Antigen Presenting Cell Defects in Autoimmune Diabetes

在人类和NOD小鼠中，1型糖尿病（T1 D）是由多种糖尿病之间的相互作用引起的。 诱导T细胞介导的自身免疫性破坏胰岛素产生的易感性（Idd）基因 胰腺纤维细胞我们已经发现，在NOD小鼠中，Idd基因之间的相互作用， H297单倍型以外的MHC在造血来源的抗原呈递细胞中产生缺陷 (ARC)其有助于致糖尿病性T细胞的产生和活化。我们的总体目标是 确定NOD小鼠中导致糖尿病性ARC功能障碍的基因的身份和功能。 ARC亚群包括B淋巴细胞、巨噬细胞和树突状细胞（DC）。这些ARC子集 在不同水平的T细胞发育和活化下，N 0 D小鼠中的T1 D发育。 NOD巨噬细胞和DC不能正常成熟，这似乎有助于该菌株的受损。 在胸腺或胸腺发育过程中删除或清除自身反应性T细胞的能力 外围我们的数据表明，NOD小鼠中受损的DC分化反过来与以下缺陷有关： 自然杀伤T（NKT）细胞也是该菌株的特征。用超激动剂a- 半乳糖神经酰胺抑制NOD小鼠的T1 D发展，我们的数据表明这一结果来自于 DC的下游成熟，其在胰腺淋巴结（PLN）中积累，在那里它们阻断了 病原性T细胞反应通过未知的机制。我们的第一个具体目标是确定 NKT细胞活化克服NOD小鼠中DC成熟缺陷的机制，以及这一机制如何影响NOD小鼠中的DC成熟缺陷。 随后抑制T1 D。由于其独特的能力，以采取&细胞抗原通过特定的血浆 膜结合免疫球蛋白（IG）分子，B淋巴细胞作为ARC亚型， 在NOD小鼠中有效激活致糖尿病性CD 4 T细胞应答。我们发现NOD小鼠 其特征在于在正常情况下缺失或使B淋巴细胞表达无活力的过程中存在缺陷， 自身反应性IG分子，但这是否代表Idd基因控制的功能障碍仍然未知。 因此，目的2是定位NOD小鼠中导致B淋巴细胞耐受诱导缺陷的基因 以最终确定他们的身份我们的第三个目标是机械地描述 NOD小鼠B淋巴细胞耐受诱导缺陷的基因。尽管有 尽管使用胰岛素治疗，但T1 D的并发症仍然经常具有致命的影响。成功完成 我们提出的研究可能最终提供防止这种发展的方法， 毁灭性的疾病

In both humans and NOD mice type 1 diabetes (T1D) results from interactions between multiple susceptibility (Idd) genes that elicit T cell mediated autoimmune destruction of insulin producing pancreatic fi cells. We have found that in NOD mice interactions between Idd genes both within and outside the H297 MHC haplotype engender defects in hematopoietically derived antigen presenting cells (ARC) which contribute to the generation and activation of diabetogenic T cells. Our overall goal is to determine the identity and function of genes contributing to diabetogenic ARC dysfunctions in NOD mice. ARC subsets include B-lymphocytes, macrophages, and dendritic cells (DC). These ARC subsets contribute to T1D development in NOD mice at different levels of T cell development and activation. NOD macrophages and DC do not mature normally which appears to contribute to this strain's impaired ability to delete or inactivate autoreactive T cells either during their development in the thymus or in the periphery. Our data indicate impaired DC differentiation in NOD mice is in turn linked to defects in natural killer T (NKT) cells that also characterize this strain. NKT cell activation with the superagonist a- galactosylceramide inhibits T1D development in NOD mice, and our data suggests this results from the downstream maturation of DC which accumulate in the pancreatic lymph nodes (PLN) where they block pathogenic T cell responses through unknown mechanisms. Our first specific aim is to determine the mechanisms by which NKT cell activation overrides DC maturation defects in NOD mice, and how this subsequently inhibits T1D. Due to their unique ability to take up & cell antigens through specific plasma membrane bound immunoglobulin (Ig) molecules, B-lymphocytes serve as the ARC subtype which most efficiently activates diabetogenic CD4 T cell responses in NOD mice. We have found NOD mice are characterized by defects in processes that normally delete or anergize B-lymphocytes expressing autoreactive Ig molecules, but it remains unknown if this represents an Idd gene controlled dysfunction. Hence, aim 2 is to map the genes contributing to B-lymphocyte tolerance induction defects in NOD mice in order to ultimately determine their identity. Our third aim is to then mechanistically characterize the genes contributing to B-lymphocyte tolerance induction defects in NOD mice. Despite the availability of insulin treatment, the complications of T1D can still too often have lethal effects. Successful completion of our proposed studies might ultimately provide means for preventing the development of this devastating disease.