Recent advances in understanding and managing contact dermatitis

Martin, Stefan F.; Rustemeyer, Thomas; Thyssen, Jacob P.

doi:10.12688/f1000research.13499.1

Cited by 60 publications

(52 citation statements)

References 67 publications

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“…The CHS response was enhanced in Il36rn −/− mice, and we considered that this is attributable to the increase in neutrophils. Actually, several recent studies have reported that neutrophils play an important role in both the sensitization and elicitation phases of contact dermatitis [21][22][23] . When there is a deficiency in IL-36Ra function, the signal transduction continues via IL-36R.…”

Section: Discussionmentioning

confidence: 99%

TAK-242 ameliorates contact dermatitis exacerbated by IL-36 receptor antagonist deficiency

Fukushima

Iwata

Watanabe

et al. 2020

Sci Rep

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Loss-of-function mutations in IL36RN cause generalized pustular psoriasis (GPP), which is characterized by neutrophil-infiltrated lesions. Neutrophils are important during contact hypersensitivity in mice. However, it has never been determined whether interleukin-36 receptor antagonist (IL-36Ra) deficiency is an exacerbating factor in contact dermatitis. We examined whether a loss-of-function IL36RN mutation exacerbates contact dermatitis and evaluated the changes in contact dermatitis-related cytokines. Wild-type and Il36rn −/− mice were treated with 1-fluoro-2,4-dinitorobenzene (DNFB) and evaluated for ear thickness, histopathological features, numbers of infiltrated neutrophils, and numbers of CD4 + and CD8 + T cells. Furthermore, mRNA levels of contact dermatitis-related cytokines were measured by real-time polymerase chain reaction, and effects of TAK-242, a toll-like receptor 4 (TLR4) inhibitor, on the contact hypersensitivity (CHS) response were evaluated. We found that the ear thickness, cytokine expression, and neutrophil infiltration significantly increased in Il36rn −/− mice compared with that in wild-type mice. TAK-242 alleviated CHS and prevented neutrophil infiltration, cytokine expression, and ear thickening in Il36rn −/− mice. These data indicate that Il36rn −/− mutations are an exacerbating factor for CHS and that TAK-242 can reduce the inflammatory responses that are associated with the CHS response.Homozygous or compound heterozygous IL36RN gene mutations underlie the pathogenesis of psoriasis-related pustular eruptions, including generalised pustular psoriasis, palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau, and acute generalised exanthematous pustular eruptions 1 . Loss-of-function mutations in IL36RN define a recessively inherited autoinflammatory disease called "deficiency of interleukin-36 receptor antagonist (IL-36Ra)" (DITRA), which is a type of autoinflammatory keratinization disease 2-7 . Previously, we generated Il36rn −/− mice and established a DITRA murine model 8 . The IL36RN gene encodes IL-36Ra, a protein in the IL-1 cytokine family responsible for the tight regulation of IL-36 signalling. The IL-36 pathway is activated when one of the three IL-36 agonists (IL-36α, β, and γ) binds to their common but specific receptor interleukin 1 receptor-related protein 2 (IL-1Rrp2), which recruits the co-receptor, IL-1 receptor accessory protein (IL-1RacP), and triggers downstream activation of NF-κB and MAPK kinase signalling pathways to ultimately enhance transcription and release of pro-inflammatory cytokines 9,10 that initiate the recruitment of inflammatory cells, including neutrophils, T cells, and myeloid dendric cells, in the skin. Abnormal IL-36 receptor (IL-36R) signalling results in transient skin inflammation characterised by acanthosis, hyperkeratosis, and neutrophil-dominant mixed-cell infiltration [11][12][13] .According to the Human Genetic Variation Database, two IL36RN founder mutations (c.28 C > T (p.Arg10X) and c.115 + 6 T > C (p.ArgfsX1)) are found ...

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Section: Discussionmentioning

confidence: 99%

TAK-242 ameliorates contact dermatitis exacerbated by IL-36 receptor antagonist deficiency

Fukushima

Iwata

Watanabe

et al. 2020

Sci Rep

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“…Metal exposure is a known cause of allergic contact dermatitis (ACD) 1 . The prevalence of metal allergy has decreased since governments regulated the incorporation of sensitizing metals in jewellery and other articles that come into long‐lasting contact with the skin.…”

Section: Introductionmentioning

confidence: 99%

Non–heat inactivated autologous serum increases accuracy of in vitro CFSE lymphocyte proliferation test (LPT) for nickel

Graaf

Bontkes

Roffel

et al. 2020

Clin Experimental Allergy

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Background: Skin patch testing is still seen as the gold standard for the diagnosis of allergic hypersensitivity. For several metals and for patients with a suspected adverse reaction to their medical device implant material, patch testing can be unreliable. The current alternative to metal allergy patch testing is the in vitro lymphocyte proliferation test (LPT) using tritiated thymidine. This method is well-established but requires handling of radioactive material, often uses heat-inactivated allogenic human pooled serum and cannot determine T cell subsets. Objective: To develop a radioactive free LPT by using carboxyfluorescein succinimidyl ester (CFSE) and to evaluate the influence of serum source (heat-inactivated human pooled serum [HI HPS] vs autologous serum) on the sensitivity and specificity of the nickel-specific LPT. Methods: Peripheral blood mononuclear cells derived from nickel-allergic patients and healthy controls were collected, labelled with CFSE and cultured in medium containing 10% HI HPS or 10% autologous serum with or without additional T cell skewing cytokine cocktails (Th1: IL-7/IL-12, Th2: IL-7/IL-4 or Th17: IL-7/IL-23/IL-1β) in the absence or presence of NiSO 4 . The stimulation index (SI) was calculated as the ratio of divided cells, that is the percentage of CFSE low/neg CD3 + CD4 + T-lymphocytes upon nickel stimulation compared to the percentage of CFSE low/neg CD3 + CD4 + T-lymphocytes without antigen. These results were compared with the history of Ni allergy, patch test results and the MELISA test.Results: Autologous serum positively influenced Ni-specific proliferation while HI HPS negatively influenced Ni-specific proliferation. The test protocol analysing CD4 + cells and autologous serum without skewing cytokines scored the best diagnostic values (sensitivity 95%; specificity 93%; and overall accuracy 94%) compared to the parallel test using HI HPS (accuracy 60%). Cytokine supplements did not further improve the test protocol which used autologous serum. The protocol using HI HPS could be further improved by addition of the cytokine skewing cocktails. | 723 de GRAAF et Al.

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“…Danger signals stimulate Toll‐like receptors and NOD‐like receptor family and pyrin containing 3 (NLRP3), and this results in dendritic cell maturation, which can be visualized by up‐regulation of cell surface receptors and cytokine secretion . Haptenic chemicals and certain drugs have also been shown to stimulate dendritic cell maturation in vitro .…”

Section: Discussionmentioning

confidence: 99%

Exosomal Transport of Hepatocyte‐Derived Drug‐Modified Proteins to the Immune System

et al. 2019

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Idiosyncratic drug‐induced liver injury (DILI) is a rare, often difficult‐to‐predict adverse reaction with complex pathomechanisms. However, it is now evident that certain forms of DILI are immune‐mediated and may involve the activation of drug‐specific T cells. Exosomes are cell‐derived vesicles that carry RNA, lipids, and protein cargo from their cell of origin to distant cells, and they may play a role in immune activation. Herein, primary human hepatocytes were treated with drugs associated with a high incidence of DILI (flucloxacillin, amoxicillin, isoniazid, and nitroso‐sulfamethoxazole) to characterize the proteins packaged within exosomes that are subsequently transported to dendritic cells for processing. Exosomes measured between 50 and 100 nm and expressed enriched CD63. Liquid chromatography–tandem mass spectrometry (LC/MS‐MS) identified 2,109 proteins, with 608 proteins being quantified across all exosome samples. Data are available through ProteomeXchange with identifier PXD010760. Analysis of gene ontologies revealed that exosomes mirrored whole human liver tissue in terms of the families of proteins present, regardless of drug treatment. However, exosomes from nitroso‐sulfamethoxazole‐treated hepatocytes selectively packaged a specific subset of proteins. LC/MS‐MS also revealed the presence of hepatocyte‐derived exosomal proteins covalently modified with amoxicillin, flucloxacillin, and nitroso‐sulfamethoxazole. Uptake of exosomes by monocyte‐derived dendritic cells occurred silently, mainly through phagocytosis, and was inhibited by latrunculin A. An amoxicillin‐modified 9‐mer peptide derived from the exosomal transcription factor protein SRY (sex determining region Y)‐box 30 activated naïve T cells from human leukocyte antigen A*02:01–positive human donors. Conclusion: This study shows that exosomes have the potential to transmit drug‐specific hepatocyte‐derived signals to the immune system and provide a pathway for the induction of drug hapten‐specific T‐cell responses.

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Recent advances in understanding and managing contact dermatitis

Cited by 60 publications

References 67 publications

TAK-242 ameliorates contact dermatitis exacerbated by IL-36 receptor antagonist deficiency

TAK-242 ameliorates contact dermatitis exacerbated by IL-36 receptor antagonist deficiency

Non–heat inactivated autologous serum increases accuracy of in vitro CFSE lymphocyte proliferation test (LPT) for nickel

Exosomal Transport of Hepatocyte‐Derived Drug‐Modified Proteins to the Immune System

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