Regulatory and effector T cells in SLE

描述（由申请人提供）： 系统性红斑狼疮（SLE）是一种临床表现多变的系统性自身免疫性疾病， 表现和可变的结果;肾小球肾炎（GN）是SLE的严重表现。SLE患者和狼疮易感小鼠表现出B细胞和T细胞耐受及其应答状态的异常。它们对多种自身抗原（Ag）产生自身抗体（autoAb）反应，并在组织中沉积免疫复合物（IQ）。CD 4 + CD 25+调节性T细胞通常预防器官特异性自身免疫性疾病的发生。在此，我们通过研究狼疮易感小鼠胸腺切除第3天（d3 tx）的影响来研究调节性T细胞在SLE中的作用。d3 tx狼疮易感NZM 2328小鼠表现出更早的自身抗体应答，积累更多的肾小球IC，并发展为加速的急性GN。 值得注意的是，严重的急性GN发生在约90%的雄性NZM 2328小鼠中，这些小鼠通常对狼疮GN更具抵抗力。这些结果导致了以下假设。首先，调节性T细胞可以负面影响SLE的发展。其次，急性狼疮性肾炎是一种靶向肾小球的T细胞介导的自身免疫性疾病。CD 4 + CD 25效应T细胞通过靶向肾脏抗原或肾小球1C提供的抗原参与肾小球损伤。 因此，在SLE中，自身反应性T细胞：1）驱动自身抗体应答，和2）直接引起急性GN。第三、 急性GN是狼疮GN中的一个检查点，雄性小鼠从该检查点退化，而雌性小鼠进展为慢性GN。因此，雄性NZM 2328小鼠可能具有更低有效性或更多调节性T细胞功能。该模型还将允许对负责狼疮GN的进展和消退的因素进行研究。我们将在我们提案的目标I中研究这些假设。在对易患狼疮的雌性SNF 1小鼠的研究中出现了一个非常不同的故事。在d3 tx后，还观察到加速的自身抗体应答，但这与致死性GN的显著降低相关。他们的血清和肾小球自身抗体同种型的分析表明，自身免疫反应具有很强的Th 2偏置。在目标2中，我们将测试SNF 1小鼠的d3 tx保留非致病性新生儿Th 2应答性的假设。与此同时，他们的抗原特异性Th 1反应降低，这是致病性自身抗体产生和狼疮性肾炎所必需的。最后，我们将寻求一个解释的不同反应d3 tx之间的两个狼疮易感小鼠。因此，我们将通过除d3 tx以外的方法确定SNF 1小鼠中CD 4 + CD 25 + T细胞耗竭的结果。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with protean clinical presentation and variable outcome; and glomerulonephritis (GN) is a serious manifestation of SLE. SLE patients and lupus prone mice exhibit abnormalities in B cell and T cell tolerance and their responsive state. They produce autoantibody (autoAb) response to multiple self antigens (Ag) and have immune complex (IQ deposits in tissues. The CD4+CD25+ regulatory T cells normally prevent organ specific autoimmune disease occurrence. Herein we investigate the role of the regulatory T cells in SLE by studying the effect of thymectomized on day 3 (d3tx) in lupus prone mice. The d3tx lupus prone NZM2328 mice exhibited earlier autoAb response, accumulated more glomerular IC, and developed accelerated acute GN. Remarkably, severe acute GN occurred in - 90% of male NZM2328 mice that are normally more resistant to lupus GN. These results have led to the following hypotheses. First, regulatory T cells can negatively influence development of SLE. Second, acute lupus GN is a T cellmediated autoimmune disease that targets the renal glomerulus. The CD4+CD25effector T cells participate in renal glomerular injury by targeting either renal Ag or Ag provided by the glomerular 1C. Thus, in SLE, autoreactive T cells: 1) drive an autoAb response, and 2) directly elicit acute GN. Third, acute GN is a checkpoint in lupus GN, from which the male mice regress and the female mice progress to chronic GN. Thus male NZM2328 mice may have less effective or more regulatory T cell function. The model will also permit the study on factors responsible for the progression and regression of lupus GN. We will investigate these hypotheses in Aim I of our proposal. A very different story emerged from the study on the lupus prone female SNF1 mice. Following d3tx, an accelerated autoAb response was also noted but this was associated with significant reduction in fatal GN. Analysis of their serum and glomerular autoAb isotypes revealed an autoimmune response with a strong Th2-bias. In Aim 2, we will test the hypothesis that d3tx of the SNF1 mice retains the nonpathogenic neonatal Th2 responsiveness. At the same time, they had a reduced Ag specific Th1 response that is required for pathogenic autoAb production and for lupus GN. Finally, we will seek an explanation for the different responses to d3tx between the two lupus prone mice. Accordingly, we will determine the outcome of CD4+CD25+ T cell depletion by methods other than d3tx in SNF1 mice.