Proximal Determinants of Nephritogenic Autoimmunity

自身免疫性肾炎是慢性肾脏疾病和肾功能衰竭的主要原因。 在世界范围内，是同种异体移植物损伤和损失的主要来源。然而，可用的治疗方法是 仅限于非特定的毒性疗法。抗原和细胞特异性治疗效果显著 但这些新的基于机制的干预措施的发展需要 对潜在发病机制的理解。拟议的研究将确定 调节致肾炎淋巴细胞的耐受机制 自身抗体和B细胞。一个重要的假设是，在 肾脏受限和全身性自身免疫中维持耐受的过程。目标1 使用一种新的抗体(Ig)转基因(Tg)模型来靶向Good及ure抗原 测试以下假设：i)识别胶原表面致病表位的B细胞 在体内调节；ii)α3(IV)NC1胶原是一种耐受性，以及iii)抗α3(IV)的一个子集( IV)NC1B细胞容易逃避或逃避耐受性。免疫表型将是 在转基因和信息丰富的突变回交品系中进行测量。一条免疫球蛋白重链 将生成基因靶向(敲门)模型来测量亲和力的调节 成熟的细胞。目标2将确定遗传自身免疫易感性在 改变肾性B细胞的命运和最低分子要求 无能。这一目标验证了寄主修饰基因调节耐受性的假设。 细胞和分子水平。这些研究是可能的，因为LAMH Ig Tg具有 狼疮易感菌株已经建立了良好的耐受性表型 MRL、NZB和BXSB，每一种都带有独特的疾病星座 易感基因，并发展成类似于人类疾病的严重肾炎。免疫 将测量和比较这些和相关的BWF1 TG株的表型。 跨不同基因维持无能的关键调节分子或途径 背景和对不同耐受菌的鉴定将使用寡核苷酸阵列进行测量 细胞抄本。Galectins 1和Galectins 3的调节作用，这是最近才出现的重要蛋白质 是否与B细胞耐受有关，将通过遗传的Galectin缺乏来确定。它是 预计对肾炎性自身免疫调节的机械论洞察力将 为免疫性肾炎的治疗提供新的靶点。

Autoimmune nephritis is a leading cause of chronic kidney disease and renal failure worldwide and a major source of allograft injury and loss. Yet available therapies are limited to nonspecific toxic regimens. Antigen- and cell-specific therapies hold great promise but development of these novel mechanism-based interventions requires understanding of underlying pathogenesis. The proposed research will determine tolerance mechanisms that regulate nephritogenic lymphocytes with a focus on autoantibodies and B cells. An overarching hypothesis is that commonalities exist in the processes maintaining tolerance in kidney-restricted and systemic autoimmunity. Aim 1 uses a novel antibody (Ig) transgenic (Tg) model that targets the Goodpasture antigen to test the hypotheses that: i) B cells recognizing pathogenic epitopes on collagen are regulated in vivo; ii) alpha3(IV)NC1 collagen is a tolerogen, and iii) a subset of antialpha3( IV)NC1 B cells readily evade or escape tolerance. Immune phenotype will be measured in transgenic and informative mutant backcross strains. An Ig heavy-chain gene-targeted (knockin) model will be generated to measure regulation of affinity matured cells. Aim 2 will determine the role of genetic autoimmune susceptibility in altering the fate of nephrotropic B cells and the minimum molecular requirements for anergy. This aim tests the hypothesis that host modifier genes modulate tolerance at cellular and molecular levels. These studies are possible because the LamH Ig Tg with a well characterized tolerance phenotype has been established on lupus-prone strains MRL, NZB and BXSB, each of which carries a unique constellation of disease susceptibility genes and develops severe nephritis similar to disease in man. Immune phenotype will be measured and compared in these and the related BWF1 Tg strain. Key regulatory molecules or pathways maintaining anergy across different genetic backgrounds and to different tolerogens will be identified using oligoarray to measure cell transcripts. The regulatory role of galectins 1 and 3, prominent proteins only recently implicated in B cell tolerance, will be determined using genetic galectin deficiency. It is anticipated that mechanistic insight into regulation of nephritogenic autoimmunity will yield new targets for therapy in immune nephritis.