Anti-NC16A IgA from Patients with Linear IgA Bullous Dermatosis Induce Neutrophil-Dependent Subepidermal Blistering in Mice.
Anti-NC16A IgA from Patients with Linear IgA Bullous Dermatosis Induce Neutrophil-Dependent Subepidermal Blistering in Mice.
复制标题
来自线性 IgA 大疱性皮肤病患者的抗 NC16A IgA 会诱导小鼠中性粒细胞依赖性表皮下水疱。
DOI：
10.1016/j.jid.2023.05.027
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Liu,Zhi
中科院分区：
文献类型：
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作者：
Jing,Ke;Jordan,TylerJM;Li,Ning;Burette,Susan;Yang,Baoqi;Marinkovich,MPeter;Diaz,LuisA;Googe,Paul;Thomas,NancyE;Feng,Suying;Liu,Zhi
线性伊加大疱性皮肤病（LABD）是一种获得性自身免疫性表皮下起泡性皮肤病，其特征在于循环和组织结合的伊加自身抗体，其识别半桥粒蛋白BP 180内的表位，包括其NC 16 A结构域。组织学上，LABD长期以来被定义为中性粒细胞浸润和真皮-表皮分离。然而，抗NC 16 A伊加和中性粒细胞在LABD中的致病作用，以及它们之间的相互作用，还没有得到彻底的研究。我们表明，被动转移患者源性抗NC 16 A IgA诱导临床和组织学LABD病理学的人源化NC 16 A小鼠，重建局部或全身与人类中性粒细胞。小鼠的病变皮肤表现出显著升高的中性粒细胞趋化因子CXCL-1和CXCL-2水平。此外，我们发现LABD患者水疱液中中性粒细胞趋化因子IL-8水平显著升高。这项研究提供了直接的证据表明，抗NC 16 A伊加在LABD患者是致病性的，并与中性粒细胞介导的组织损伤和表皮下水疱形成。本研究进一步证实了嗜中性粒细胞介导的组织损伤在LABD疾病生理学中的重要性，并建立了一个临床相关的体内模型系统，可用于系统地剖析LABD的免疫发病机制。
Linear IgA bullous dermatosis (LABD) is an acquired autoimmune subepidermal blistering skin disease characterized by circulating and tissue-bound IgA autoantibodies that recognize epitopes within the hemidesmosomal protein BP180, including its NC16A domain. Histologically, LABD has long been defined by neutrophil infiltration and dermal-epidermal separation. However, the pathogenic roles of anti-NC16A IgA and neutrophils in LABD, as well as their interactions, have not been thoroughly studied. We show that passive transfer of patient-derived anti-NC16A IgA induce clinical and histologic LABD pathology in humanized NC16A mice that are reconstituted locally or systemically with human neutrophils. The lesional skin of mice exhibits significantly elevated levels of the neutrophil chemoattractants CXCL-1 and CXCL-2. Furthermore, we show significantly increased levels of the neutrophil chemoattractant IL-8 in blister fluids of patients with LABD. This study provides direct evidence that anti-NC16A IgA in patients with LABD are pathogenic and interact with neutrophils to mediate tissue injury and subepidermal blister formation. This study further corroborates the importance of neutrophil-mediated tissue injury in LABD disease physiology and establishes a clinically relevant in vivo model system that can be used to systematically dissect the immunopathogenesis of LABD.