TRANSGENIC MOUSE MODELS FOR B LYMPHOCYTE TOLERANCE AND AUTOIMMUNITY

针对各种自身抗原的自身抗体具有特异性诊断作用 许多自身免疫性疾病的标志物，它们的致病作用很好 建立在这些疾病的一个子集上。背后的事件 然而，自身抗体的产生仍然模糊不清。 B细胞自身耐受和自身免疫的研究受到 不同自身抗原的复杂性和基因的巨大变异性 抗原特异性B细胞的频率、亲和力和同型。至 为了绕过这些问题，将采用转基因小鼠模型。这个 对单一新自身抗原--母鸡的耐受性或自身免疫 鸡蛋溶菌酶，将使用表达基因的转基因动物进行研究 溶菌酶具有不同的形式、水平和组织。同时， 表达重排的转基因小鼠新品系的建立 免疫球蛋白基因将提供一种同源的特异性抗原 B细胞，表达具有明显亲和力的溶菌酶结合受体或 同型。溶菌酶特异性辅助T细胞将从类似的 TCR基因转基因小鼠。在《目标L 2》中，这些动物将被用来 体内筛选自身反应性B和T细胞的跟踪机制，以及 定义针对特定类别的自身抗原的自身抗体是否会导致 从B和T细胞审查的自然限制或由于 允许自我反应的B细胞抵抗审查。 在AIMS 1和2中开发的转基因动物模型将用于 目标3确定是否存在额外的免疫调节机制来 控制逃避审查的自我反应性B细胞和T细胞。两个截然不同的 并将研究相关场景，其中自体反应的B细胞和T细胞 逃避审查，有可能启动对溶菌酶的自身免疫 以细胞膜自身抗原的形式系统或定位表达 转移到甲状腺。自身反应性B细胞和自身抗体的作用 在全身或甲状腺病理的发展中不同的同型将是 下定决心。这些研究应该会为 一系列人类自身免疫性疾病的发病机制，如系统性 红斑狼疮和格雷夫病。

Autoantibodies to a variety of self antigens are specific diagnostic markers for many autoimmune diseases, and their pathogenic role is well established in a subset of these disorders. The events underlying autoantibody production nevertheless remain obscure. Studies of B cell self-tolerance and auto immunity have been confounded by the complexity of different self antigens and the enormous variability in the frequency, affinity, and isotype of antigen-specific B cells. To circumvent these problems, a transgenic mouse model will be employed. The development of tolerance or autoimmunity to a single neo-self antigen, hen egg lysozyme, will be studied using transgenic animals that express lysozyme in different forms, levels, and tissues. In parallel, established and new lines of transgenic mice expressing rearranged immunoglobulin genes will provide a source of homogenous antigen specific B cells, expressing lysozyme-binding receptors with a distinct affinity or isotype. Lysozyme-specific helper T cells will be obtained from similar TCR gene transgenic mice. In AIMS l and 2, these animals will be used to track mechanisms for censoring self-reactive B and T cells in vivo, and define whether autoantibodies to particular classes of autoantigens result from natural limits in B and T cell censoring or by circumstances that allow self-reactive B cells to resist censoring. Transgenic animal models developed in AIMS 1 and 2 will then be used in AIM 3 to determine if additional immunoregulatory mechanisms exist to control self-reactive B and T-cells that escape censoring. Two distinct and relevant scenarios will be studied, where autoreactive B and T-cells escape censoring and can potentially initiate autoimmunity to lysozyme expressed as a cell membrane autoantigen either systemically or localized to the thyroid gland. The role of autoreactive B cells and autoantibody of different isotypes in development of systemic or thyroid pathology will be determined. These studies should provide important insights into the pathogenesis of a range of human autoimmune diseases, such as systemic lupus erythematosus and Grave's disease.