Lupus Glomenulonephritis and NK T cells

描述(申请人提供)：系统性红斑狼疮是一种自身免疫性疾病，在NZB/W小鼠和人类中导致免疫复合体肾炎。我们在狼疮小鼠和人类身上的研究表明，CD4自然杀伤(NK)T细胞通过BALB/c细胞表面的CD1d抗原提呈分子自发地与自体B细胞相互作用，并通过分泌IgM、Ig G和Ig G抗dsDNA自身抗体诱导B细胞的多克隆激活。传统的CD4T细胞(非NK T细胞)几乎没有抗体分泌的辅助活性。这项研究的目的是通过研究脾、血和病变肾脏中的免疫细胞，阐明NK T细胞促进狼疮肾小球肾炎的细胞和分子机制。我们推测，肾小球肾炎及其伴发的间质性肾炎伴发淋巴细胞浸润依赖于NK T细胞分泌IL-4、干扰素-β和IL-17的异常，以及与B细胞的异常相互作用，这与狼疮的发病活动相一致。我们将通过研究流式细胞仪纯化的NK T细胞和B细胞亚群的异常，以及通过多色免疫组织病理学鉴定生发中心的形成、T和B细胞亚群的并列和定位、细胞内细胞因子和抗体的表达以及免疫细胞的激活状态来验证这一假说。我们将比较狼疮易感小鼠在接受和不接受特定NK T细胞阻断治疗以改善肾小球肾炎的情况下的这些参数，并在接受来自活动性疾病小鼠的纯化的NK T细胞和B细胞的过继宿主中进行比较。这些研究将为人类狼疮肾小球肾炎的治疗提供新的分子靶点的重要信息。与公共卫生相关：狼疮是一种自身免疫性疾病，自身抗体与自身抗原形成复合体，在肾小球沉积后损害肾脏，肾小球过滤血液中的废物。自身抗体是由一种罕见的免疫细胞--NK T细胞激活的B细胞产生的。这项研究计划研究免疫组织和炎症肾脏中NK T细胞和B细胞之间的相互作用，从而导致自身抗体的形成，并研究抑制这种相互作用和改善肾脏疾病的方法

DESCRIPTION (provided by applicant): Systemic lupus is an autoimmune disease that results in immune complex glomerulonephritis in NZB/W mice and humans. Our studies in mice and humans with lupus show that CD4+ natural killer (NK) T cells spontaneously interact with autologous B cells via the CD1d antigen presenting molecule on the BALB/c cell surface, and induce polyclonal activation of the B cells with secretion of IgM, IgG and IgG anti-dsDNA autoantibodies. Conventional CD4+ T cells (non-NK T cells) have little helper activity for antibody secretion. The goal of the proposed research is to elucidate the cellular and molecular mechanisms by which NK T cells promote lupus glomerulonephritis in mice and man by studying the immune cells in the spleen, blood, and diseased kidneys. We hypothesize that the glomerulonephritis and the associated interstitial nephritis with lymphocytic infiltrates is dependent upon NK T cells with abnormal secretion of IL-4, IFN-?, and IL-17, and abnormal interactions with B cells that coincide with the onset of lupus disease activity. We will test the hypothesis by studying abnormalities in NK T cells and B cell subsets purified by flow cytometry, and by performing multi-color immunohistopathology that will identify germinal center formation, juxtaposition and localization of T and B cell subsets, intracellular cytokine and antibody expression, and activation state of immune cells. We will compare these parameters in lupus prone mice with and without specific NK T cell blocking treatment that ameliorates glomerulonephritis, and in adoptive hosts that are given purified NK T cells and B cells from mice with active disease. These studies should provide important information about new molecular targets for the treatment of lupus glomerulonephritis in humans. PUBLIC HEALTH RELEVANCE: Lupus is an autoimmune disease in which autoantibodies form complexes with self antigens, and the complexes injure the kidney after deposition in the glomeruli that filter waste products from the blood. Autoantibodies are produced by B cells that are activated by a rare immune cell, the NK T cell. The proposed research studies the interactions between the NK T cells and B cells in the immune tissues and inflamed kidneys that cause autoantibody formation, and studies ways to inhibit the interactions and ameliorate the kidney disease