Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 138, Issue 6, Pages 1338-1347Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2017.12.024
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [PR 241/5-1]
- BMBF [VIP0376]
- Biogen-Idec
- Uehara foundation
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Generalized pustular psoriasis (GPP) is the most severe psoriasis variant. Mutations in the IL-36 antagonist IL36RN, in CARD14 or AP1S3 provide genetic evidence for autoinflammatory etiology but cannot explain its pathogenesis completely. Here we demonstrate that unopposed IL-36 signaling promotes antigen-driven and likely pathogenic T-helper type 17 (Th17) responses in GPP. We observed that CD4(+) T cells in blood and skin lesions of GPP patients were characterized by intense hyperproliferation, production of the GPP key mediator, IL-17A, and highly restricted TCR repertoires with identical T-cell clones in blood and skin lesions, indicating antigen-driven T-cell expansions. The clonally expanded CD4(+) T cells were major producers of IL-17A. IL-36 signaling substantially enhanced TCR-mediated proliferation of CD4(+) T cells. Moreover, GPP patients showed preferences for HLA-DRB1*14, HLA-DQB1*05, and HLA-DQB1*03. We conclude that in GPP unopposed IL-36 signaling and certain HLA-class II alleles may cooperate in promoting antigen-driven Th17 responses, which in the obvious absence of exogenous triggers may reflect autoimmune reactions. This study reveals a pathogenic pathway where innate immune dysregulation promotes T-cell-mediated inflammation in GPP.
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