Immunopathological studies have shown that not only T cells play a role in drug reactions, especially in AGEP, but also IL36 cytokines and other mediators are involved. These findings are relevant to the further development of prevention strategies and targeted treatment options for AGEP.
Acute generalized exanthematous pustulosis (AGEP) is characterized by numerous pustules on erythematous skin accompanied by fever and neutrophilia in the blood. The pathomechanism of AGEP is thought to be that the drug binds to a protein as a hapten and is presented on antigen-presenting cells after uptake and processing by MHC molecules. The hapten-protein complexes are recognized by specific T-cell receptors, resulting in immune cell activation and migration into the skin. Previous studies have focused on the involvement of specific T cells, but the exact pathophysiology of AGEP and mechanisms of neutrophilic inflammation have not been fully elucidated.
IL-36γ overexpressed in AGEP patients.
In the context of this year’s annual meeting of the SGDV, Dr. med. reported Dr. sc. nat. Barbara Meier-Schiesser from the Department of Dermatology, University Hospital Zurich [1] on a recent study project demonstrating that interleukin36 (IL36) plays an important role in the pathogenesis of AGEP. It leads to increased secretion of IL8, resulting in neutrophil recruitment and pustule formation. In the presented study, a large gene expression array and RNA sequencing were first performed. Here, there were clear differences between the gene expression profile of lesional skin in AGEP, maculopapular exanthema, and normal skin. AGEP showed in particular an upregulation of genes of the innate immune system and less of genes of the adaptive immune system. These data could be confirmed by serological tests. Analysis of blood samples from patients with AGEP revealed that IL6, IL8, and IL36 in particular had significantly elevated levels compared with the control group.
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Detection of mutations in the gene IL-36RN A research group led by Dr. med. sc. nat. Barbara Meier-Schiesser from the Dermatology Clinic of the University Hospital Zurich found that, among other things, the secretion of IL-36γ by monocytes/macrophages and keratinocytes in the context of a drug-induced intolerance reaction plays a key role in the pathogenesis of AGEP. This finding is based on a finding that mutations in IL-36RN, a gene encoding the IL36 receptor antagonist, are more common in AGEP sufferers and in patients with pustular psoriasis. IL36 cytokines, particularly IL-36γ from keratinocytes and macrophages, were found to be upregulated in lesional skin samples from AGEP patients. Such overexpression of IL-36γ was not observed in patients with drug-induced maculopapular rash. In vitro, secretion of IL-36γ specific for AGEP triggered by the corresponding drug and involving Toll receptor-4 was detected. |
Genetic polymorphisms identified
Subsequently, the ELISpot in vitro test procedure was performed. All subjects had a history of AGEP that was at least six weeks old. Immune cells, so-called PBMCs (peripheral blood mononuclear cells), were isolated from blood samples of the study participants and treated with the triggering drug. Subsequently, various cytokines were measured. It was found that IL36-γ and IL1-β, increased after only a few hours. “We then wanted to explore which cells from the PBMC pool were the drivers of inflammation, so we split the cells into CD14-positive monocytes and CD3-positive T cells,” the speaker explained. Originally, they assumed that there should be no reaction because both cell types are needed, Dr. Meier-Schiesser said. However, as it turned out, monocytes alone showed very strong cytokine secretion. In addition, they discovered by chance that positive control LPS (Toll-like receptor-4 agonist) caused very strong secretion of IL36 and IL1-β, and to a much greater extent in the AGEP than in the control group. “For this reason, we wondered if something might be wrong in the Toll-like receptor and NF-kappa-b signaling pathway.” With this in mind, the researchers investigated whether upregulation of the genes was measurable, but this was not detectable in skin or serum. Therefore, in collaboration with Prof. Alexander Navarini, MD, Chief of Dermatology at the University Hospital Basel [3], a large database of AGEP patients was analyzed for genes involved in this pathway. Dr. Meier Schiesser found two polymorphisms in the Toll-like receptor 4 gene that were significantly more prevalent in AGEP patients compared to the normal population (20% vs. <5%). Since it is known that not every genetic polymorphism has meaning, additional functional experiments were performed. One involved blocking Toll-like receptor-4 and other adaptor proteins with antibodies and inhibitors and treating them with the drug. In fact, this was able to block the immune response.
Possible implications of these research findings for future targeted treatment of AGEP patients: A new therapeutic strategy could be to refrain from dispensing certain drugs to an at-risk population based on a measurement of polymorphisms, the speaker said. In addition, targeted drugs with rapid onset of action and a short half-life could be used as an alternative therapeutic option in severe courses. The use of biologicals, whose effect is delayed, is rather unsuitable in AGEP. At the current time, steroids are still the standard therapy in clinical practice.
Source: SGDV 2020
Literature:
- Meier-Schiesser B, et al: Culprit Drugs Induce Specific IL-36 Overexpression in Acute Generalized Exanthematous Pustulosis. J Invest Dermatol 2019; 139(4): 848-858.
- Meier-Schiesser B: Free Communications: Acute Generalized Exanthematous Pustulosis – not only a T-cell driven disease? SGDV 2020, Livestream, 18.09.2020.
- University Hospital Basel, Prof. Alexander Navarini, MD, www.unispital-basel.ch
DERMATOLOGIE PRAXIS 2020; 30(6): 53 (published 8/12/20, ahead of print).
