Culprit drugs induce specific IL-36 overexpression in Acute Generalized Exanthematous Pustulosis.

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)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology, Clinical Immunology and Allergology
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Dermatology

UniBE Contributor:

Feldmeyer, Laurence; Yerly, Daniel and Yawalkar, Nikhil

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0022-202X

Publisher:

Elsevier

Language:

English

Submitter:

Sandra Nyffenegger

Date Deposited:

07 Dec 2018 08:55

Last Modified:

26 Mar 2019 01:31

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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