T cell regulation of pathogenic B cell in systemic autoimmunity

系统性自身免疫中致病性 B 细胞的 T 细胞调节

• 批准号: 10461956
• 负责人: Jason Weinstein
• 金额: $ 32.17万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461956
• 关键词: Acute; Address; Affinity; Antibodies; Architecture; Autoantibodies; Autoimmune Diseases; Autoimmunity; Automobile Driving; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Biological Models; CD4 Positive T Lymphocytes; Cell Maturation; Cells; Cellular Immunology; Chromatin; Chronic; Development; Disease; Disease Progression; Epigenetic Process; Event; Future; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genetic Transcription; Genomic approach; Genomics; Goals; Helper-Inducer T-Lymphocyte; Human; ITGAX gene; Immune response; Immunization; Immunoglobulin Class Switching; Immunoglobulin Isotypes; Immunoglobulins; Infection; Inflammatory; Interferon Type II; Interferon-beta; Interferons; Interleukin-12; Kidney; Lupus; Memory; Modeling; Mus; Output; Pathogenicity; Patients; Pattern; Phenotype; Plasma Cells; Population; Production; Regulation; Regulatory Element; Reporter; Rheumatoid Arthritis; Role; STAT protein; Side; Signal Transduction; Site; Structure of germinal center of lymph node; System; Systemic Lupus Erythematosus; T cell regulation; T-Cell Activation; T-Lymphocyte; T-bet protein; Techniques; Th1 Cells; Therapeutic; Time; Transcriptional Regulation; Viral; Virus Diseases; Wild Type Mouse; Work; acute infection; autoreactive B cell; autoreactivity; cytokine; design; effector T cell; genetic manipulation; inflammatory milieu; novel; novel therapeutic intervention; novel therapeutics; pathogenic autoantibodies; programs; response; secondary lymphoid organ; systemic autoimmune disease; systemic autoimmunity; tissue injury

ABSTRACT Systemic lupus erythematosus (SLE, lupus) is characterized by the generation of pathogenic autoantibodies that promote tissue injury, including in the kidney. Pathogenic autoantibodies in lupus undergo affinity maturation and immunoglobulin (Ig) isotype switching in germinal centers (GCs) within secondary lymphoid organs (SLOs), a site of CD4+ T cell-dependent (TD) B cell maturation. Yet, the specific subsets of effector CD4+ T cells that promote autoreactive B development, and the regulation of these cells, are not well defined. T follicular helper (Tfh) cells comprise a subset of CD4+ T helper (Th) cells, phenotypically and functionally distinct from other Th cells, such as the classical the Th1, Th2 and Th17 subsets. I have used model systems to explore Tfh-cell cytokine production and its role in B cell maturation, with the long-term goal to investigate these events in pathogenic autoantibody production in SLE. We show that expression of the transcription factor T-bet is required for Tfh and Th1 cell expansion and IFN-γ production, and viral-specific GC output. Activated STAT4 promotes T-bet expression in Tfh cells, as in Th1 cells, along with IL-21. STAT4 and T-bet expression is driven by IL-12 and IFN-β, which are needed to transcriptionally regulate Tfh cell expansion and co- production of IL-21 and IFN-γ, to enable a proper GC response upon type 1 immune response. Similar to viral infection Tfh and Th1 cells expand and persist in murine and human lupus, with similar patterns of STAT4 and T-bet expression, alongside co-expression of IFN-γ and IL-21. Yet, despite their robust co-production of IFN-γ and IL-21, Tfh and not Th1 cells in murine lupus extinguish T-bet expression over time, with its absence also in human cTfh cells from lupus patients. We hypothesize that the chronic inflammatory milieu of lupus alters the genetic expression of effector Th cells leading to aberrant regulation of pathogenic B cells that contribute to disease. Accordingly, we will explore temporal changes in genetic regulation that functionally impact pathognic Tfh cell and GC B cell developemnt in autoimmune disease compared to an acute type 1 viral infection. We will combine cellular techniques with novel genomic approaches to investigate chromatin architecture influencing functional gene expression, followed by identification of the controlling cis-regulatory elements in a side by side comparison of these T and B cells as disease progresses. This will allow us to explore the temproal interplay of transcriptional regulation, dynamic chromatin architecture and genomic organization in the regulation of pathogenic T and B cells. Using cellular techniques, we will also examine the developmental requirements for the T-bet expressing inflammatory B cell subset. We will determine the cytokines and the T cells that promote the genesis of these autoantibody secreting B cells. Ultimately, this work should help distinguish pathogenic and nonpathogenic effector T cells, aiding new avenues of therapeutic design. `

摘要 系统性红斑狼疮(SLE，狼疮)的特征是产生致病性自身抗体 这会促进组织损伤，包括肾脏。狼疮的致病自身抗体经历亲和力 次级淋巴生发中心(GC)的成熟与免疫球蛋白(Ig)同型转换 器官(SLO)，CD4+T细胞依赖(TD)B细胞成熟的场所。然而，效应器的特定子集 促进自身反应性B细胞发育的CD4+T细胞，以及对这些细胞的调节，还没有很好的定义。 T滤泡辅助性细胞(TFH)包括一个亚群的CD4+辅助性T细胞(Th)的表型和功能 区别于其他Th细胞，如经典的Th1、Th2和Th17亚群。我用过模型系统 探讨TFH细胞因子的产生及其在B细胞成熟中的作用，并进行长期研究 这些事件在SLE病理性自身抗体的产生中起作用。我们证明了转录因子的表达 T-bet是Tfh和Th1细胞扩增和干扰素-γ产生以及病毒特异性GC输出所必需的。已激活 与Th1细胞一样，STAT4促进T-bet在Tfh细胞和IL-21的表达。STAT4和T-bet表达式 是由IL-12和干扰素-β驱动的，它们在转录上调节TFH细胞的增殖和协同作用。 产生IL-21和干扰素-γ，以实现对1型免疫反应的适当GC反应。类似于病毒 感染Tfh和Th1细胞在小鼠和人类狼疮中扩张并持续存在，其STAT4和Th1细胞的模式相似 T-bet表达，以及干扰素-γ和IL-21的共同表达。然而，尽管它们强劲地联合生产干扰素-γ 随着时间的推移，小鼠狼疮中IL-21、Tfh和Not Th1细胞可以消除T-bet的表达，但在 狼疮患者的人cTfh细胞。我们假设狼疮的慢性炎症环境改变了 效应Th细胞的基因表达导致致病B细胞的异常调节 疾病。因此，我们将探索影响病原学功能的基因调控的时间变化。 与急性1型病毒感染相比，TFH细胞和GC B细胞在自身免疫性疾病中发育。我们会 结合细胞技术和新的基因组方法研究染色质结构对 功能基因表达，随后并排鉴定控制顺式调控元件 随着疾病的进展，对这些T和B细胞进行比较。这将使我们能够探索临时性相互作用 转录调控、动态染色质结构和基因组结构在调控中的作用 致病T细胞和B细胞。利用细胞技术，我们还将研究 表达炎性B细胞亚群的T-bet。我们将确定细胞因子和T细胞促进 这些分泌B细胞的自身抗体的起源。归根结底，这项工作应该有助于区分病原体 和非致病效应T细胞，有助于治疗设计的新途径。 `