Cytokine Dysregulation in Autoimmune Hemolytic Anemia

描述（由申请人提供）： 自身免疫性溶血性贫血（AIHA）的特征是产生针对自身红细胞的抗体。鉴于AIHA和其他自身免疫性疾病之间的频繁关联，全身性免疫功能障碍可能在疾病过程中发挥作用。在正常情况下，自身反应性淋巴细胞被调节性T细胞杀死、灭活或抑制，导致对自身抗原无反应性。这些控制机制的破坏导致自身反应性淋巴细胞的存活和致病性激活。目前尚不清楚自身反应性淋巴细胞如何在没有明显感染或其他刺激的情况下自发激活，导致自身免疫性疾病。如果激活和随后的疾病的启动子可以划定，并确定病原性抗体的抗原靶点，控制这些自身免疫反应的方法可能会被发现。在这项研究中，我们使用一个自发的，急性全身性自身免疫，主要表现为AIHA的小鼠模型，以确定所需的刺激发展的自身免疫性疾病。本提案的总体目标是定义自发性自身免疫模型中的免疫异常，并确定该疾病的靶抗原。这一提议的核心假设是，由于缺乏调节性T细胞抑制导致的异常细胞因子产生和树突状细胞的不受控制的活化导致自身免疫。该项目的成功完成将阐明AIHA发展中的免疫异常（包括树突状细胞，细胞因子和抗原特异性淋巴细胞的作用），并加强我们对触发和维持自身免疫的理解。我将在加州大学旧金山弗朗西斯科的阿布·阿巴斯博士的指导下继续这个项目的指导阶段，然后期待着作为一名独立的调查员完成这些目标。(End摘要）

DESCRIPTION (provided by applicant): Autoimmune hemolytic anemia (AIHA) is characterized by the production of antibodies directed against self red blood cells. Given the frequent association between AIHA and other autoimmune disorders, generalized immune dysfunction likely plays a role in the disease process. Under normal conditions, self-reactive lymphocytes are killed, inactivated or suppressed by regulatory T cells, resulting in unresponsiveness to selfantigens. Disruption of these control mechanisms results in the survival and pathogenic activation of selfreactive lymphocytes. It is unclear how self-reactive lymphocytes are spontaneously activated in the absence of overt infection or other stimuli, leading to autoimmune disease. If the initiators of activation and subsequent disease can be delineated, and the antigen targets of pathogenic antibodies identified, means of controlling these autoimmune reactions may be uncovered. In this study, we use a mouse model of spontaneous, acute systemic autoimmunity that principally manifests as AIHA to define the stimuli that are required for the development of autoimmune disease. The overall objective of this proposal is to define the immunological abnormalities in a model of spontaneous autoimmunity and to identify the target antigens in this disease. The central hypothesis underlying this proposal is that abnormal cytokine production and uncontrolled activation of dendritic cells due to the absence of regulatory T cell suppression results in autoimmunity. The successful completion of this project will elucidate the immune abnormalities (including the role of dendritic cells, cytokines and antigen-specific lymphocytes) in AIHA development, and strengthen our understanding of what triggers and maintains autoimmunity. I will proceed with the mentored phase of this project under the guidance of Dr. Abul Abbas at the University of California San Francisco, and then look forward to completing these aims as an independent investigator. (End of Abstract)