Pathogenic Role of Islet Cell Abs in Autoimmune Diabetes

外周T细胞耐受性与自身免疫性的关系是由树突状细胞呈递抗原决定的。 我们以前的工作，使用外来抗原，已经表明，抗体介导的抗原增强， 树突状细胞的递呈在体内诱导有效的效应器CDS应答，其方式受 激活性和抑制性Fc受体的相反作用。 我们使用模型自身抗原的初步工作表明，自身抗体有效地诱导 体内自身反应性T细胞对胰岛细胞抗原的活化。胰岛特异性CDST细胞和 自身抗体单独足以诱导糖尿病，然而抗体和T细胞一起诱导糖尿病。 疾病协同。 胰岛细胞抗原的自身抗体在IDDM临床发病前就已发现。与其他 自身抗体通常在自身免疫状态中发现，其中T细胞是效应子，胰岛细胞抗体是 被广泛认为是一个标志物，但不是疾病的促成因素。这是因为与自身反应性T 细胞，胰岛细胞抗体缺乏内在致病性。因此，糖尿病患者对B细胞的需求已经被证实。 解释为揭示了B细胞作为APC的作用。我们发现树突状细胞对免疫球蛋白的摄取 复合物有效地增强了自身攻击性T细胞的活化。因此，B细胞及其分泌的 免疫球蛋白产物通过其在易化抗原中的作用导致T细胞介导的耐受性的丧失 演示文稿.我们已经确定了一种新的自身免疫发病机制， 使用临床相关治疗剂（IVIg）中断。我们进一步表明，IVIg减弱糖尿病， 该模型通过对体内抗原呈递的抑制作用。 我们已经建立了一个优雅的遗传系统来解决自身抗体如何断裂的机制 外周T细胞耐受性使用遗传系统激活Fc受体和补体 已经被确认。目的1和2中的实验使用OVA作为模型抗原，并将提供基本的 定义DCs、补体和Fc受体在触发 抗体触发的自身攻击性T细胞及其通过IVIg的阻断。我们在目标3中建议扩展这项工作 为了测试与抗体介导的胰岛素交叉呈递的相关性， 糖尿病

Peripheral T cell tolerance versus autoimmunity Is determined by dendritic cell presentation of antigen. Our prior work, using foreign antigens, has shown that antibody-mediated enhancement of antigen presentation by dendritic cells induces potent effector CDS responses in vivo, in a manner regulated by the opposing actions of the activating and inhibitory Fc receptors. Our preliminary work using a model self-antigen, has shown that autoantibody potently induces autoreactive T cell activation to islet cell antigens in vivo. Neither islet-specific CDST cells nor autoantibodies alone are sufficient to induce diabetes, however together antibodies and T cells induce disease synergistically. Autoantibodies to islet cell antigens are found prior to clinical onset of IDDM. Yet as with other autoantibodies commonly found in autoimmune states in which T cells are effectors, islet cell antibodies are widely believed to be a marker but not a contributing factor in disease. This is because unlike autoreactive T cells, islet cell antibodies lack intrinsic pathogenicity. Thus the requirement for B cells in diabetes has been interpreted as revealing a role for B cells as APCs. Here we show that dendritic cell uptake of immune complexes potently enhances the activation of auto-aggressive T cells. Thus both B cells and their secreted immunoglobulin products contribute to loss of T cell mediated tolerance via their roles in facilitated antigen presentation. We have identified a novel pathway of autoimmune pathogenesis and subsequently interrupted it using a clinically relevant therapeutic (IVIg). We further show that IVIg attenuates diabetes in this model via inhibitory effects on antigen presentation in vivo. We have established an elegant genetic system to address the mechanism of how autoantibody breaks peripheral T cell tolerance. Using genetic systems a role for both activating Fc receptors and complement have been identified. Experiments in Aims 1 and 2 use OVA as a model antigen and will provide basic knowledge for defining the role of DCs, complement and Fc receptors in triggering the emergence of antibody-triggered autoaggressive T cells and its blockade by IVIg. We propose in Aim 3 to extend this work to test relevance to the antibody-mediated cross-presentation of insulin, an antigen of singular importance to diabetes.