Lupus Glomenulonephritis and NK T cells

描述（由申请人提供）：系统性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物肾小球肾炎。我们对狼疮小鼠和人的研究表明，CD4+ NK T细胞通过BALB/c细胞表面的CD1d抗原呈递分子自发地与自体B细胞相互作用，并通过分泌IgM、IgG和IgG抗dsdna自身抗体诱导B细胞的多克隆活化。传统的CD4+ T细胞（非nk T细胞）对抗体分泌几乎没有辅助活性。本研究的目的是通过研究脾脏、血液和病变肾脏中的免疫细胞，阐明NK T细胞促进小鼠和人狼疮性肾小球肾炎的细胞和分子机制。我们推测伴有淋巴细胞浸润的肾小球肾炎和相关间质性肾炎依赖于NK T细胞分泌异常的IL-4、IFN-？和IL-17，以及与B细胞的异常相互作用，这些细胞与狼疮疾病活动的开始相吻合。我们将通过研究流式细胞术纯化的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来鉴定生发中心的形成、T细胞和B细胞亚群的并置和定位、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设。我们将比较这些参数在有和没有特异性NK T细胞阻断治疗（改善肾小球肾炎）的狼疮易感小鼠中，以及在从活动性疾病小鼠中获得纯化NK T细胞和B细胞的过继宿主中。这些研究将为人类狼疮性肾小球肾炎的治疗提供新的分子靶点。公共卫生相关性：狼疮是一种自身免疫性疾病，其自身抗体与自身抗原形成复合物，复合物沉积在过滤血液废物的肾小球后损伤肾脏。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。本课题拟研究免疫组织和炎症肾脏中NK T细胞和B细胞相互作用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