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  • Review Article
  • Published:

Early immune events in the induction of allergic contact dermatitis

Key Points

  • The ability of a chemical to react covalently with a 'carrier protein' is a major determinant factor in its ability to act as a skin sensitizer. The formation of the hapten–carrier complex generates a neo-antigen that is eventually recognized by the immune system as 'altered self'.

  • Haptens induce the production of endogenous ligands for Toll-like receptors (TLRs) and NOD-like receptors (NLRs). These pattern-recognition receptors activate an innate immune response that is required for adaptive immune responses to the hapten–carrier complex.

  • Keratinocytes and mast cells produce pro-inflammatory cytokines in response to hapten exposure. These cytokines mobilize skin-resident dendritic cells and recruit effector lymphocytes into the skin, a process that is responsible for the immune cell-mediated inflammatory response associated with allergic contact dermatitis.

  • Skin-resident dendritic cells are required for the development of hapten-specific T cell responses. The Langerhans cell subset of skin dendritic cells is not required for the generation of the hapten-specific response, but the precise contribution of each dendritic cell subset to this process is unclear.

Abstract

The skin is a barrier site that is exposed to a wide variety of potential pathogens. As in other organs, pathogens that invade the skin are recognized by pattern-recognition receptors (PRRs). Recently, it has been recognized that PRRs are also engaged by chemical contact allergens and, in susceptible individuals, this elicits an inappropriate immune response that results in allergic contact dermatitis. In this Review, we focus on how contact allergens promote inflammation by activating the innate immune system. We also examine how innate immune cells in the skin, including mast cells and dendritic cells, cooperate with each other and with T cells and keratinocytes to initiate and drive early responses to contact allergens.

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Figure 1: Innate recognition of haptens.
Figure 2: Anatomy of the skin.
Figure 3: Cellular responses to cutaneous antigens.

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Acknowledgements

The authors thank R. Tigelaar, P. Stoitzner and P. Bryce for their helpful discussions and critical reading of the manuscript. D.H.K. is supported by the Al Zelickson Professorship and US National Institutes of Health grants AR060744 and AR056632. B.Z.I. is supported by the Dermatology Foundation. A.A.G. is supported by the Albert Shapiro Professorship and a Veterans Administration merit award (1I01BX0004405).

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Glossary

Delayed-type hypersensitivity

(DTH). A T cell-mediated immune response marked by monocyte and/or macrophage infiltration and activation. DTH skin tests have classically been used for the diagnosis of infection with intracellular pathogens such as Mycobacterium tuberculosis and as a measure of the vigour of the cellular immune system. Classical DTH responses to intracellular pathogens are thought to depend on CD4+ T cells that produce T helper 1-type cytokines, such as interferon-γ.

Hapten

A low-molecular-weight xenobiotic chemical that penetrates into the skin and chemically reacts with self proteins (either through covalent modification or the formation of a chelation complex). It is this hapten–self complex that is recognized by the immune system as a neo-antigen and is recognized by allergen-specific effector T cells in allergic contact dermatitis.

Dendritic epidermal T cells

(DETCs). γδ T cells that are localized purely in the epidermis. They are present in rodents and cattle but not in humans. In mice, essentially all DETCs express precisely the same T cell receptor, forming a prototype lymphocyte repertoire of limited diversity.

NKG2D

(Natural killer group 2, member D). A lectin-type activating receptor that is encoded by the NK complex and is expressed at the surface of NK cells, NKT cells, γδ T cells and some cytolytic CD8+ αβ T cells. The ligands for NKG2D are MHC class I polypeptide-related sequence A (MICA) and MICB in humans, and retinoic acid early-inducible protein 1 (RAE1) and H60 in mice. Such ligands are generally expressed at the surface of infected, stressed or transformed cells.

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Kaplan, D., Igyártó, B. & Gaspari, A. Early immune events in the induction of allergic contact dermatitis. Nat Rev Immunol 12, 114–124 (2012). https://doi.org/10.1038/nri3150

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