectrum of autoimmune diseases are[unreadable] cleaved efficiently by granzyme B (GrB) during cytotoxic lymphocyte granule-induced cell death, generating[unreadable] unqiue forms of these molecules not observed during other forms of apoptosis. Taken together with the[unreadable] numerous observations that cytotoxic lymphocytes are active in several autoimmune phenotypes, including[unreadable] scleroderma, lupus, polymyositis, and Sjogren's syndrome, these findings suggest that GrB may play a role[unreadable] in the generation and propagation of rheumatic diseases. It remains unknown whether differences in the[unreadable] expression and/or function of GrB influence the development or expression of any autoimmune disease.[unreadable] In this pilot proposal, we will address this question in a population of well-characterized and[unreadable] phenotypieally diverse scleroderma patients from the Johns Hopkins Scleroderma Center and controls[unreadable] matched for age, sex, and ethnicity from genetic studies ongoing at our institution. Scleroderma patients will[unreadable] include those with either the limited or diffuse form of the disease. These patients have been followed[unreadable] longitudinally and phenotyped thoroughly with respect to the presence or absence of overt (?) vascular[unreadable] disease, ischemic digital loss, interstitial lung disease, renal crisis, and pulmonary hypertension. DMA[unreadable] samples on these patients have been saved in the Bioassay Core. In order to define SNP haplotypes in Aim[unreadable] 1, we will sequence the entire GrB gene in 25 patients and 25 controls, including 1000 bp from the 5' and 3'[unreadable] UTRs. We will then perform SNP genotyping on 200 scleroderma and 200 control subjects, to define the[unreadable] allelic frequencies for GrB. In Aim 2, we will test for association between SNPs in the GrB gene and distinct[unreadable] clinical phenotypes and/or serological subsets of scleroderma.