Immune Response to Small Nuclear Ribonucleoprotein Autoantigens

描述（由申请人提供）：我们研究的重点是了解对小核核糖核蛋白（snRNP）自身抗原的免疫应答如何有助于系统性红斑狼疮（SLE）和混合性结缔组织病（MCTD）的发病机制。这些是慢性的，目前无法治愈的疾病，通常影响妇女，有显着的发病率/死亡率，并出现在西班牙裔和非洲裔美国人的患病率增加。免疫snRNP自身抗原，包括史密斯（Sm）和核糖核蛋白（RNP）抗原的U1- 70 RD多肽，似乎在这些疾病中发挥了重要作用。我们以前分离和研究Sm-反应性和U1- 70 kD-反应性T细胞从SLE和MCTD患者的外周血，并已开始表征的作用，鼠CD 4 + T细胞特异性U1- 70 kD自身抗原在一个新的模型MCTD。这些研究旨在检验的假设是：免疫暴露于snRNP片段，U1- 70 kD，通常在凋亡过程中产生并含有RNA结合结构域（RBD），足以打破免疫耐受并诱导自身反应性CD 4 + T细胞;而且，U1- 70 kD自身抗原反应性CD 4+的克隆型限制性群体，T细胞在自身免疫性组织损伤（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）表征系统性自身免疫的新鼠模型，其发展针对U1- 70 kD的T免疫以及与针对U1- 70 kD的免疫直接相关的肺病，2）使用过继转移鉴定模型中自身免疫疾病发展所必需的细胞，3）定义间质性肺病的自然史并鉴定介导模型中肺组织损伤的因素，4）对在活动性疾病期间在MCTD患者的外周血中扩增的不同T细胞亚群进行比较分析。我们认为这些细胞将表现出与抗U1 - 70 kD反应性人T细胞克隆和来自U1 - 70 kD诱导模型的活化鼠T细胞系相似的细胞表面表型、自身抗原反应性、表位精细特异性、T细胞受体（TCR）基因使用、效应子功能和细胞因子表达。简单总结：系统性红斑狼疮和混合性结缔组织病是目前侵袭年轻女性，特别是黑人和西班牙裔女性的慢性不治之症。我们的研究目标是开发新的和有效的治疗这些疾病。

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.