Lupus Glomenulonephritis and NK T cells

狼疮性肾小球肾炎和 NK T 细胞

基本信息

批准号：
8150359
负责人：
SAMUEL STROBER
金额：
$ 46.61万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8150359
关键词：
Agonist Antibodies Autoantibodies Autoantigens Autoimmune Diseases Autologous B-Cell Activation B-Lymphocyte Subsets B-Lymphocytes Blood CD1d antigen CD4 Positive T Lymphocytes Cell physiology Cell surface Cells Color Complex Deposition Disease Female Flow Cytometry Glomerulonephritis Glycolipids Goals Health Human Immune Immune Cell Activation Immune Complex Glomerulonephritis Immunoglobulin A Immunoglobulin G Immunoglobulin M Immunohistochemistry In Vitro Inbred BALB C Mice Injury Interferons Interleukin-17 Interleukin-4 Interstitial Nephritis Kidney Kidney Diseases Lupus Lupus Nephritis Lymphocytic Infiltrate Molecular Molecular Target Mus Pathogenesis Patients Play Production Research Role Series Spleen Structure of germinal center of lymph node Surface Systemic Lupus Erythematosus T-Lymphocyte Testing Time Tissues Transgenic Organisms Waste Products anti-dsDNA autoantibody cytokine design in vitro Assay in vivo injured killer T cell lupus prone mice man receptor research study

项目摘要

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

描述（由申请人提供）：全身性狼疮是一种自身免疫性疾病，可导致NZB/W小鼠和人类中免疫复杂的肾小球肾炎。我们在小鼠和人类中使用狼疮的研究表明，CD4+天然杀伤（NK）T细胞通过CD1D抗原在BALB/C细胞表面自发与自动B细胞自发相互作用，并诱导B细胞的多克隆激活IgM，IgM，IgG和IgG抗抗DSDNA自动抗体。常规的CD4+ T细胞（非NK T细胞）几乎没有用于抗体分泌的辅助活性。拟议的研究的目的是阐明NK T细胞通过研究脾脏，血液和患病肾脏中的免疫细胞来促进小鼠和人的细胞和分子机制。我们假设肾小球肾炎和与淋巴细胞浸润的相关间质肾炎依赖于IL-4，IFN-？和IL-17异常分泌的NK T细胞，以及与B细胞异常相互作用，与B细胞的异常相互作用，与Lupus疾病疾病活性的伴侣相吻合。我们将通过研究通过流式细胞仪纯化的NK T细胞和B细胞子集的异常，以及进行多色免疫组织病理学纯化的B细胞子集，该假设将确定生发中心的形成，T和B细胞群的并置和定位，细胞内细胞因子和抗体表达和免疫细胞的活化状态。我们将比较有或没有特定NK T细胞阻断治疗的狼疮小鼠中的这些参数，可改善肾小球肾炎，并在具有活性疾病的小鼠的纯化的NK T细胞和B细胞中给予纯化的NK T细胞和B细胞。这些研究应提供有关人类狼疮肾小球肾炎的新分子靶标的重要信息。公共卫生相关性：狼疮是一种自身免疫性疾病，其中自身抗体与自抗原形成复合物，而复合物则在肾小球沉积后伤害肾脏，该肾脏从血液中释放出浪费的肾脏。自身抗体是由B细胞产生的，B细胞被罕见的免疫细胞NK T细胞激活。拟议的研究研究了免疫组织中NK T细胞与B细胞之间的相互作用，并发炎引起自身抗体形成的肾脏，并研究了抑制相互作用并改善肾脏疾病的方法