In situ tolerance in autoimmunity

在狼疮性肾炎(LN)中，肾活检被用来评估肾脏受累的程度，判断预后 并帮助做出治疗决定。我们和其他组织已经证明了 肾小管间质炎症(TH)和瘢痕形成，与肾小球病理无关 特征，预测进展为肾功能衰竭。如初步结果所示，在发炎的 肾小管间质有对相关分子特异的抗体谱系的选择 炎症包括包被在浸润性T细胞和巨噬细胞表面的波形蛋白。 这些结果表明了一种原位适应性免疫放大炎症的模型。而这些 研究结果确定了驱动原位选择的抗原，目前还不清楚什么是共刺激信号 有助于B细胞的原位激活。随着新的定量成像方法(细胞 距离映射和分析，码分多址，初步结果)，我们能够证明T卵泡 辅助性细胞(TFH)与B细胞呈紧密同源关系。TFH样细胞和B细胞在脑内可见 TIL与移植肾T细胞介导的排斥反应(TCMR)和混合性排斥反应(MR)相关。 然而，在MR中存在TFH依赖和独立的B细胞群，而在TCMR中存在TFH 细胞似乎不能与B细胞形成偶联。这些和其他数据表明，我们可以 原位鉴定不同功能群体的TFH和B细胞。我们假设这些T细胞能够 在原位与B细胞形成同源对将具有成熟TFH细胞的分子特征。此外， 我们假设，有能力的TFH细胞的分子特征将是每个疾病的特征。 最后，我们假设对于每一种疾病，对于每一种TFH细胞群，不同的B细胞功能 将选择曲目。这些假设将在以下具体目标中得到检验： 目的1.测定狼疮性肾炎患者外周血中TFH细胞原位选择的B细胞亚群。 目的2.鉴定原位TFH选择的和不选择的B细胞的谱系。 目的3.了解T细胞在原位自身免疫中的作用。

In lupus nephritis (LuN) renal biopsies are used to assess the extent of renal involvement, assign prognosis and to aid in making therapeutic decisions. We and other groups have demonstrated that the degree of tubulointerstitial inflammation (TH) and scarring, independent of co-variance with glomerular pathological features, predict progression to renal failure. As demonstrated in Preliminary Results, within the inflamed tubulointerstitium there was selection for repertoires of antibodies that were specific for molecules associated with inflammation including vimentin which coated the surfaces of infiltrating T cells and macrophages. These results suggest a model in which in situ adaptive immunity amplifies inflammation. While these findings identified the antigens driving in situ selection, it was not clear what co-stimulatory signals were also contributing to in situ B cell activation. With the development of novel quantitative imaging methods (Cell Distance Mapping and Analysis, CDMA, Preliminary Results), we were able to demonstrate that T follicular helper cells (TFH) cells were in tight cognate pairs with B cells. TFH-like cells and B cells were observed in the Til associated with both renal allograft T cell mediated rejection (TCMR) and mixed rejection (MR). However, in MR there were TFH-dependent and independent B cell populations while in TCMR the TFH cells appeared incompetent to form conjugates with B cells. These and other data indicate that we can identify functionally different populations of both TFH and B cells in situ. We hypothesize those T cells able to form cognate pairs with B cells in situ will have the molecular features of mature TFH cells. Furthermore, we hypothesize that the molecular signatures of competent TFH cells will be characteristic of each disease. Finally, we hypothesize that for each disease, and for each TFH cell population, different B cell functional repertoires will be selected. These hypotheses will be tested in the following Specific Aims: Aim 1. Determine the B cell repertoire selected in situ by TFH cells in lupus nephritis. Aim 2. To characterize the repertoire of B cells that are, and are not, selected by TFH in situ. Aim 3. Understanding the role of T cell help in in situ autoimmunity.