Pathogenic Role of Islet Cell Abs in Autoimmune Diabetes

描述（由申请人提供）：外周T细胞耐受性与自身免疫性通过树突状细胞呈递抗原来确定。我们先前的工作，使用外来抗原，已经表明，抗体介导的增强抗原呈递的树突状细胞诱导有效的效应CD8在体内的反应，在一种方式调节的激活和抑制性Fc受体的相反的行动。我们的初步工作使用的模型自身抗原，已经表明，自身抗体有效地诱导自身反应性T细胞活化胰岛细胞抗原在体内。胰岛特异性CD8 T细胞和自身抗体都不足以单独诱导糖尿病，然而抗体和T细胞一起协同诱导疾病。胰岛细胞抗原的自身抗体在IDDM临床发病前就已发现。然而，与T细胞是效应器的自身免疫状态中常见的其他自身抗体一样，胰岛细胞抗体被广泛认为是疾病的标志物，但不是促成因素。这是因为与自身反应性T细胞不同，胰岛细胞抗体缺乏内在致病性。因此，糖尿病中对B细胞的需求被解释为揭示了B细胞作为APC的作用。在这里，我们表明，树突状细胞摄取免疫复合物有力地增强了自身攻击性T细胞的激活。因此，B细胞及其分泌的免疫球蛋白产物通过其在促进抗原呈递中的作用而导致T细胞介导的耐受性的丧失。我们已经确定了一种新的自身免疫发病机制的途径，并随后中断它使用临床相关的治疗（IVIg）。我们进一步表明，静脉注射免疫球蛋白减弱糖尿病在这个模型中，通过抑制体内抗原呈递的影响。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打破外周T细胞耐受的机制。使用遗传系统，已经鉴定了激活Fc受体和补体的作用。目的1和2中的实验使用OVA作为模型抗原，并将提供用于定义DC、补体和Fc受体在触发抗体触发的自身攻击性T细胞的出现及其被IVIg阻断中的作用的基础知识。我们在目标3中建议将这项工作扩展到测试与抗体介导的胰岛素交叉呈递的相关性，胰岛素是对糖尿病具有独特重要性的抗原。

DESCRIPTION (provided by applicant): 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 CD8 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 CD8 T 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.