Macconi Daniela, Chiabrando Chiara, Schiarea Silvia, Aiello Sistiana, Cassis Linda, Gagliardini Elena, Noris Marina, Buelli Simona, Zoja Carla, Corna Daniela, Mele Caterina, Fanelli Roberto, Remuzzi Giuseppe, Benigni Ariela
Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy.
J Am Soc Nephrol. 2009 Jan;20(1):123-30. doi: 10.1681/ASN.2007111233. Epub 2008 Dec 17.
The role of dendritic cells (DC) that accumulate in the renal parenchyma of non-immune-mediated proteinuric nephropathies is not well understood. Under certain circumstances, DC capture immunologically ignored antigens, including self-antigens, and present them within MHC class I, initiating an autoimmune response. We studied whether DC could generate antigenic peptides from the self-protein albumin. Exposure of rat proximal tubular cells to autologous albumin resulted in its proteolytic cleavage to form an N-terminal 24-amino acid peptide (ALB1-24). This peptide was further processed by the DC proteasome into antigenic peptides that had binding motifs for MHC class I and were capable of activating syngeneic CD8+ T cells. In vivo, the rat five-sixths nephrectomy model allowed the localization and activation of renal DC. Accumulation of DC in the renal parenchyma peaked 1 wk after surgery and decreased at 4 wk, concomitant with their appearance in the renal draining lymph nodes. DC from renal lymph nodes, loaded with ALB1-24, activated syngeneic CD8+ T cells in primary culture. The response of CD8+ T cells of five-sixths nephrectomized rats was amplified with secondary stimulation. In contrast, DC from renal lymph nodes of five-sixths nephrectomized rats treated with the proteasomal inhibitor bortezomib lost their capacity to stimulate CD8+ T cells in primary and secondary cultures. These data suggest that albumin can be a source of potentially antigenic peptides upon renal injury and that renal DC play a role in processing self-proteins through a proteasome-dependent pathway.
在非免疫介导的蛋白尿性肾病肾实质中积聚的树突状细胞（DC）的作用尚未完全明确。在某些情况下，DC捕获包括自身抗原在内的免疫忽视抗原，并将其呈递于MHC I类分子内，引发自身免疫反应。我们研究了DC是否能够从自身蛋白白蛋白产生抗原肽。大鼠近端肾小管细胞暴露于自体白蛋白后，白蛋白发生蛋白水解裂解，形成一个N端含24个氨基酸的肽段（ALB1 - 24）。该肽段被DC蛋白酶体进一步加工成具有MHC I类分子结合基序且能够激活同基因CD8⁺ T细胞的抗原肽。在体内，大鼠六分之五肾切除模型可实现肾DC的定位与激活。肾实质中DC的积聚在术后1周达到峰值，4周时减少，与此同时它们出现在肾引流淋巴结中。来自肾淋巴结且负载ALB1 - 24的DC在原代培养中激活了同基因CD8⁺ T细胞。经二次刺激后，六分之五肾切除大鼠的CD8⁺ T细胞反应增强。相比之下，用蛋白酶体抑制剂硼替佐米处理的六分之五肾切除大鼠肾淋巴结中的DC在原代和二次培养中失去了刺激CD8⁺ T细胞的能力。这些数据表明，肾损伤时白蛋白可能是潜在抗原肽的来源，且肾DC通过蛋白酶体依赖途径在加工自身蛋白过程中发挥作用。
