Unopposed IL-36 Activity Promotes Clonal CD4+ T-Cell Responses with IL-17A Production in Generalized Pustular Psoriasis.
J Invest Dermatol
; 138(6): 1338-1347, 2018 06.
Article
em En
| MEDLINE
| ID: mdl-29288651
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Psoríase
/
Autoimunidade
/
Interleucina-1
/
Interleucina-17
/
Células Th17
Limite:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
J Invest Dermatol
Ano de publicação:
2018
Tipo de documento:
Article