VIRUS ENCODED MIMITOPE PROCESSING IN AUTOIMMUNE DIABETES

描述(改编自申请者的摘要)：在人类和点头中 胰岛素依赖型糖尿病(IDDM)小鼠模型由自身免疫引起 T淋巴细胞对胰岛β细胞的破坏作用到目前为止，它还不是 已知哪些特定的抗原提呈细胞亚群(APC-B 淋巴细胞、巨噬细胞或树突状细胞)有助于发育 和糖尿病T淋巴细胞的激活。初步数据显示，B 淋巴细胞起着至关重要的作用，因为疾病的发病率完全是 同源基因抑制致B淋巴细胞缺陷的NOD小鼠 转移功能中断的Ig-Mu等位基因(NOD.Ig-Mu为空)。 初步数据还显示，B淋巴细胞是唯一的APC群体 可以免疫地处理谷氨酸脱羧酶(GAD)，这是 可能是自身反应性T淋巴细胞靶向的最早的β细胞抗原 在NOD小鼠身上。此外，GAD中的一个表位据报道是 APC优先递呈给两个结节中的自身反应性T淋巴细胞 小鼠和人类IDDM患者与部分IDDM患者高度同源 柯萨奇病毒P2-C蛋白。因此，柯萨奇病毒感染可能提供一种 糖尿病原性GAD激活的交叉反应抗原触发 遗传易感个体的自身反应性T淋巴细胞。 此外，正常静止的、致糖尿病的T淋巴细胞可能仍然 B淋巴细胞缺陷型NOD.Ig-MU缺陷型小鼠的发育 APC亚群具有产生β细胞模拟物的能力 来自传染病病原体的自身抗原，如柯萨奇病毒。为了测试这一点 假设，调查人员将追求两个主要目标。第一个是 确定B淋巴细胞是否是发育所必需的 T淋巴细胞对不同免疫应答的功能激活 NOD小鼠体内的GAD衍生肽。二是确定IDDM是否 GAD可消除NOD、Ig-MU缺陷型小鼠的抵抗力 衍生多肽或柯萨奇病毒感染可能绕过正常 B淋巴细胞产生天然抗原表位的要求 盖德。这些研究将提供对以下基本机制的见解 在IDDM中，β细胞抗原被提呈给自身反应性T淋巴细胞，并且 柯萨奇病毒感染如何影响这些过程。

DESCRIPTION (adapted from applicant's abstract): In both humans and the NOD mouse model, insulin dependent diabetes (IDDM) results from autoimmune destruction of pancreatic beta cells by T lymphocytes. Thus far, it is not known which specific subpopulations of antigen presenting cells (APCs - B lymphocytes, macrophages or dendritic cells) contribute to the development and activation of diabetogenic T lymphocytes. Preliminary data show that B lymphocytes play an essential role, since disease incidence is completely inhibited in a stock of NOD mice made B lymphocyte deficient by congenic transfer of a functionally disrupted Ig-mu allele (NOD.Ig-mu null). Preliminary data also show that B lymphocytes are the only APC population that can immunologically process glutamic acid decarboxylase (GAD), which may be the earliest beta cell antigen targeted by autoreactive T lymphocytes in NOD mice. In addition, an epitope in GAD that is reported to be preferentially presented by APC to autoreactive T lymphocytes in both NOD mice and human IDDM patients is highly homologous with a segment of the Coxsackie virus P2-C protein. Thus Coxsackie virus infection may provide a cross-reactive antigenic trigger for the activation of diabetogenic GAD autoreactive T lymphocytes in genetically susceptible individuals. Furthermore, normally quiescent, diabetogenic T lymphocytes may still develop in B lymphocyte deficient NOD.Ig-mu null mice if other subpopulations of APC have the capacity to generate mimics of beta cell autoantigens from infectious agents such as Coxsackie virus. To test this hypothesis, the investigators will pursue two major aims. The first is to determine whether B lymphocytes are required for the development as well the functional activation of T lymphocytes capable of responding to various GAD-derived peptides in NOD mice. The second is to determine if IDDM resistance in NOD.Ig-mu null mice can be abrogated by priming with GAD derived peptides or a Coxsackie viral infection that may bypass the normal requirement for B lymphocytes to generate antigenic epitopes from native GAD. These studies will provide insights to the basic mechanisms by which beta cell antigens are presented to autoreactive T lymphocytes in IDDM, and how these processes may be influenced by a Coxsackie viral infection.