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首页> 外文学位 >Investigating B cell and T cell Cognate Interactions in Systemic Lupus Erythematosus: A Novel System for the Study of Lupus Antigen-Specific T cells.
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Investigating B cell and T cell Cognate Interactions in Systemic Lupus Erythematosus: A Novel System for the Study of Lupus Antigen-Specific T cells.

机译：研究系统性红斑狼疮中B细胞和T细胞同源相互作用：研究狼疮抗原特异性T细胞的新型系统。

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摘要

Systemic lupus erythematosus (SLE) is a debilitating disease caused by a misdirected immune response towards self tissues that results from a combination of allelic risk factors, environmental influences, and stochastic events. While the various permutations of these components can be distinct for individual patients, the interactions between autoreactive B cells and T cells are likely to be a common critical force that drives disease pathogenesis.;Previous work has demonstrated that B cells have multiple antibody-dependent and -independent roles in SLE. Studies using B cell deficient lupus-prone mice suggest that B cells may be critical antigen presenting cells (ADCs) for initiating the T cell response, but this has never been directly tested. By specifically deleting MHC class II (MHCII) on B cells, we demonstrated that B cells do play a non-redundant role in activating T cells in a spontaneous, polygenic murine model of lupus. We also show that the ability of B cells to interact with T cells in a cognate manner significantly enhanced B cell proliferation and differentiation into antibody forming cells (AFCs). In the absence of these antigen-specific interactions, clinical disease was significantly reduced.;Understanding the mechanistic detail of these interactions has been significantly hampered by the absence of a lupus antigen-specific T cell model. This is in large part because identifying T cells that recognize ubiquitous self antigens has been extremely challenging. We developed a system to identify immune complex (IC)-specific T cells using rheumatoid factor (RF) B cells and autoantibodies which form spontaneous immune complexes. Since ICs are complex, undefined self antigens, they provided the opportunity to discover previously unknown T cell self antigens. Proteomic techniques and bioinformatic analysis identified several potential self antigens for these T cells, most of which were from ubiquitous nucleic acid-binding proteins.;We used one of these newly characterized autoreactive T cell clones to investigate cognate T cell-B cell interactions in response to lupus autoantigens. We found the IC-specific T cells significantly enhanced the RF B cell response to nucleic acid-reactive autoantibodies. In vitro, the cognate help provided by the IC-specific T cells alleviated the requirement of TLR signaling for the RF B cell proliferative response. In vivo, the presence of IC-specific T cells dramatically altered B cell differentiation, directing anti-chromatin stimulated-B cells from a plasmablast to a germinal center (GC) fate.;The work described here established a new method for identifying autoreactive T cells and discovering new T cell antigen relevant for systemic autoimmune disease.
机译：系统性红斑狼疮（SLE）是一种由于对等组织风险因素，环境影响和随机事件的综合作用而导致的针对自身组织的错误免疫反应所致的虚弱性疾病。虽然这些成分的不同排列对于个别患者可能是不同的，但自身反应性B细胞与T细胞之间的相互作用可能是驱动疾病发病机理的共同关键力量。 SLE中的独立角色。使用缺乏B细胞的易患狼疮的小鼠的研究表明，B细胞可能是引发T细胞反应的关键抗原呈递细胞（ADC），但这从未经过直接测试。通过在B细胞上特异性删除II类MHC（MHCII），我们证明了B细胞在狼疮的自发多基因鼠模型中激活T细胞时确实发挥了非冗余作用。我们还表明，B细胞以同源方式与T细胞相互作用的能力显着增强了B细胞的增殖和分化为抗体形成细胞（AFC）。在没有这些抗原特异性相互作用的情况下，临床疾病显着减少。；由于缺乏狼疮抗原特异性T细胞模型，对这些相互作用的机制细节的了解已大大受到阻碍。这在很大程度上是因为鉴定可识别普遍存在的自身抗原的T细胞具有极大的挑战性。我们开发了使用类风湿因子（RF）B细胞和形成自发免疫复合物的自身抗体来鉴定免疫复合物（IC）特异性T细胞的系统。由于IC是复杂的，不确定的自身抗原，因此它们提供了发现以前未知的T细胞自身抗原的机会。蛋白质组学技术和生物信息学分析确定了这些T细胞的几种潜在自身抗原，其中大多数来自无处不在的核酸结合蛋白。我们使用这些新近鉴定的自身反应性T细胞克隆之一研究了同源T细胞与B细胞的相互作用狼疮自身抗原。我们发现IC特异性T细胞显着增强了RF B细胞对核酸反应性自身抗体的反应。在体外，由IC特异性T细胞提供的同源帮助减轻了TLR信号传递对RF B细胞增殖反应的需求。在体内，IC特异性T细胞的存在极大地改变了B细胞的分化，将抗染色质刺激的B细胞从成浆细胞引导到生发中心（GC）的命运。本文所述的工作建立了一种识别自身反应性T的新方法细胞并发现与全身性自身免疫疾病相关的新T细胞抗原。

著录项

  • 作者

    Giles, Josephine Ruth.;

  • 作者单位

    Yale University.;

  • 授予单位 Yale University.;
  • 学科 Immunology.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 215 p.
  • 总页数 215
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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