Complement profiling on sural nerves of patients with chronic inflammatory demyelinating polyneuropathy

Overall, 55 sural nerve biopsies from patients with CIDP (n=36) and CIDP-variants (n=18) were included into the study. Immunohistochemical analysis of the sural nerve specimens showed an aberrant deposition of terminal complement complex C5b-9 on endoneural capillaries in 52 (94%) of patients in addition to endoneural CD8+ T cell- and CD68+ macrophage infiltration. Gene expression studies showed an increase of factors C3 and C6 compared to NDCs with no difference in regard to clinical phenotype, whereas levels of IL6 or TNF-alpha were not significantly elevated. Our proteomic profiling approach revealed the statistically significant dysregulation of 50 proteins, which based on their respective functions suggest altered mitochondrial activity, perturbed cytoskeleton, and increased oxidative stress. The majority of patients with high to moderate complement deposition presented with a progressive disease course, however without any correlation with disease severity as measured by INCAT or MRC at baseline and follow-up. Our combined data supports the role of complement in CIDP pathogenesis. Based on these findings, we propose to further evaluate complement inhibition therapies as new targeted treatment option for patients with CIDP.

本研究共纳入55例腓肠神经活检标本，供者包括36例慢性炎症性脱髓鞘性多发性神经病（Chronic Inflammatory Demyelinating Polyneuropathy，CIDP）患者与18例CIDP变异型患者。对腓肠神经标本的免疫组化分析显示，52例（94%）患者的神经内膜毛细血管上存在末端补体复合物C5b-9的异常沉积，同时伴有神经内膜CD8阳性T细胞与CD68阳性巨噬细胞浸润。基因表达研究结果表明，相较于正常对照神经（Normal Control Nerves，NDCs），患者样本中补体因子C3与C6的表达水平显著升高，且临床表型无明显差异；而白细胞介素6（Interleukin-6，IL-6）与肿瘤坏死因子α（Tumor Necrosis Factor-α，TNF-α）的水平未出现显著升高。本研究采用的蛋白质组学分析方法显示，共有50种蛋白质出现具有统计学意义的表达失调；根据这些蛋白质的功能推测，患者体内存在线粒体活性改变、细胞骨架紊乱及氧化应激增强的病理改变。大多数补体沉积程度为中至重度的患者呈现进行性疾病病程，但在基线与随访阶段，通过炎性神经病病因与治疗组（Inflammatory Neuropathy Cause and Treatment Group，INCAT）评分及医学研究委员会（Medical Research Council，MRC）肌力评分评估的疾病严重程度，与补体沉积程度无显著相关性。综合上述研究数据，证实了补体系统在CIDP发病机制中的作用。基于本研究结果，我们建议进一步评估补体抑制疗法作为CIDP患者新型靶向治疗方案的可行性。