Institute of Immunology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany.
Section of Translational Immunology, III. Department of Medicine, University Medical Center Hamburg-Eppendorf , Hamburg , Germany.
Am J Physiol Renal Physiol. 2019 Mar 1;316(3):F572-F581. doi: 10.1152/ajprenal.00558.2018. Epub 2019 Jan 16.
Anti-glomerular basement membrane (anti-GBM) disease is characterized by antibodies and T cells directed against the Goodpasture antigen, the noncollagenous domain of the α3-chain of type IV collagen [α3(IV)NC1] of the GBM. Consequences are the deposition of autoantibodies along the GBM and the development of crescentic glomerulonephritis (GN) with rapid loss of renal function. Forkhead box protein P3 (Foxp3) regulatory T (Treg) cells are crucial for the maintenance of peripheral tolerance to self-antigens and the prevention of immunopathology. Here, we use the mouse model of experimental autoimmune GN to characterize the role of Treg cells in anti-GBM disease. Immunization of DBA/1 mice with α3(IV)NC1 induced the formation of α3(IV)NC1-specific T cells and antibodies and, after 8-10 wk, the development of crescentic GN. Immunization resulted in increased frequencies of peripheral Treg cells and renal accumulation of these cells in the stage of acute GN. Depletion of Treg cells during immunization led to enhanced generation of α3(IV)NC1-specific antibodies and T cells and to aggravated GN. In contrast, depletion or expansion of the Treg cell population in mice with established autoimmunity had only minor consequences for renal inflammation and did not alter the severity of GN. In conclusion, our results indicate that in anti-GBM disease, Treg cells restrict the induction of autoimmunity against α3(IV)NC1. However, Treg cells are inefficient in preventing crescentic GN after autoimmunity has been established.
抗肾小球基底膜 (anti-GBM) 病的特征是针对 Goodpasture 抗原（GBM 中Ⅳ型胶原α3 链非胶原域 [α3(IV)NC1]）的抗体和 T 细胞。其结果是自身抗体在 GBM 中沉积，并形成新月体性肾小球肾炎（GN），导致肾功能迅速丧失。叉头框蛋白 P3（Foxp3）调节性 T（Treg）细胞对于维持外周对自身抗原的耐受性和防止免疫病理学至关重要。在这里，我们使用实验性自身免疫性 GN 的小鼠模型来描述 Treg 细胞在抗-GBM 病中的作用。用α3(IV)NC1 免疫 DBA/1 小鼠可诱导形成α3(IV)NC1 特异性 T 细胞和抗体，并在 8-10 周后发展为新月体性 GN。免疫可导致外周 Treg 细胞频率增加，且在急性 GN 阶段这些细胞在肾脏中蓄积。在免疫过程中耗竭 Treg 细胞可导致α3(IV)NC1 特异性抗体和 T 细胞生成增强，并导致 GN 加重。相比之下，在已建立自身免疫的小鼠中耗竭或扩增 Treg 细胞群对肾脏炎症仅有较小的影响，且不改变 GN 的严重程度。总之，我们的结果表明，在抗-GBM 病中，Treg 细胞限制了针对α3(IV)NC1 的自身免疫的诱导。然而，Treg 细胞在自身免疫已经建立后，不能有效地预防新月体性 GN。
