Delayed type hypersensitivity reactions to various allergens may differently model inflammatory skin diseases

Abstract

Background: Treatment of inflammatory skin diseases, including atopic dermatitis (AD) and psoriasis, is undergoing transformative changes, highlighting the need to develop experimental models of skin inflammation in humans to predict treatment responses. Methods:We topically or intradermally administered four common sensitizers (dust mite (DM), diphencyprone (DPCP), nickel (Ni), and purified protein derivative (PPD)) to the backs of 40 healthy patients and the skin hypersensitivity response was biopsied and evaluated using immunohistochemistry, RNA-seq, and RT-PCR.Results: All agents induced strong increases in cellular infiltrates (T-cells and dendritic cells) as compared to untreated skin (p < .05), with variable T helper polarization.Overall, DPCP induced the strongest immune responses across all pathways, including innate immunity (IL-1α, IL-8), Th1 (IFNγ, CXCL10), Th2 (IL-5, CCL11), and Th17 (CAMP/LL37) products, as well as the highest regulatory tone (FOXP3, IL-34, IL-37) (FDR <0.01). Nickel induced Th17 (IL-17A), Th1 (CXCL10) and Th2 (IL-4R) immune responses to a lesser extent than DPCP (p < .05). PPD induced predominantly Th1 (IFNγ, CXCL10, STAT1) and Th17 inflammation (IL-17A) (p < .05). DM induced modulation of Th2 (IL-13, CCL17, CCL18), Th22 (IL-22), and Th17/Th22 (S100A7/9/12) pathways (p < .05). Barrier defects that characterize both AD and psoriasis were best modeled by DPCP and Ni, followed by PPD, including downregulation of terminal differentiation (FLG, FLG2, LOR, LCEs), tight junction (CLDN1/CLDN8), and lipid metabolism (FA2H, FABP7)-related markers. Conclusion:Our data imply that DPCP induced the strongest immune response across all pathways, and barrier defects characteristic of AD and psoriasis.

Oral prednisone regulates human skin T cells in delayed‐type hypersensitivity reaction elicited by diphencyprone

“…DPCP had the highest cell infiltration and elicited a strong multipolar Th1/ Th2/Th17 and Tc1 inflammatory profile when compared to the other contact sensitizers. These observations corroborate the molecular study in the clinical trial which showed that DPCP induced a broad polarization signature 16. The bulk RNA-seq molecular study provides an overall Type 1, Type 2, and/or Type 17 polarization in terms of cytokines, chemokines and their receptors, transcription factors and innate immune signatures as well as changes in barrier differentiation genes for the four sensitizers 16.…”

“…Lack of access to allergen unexposed skin biopsies from allergensensitized healthy volunteers for flow cytometry as compared to the molecular arm of the study, 16…”

“…The remaining biopsy was used for transcriptomic and immunohistological analyses. 16 In an independent group, Cohort B, 20 HVs were sensitized to DPCP and randomized (1:1) to either prednisone 40 mg in decreasing doses (Teva Canada Limited) or placebo (lactose monohydrate; Odan) once daily. Following a sensitization to DPCP on Day 1, HVs started on Day 13 (2 days before rechallenge) 40 mg for three consecutive days, then 30 mg, 20 mg, 10 mg, and 5 mg daily for two consecutive days for each dose level for a total of 11 days of treatment.…”

Metal Allergy: State-of-the-Art Mechanisms, Biomarkers, Hypersensitivity to Implants

“…CD3 + T-cells, CD11c + myeloid dendritic cells (DC), DC lysosomal associated membrane glycoprotein (DC-LAMP) + mature DCs, myelin basic protein (MBP) + eosinophils and forkhead box P3 (FOXP3) + T regulatory cells (Tregs) were significantly enriched. Ni application caused barrier defects by reduction of terminal differentiation (filaggrin (FLG), FLG2, loricrin (LOR), and late cornified envelope proteins (LCEs)), tight junction (claudin (CLDN)1/CLDN8), and lipid metabolism (fatty acid 2-hydroxylase (FA2H), fatty acid binding protein 7, brain (FABP7)) AD-related markers [ 73 ]. After positive Ni-PT, skin biopsies were taken at different time points (0 to 96 h).…”

“… Outcomes Exposition to Metal Ref. ↑ metal-specific CD154 + CD4 + Tmem (overexpression of TRAV9-2 and CDR3 histidine) Allergic and non-allergic subjects stimulated with Ni, Co or Pd (PBMC) [ 67 , 68 ] ↑ IL-5 Ni-allergic patients (PBMC) [ 69 ] Ni-allergy patients, differentiation between independent Ni or cross-reactivity of Ni/Pd allergy (PBMC) [ 71 ] Cross reactivity between Ni/Cr and Pd Sensitization with Ni or Cr, challenge with Pd (mice model) [ 70 ] Skin barrier defects: ↓ terminal differentiation—FLG, FLG2, LOR, LCEs, tight junction—CLDN1/CLDN8, lipid metabolism—FA2H, FABP7 Biopsies from healthy subjects after Ni-topical application [ 73 ] Cellular infiltrates: ↑ CD3 + T, CD11c + myeloid DC, DC-LAMP + mature DC, MBP + eosinophils, FOXP3 + Treg ↑ M1, mast cells, neutrophils, NK, CD4 + Tmem, CD8 + T Biopsies from Ni-allergic patients [ 74 ] ↓ M2, resting mast cells, Tγδ, Treg ↓ SBSN Ni-allergic patients (serum) [ 75 ] ↑ Sema3A (activates MAPK and TNF-α) Ni-induced allergy (mouse ear tissue) [ 76 ...…”