title: The cutaneous biochemical redox barrier: a component of the innate immune defenses against sensitization by highly reactive environmental xenobiotics.
abstract: Contact allergy to environmental xenobiotics is a common and important problem, but it is unclear why some chemicals are potent sensitizers and others weak/nonsensitizers. We explored this by investigating why similar chemicals, 2,4-dinitrochlorobenzene (DNCB) and 2,4-dinitrothiocyanobenzene (DNTB), differ in their ability to induce contact hypersensitivity (CHS). DNCB induced CHS in humans, whereas at similar doses DNTB did not. However, following DNCB sensitization, DNTB elicited CHS in vivo and stimulated DNCB-responsive T cells in vitro, suggesting that differences in response to these compounds lie in the sensitization phase. In contrast to DNCB, DNTB failed to induce emigration of epidermal Langerhans cells in naive individuals. Examination for protein dinitrophenylation in skin revealed that DNCB penetrated into the epidermis, whereas DNTB remained bound to a thiol-rich band within the stratum corneum. DNTB reacted rapidly with reduced glutathione in vitro and was associated with a decrease in the free thiol layer in the stratum corneum, but not in the nucleated epidermis. By contrast, DNCB required GST facilitation to react with gluthathione and, following penetration through the stratum corneum, depleted thiols in the viable epidermis. Chemical depletion of the thiol-rich band or removing it by tape stripping allowed increased penetration of DNTB into the epidermis. Our results suggest that the dissimilar sensitizing potencies of DNCB and DNTB in humans are determined by a previously undescribed outer epidermal biochemical redox barrier, a chemical component of the innate immune defense mechanisms that defend against sensitization by highly reactive environmental chemicals.
authors.affiliation: Dermatopharmacology Unit, School of Medicine, Level F South Block (825), Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. cp@soton.ac.uk
authors.forename: Chris
authors.initials: C
authors.lastname: Pickard
authors.forename: Fethi
authors.initials: F
authors.lastname: Louafi
authors.forename: Carolann
authors.initials: C
authors.lastname: McGuire
authors.forename: Kelly
authors.initials: K
authors.lastname: Lowings
authors.forename: Pawan
authors.initials: P
authors.lastname: Kumar
authors.forename: Hywel
authors.initials: H
authors.lastname: Cooper
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Dearman
authors.forename: Marie
authors.initials: M
authors.lastname: Cumberbatch
authors.forename: Ian
authors.initials: I
authors.lastname: Kimber
authors.forename: Eugene
authors.initials: E
authors.lastname: Healy
authors.forename: Peter S
authors.initials: PS
authors.lastname: Friedmann
mesh_terms: D000328:Adult; D003877:Dermatitis, Contact / Q000276:immunology*; D004136:Dinitrobenzenes / Q000276:immunology*; D004137:Dinitrochlorobenzene / Q000276:immunology* / Q000494:pharmacology; D004781:Environmental Exposure; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007509:Irritants / Q000276:immunology / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000737:chemistry* / Q000276:immunology*; D012882:Skin Tests; D015262:Xenobiotics / Q000276:immunology* / Q000494:pharmacology
chemical_list: D004136:Dinitrobenzenes; D004137:Dinitrochlorobenzene; D007509:Irritants; D015262:Xenobiotics; C010936:2,4-dinitrothiocyanatobenzene