Granzyme B Genotypes in Scleroderma

全身性自身免疫性疾病是一组病因不明的异质性和复杂性疾病， 以产生针对各种自身抗原的高滴度自身抗体为特征的。在……里面 在许多情况下，特定的自身抗体与独特的表型有关。最近的研究表明 证明了针对自身免疫性疾病的大多数自身抗原是 在细胞毒性淋巴细胞颗粒诱导细胞死亡过程中被颗粒酶B(GRB)有效切割，生成 在其他形式的细胞凋亡中没有观察到这些分子的独特形式。与 大量观察表明，细胞毒性淋巴细胞在几种自身免疫表型中都是活跃的，包括 硬皮病、狼疮、多发性肌炎和干燥综合征，这些发现表明GRB可能在 在风湿病的产生和传播中。目前尚不清楚是否存在差异 GRB的表达和/或功能影响任何自身免疫性疾病的发生或表达。 在这项试点提案中，我们将在一群特征良好的和 来自约翰霍普金斯硬皮病中心的表型多样化的硬皮病患者和对照 与我们机构正在进行的基因研究中的年龄、性别和种族相匹配。硬皮病患者会 包括患有局限性或弥漫性疾病的人。对这些患者进行了跟踪调查 根据是否存在明显的(？)血管 疾病、缺血性手指丧失、间质性肺疾病、肾危象和肺动脉高压。DMA 这些患者的样本已经保存在生物分析核心中。为了在AIM中定义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个碱基 UTRs。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，以确定 GRB等位基因频率。在目标2中，我们将测试GRB基因中的SNPs与不同基因之间的关联 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.