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T-bet expressing B cells in autoimmunity

T-bet 在自身免疫中表达 B 细胞

基本信息

批准号：
10378006
负责人：
Anne B Satterthwaite
金额：
$ 20.5万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378006
关键词：
Age Antibodies Antibody Formation Antigen-Antibody Complex Antigens Autoantibodies Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity B cell differentiation B-Cell Activation B-Lymphocyte Subsets B-Lymphocytes Cells Complement Complex Deposition Development Frequencies Future Genes Human IRF4 gene ITGAX gene Immune response Immune system Immunoglobulin-Secreting Cells Immunosuppression Infection Interferons Kidney Label Lupus Maps Memory Methods Modeling Mus Nucleic Acids Organ Pathology Patients Phenotype Plasma Cells Population Production Role Signal Transduction Specificity Stimulus Structure of germinal center of lymph node Suggestion Supporting Cell System Systemic Lupus Erythematosus Systemic Therapy T-Lymphocyte T-bet protein TLR7 gene Testing Tissues Tomatoes autoreactive B cell autoreactivity inflammatory milieu novel therapeutic intervention pathogenic autoantibodies plasma cell differentiation preservation prevent renal damage response side effect targeted treatment therapeutic target transcription factor

项目摘要

Systemic Lupus Erythematosus (SLE) is a potentially fatal autoimmune disease characterized by the production of pathogenic autoantibodies that recognize nucleic acid containing antigens. These antibodies form immune complexes that promote tissue damage in multiple organs and perpetuate a systemic inflammatory environment. The majority of current therapies for SLE involve non-specific immunosuppression and have undesirable side effects. Thus there is an urgent need for more targeted therapies. Recent studies have demonstrated that autoreactive B cells have unique requirements for their activation, participation in germinal centers, and differentiation into antibody secreting plasma cells compared to B cells reactive with foreign antigens. Understanding the consequences of these differential signals may reveal new therapeutic strategies to prevent autoimmune responses while maintaining the ability to respond to infection. The transcription factor T-bet is a) upregulated by stimuli that are uniquely required for autoreactive B cell responses and b) increased in germinal center B cells and ABCs in mouse lupus models and in DN2 cells from SLE patients. ABCs and DN2s are B cell subsets that accumulate in lupus and differentiate efficiently into plasma cells that secrete elevated levels of autoantibodies. However, the degree to which T-bet expressing B cells contribute to the production of pathogenic autoantibodies is unclear, as prior results have been contradictory. A better understanding of this is necessary in order to support these cells as a therapeutic target for lupus. We posit that T-bet expression is a marker for cells that give rise to autoantibodies in lupus models, even if it is not itself absolutely required for autoantibody production. We will test this hypothesis by 1) using a fate mapping strategy to determine the contribution of cells that express, or once expressed, T-bet to the accumulation of autoreactive plasma cells, and 2) preventing T-bet expressing B cells from differentiating into plasma cells in a lupus model. Successful completion of these studies will highlight T-bet expressing B cells or stimuli that induce them as potential therapeutic targets for SLE. The methods developed here to delete genes specifically in T-bet expressing B cells will also be valuable for future mechanistic studies involving these cells both in autoimmune disease and during immune response to infections.

系统性红斑狼疮（SLE）是一种潜在的致命性自身免疫性疾病，其特征在于：产生识别含有抗原的核酸的病原性自身抗体。这些抗体形成免疫复合物，促进多个器官的组织损伤，并使系统性炎症环境。目前SLE的大多数治疗方法涉及非特异性免疫抑制并且具有不希望的副作用。因此，迫切需要更多的靶向治疗。最近的研究已经证明自身反应性B细胞对它们的激活、参与免疫应答具有独特的要求。和分化成抗体分泌浆细胞相比，B细胞与外来抗原了解这些差异信号的后果可能会揭示新的治疗方法。预防自身免疫反应的策略，同时保持对感染的反应能力。的转录因子T-bet a）被自身反应性B细胞所独特需要的刺激物上调 b）在小鼠狼疮模型中的生发中心B细胞和ABC中以及在小鼠狼疮模型中的DN 2细胞中， SLE患者。ABC和DN 2是B细胞亚群，其在狼疮中积累并有效地分化为分泌高水平自身抗体的浆细胞。然而，表达B的T-bet的程度细胞有助于致病性自身抗体的产生是不清楚的，因为先前的结果已经自相矛盾为了支持将这些细胞作为治疗靶点，有必要更好地理解这一点治疗狼疮我们认为T-bet表达是狼疮模型中产生自身抗体的细胞的标志物，即使其本身不是自身抗体产生所绝对需要的。我们将通过1）使用一个命运定位策略，以确定表达或一旦表达T-bet的细胞对细胞凋亡的贡献。自身反应性浆细胞的积累，以及2）阻止表达T-bet的B细胞分化为狼疮模型中的浆细胞这些研究的成功完成将突出表达T-bet的B细胞或刺激诱导它们作为SLE的潜在治疗靶点。这里开发的方法可以删除在表达T-bet的B细胞中特异的基因也将对未来的机制研究有价值，这些细胞在自身免疫性疾病和对感染的免疫反应中。