Cytokine Dysregulation in Autoimmune Hemolytic Anemia

自身免疫性溶血性贫血中的细胞因子失调

• 批准号: 7586913
• 负责人: Katrina K Hoyer
• 金额: $ 9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586913
• 关键词: Acute; Address; Animals; Antibodies; Antibody Formation; Antigen Targeting; Antigens; Atypical lymphocyte; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune hemolytic anemia; Autoimmunity; CD28 gene; CD4 Positive T Lymphocytes; California; Cells; Cessation of life; Cytokine Signaling; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Employee Strikes; Erythrocytes; Evolution; Genetic Models; Hybridomas; Immune; Immune System Diseases; Immunization; Infection; Inflammation; Inflammatory; Lead; Lymphocyte; Lymphocyte Function; Lymphoproliferative Disorders; Mediating; Mentors; Modeling; Mus; Organ; Pathway interactions; Phase; Phenotype; Play; Principal Investigator; Process; Production; Reaction; Reagent; Research Personnel; Role; San Francisco; Secondary to; Self Tolerance; Serum; Signal Transduction; Stimulus; Surface; T-Cell Activation; T-Lymphocyte; Tissues; Universities; Work; abstracting; anergy; anti-IgG; autoreactive T cell; base; cytokine; killings; mouse model; novel; overexpression; prevent; response

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)

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 与其他自身免疫性疾病之间的频繁关联，全身免疫功能障碍可能在疾病过程中发挥作用。正常情况下，自身反应性淋巴细胞被调节性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身反应性淋巴细胞的存活和致病性激活。目前尚不清楚在没有明显感染或其他刺激的情况下，自身反应性淋巴细胞如何自发激活，从而导致自身免疫性疾病。如果可以描述激活和随后疾病的引发剂，并确定致病性抗体的抗原靶标，则可能会发现控制这些自身免疫反应的方法。在这项研究中，我们使用主要表现为 AIHA 的自发性急性全身性自身免疫小鼠模型来定义自身免疫性疾病发展所需的刺激。该提案的总体目标是定义自发性自身免疫模型中的免疫学异常，并确定该疾病的靶抗原。该提议的核心假设是，由于缺乏调节性 T 细胞抑制，细胞因子的异常产生和树突状细胞的不受控制的激活会导致自身免疫。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了解。我将在加州大学旧金山分校的 Abul Abbas 博士的指导下继续该项目的指导阶段，然后期待以独立研究者的身份完成这些目标。 （摘要完）