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Impaired expression of metallothioneins contributes to allergen-induced inflammation in patients with atopic dermatitis.

ABSTRACT: Regulation of cutaneous immunity is severely compromised in inflammatory skin disease. To investigate the molecular crosstalk underpinning tolerance versus inflammation in atopic dermatitis, we utilise a human in vivo allergen challenge study, exposing atopic dermatitis patients to house dust mite. Here we analyse transcriptional programmes at the population and single cell levels in parallel with immunophenotyping of cutaneous immunocytes revealed a distinct dichotomy in atopic dermatitis patient responsiveness to house dust mite challenge. Our study shows that reactivity to house dust mite was associated with high basal levels of TNF-expressing cutaneous Th17 T cells, and documents the presence of hub structures where Langerhans cells and T cells co-localised. Mechanistically, we identify expression of metallothioneins and transcriptional programmes encoding antioxidant defences across all skin cell types, that appear to protect against allergen-induced inflammation. Furthermore, single nucleotide polymorphisms in the MTIX gene are associated with patients who did not react to house dust mite, opening up possibilities for therapeutic interventions modulating metallothionein expression in atopic dermatitis.

SUBMITTER: Sirvent S

PROVIDER: S-EPMC10199008 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Impaired expression of metallothioneins contributes to allergen-induced inflammation in patients with atopic dermatitis.

Sirvent Sofia S Vallejo Andres F AF Corden Emma E Teo Ying Y Davies James J Clayton Kalum K Seaby Eleanor G EG Lai Chester C Ennis Sarah S Alyami Rfeef R Douilhet Gemma G Dean Lareb S N LSN Loxham Matthew M Horswill Sarah S Healy Eugene E Roberts Graham G Hall Nigel J NJ Friedmann Peter S PS Singh Harinder H Bennett Clare L CL Ardern-Jones Michael R MR Polak Marta E ME

Nature communications 20230519 1

Regulation of cutaneous immunity is severely compromised in inflammatory skin disease. To investigate the molecular crosstalk underpinning tolerance versus inflammation in atopic dermatitis, we utilise a human in vivo allergen challenge study, exposing atopic dermatitis patients to house dust mite. Here we analyse transcriptional programmes at the population and single cell levels in parallel with immunophenotyping of cutaneous immunocytes revealed a distinct dichotomy in atopic dermatitis patie ...[more]

PMID: 37208336

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Project description:Atopic dermatitis (AD) is a skin barrier dysfunction characterized by tissue eosinophilia. In patients with AD, we evaluated the effect of eosinophil depletion with benralizumab on markers of inflammation in skin after intradermal allergen challenge. A total of 20 patients with moderate-to-severe AD completed a randomized, double-blind, placebo-controlled parallel-group study comparing 3 doses of benralizumab (30 mg each) administered subcutaneously every 4 weeks (n = 9) with placebo (n = 11). Allergen and saline control intradermal challenges were conducted before and after treatment, with skin biopsy samples collected 24 hours after challenge. Early and late cutaneous responses were measured by skin wheal size. Levels of eosinophils and IL-5 receptor-α-bearing cells, including eosinophil progenitor (EoP) cells, basophils, and mast cells, in papillary dermis were measured by immunofluorescence microscopy, and levels of EoP cells, hematopoietic progenitor cells, and type 2 innate lymphoid cells in the blood were measured by flow cytometry. Outcomes were compared between the placebo and benralizumab treatment groups by using the Mann-Whitney U test. Benralizumab reduced eosinophil counts in the blood (P < .0001) and allergen-challenged skin, as measured by hematoxylin and eosin staining and eosinophil cationic protein antibody concentration (P < .05). Benralizumab lowered the levels of EoP cells, mast cells, and basophils in the skin, as well as the levels of EoP cells, hematopoietic progenitor cells, and type 2 innate lymphoid cells in the blood (all P < .05). There was a trend toward improvement in the early cutaneous response (P = .095) but no effect on the late cutaneous response. In patients with moderate-to-severe AD, benralizumab treatment significantly inhibited accumulation of eosinophils and other IL-5 receptor-α-expressing cells in the papillary dermis after intradermal allergen challenge. Targeting IL-5 receptor-α-positive cells did not modulate the size of the allergen-induced skin wheal (ClincialTrials.gov identifier NCT03563066).

Dataset Information

Impaired expression of metallothioneins contributes to allergen-induced inflammation in patients with atopic dermatitis.

Publications

Impaired expression of metallothioneins contributes to allergen-induced inflammation in patients with atopic dermatitis.

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