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的抗体 红血球。鉴于AIHA和其他自身免疫性疾病之间的频繁联系，广义的 免疫功能障碍可能在疾病过程中发挥作用。在正常情况下，自我反应 淋巴细胞被调节性T细胞杀死、失活或抑制，导致对自身抗原无反应。 这些控制机制的破坏导致自主性细胞的存活和致病性激活 淋巴细胞。目前尚不清楚在缺乏的情况下，自我反应的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。如果激活的发起人和 可以描绘出后续的疾病，并识别致病抗体的抗原靶标，手段 控制这些自身免疫反应可能会被揭开。在这项研究中，我们使用了一个小鼠模型 自发性、急性全身性自身免疫，主要表现为AIHA，以定义 是自身免疫性疾病发展所必需的。这项提案的总体目标是定义 自发性自身免疫模型的免疫学异常及其靶抗原的鉴定 这种病。支持这一建议的中心假设是异常细胞因子的产生和 由于缺乏调节性T细胞抑制导致树突状细胞的不受控制的激活 自身免疫力。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发生中的作用)，并加强 我们对触发和维持自身免疫力的理解。

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.