Antigen Presenting Cell Defects in Autoimmune Diabetes

描述（由申请人提供）：在人类和NOD小鼠中，1型糖尿病（T1 D）是由多种易感性（Idd）基因之间的相互作用引起的，这些基因引起T细胞介导的自身免疫性破坏胰岛素产生胰腺β细胞。我们已经发现，在NOD小鼠中，H2 g7 MHC单倍型内部和外部的Idd基因之间的相互作用在造血来源的抗原呈递细胞（APC）中产生缺陷，这有助于糖尿病致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APC功能障碍的基因的身份和功能。APC亚群包括B淋巴细胞、巨噬细胞和树突状细胞（DC）。这些APC亚群以不同的T细胞发育和活化水平促进NOD小鼠中的T1 D发育。NOD巨噬细胞和DC不正常成熟，这似乎有助于该菌株在胸腺或外周中发育期间删除或清除自身反应性T细胞的能力受损。我们的数据表明，NOD小鼠中受损的DC分化反过来与自然杀伤T（NKT）细胞的缺陷有关，这也是该品系的特征。用超激动剂α-半乳糖神经酰胺激活NKT细胞抑制NOD小鼠中的T1 D发展，并且我们的数据表明这是由DC的下游成熟引起的，DC在胰腺淋巴结（PLN）中积累，在那里它们通过未知机制阻断致病性T细胞应答。我们的第一个具体目标是确定NKT细胞激活覆盖NOD小鼠中DC成熟缺陷的机制，以及随后如何抑制T1 D。由于B淋巴细胞通过特异性质膜结合免疫球蛋白（IG）分子摄取β细胞抗原的独特能力，B淋巴细胞作为APC亚型，其最有效地激活NOD小鼠中的致糖尿病性CD 4 T细胞应答。我们已经发现NOD小鼠的特征是在正常情况下缺失表达自身反应性IG分子的B淋巴细胞或使其无反应性的过程中存在缺陷，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是绘制NOD小鼠中导致B淋巴细胞耐受诱导缺陷的基因，以最终确定其身份。我们的第三个目标是，然后机械特性的基因有助于B淋巴细胞耐受性诱导NOD小鼠的缺陷。尽管胰岛素治疗的可用性，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为预防这种毁灭性疾病的发展提供手段。

DESCRIPTION (provided by applicant): 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 beta cells. We have found that in NOD mice interactions between Idd genes both within and outside the H2g7 MHC haplotype engender defects in hematopoietically derived antigen presenting cells (APC) 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 APC dysfunctions in NOD mice. APC subsets include B-lymphocytes, macrophages, and dendritic cells (DC). These APC 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 alpha-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 beta cell antigens through specific plasma membrane bound immunoglobulin (Ig) molecules, B-lymphocytes serve as the APC 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.