ANTIGEN PRESENTING CELL DEFECTS IN AUTOIMMUNE DIABETES

描述：(改编自《调查者摘要》)：T细胞介导 自身免疫性IDDM是多种易感性(IDD)相互作用的结果 位于MHC内外的基因。在NOD小鼠中，其中一些 多基因相互作用通过降低T细胞的 血源性抗原提呈细胞(APC)的激活能力 具有多种免疫调节功能。APC的亚群包括 B淋巴细胞、巨噬细胞和树突状细胞。部分解决哪个APC 亚群导致IDDM，研究人员制造了NOD小鼠 功能失活的免疫球蛋白u基因导致的B淋巴细胞缺陷。这些B 淋巴细胞缺陷型NOD。Ig MU基因缺失的小鼠对IDDM具有抵抗力。他们的总体情况 目的是阐明B淋巴细胞参与免疫反应的机制(S)。 T细胞介导的自身免疫性1DDM的研究进展他们找到了一个 B淋巴细胞参与IDDM的机制是APC的一个亚群 优先将某些胰腺B细胞抗原呈递给 自身反应性MHC II类限制性T细胞。具体目标1是确定 介导这一过程的B淋巴细胞必须表达免疫球蛋白(Ig) 能够特异性捕获B细胞自身抗原的分子，如果是这样的话，确实 这些糖尿病致病的APC是通过耐受诱导缺陷产生的。这些问题 将通过使用NOD小鼠表达重排的Ig转基因来解决。 另一个未知因素是Nod B淋巴细胞是否也表现出IDD基因 APC介导的耐受诱导中的受控缺陷 糖尿病T细胞的初步发育。抗性变异体的表达 所有APC亚型上的某些MHC Idd基因会阻止APC的发展或 糖尿病T细胞的功能激活。目标2是确定 赋予IDDM抗性的特定MHC基因集必须在 特异性APC亚型使NOD T细胞对胰腺B细胞耐受 抗原。这些研究将利用NOD小鼠和相关菌株表达 不同MHC基因在特定APC亚群上的IDDM抗性变异。非MHC 基因也对nod B淋巴细胞的糖尿病原发APC活性起作用。 具体目标3是确定非MHC基因的作用机制 对NOD小鼠体内具有促糖尿病活性的B淋巴细胞发育的影响。 这个问题将通过一个嵌合系统来解决，在这个系统中，Nod T细胞可以 只有在选定的B淋巴细胞群存在的情况下，才能成熟和发挥功能。 总体而言，拟议的研究将描绘出B 淋巴细胞在T细胞介导的发育中起关键作用 自身免疫性IDDM。

DESCRIPTION: (Adapted from the Investigator's abstract): T cell mediated autoimmune IDDM results from interactions between multiple susceptibility (Idd) genes located within and outside of the MHC. In NOD mice some of these polygenic interactions engender diabetogenic T cell development by reducing the ability of hematopoietically derived antigen presenting cells (APC) to activate various immunoregulatory functions. Subpopulations of APC include B-lymphocytes, macrophages, and dendritic cells. To partially address which APC subpopulations contribute to IDDM, the investigators produced NOD mice made deficient in B lymphocytes by a functionally inactivated Ig mu gene. These B lymphocyte deficient NOD.Ig mu null mice are IDDM resistant. Their overall objective is to delineate the mechanism(s) by which B lymphocytes contribute to the development of T cell mediated autoimmune 1DDM. They have found one mechanism that B lymphocytes contribute to IDDM is as a subpopulation of APC with a preferential ability to present certain pancreatic B cell antigens to autoreactive MHC class II restricted T cells. Specific aim 1 is to determine if the B lymphocytes mediating this process must express immunoglobulin (Ig) molecules capable of specifically capturing B cell autoantigens, and if so, do these diabetogenic APC arise through tolerance induction defects. These issues will be addressed through use of NOD mice expressing rearranged Ig transgenes. Another unknown factor is if NOD B lymphocytes also manifest any Idd gene controlled defects in APC mediated tolerance induction that underlie the initial development of diabetogenic T cells. Expression of resistance variants of certain MHC Idd genes on all APC subtypes blocks the development or functional activation of diabetogenic T cells. Aim 2 is to determine if particular sets of MHC genes that confer IDDM resistance must be expressed on specific APC subtypes to render NOD T cells tolerant to pancreatic B cell antigens. These studies will utilize NOD mice and related strains that express IDDM resistance variants of various MHC genes on specific APC subsets. Non-MHC genes also contribute to the diabetogenic APC activity of NOD B lymphocytes. Specific aim 3 is to determine the mechanisms by which non-MHC genes contribute to the development of B-lymphocytes with diabetogenic APC activity in NOD mice. This issue will be addressed through a chimeric system in which NOD T cells can only mature and function in the presence of selected B lymphocyte populations. Collectively, the proposed studies will delineate mechanisms by which B lymphocytes make critical contributions to the development of T cell mediated autoimmune IDDM.