Cytokine Dysregulation in Autoimmune Hemolytic Anemia

自身免疫性溶血性贫血（AIHA）的特征是产生针对自身免疫缺陷的抗体。 红细胞考虑到AIHA和其他自身免疫性疾病之间的频繁关联， 免疫功能障碍可能在疾病过程中起作用。正常情况下，自反应 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反应的存活和致病性激活。 淋巴细胞目前还不清楚在缺乏免疫刺激的情况下，自身反应性淋巴细胞是如何自发激活的。 明显的感染或其他刺激，导致自身免疫性疾病。如果激活的发起者和 可以描绘随后的疾病，并鉴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，我们使用了一个小鼠模型， 自发的急性全身性自身免疫，主要表现为AIHA，以定义 自身免疫性疾病的发展所必需的。本提案的总体目标是界定 免疫异常的自发性自身免疫模型，并确定靶抗原， 这种疾病。这一建议的核心假设是，异常的细胞因子产生和 由于缺乏调节性T细胞抑制，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）在AIHA发展中的作用，并加强 我们对自身免疫的触发和维持机制的理解

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.