Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany.
SYNLAB Pathology Hannover, SYNLAB Holding Germany, 86156 Augsburg, Germany.
Int J Mol Sci. 2023 Feb 3;24(3):2975. doi: 10.3390/ijms24032975.
Immune checkpoint inhibitors (ICIs) have made an important contribution to the survival of patients with certain cancers. ICIs interrupt co-inhibitory signaling pathways mediated by programmed cell death protein 1 (PD-1), programmed cell death protein ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen (CTLA-4) that result in the elimination of cancer cells by stimulating the immune system. However, immune-related adverse events have also been described and attributed to an enhanced immune system activation. Recent observations have suggested a dysregulation of immune checkpoints in active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We here analyzed intrarenal PD-1 and PD-L1 by immunostaining in a total of 15 kidney biopsies with ANCA-associated renal vasculitis in correlation with glomerular and tubulointerstitial lesions. For independent validation, publicly available datasets were analyzed for PD-1 expression (encoded by ). We here observed a predominant tubulointerstitial expression of PD-1 that is decreased in ANCA-associated renal vasculitis. Moreover, loss of tubulointerstitial PD-1 correlated with active ANCA-associated renal vasculitis. Consistent with the observed association with active glomerular and tubulointerstitial lesions, we identified that interstitial PD-1 correlated with tubular and/or glomerular PD-L1 positivity. Finally, PD-1 was associated with decreased local synthesis of complement factor B. Interestingly, we did not observe a correlation between PD-1 and complement C5 or its C5a receptor. Combined with our observations, this may implicate a link between impaired PD-1/PD-L1 signaling, complement factor B and active ANCA-associated renal vasculitis. These findings could be of relevance because experimental data have already described that PD-1 agonism can be used therapeutically to attenuate autoimmunity in multiple disease models. Furthermore, targeted therapy against a complement C5/C5a receptor and factor B are both available and currently evolving in the treatment of AAV. Therefore, this pilot study expands our current knowledge and describes a potential interplay between immune checkpoints and the alternative complement pathway in active ANCA-associated renal vasculitis.
免疫检查点抑制剂（ICIs）为某些癌症患者的生存做出了重要贡献。ICIs 阻断程序性细胞死亡蛋白 1（PD-1）、程序性细胞死亡配体 1（PD-L1）和细胞毒性 T 淋巴细胞相关抗原（CTLA-4）介导的共抑制信号通路，通过刺激免疫系统导致癌细胞消除。然而，也已经描述了与增强的免疫系统激活相关的免疫相关不良反应。最近的观察结果表明，活性抗中性粒细胞胞质抗体（ANCA）相关性血管炎（AAV）中免疫检查点失调。我们在这里通过免疫染色分析了总共 15 例 ANCA 相关性肾血管炎的肾内 PD-1 和 PD-L1，并与肾小球和肾小管间质病变相关。为了进行独立验证，我们分析了公共可用数据集以检测 PD-1 表达（由 编码）。我们在这里观察到 PD-1 的主要肾小管间质表达，在 ANCA 相关性肾血管炎中减少。此外，肾小管间质 PD-1 的丧失与活动性 ANCA 相关性肾血管炎相关。与观察到的与活动性肾小球和肾小管间质病变的相关性一致，我们发现间质 PD-1 与肾小管和/或肾小球 PD-L1 阳性相关。最后，PD-1 与局部补体因子 B 的合成减少相关。有趣的是，我们没有观察到 PD-1 与补体 C5 或其 C5a 受体之间的相关性。结合我们的观察结果，这可能暗示 PD-1/PD-L1 信号传导、补体因子 B 和活动性 ANCA 相关性肾血管炎之间存在联系。这些发现可能具有相关性，因为实验数据已经描述了 PD-1 激动剂可用于治疗多种疾病模型中的自身免疫。此外，针对补体 C5/C5a 受体和因子 B 的靶向治疗均可用，并且在 AAV 的治疗中正在不断发展。因此，这项初步研究扩展了我们目前的知识，并描述了活动性 ANCA 相关性肾血管炎中免疫检查点和替代补体途径之间的潜在相互作用。
