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Cytokine Dysregulation in Autoimmune Hemolytic Anemia

自身免疫性溶血性贫血中的细胞因子失调

基本信息

批准号：
8464352
负责人：
Katrina K Hoyer
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CALIFORNIA, MERCED
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8464352
关键词：
Acute Address Age Animals Antibodies Antibody Formation Antibody Specificity Antigen Targeting Antigens Applications Grants Area Atypical lymphocyte Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune hemolytic anemia Autoimmunity Award B Cell Proliferation B-Lymphocytes CD4 Positive T Lymphocytes Cell Communication Cell Extracts Cell Separation Cells Cessation of life Clinical Markers Collecting Cell Cytokine Signaling Data Dendritic Cells Dendritic cell activation Development Diagnostic Disease Disease Progression Employee Strikes Environment Erythrocytes Evolution Future Gene Family Genes Genetic Models Goals Grant Human Hybridomas Immune Immune System Diseases Immunization Immunoglobulin Class Switching Immunologic Memory Immunology Infection Inflammation Interferons Interleukin-12 Interleukin-2 Journals Knockout Mice Lymphocyte Lymphocyte Count Lymphoid Tissue Lymphoproliferative Disorders Manuscripts Mediating Methods Modeling Molecular Weight Mono-S Multiple Pregnancy Mus Peripheral Phase Phenotype Play Process Production Proteins Published Comment RNA Reaction Reagent Regulation Regulatory T-Lymphocyte Research Proposals Role Sampling Screening procedure Secondary to Self Tolerance Serum Severity of illness Signal Pathway Specificity Stimulus Suggestion Surface T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Time Tissues Transgenic Mice Western Blotting anergy autoreactive T cell base cytokine insight killings lymph nodes migration mouse model overexpression prevent research study response tool

项目摘要

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.

自身免疫性溶血性贫血（AIHA）的特点是产生针对自身的抗体红细胞。鉴于 AIHA 与其他自身免疫性疾病之间的频繁关联，一般而言免疫功能障碍可能在疾病过程中发挥作用。正常情况下，自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身反应性的存活和致病激活淋巴细胞。目前尚不清楚自身反应性淋巴细胞在缺失的情况下如何自发激活。明显感染或其他刺激，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，并确定致病性抗体的抗原靶标，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，我们使用了小鼠模型自发性、急性全身性自身免疫，主要表现为 AIHA 来定义刺激自身免疫性疾病的发展所必需的。该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鉴定目标抗原这种病。该提议的核心假设是细胞因子的异常产生和由于缺乏调节性 T 细胞抑制，树突状细胞的激活不受控制，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，并加强我们对触发和维持自身免疫的原因的理解。