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，可导致NZB/W小鼠和人类的免疫复合物肾小球肾炎。我们在患有狼疮的小鼠和人类中的研究表明，CD 4+自然杀伤（NK）T细胞通过BALB/c细胞表面的CD 1d抗原呈递分子自发地与自体B细胞相互作用，并诱导B细胞的多克隆活化，分泌IgM、IgG和IgG抗dsDNA自身抗体。传统的CD 4 + T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脏、血液和患病肾脏中的免疫细胞，阐明NK T细胞促进小鼠和人类狼疮性肾小球肾炎的细胞和分子机制。我们假设肾小球肾炎和伴有淋巴细胞浸润的间质性肾炎依赖于NK T细胞，其分泌异常的IL-4、IFN-γ，和IL-17，以及与B细胞的异常相互作用，这些异常相互作用与狼疮疾病活动的发作一致。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，并通过进行多色免疫组织病理学来验证这一假设，该病理学将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表达以及免疫细胞的活化状态。我们将比较这些参数在狼疮易感小鼠与不特定的NK T细胞阻断治疗，改善肾小球肾炎，并在过继宿主，从小鼠与活动性疾病的纯化NK T细胞和B细胞。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，其中自身抗体与自身抗原形成复合物，并且复合物在肾小球中沉积后损伤肾脏，肾小球从血液中过滤废物。自身抗体是由B细胞产生的，B细胞被一种罕见的免疫细胞NK T细胞激活。该研究旨在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