Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Gdańsk, Poland.
Department of Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany.
Front Immunol. 2022 Apr 20;13:877958. doi: 10.3389/fimmu.2022.877958. eCollection 2022.
Stress-induced heat shock protein 70 (Hsp70) is a key intra- and extracellular molecular chaperone implicated in autoimmune processes. Highly immunogenic extracellular Hsp70 can activate innate and acquired (adaptive) immune responses driving the generation of anti-Hsp70 autoantibodies that are frequently observed in inflammatory/autoimmune disorders. We recently described the direct pathological role of extracellular Hsp70 in epidermolysis bullosa acquisita (EBA), an anti-type VII collagen autoantibody-mediated autoimmune blistering skin disease. Here, we determined the role of anti-Hsp70 autoantibodies in EBA. We observed that circulating anti-Hsp70 IgG autoantibodies were significantly elevated in EBA patients compared to healthy individuals and positively correlated with serum levels of pro-inflammatory interferon gamma (IFN-γ). The pathophysiological relevance of anti-Hsp70 IgG autoantibodies was demonstrated in an antibody transfer-induced EBA mouse model in which elevated serum levels of anti-Hsp70 IgG were found. In addition, anti-Hsp70 IgG-treated animals had a more intense clinical and histological disease activity, as well as upregulated nuclear factor kappa B (NF-κB) activation in skin biopsies compared to isotype-treated animals. Our results suggest that autoantibodies to Hsp70 may contribute to EBA development enhanced neutrophil infiltration to the skin and activation of the NF-κB signaling pathway in an IFN-γ-associated manner.
应激诱导的热休克蛋白 70（Hsp70）是一种重要的细胞内和细胞外分子伴侣，与自身免疫过程有关。高度免疫原性的细胞外 Hsp70 可以激活先天和获得性（适应性）免疫反应，驱动抗 Hsp70 自身抗体的产生，这种自身抗体在炎症/自身免疫性疾病中经常观察到。我们最近描述了细胞外 Hsp70 在获得性大疱性表皮松解症（EBA）中的直接病理作用，EBA 是一种抗 VII 型胶原自身抗体介导的自身免疫性水疱性皮肤病。在这里，我们确定了抗 Hsp70 自身抗体在 EBA 中的作用。我们观察到，与健康个体相比，EBA 患者循环中的抗 Hsp70 IgG 自身抗体显著升高，并与促炎干扰素 γ（IFN-γ）的血清水平呈正相关。在抗体转移诱导的 EBA 小鼠模型中，观察到抗 Hsp70 IgG 水平升高，证明了抗 Hsp70 IgG 自身抗体的病理生理学相关性。此外，与同型 IgG 处理的动物相比，抗 Hsp70 IgG 处理的动物具有更严重的临床和组织学疾病活动，以及皮肤活检中核因子 kappa B（NF-κB）激活上调。我们的结果表明，针对 Hsp70 的自身抗体可能通过与 IFN-γ 相关的方式，促进 EBA 的发展，增强中性粒细胞向皮肤的浸润和 NF-κB 信号通路的激活。
