Bao Lei, Guerrero-Juarez Christian F, Li Jing, Pigors Manuela, Emtenani Shirin, Liu Yingzi, Mansini Adrian P, Wang Yulu F, Ahmed Aadil, Ishii Norito, Hashimoto Takashi, Perez White Bethany E, Green Stefan, Kunstman Kevin, Nowak Nicole C, Cole Connor, Sarkar Mrinal K, Gudjonsson Johann E, Virgilia Macias, Sverdlov Maria, McAlexander M Allen, McCrae Christopher, Nazaroff Christopher D, Schmidt Enno, Amber Kyle T
Department of Dermatology, Rush University Medical Center, Chicago, IL, USA.
Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Nat Commun. 2025 Aug 6;16(1):7254. doi: 10.1038/s41467-025-62495-2.
Autoantibodies in bullous pemphigoid (BP) are known to activate the innate immune response. Nevertheless, the direct effect of autoantibodies on keratinocytes and the contribution of keratinocyte responses to the pathology of BP are largely unknown. Here, by performing multiplex immunoassays and RNA-seq on primary keratinocytes treated with IgG derived from BP patients, we identify a MyD88-dependent pro-inflammatory and proteolytic response characterized by the release of several cytokines (IL-6, IL-24, TGF-β1), chemokines (CXCL16, MIP-3β, RANTES), C1s, DPP4, and MMP-9. The activation of this MyD88-dependent response is further validated using spatial transcriptomics and scRNA-seq of diseased skin. Blistering of the skin appears to significantly impact this inflammatory response, with attached BP skin and spongiotic dermatitis revealing indistinguishable transcriptomes. In a preclinical mouse model of BP, Krt14-specific Myd88 knockout significantly decreases disease severity and reduces serum levels of IL-4 and IL-9, indicating a contributory role of keratinocyte-derived skin inflammation in the systemic response. Thus, our work highlights key contributions of keratinocytes in response to autoantibodies in BP.
已知大疱性类天疱疮（BP）中的自身抗体可激活先天性免疫反应。然而，自身抗体对角质形成细胞的直接作用以及角质形成细胞反应对BP病理的贡献在很大程度上尚不清楚。在这里，通过对用BP患者来源的IgG处理的原代角质形成细胞进行多重免疫分析和RNA测序，我们确定了一种依赖MyD88的促炎和蛋白水解反应，其特征是释放几种细胞因子（IL-6、IL-24、TGF-β1）、趋化因子（CXCL16、MIP-3β、RANTES）、C1s、DPP4和MMP-9。使用患病皮肤的空间转录组学和单细胞RNA测序进一步验证了这种依赖MyD88的反应的激活。皮肤水疱似乎对这种炎症反应有显著影响，附着的BP皮肤和海绵状皮炎显示出难以区分的转录组。在BP的临床前小鼠模型中，Krt14特异性Myd88基因敲除显著降低了疾病严重程度，并降低了IL-4和IL-9的血清水平，表明角质形成细胞衍生的皮肤炎症在全身反应中起作用。因此，我们的工作突出了角质形成细胞在BP中对自身抗体反应的关键作用。
