VIRUS ENCODED MIMITOPE PROCESSING IN AUTOIMMUNE DIABETES

描述（改编自申请人摘要）：在人类和NOD中 小鼠模型，胰岛素依赖性糖尿病（IDDM）的结果，从自身免疫性 T淋巴细胞对胰腺β细胞的破坏。 到目前为止， 已知抗原呈递细胞（APCs - B）的特定亚群 淋巴细胞、巨噬细胞或树突状细胞）有助于发育 和致糖尿病T淋巴细胞的活化。 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 抑制NOD小鼠的储备B淋巴细胞缺陷的同类基因 转移功能性破坏的Ig-mu等位基因（NOD.Ig-mu null）。 初步数据还表明，B淋巴细胞是唯一的APC群体 谷氨酸脱羧酶（GAD）， 可能是自身反应性T淋巴细胞靶向的最早β细胞抗原 NOD小鼠。 此外，GAD中的一个表位据报道是 在两种NOD中，APC优先呈递给自身反应性T淋巴细胞。 小鼠和人的胰岛素依赖型糖尿病患者与一个片段高度同源， 科萨基病毒P2-C蛋白。 因此，科萨基病毒感染可能提供了一个 致糖尿病GAD激活的交叉反应性抗原触发剂 自身反应性T淋巴细胞在遗传易感个体。 此外，正常静止的致糖尿病性T淋巴细胞仍可能 在B淋巴细胞缺陷型NOD.Ig-mu敲除小鼠中发展，如果其他 APC的亚群具有产生β细胞模拟物的能力， 来自感染原如科萨基病毒的自身抗原。 为了验证这一 假设，调查人员将追求两个主要目标。 一是 确定是否需要B淋巴细胞的发展，以及 T淋巴细胞的功能活化，能够响应各种 NOD小鼠中的GAD衍生肽。 第二是确定IDDM是否 Ig-mu敲除小鼠中的抗性可以通过用GAD引发而消除 衍生肽或科萨基病毒感染，可能绕过正常的 B淋巴细胞从天然抗原表位产生抗原表位的要求 GAD。 这些研究将提供对基本机制的见解， β细胞抗原呈递给IDDM患者的自身反应性T淋巴细胞， 这些过程如何受到科萨基病毒感染的影响。

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.