Granzyme B Genotypes in Scleroderma

系统性自身免疫性疾病是一组病因不明的异质性和复杂的疾病， 其特征在于产生针对多种自身抗原的高滴度自身抗体。在 在许多情况下，特异性自身抗体与独特的表型相关。最近的研究 证明了在自身免疫性疾病谱中靶向的大多数自身抗原是 在细胞毒性淋巴细胞颗粒诱导的细胞死亡过程中被颗粒酶B（GrB）有效切割，产生 这些分子的独特形式在其他形式的细胞凋亡中未观察到。再加上 大量观察表明，细胞毒性淋巴细胞在几种自身免疫表型中具有活性，包括 硬皮病、狼疮、多发性肌炎和干燥综合征，这些研究结果表明GrB可能发挥作用 在风湿性疾病的产生和传播中。目前尚不清楚， GrB的表达和/或功能影响任何自身免疫性疾病的发展或表达。 在这项试验性建议中，我们将在一个特征明确的人群中解决这个问题， 来自约翰霍普金斯硬皮病中心和对照组的表型多样性硬皮病患者 年龄、性别和种族都与我们机构正在进行的遗传学研究相匹配。硬皮病患者将 包括患有局限性或弥漫性形式的疾病的患者。这些病人已经被跟踪 纵向和表型彻底相对于存在或不存在明显的（？）血管 疾病、缺血性手指缺失、间质性肺病、肾危象和肺动脉高压。DMA 这些患者的样本已保存在生物测定核心中。为了确定Aim中的SNP单倍型， 1，我们将对25名患者和25名对照的整个GrB基因进行测序，包括5'和3'端的1000 bp， UTR。然后，我们将对200名硬皮病患者和200名对照受试者进行SNP基因分型， GrB等位基因频率在目标2中，我们将测试GrB基因中的SNP与不同的 硬皮病的临床表型和/或血清学亚型。

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. In many cases, specific autoantibodies are associated with unique phenotypes. Recent studies have demonstrated that the majority of autoantigens targeted across the spectrum of autoimmune diseases are cleaved efficiently by granzyme B (GrB) during cytotoxic lymphocyte granule-induced cell death, generating unqiue forms of these molecules not observed during other forms of apoptosis. Taken together with the numerous observations that cytotoxic lymphocytes are active in several autoimmune phenotypes, including scleroderma, lupus, polymyositis, and Sjogren's syndrome, these findings suggest that GrB may play a role in the generation and propagation of rheumatic diseases. It remains unknown whether differences in the expression 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 and phenotypieally diverse scleroderma patients from the Johns Hopkins Scleroderma Center and controls matched for age, sex, and ethnicity from genetic studies ongoing at our institution. Scleroderma patients will include those with either the limited or diffuse form of the disease. These patients have been followed longitudinally and phenotyped thoroughly with respect to the presence or absence of overt (?) vascular disease, ischemic digital loss, interstitial lung disease, renal crisis, and pulmonary hypertension. DMA samples on these patients have been saved in the Bioassay Core. In order to define SNP haplotypes in Aim 1, 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 the allelic frequencies for GrB. In Aim 2, we will test for association between SNPs in the GrB gene and distinct clinical phenotypes and/or serological subsets of scleroderma.