Department of Internal Medicine D, Experimental Nephrology, University Clinics Münster, 48143 Münster, Germany.
Department of Medicine, Division of Nephrology, The University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Cells. 2021 Dec 10;10(12):3499. doi: 10.3390/cells10123499.
In the context of transplantation, complement activation is associated with poor prognosis and outcome. While complement activation in antibody-mediated rejection is well-known, less is known about complement activation in acute T cell-mediated rejection (TCMR). There is increasing evidence that complement contributes to the clearance of apoptotic debris and tissue repair. In this regard, we have analysed published human kidney biopsy transcriptome data clearly showing upregulated expression of complement factors in TCMR. To clarify whether and how the complement system is activated early during acute TCMR, experimental syngeneic and allogeneic renal transplantations were performed. Using an allogeneic rat renal transplant model, we also observed upregulation of complement factors in TCMR in contrast to healthy kidneys and isograft controls. While staining for C4d was positive, staining with a C3d antibody showed no C3d deposition. FACS analysis of blood showed the absence of alloantibodies that could have explained the C4d deposition. Gene expression pathway analysis showed upregulation of pro-apoptotic factors in TCMR, and apoptotic endothelial cells were detected by ultrastructural analysis. Monocytes/macrophages were found to bind to and phagocytise these apoptotic cells. Therefore, we conclude that early C4d deposition in TCMR may be relevant to the clearance of apoptotic cells.
在移植背景下，补体激活与不良预后和结局相关。虽然抗体介导排斥反应中的补体激活已广为人知，但补体在急性 T 细胞介导排斥反应（TCMR）中的激活知之甚少。越来越多的证据表明，补体有助于清除凋亡碎片和组织修复。在这方面，我们分析了已发表的人类肾脏活检转录组数据，清楚地显示了 TCMR 中补体因子的上调表达。为了阐明补体系统是否以及如何在急性 TCMR 早期被激活，我们进行了实验性同基因和同种异体肾移植。使用同种异体大鼠肾移植模型，我们还观察到 TCMR 中补体因子的上调，与健康肾脏和同系移植物对照形成对比。虽然 C4d 染色呈阳性，但 C3d 抗体染色未见 C3d 沉积。血液的 FACS 分析显示不存在可解释 C4d 沉积的同种抗体。基因表达途径分析显示 TCMR 中促凋亡因子的上调，并通过超微结构分析检测到凋亡的内皮细胞。发现单核细胞/巨噬细胞与这些凋亡细胞结合并吞噬它们。因此，我们得出结论，TCMR 中早期 C4d 沉积可能与凋亡细胞的清除有关。
