IgG autoantibodies in bullous pemphigoid induce a pathogenic MyD88-dependent pro-inflammatory response in keratinocytes

Lei Bao, Christian F. Guerrero-Juarez, Jing Li, Manuela Pigors, Shirin Emtenani, Yingzi Liu, Adrian P. Mansini, Yulu F. Wang, Aadil Ahmed, Norito Ishii, Takashi Hashimoto, Bethany E. Perez White, Stefan Green, Kevin Kunstman, Nicole C. Nowak, Connor Cole, Mrinal K. Sarkar, Johann E. Gudjonsson, Macias Virgilia, Maria Sverdlov, M. Allen McAlexander, Christopher McCrae, Christopher D. Nazaroff, Enno Schmidt and Kyle T. Amber ()
Additional contact information
Lei Bao: Rush University Medical Center
Christian F. Guerrero-Juarez: Rush University Medical Center
Jing Li: Rush University Medical Center
Manuela Pigors: University of Lübeck
Shirin Emtenani: University of Lübeck
Yingzi Liu: University of California, Irvine
Adrian P. Mansini: Rush University Medical Center
Yulu F. Wang: Rush University Medical Center
Aadil Ahmed: Rush University Medical Center
Norito Ishii: and Kurume University Institute of Cutaneous Cell Biology
Takashi Hashimoto: Osaka Metropolitan University
Bethany E. Perez White: Rush University Medical Center
Stefan Green: Rush University Medical Center
Kevin Kunstman: Rush University Medical Center
Nicole C. Nowak: Rush University Medical Center
Connor Cole: Rush University Medical Center
Mrinal K. Sarkar: University of Michigan
Johann E. Gudjonsson: University of Michigan
Macias Virgilia: University of Illinois at Chicago
Maria Sverdlov: University of Illinois at Chicago
M. Allen McAlexander: AstraZeneca
Christopher McCrae: AstraZeneca
Christopher D. Nazaroff: AstraZeneca
Enno Schmidt: University of Lübeck
Kyle T. Amber: Rush University Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62495-2

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