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.

Signal transduction profile of chemical sensitisers in dendritic cells: An endpoint to be included in a cell-based in vitro alternative approach to hazard identification?

“…These in vitro approaches are corroborated with in vivo studies demonstrating that DNCB reacts with glutathione and depleted thiols in the viable epidermis following penetration through the stratum corneum (Pickard et al, 2009). Furthermore, glutathione metabolism in mice is preferentially enhanced in hapten-induced allergic contact dermatitis rather than in irritant contact dermatitis (Hirai et al, 1997).…”

Idiosyncratic Adverse Drug Reactions: Current Concepts

“…Haptenic chemicals [e.g., dinitrohalobenzenes (Martin et al, 2011;Esser et al, 2012)] also trigger dendritic cell signaling via multiple pathways, including pattern recognition receptor triggering through the degradation of hyaluronic acid, the formation of reactive oxygen species, and/or the direct modification of cysteine-containing proteins. Moreover, independent studies by Pickard et al (2009) and Watanabe et al (2008) suggest that once a contact-sensitizing chemical passes through skin, its potential to cause strong immunologic reactions is determined by its ability to stimulate proinflammatory cytokine (IL-1b, IL-18) release through activation of the inflammasome (a protein complex composed of intracellular NOD-like receptors, the adaptor protein apoptosis speckledlike protein with a caspase recruitment domain and caspase-1). Modification of absorption and/or inflammasome signaling was found to convert a tolerizing chemical into a sensitizer.…”

“…Protein modifications are selective and dependent on the inherent reactivity of individual amino acids within a protein (Aleksic et al, 2007). Topical DNCB exposure activates a cellular immune response in 100% of subjects that is readily detectable after skin challenge (Friedmann et al, 1983;Pickard et al, 2009). Both CD4+ and CD8+ T cells are stimulated to secrete IFN-g in the presence of DNCB.…”

Delayed drug hypersensitivity: models of T‐cell stimulation

“…The skin, as the outermost barrier of the body's defence system, is the first organ that encounters chemical and physical factors from the environment [23]. In some instances chemical entities can act specifically as skin allergens resulting in a T-cell mediated inflammatory reaction at the site of challenge in certain hypersensitive individuals, causing skin erythema and oedema [24].…”