Neutrophil extracellular traps contribute to immune dysregulation in bullous pemphigoid via inducing B-cell differentiation and antibody production
Neutrophil extracellular traps contribute to immune dysregulation in bullous pemphigoid via inducing B-cell differentiation and antibody production
复制标题
中性粒细胞胞外陷阱通过诱导 B 细胞分化和抗体产生导致大疱性类天疱疮的免疫失调
DOI：
10.1096/fj.202100145r
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发表时间：
2021-07-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Gang
中科院分区：
文献类型：
--
作者：
Fang, Hui;Shao, Shuai;Wang, Gang
大疱性类天疱疮（BP）是一种自身免疫性皮肤病，其特点是皮肤和粘膜中存在针对半粒染色体蛋白的自身抗体。中性粒细胞浸润BP皮肤病变，但其在免疫失调中的作用尚不清楚。我们研究了BP是否与皮肤病变和循环中异常中性粒细胞胞外陷阱（NETs）的形成有关；并检查了触发因素和有害的免疫炎症后果。在本研究中，我们发现BP患者血清和水疱液中循环net相关生物标志物水平升高，且与疾病严重程度显著相关。此外，与健康对照相比，BP患者的循环中性粒细胞自发性NETs形成增强。在体外，BP180-NC16A免疫复合物诱导BP患者中性粒细胞NETosis，通过Fc γ受体和/或NADPH通路阻断可消除NETosis。此外，BP患者的NETs水平升高，通过MAPK P38级联激活介导的b细胞向浆细胞分化，促进了自身抗体的产生。总之，我们的研究结果提供了强有力的证据，证明NETs参与了一个致病环，导致B细胞过度分化和促进自身抗体的产生。因此，靶向异常中性粒细胞反应将为治疗BP提供新的潜在靶点。
Bullous pemphigoid (BP), an autoimmune skin disease, is characterized by autoantibodies against hemidesmosomal proteins in the skin and mucous membranes. Neutrophils infiltrate BP skin lesions, however, their role in immune dysregulation remains unclear. We investigated whether BP involves aberrant neutrophil extracellular traps (NETs) formation in skin lesions and circulation; and examined the triggers and deleterious immuno-inflammatory consequences. In the present study, we found that circulating NET-related biomarker levels increased in serum and blister fluid of BP patients and significantly correlated with disease severity. Additionally, circulating neutrophils from BP patients displayed enhanced spontaneous NETs formation than healthy controls. In vitro, BP180-NC16A immune complexes-induced NETosis in neutrophils from BP patients, which was abrogated by Fc gamma receptor and/or NADPH pathway blockade. Furthermore, the elevated levels of NETs from BP patients boosted autoantibody production by inducing B-cell differentiation into plasma cells, mediated by MAPK P38 cascade activation. Together, our findings provide strong evidence that NETs are involved in a pathogenic loop, causing excessive differentiation of B cells and promotion of autoantibody production. Hence, targeting aberrant neutrophil responses will provide novel potential targets for the treatment of BP.