Immune Response to Small Nuclear Ribonucleoprotein Autoantigens

描述（由申请人提供）：我们的研究重点是了解对小核核糖核蛋白（snRNP）自身抗原的免疫反应如何在系统性红斑狼疮（SLE）和混合性结缔组织病（MCTD）的疾病发病机制中起作用。这些都是慢性疾病，目前无法治愈，通常影响妇女，发病率/死亡率很高，在西班牙裔和非洲裔美国人中发病率似乎有所增加。对snRNP自身抗原的免疫，包括Smith （Sm）和核糖核蛋白（RNP）抗原的U1-70RD多肽，似乎在这些疾病中起着核心作用。我们之前已经从SLE和MCTD患者的外周血中分离并研究了sm反应性和U1-70kD反应性T细胞，并开始表征小鼠CD4+ T细胞特异性U1-70kD自身抗原在MCTD新模型中的作用。这些研究旨在测试的假设是：免疫暴露于snRNP片段U1-70kD，通常在细胞凋亡过程中产生，含有RNA结合域（RBD），足以打破免疫耐受并诱导自身反应性CD4+ T细胞；此外，克隆典型受限的U1-70kD自身抗原反应性CD4+ T细胞在自身免疫组织损伤（包括肺损伤）中发挥核心作用。为了验证这些假设，我们提出了以下具体目标：1)表征一种新的小鼠系统性自身免疫模型，该模型对U1-70kD产生T免疫，并与U1-70kD免疫直接相关的肺部疾病；2)使用过继性转移鉴定模型中自身免疫性疾病发展所必需的细胞；3)定义间质性肺疾病的自然史，并确定模型中介导肺组织损伤的因素。4)对MCTD患者在活动性疾病期间外周血中扩增的不同T细胞亚群进行比较分析。我们假设这些细胞将表现出细胞表面表型、自身抗原反应性、表位精细特异性、T细胞受体（TCR）基因使用、效应功能和细胞因子表达，类似于抗U1-70kD反应性人T细胞克隆和来自U1-70kD诱导模型的活化小鼠T细胞系。摘要：系统性红斑狼疮和混合性结缔组织病是目前困扰年轻女性的慢性、无法治愈的疾病，尤其是黑人和西班牙裔女性。我们的研究目标是开发新的有效的治疗这些疾病的方法。

DESCRIPTION (provided by applicant): The focus of our research is on understanding how the immune response to small nuclear ribonucleoprotein (snRNP) self-antigens contributes to disease pathogenesis in Systemic Lupus Erythematosus (SLE) and Mixed Connective Tissue Disease (MCTD). These are chronic, currently incurable diseases that typically affect women, have significant morbidity/mortality and appear increased in prevalence among both Hispanics and African-Americans. Immunity to snRNP autoantigens, including the Smith (Sm) and the U1-70RD polypeptide of the ribonucleoprotein (RNP) antigen, appears to have a central role in these diseases. We have previously isolated and studied Sm-reactive and U1-70kD-reactive T cells from the peripheral blood of SLE and MCTD patients and have begun to characterize the role of murine CD4+ T cells specific for U1- 70kD autoantigen in a new model of MCTD. The hypotheses that these studies are designed to test are: that immune exposure to a fragment of an snRNP, U1-70kD, normally generated during apoptosis and containing an RNA binding domain (RBD), is sufficient to break immunologic tolerance and induce autoreactive CD4+ T cells; and further, that a clonotypically restricted population of U1-70kD autoantigen reactive CD4+ T cells play a central role in autoimmune tissue injury including injury to the lungs. To test these hypotheses, we have proposed the following Specific Aims: 1) characterize a new murine model of sytemic autoimmunity that develops T immunity to the U1-70kD as well as lung disease directly linked to immunity to U1-70kD, 2) identify the cells essential for the development of autoimmune disease in the model using adoptive transfer, 3) define the natural history of interstitial lung disease and identify factors that mediate pulmonary tissue injury in the model, 4) perform a comparative analysis on a distinct subpopulation of T cells that are expanded in the peripheral blood of MCTD patients during active disease. We posit that these will exhibit cell surface phenotype, autoantigen reactivity, epitope fine specificity, T cell receptor (TCR) gene use, effector function and cytokine expression similar to anti-U1-70kD reactive human T cell clones and activated murine T cell lines from the U1-70kD induced model. Lay summary: Systemic Lupus Erythematosus and Mixed Connective Tissue Disease are currently chronic, incurable disease that strike young women, especially black and Hispanic women. Our research goal is to develop new and effective treatments of these disorders.