Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis.
Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis.
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DOI：
10.3389/fimmu.2022.895765
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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Blau 综合征是一种由核苷酸结合寡聚化结构域 2 (NOD2) 基因突变引起的系统性自身炎症肉芽肿性疾病。 NOD2 是一种细胞内病原体识别受体。与胞壁酰二肽 (MDP) 结合后，NOD2 激活 NF-κB 通路，导致促炎细胞因子上调。布劳综合征的临床表现出现在四岁之前的患者中。在某些情况下，皮肤症状会自行消失；然而，关节和眼睛的症状是进行性的，并导致严重的并发症，例如关节挛缩和失明。目前，该疾病尚无特效治疗方法。大剂量口服类固醇可改善临床表现；然而，由于副作用严重，尤其是儿童，治疗很难维持。虽然已经报道了几种新疗法，包括 JAK 抑制剂、抗 IL-6 和抗 IL-1 疗法，但抗 TNF 疗法在 Blau 综合征的治疗中发挥着核心作用。我们最近进行了一项离体研究，使用患者的外周血和诱导多能干细胞。这项研究表明，未经治疗的患者巨噬细胞中异常的细胞因子表达需要 IFNγ 刺激，而抗 TNF 治疗可以纠正与 Blau 综合征相关的异常，即使在 IFNγ 存在的情况下也是如此。因此，尽管NOD2基因突变导致肉芽肿形成的分子机制尚不清楚，但之前暴露于TNFα联合IFNγ刺激可能为Blau综合征的临床表现提供动力。
Blau syndrome is a systemic autoinflammatory granulomatous disease caused by mutations in the nucleotide-binding oligomerization domain 2 (NOD2) gene. NOD2 is an intracellular pathogen recognition receptor. Upon binding to muramyl dipeptide (MDP), NOD2 activates the NF-κB pathway, leading to the upregulation of proinflammatory cytokines. Clinical manifestations of Blau syndrome appear in patients before the age of four. Skin manifestations resolve spontaneously in some cases; however, joint and eye manifestations are progressive, and lead to serious complications, such as joint contracture and blindness. Currently, there is no specific curative treatment for the disease. Administration of high-dose oral steroids can improve clinical manifestations; however, treatments is difficult to maintain due to the severity of the side effects, especially in children. While several new therapies have been reported, including JAK inhibitors, anti-IL-6 and anti-IL-1 therapies, anti-TNF therapy plays a central role in the treatment of Blau syndrome. We recently performed an ex vivo study, using peripheral blood and induced pluripotent stem cells from patients. This study demonstrated that abnormal cytokine expression in macrophages from untreated patients requires IFNγ stimulation, and that anti-TNF treatment corrects the abnormalities associated with Blau syndrome, even in the presence of IFNγ. Therefore, although the molecular mechanisms by which the genetic mutations in NOD2 lead to granuloma formation remain unclear, it is possible that prior exposure to TNFα combined with IFNγ stimulation may provide the impetus for the clinical manifestations of Blau syndrome.
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