Table_1_Interleukin-26–DNA complexes promote inflammation and dermal-epidermal separation in a modified human cryosection model of bullous pemphigoid.docx

Bullous pemphigoid (BP) is an autoimmune disease characterized by autoantibody-mediated activation of immune cells and subepidermal blister formation. Excess amounts of extracellular DNA are produced in BP, however, it remains unclear how extracellular DNA contributes to BP pathogenesis. Here we show a possible mechanism by which interleukin (IL)-26 binds to extracellular DNA released from neutrophils and eosinophils to support DNA sensing. Patients with BP exhibited high circulating levels of IL-26, forming IL-26–DNA complexes in the upper dermis and inside the blisters. IL-26–DNA complexes played a dual role in regulating local immunity and blister formation. First, they enhanced the production of inflammatory cytokines in monocytes and neutrophils. Second, and importantly, the complexes augmented the production and activity of proteases from co-cultured monocytes and neutrophils, which induced BP180 cleavage in keratinocytes and dermal-epidermal separation in a modified human cryosection model. Collectively, we propose a model in which IL-26 and extracellular DNA synergistically act on immune cells to enhance autoantibody-driven local immune responses and protease-mediated fragility of dermal-epidermal junction in BP.

天疱疮性大疱病（BP）是一种以自身抗体介导的免疫细胞激活和表皮下疱形成为特征的自身免疫性疾病。在BP中，产生过多的细胞外DNA，然而，细胞外DNA如何参与BP的发病机制尚不清楚。本研究揭示了IL-26通过与来自中性粒细胞和嗜酸性粒细胞的释放的细胞外DNA结合，从而支持DNA传感的可能机制。BP患者的循环中IL-26水平较高，形成IL-26-DNA复合物，位于真皮上层和疱内。IL-26-DNA复合物在调节局部免疫和疱形成中发挥双重作用。首先，它们增强了单核细胞和中性粒细胞中炎症细胞因子的产生。其次，且尤为重要，这些复合物增加了共培养的单核细胞和中性粒细胞产生的蛋白酶的产生和活性，在改良的人冷冻切片模型中诱导角质形成细胞中BP180的裂解和真皮-表皮分离。总的来说，我们提出了一种模型，其中IL-26和细胞外DNA协同作用于免疫细胞，增强由自身抗体驱动的局部免疫反应和蛋白酶介导的真皮-表皮连接的脆弱性。