Pathogenic Role of Islet Cell Abs in Autoimmune Diabetes

描述(申请人提供)：外周T细胞耐受性与自身免疫是由树突状细胞提呈抗原决定的。我们先前使用外源抗原的工作表明，抗体介导的树突状细胞递呈抗原的增强在体内诱导了强大的效应器CD8反应，其方式受激活和抑制Fc受体的相反作用的调节。我们使用模型自身抗原的初步工作表明，在体内，自身抗体有效地诱导对胰岛细胞抗原的自身反应性T细胞激活。无论是胰岛特异性CD8T细胞还是自身抗体本身都不足以诱发糖尿病，然而抗体和T细胞协同作用诱发疾病。胰岛细胞抗原的自身抗体是在IDDM临床发病之前发现的。然而，就像在自身免疫状态中常见的其他自身抗体一样，T细胞是效应者，胰岛细胞抗体被广泛认为是疾病的标志，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的致病性。因此，糖尿病对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，我们展示了树突状细胞对免疫复合体的摄取有效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促进抗原提呈而导致T细胞介导的耐受性丧失。我们已经确定了一条新的自身免疫发病机制的途径，并随后使用了临床相关的治疗药物(IVIg)来阻断它。我们进一步证明，IVIg通过抑制体内的抗原提呈而减轻该模型的糖尿病。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破坏外周T细胞耐受的机制。利用基因系统，已经确定了激活Fc受体和补体的作用。AIMS 1和2中的实验使用OVA作为模式抗原，将为确定DC、补体和Fc受体在触发抗体触发的自身侵袭性T细胞的出现及其被IVIg阻断中的作用提供基础知识。我们在目标3中建议扩展这项工作，以测试与抗体介导的胰岛素交叉递呈的相关性，胰岛素是一种对糖尿病具有特殊重要性的抗原。

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.