Significance of Intrarenal T Cells in SLE Nephritis

 描述(由申请人提供)：这项研究的目标是促进对T细胞在慢性狼疮性肾炎(LN)的发展和进展中的作用的理解。它解决了为什么在近一半的病例中，LN对治疗没有反应并进展为慢性肾小球肾炎的临床问题。初步数据显示，LN肾活检组织中有一种克隆性扩增的CD4和/或CD8T细胞的可变性渗透，这些细胞的特征表明这些细胞驱动了炎症过程。某些肾脏活检显示克隆扩增的CD8 T细胞具有CD28零记忆效应表型，它们以类似于细胞毒性细胞突触的方式附着在Bowman囊或肾小管上皮细胞上。在肾功能减退患者的重复活检中，这些相同的克隆型持续多年，广泛分布于肾小球周围和肾小管内，并在外周血中发现。CD4T细胞以两种不同的形式存在：大的弥漫性肾小球周围和管间集合体，其中一些表现为多克隆或作为记忆效应的表型T细胞附着在Bowman囊或小管上，类似于CD8T细胞。克隆扩增的记忆效应CD8 T细胞具有适应性免疫应答的特点不符合目前LN的范式，我们提出的假设是急性肾炎是由免疫复合物驱动的，而慢性LN是由CD4尤其是CD8 T细胞对自体肽的克隆性识别而驱动的，导致肾小球和肾小管细胞损伤。在第一个目标中，我们将描绘浸润性肾内CD4或 CD8 T细胞在新发肾炎中的作用及其在肾损伤中的作用我们将区分可能导致肾脏损伤的克隆性扩增的CD4或CD8T细胞和继发于炎症的多克隆T细胞。我们将把这些发现与结果联系起来，以确定T细胞浸润物中预测治疗反应差和进行性肾脏疾病的特征。在第二个目的中，我们将类似地确定病例的T细胞特征 慢性狼疮性肾炎肾损害加重，需要重复活检，比较目前和以前的活检肾内T细胞的特征，可能预测进展。

 DESCRIPTION (provided by applicant): The goal of this study is to advance understanding of the role of T cells in the development and progression of chronic lupus nephritis (LN). It addresses the clinical problem of why in nearly half of cases, LN does not respond to therapy and progress to chronic glomerulonephritis. Preliminary data show LN kidney biopsies have a variable infiltrate of clonally expanded CD4 and/or CD8 T cells with features suggesting these cells drive the inflammatory process. Certain kidney biopsies exhibit clonally expanded CD8 T cells with a CD28null memory effector phenotype that adhere to Bowman's capsule or to tubular epithelium in a manner resembling a cytotoxic cell synapse. On repeat biopsies of patients with diminishing renal function, these same clonotypes persisted for many years, became widely distributed in periglomerular and intratubular sites, and were found in the peripheral blood. CD4 T cells exist in two different patterns: large diffuse periglomerular and intertubular aggregates, some of which appear either polyclonal or as a memory effector phenotype T cell adhering to Bowman's capsule or tubules, similar to the CD8 T cells. The finding of clonally expanded memory-effector CD8 T cells with features of an adaptive immune response does not fit the current paradigms of LN, and we advance the hypothesis that while acute glomerulitis is driven by immune complexes, chronic LN is driven by the development of CD4 and especially CD8 T cell clonal recognition of self-peptides, resulting in glomerular and tubular cell injury. In the frst aim we will delineate the extent and detailed characteristics of the infiltrating intrarenal CD4 or CD8 T cells in new onset nephritis and define their role in renal injury. We will discriminate between clonally expanded CD4 or CD8 T cells that potentially drive renal injury and polyclonal T cells secondarily recruited by inflammation. We will correlate these findings with outcomes to identify features in the T cell infiltrate that predict poor response to therapy and progressive renal disease. In the second aim we will similarly determine the T cell characteristics of cases of chronic LN with worsening renal involvement requiring repeat biopsy, comparing current and prior biopsies for the features of intrarenal T cells that might predict progression.