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Role of Grail in maintaining humoral immune tolerance

Grail 在维持体液免疫耐受中的作用

基本信息

批准号：
9089880
负责人：
Roza Insafetdinovna Nurieva
金额：
$ 8万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9089880
关键词：
Address Agreement Antibodies Antigens Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmunity B-Cell Activation B-Lymphocytes Bone Marrow CD28 gene CD4 Positive T Lymphocytes Cell physiology Cells Cellular biology Chimera organism Clinical Complex Congenic Mice Data Detection Development Disease Down-Regulation Gene Expression Microarray Analysis Gene Targeting Generations Genes Genetic Programming Goals Health Helper-Inducer T-Lymphocyte Humoral Immunities Immune Tolerance Immune response Immunization In Vitro Investigation Knockout Mice Knowledge Lead Lupus Lymphocyte Lymphocyte Function Lymphoid Tissue Maintenance Mediating Methods Mus Pathogenesis Patients Phenotype Play Prevention Production Property Reagent Regulation Reporter Reporting Role Serum Signal Transduction Staging Structure Structure of germinal center of lymph node Symptoms Systemic Lupus Erythematosus T-Cell Development T-Lymphocyte Technology Testing Time Work aging gene anergy anti-dsDNA antibodies autoreactive B cell autoreactive T cell body system central tolerance ds-DNA gene function gene repression insight knock-down lupus prone mice lupus-like mouse model new therapeutic target novel novel therapeutic intervention peripheral tolerance prevent programs research study screening systemic autoimmune disease ubiquitin ligase ubiquitin-protein ligase yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Autoimmunity is initiated by the dysregulation of central or peripheral tolerance, resulting in the escape of autoreactive T and B cells from normal selection. There is rising evidence that expansion of follicular helper T (Tfh) and B cells results in humoral and cellular abnormalities and leads to the development of systemic autoimmune diseases such as Systemic lupus erythematosus (SLE); however, current knowledge of the mechanisms that control autoreactive B and T cell function remains incomplete. Thus, today it is becoming clear that understanding of Tfh and B cell biology and ways to manipulate their function may prove to be invaluable for the treatment of autoantibody-driven diseases. Recently, we generated and analyzed mice deficient in GRAIL and found that aged GRAIL deficient mice developed SLE-like symptoms characterized by massive germinal center formation, accumulation of Tfh and B cells in the lymphoid tissues and high titers of anti-dsDNA antibodies. In addition, GRAIL KO mice crossed with lupus prone B6.Faslpr/lpr mice developed severe lupus phenotype compared to control mice. Moreover, GRAIL expression was down regulated in T and B lymphocytes of patients with active SLE and lupus prone mice, further supporting the role of GRAIL in controlling humoral immune responses. All these findings suggest that GRAIL could be essential in controlling T and B cell functions, and importantly GRAIL down-regulation could serve as a marker for SLE-like disorders. However, it is not clear whether lack of GRAIL in T and/or B cells is responsible for development of lupus-like autoimmunity. We therefore hypothesize that regulation of B and Tfh cell function by GRAIL may be an important checkpoint in humoral tolerance, which is crucial to prevent development of autoimmunity. In Aim1, we will investigate the role of GRAIL in Tfh cell development and function by utilizing gene knockdown approaches. We will employ unique Bcl6-RFP and Bcl6-RFP/Foxp3GFP reporter mouse models to define the function of GRAIL in Tfh and T follicular regulatory (Tfr) cell development in normal and autoimmune settings. In addition, we will identify targets of GRAIL through which it facilitates control of Tfh cell programming by using microarray analysis of gene expression. We have developed a new method of generation of Tfh cells in vitro, which will allow generation of sufficient amount of cells for the proposed analysis. In Aim2, we will assess the role of GRAIL in B cell activation and function. Importantly, we will employ cutting edge technologies, including two-hybrid screening, to identify the exact target(s) of GRAIL that determines its function in B cells. Our results will provide mechanistic insights into the understanding of autoantibody-mediated autoimmune diseases and may lead to identify new therapeutic targets for their detection and prevention.