In situ tolerance in autoimmunity

在狼疮性肾炎（LuN）中，肾活检用于评估肾脏受累的程度，确定预后， 并帮助做出治疗决定。我们和其他团体已经证明， 肾小管间质炎症（TH）和瘢痕形成，与肾小球病理学的协方差无关 肾功能衰竭的发生与发展如初步结果所示，在发炎的 在tubuloacetium中，选择了对相关分子具有特异性的抗体库， 炎症包括波形蛋白，它覆盖了浸润性T细胞和巨噬细胞的表面。 这些结果表明原位适应性免疫放大炎症的模型。虽然这些 研究结果确定了驱动原位选择的抗原，但尚不清楚什么共刺激信号也是 有助于原位B细胞活化。随着新型定量成像方法（Cell 距离映射和分析，CDMA，初步结果），我们能够证明T滤泡 辅助细胞（TFH）细胞与B细胞紧密同源配对。TFH样细胞和B细胞在 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）均相关。 然而，在MR中存在TFH依赖性和非依赖性B细胞群，而在TCMR中TFH依赖性和非依赖性B细胞群。 细胞似乎不能与B细胞形成缀合物。这些和其他数据表明，我们可以 原位鉴定功能不同的TFH和B细胞群体。我们假设这些T细胞能够 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，委员会认为， 我们假设感受态TFH细胞的分子特征将是每种疾病的特征。 最后，我们假设，对于每种疾病，对于每种TFH细胞群，不同的B细胞功能， 节目将予甄选。这些假设将在以下具体目标中进行检验： 目标1.狼疮性肾炎中TFH细胞原位选择性B细胞库的测定 目标2.表征原位TFH选择和未选择的B细胞库。 目标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.