Institute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Ludwig-Maximillian University, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Germany.
Albert-Ludwigs-University, Freiburg, Germany.
Clin Immunol. 2019 Jun;203:45-52. doi: 10.1016/j.clim.2019.04.004. Epub 2019 Apr 8.
To determine the role of the NLRP3 inflammasome by using the selective NLRP3 inhibitor MCC950 in patients with NLRP3 low penetrance variants and clinical symptoms suggestive for an autoinflammatory syndrome including central nervous system (CNS) involvement.
Nineteen symptomatic patients with low penetrance NLRP3 variants (Q703K n = 17, V198M n = 2) recruited between 2011 and 2017 were included in this monocentric study. A functional inflammasome activation assay was performed in patients in comparison to healthy controls (HC), including the determination of interleukin-1beta (IL-1β), interleukin-6 (IL-6) and tumor-necrosis factor alpha (TNF-α) secretion in the presence of the NLRP3 selective small-molecule inhibitor MCC950. Detailed clinical features were assessed and anti-IL-1 treatment response was determined.
Peripheral blood mononuclear cells (PBMC) from patients with low penetrance NLRP3 variants displayed enhanced IL-1β levels following inflammasome activation compared to HC. Furthermore, IL-1β release was NLRP3-dependent as it was blocked by MCC950. The production of IL-6 and TNF-α was also increased in patients with low penetrance NLRP3 variants. Clinically, they presented with a heterogenous spectrum of neurological manifestations, while cranial nerve inflammation was the most common feature. Overall inflammasome activation did not correlate with disease severity. Eight of ten treated patients responded to anti IL-1 treatment, however a complete response was only documented in four patients.
PBMC of several patients with NLRP3 low penetrance variants and CNS manifestation showed increased NLRP3-specific IL-1β release upon stimulation and elevated NLRP3-independent IL-6 and TNF-α levels as those were not suppressed by MCC950. Our data suggest that beside the possible causal involvement of the NLRP3 inflammasome additional, yet unidentified genetic or environmental factors may contribute to the multi-organ inflammation in our patients and explain the partial response to IL-1 targeting therapies.
通过使用选择性 NLRP3 抑制剂 MCC950 ，在具有 NLRP3 低穿透性变异且具有中枢神经系统（CNS）受累等自身炎症综合征临床症状的患者中，确定 NLRP3 炎性小体的作用。
本研究纳入了 2011 年至 2017 年间招募的 19 名具有 NLRP3 低穿透性变异（Q703K n=17，V198M n=2）的症状性患者。在存在 NLRP3 选择性小分子抑制剂 MCC950 的情况下，对患者和健康对照者（HC）进行了功能性炎性小体激活测定，包括白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的分泌。评估了详细的临床特征并确定了抗 IL-1 治疗反应。
与 HC 相比，具有 NLRP3 低穿透性变异的患者外周血单核细胞（PBMC）在炎性小体激活后显示出增强的 IL-1β水平。此外，IL-1β释放是 NLRP3 依赖性的，因为它被 MCC950 阻断。IL-6 和 TNF-α的产生在 NLRP3 低穿透性变异患者中也增加了。临床上，他们表现出神经表现的异质谱，而颅神经炎症是最常见的特征。总体炎性小体激活与疾病严重程度无关。10 名接受治疗的患者中有 8 名对 IL-1 治疗有反应，但只有 4 名患者完全缓解。
几种 NLRP3 低穿透性变异且有 CNS 表现的患者的 PBMC 在刺激后显示出增加的 NLRP3 特异性 IL-1β释放，并且升高的 NLRP3 非依赖性 IL-6 和 TNF-α水平不受 MCC950 抑制。我们的数据表明，除了 NLRP3 炎性小体的可能因果作用之外，其他尚未确定的遗传或环境因素可能导致我们患者的多器官炎症，并解释了对 IL-1 靶向治疗的部分反应。
