Meier-Schiesser, Barbara; Feldmeyer, Laurence; Jankovic, Dragana; Mellett, Mark; Satoh, Takashi K; Yerly, Daniel; Navarini, Alexander; Abe, Riichiro; Yawalkar, Nikhil; Chung, Wen-Hung; French, Lars E; Contassot, Emmanuel (2019). Culprit drugs induce specific IL-36 overexpression in Acute Generalized Exanthematous Pustulosis. Journal of Investigative Dermatology, 139(4), pp. 848-858. Elsevier 10.1016/j.jid.2018.10.023
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Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous drug reaction. Although an involvement of drug-specific T cells has been reported, the physiopathology of AGEP and mechanism of neutrophilic skin inflammation remains incompletely understood. Recently, mutations in IL-36RN, the gene encoding the IL-36 receptor antagonist, have been reported to be more frequent in AGEP patients and pustular psoriasis. Here, we show that IL-36 cytokines, in particular IL-36γ, is highly expressed in lesional skin of AGEP patients, keratinocytes and macrophages being a major source of IL-36γ. Such an IL-36γ overexpression could not be observed in patients with drug-induced maculo-papular rash (MPR). In vitro, the causative drug specifically induced IL-36γ release either directly by peripheral blood monocytes from AGEP patients, or indirectly by keratinocytes in presence of autologous peripheral blood mononuclear cells. Such culprit drug induction of IL-36γ secretion in vitro was specific for AGEP and involved the sensing of drug/albumin complex as danger signal by Toll-like receptor 4. Our results suggest that IL-36γ secretion by monocytes/macrophages and keratinocytes in response to culprit drug exposure likely plays a key role in the pathogenesis of AGEP.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology and Immunology 04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Dermatology |
UniBE Contributor: |
Feldmeyer, Laurence, Yerly, Daniel, Yawalkar, Nikhil |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
0022-202X |
Publisher: |
Elsevier |
Language: |
English |
Submitter: |
Andrea Studer-Gauch |
Date Deposited: |
07 Dec 2018 08:55 |
Last Modified: |
05 Dec 2022 15:21 |
Publisher DOI: |
10.1016/j.jid.2018.10.023 |
PubMed ID: |
30395846 |
BORIS DOI: |
10.7892/boris.121882 |
URI: |
https://boris.unibe.ch/id/eprint/121882 |
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