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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Mowad, C. M. Patch testing: pitfalls and performance. Curr. Opin. Allergy Clin. Immunol. 6, 340–344 (2006).
Thyssen, J. P., Linneberg, A., Menne, T. & Johansen, J. D. The epidemiology of contact allergy in the general population — prevalence and main findings. Contact Dermatitis 57, 287–299 (2007).
Diepgen, T. L. Occupational skin-disease data in Europe. Int. Arch. Occup. Environ. Health 76, 331–338 (2003).
Diepgen, T. L. & Coenraads, P. J. The epidemiology of occupational contact dermatitis. Int. Arch. Occup. Environ. Health 72, 496–506 (1999).
Martin, S. F. T lymphocyte-mediated immune responses to chemical haptens and metal ions: implications for allergic and autoimmune disease. Int. Arch. Allergy Immunol. 134, 186–198 (2004).
Vocanson, M. et al. Contribution of CD4+ and CD8+ T-cells in contact hypersensitivity and allergic contact dermatitis. Expert Rev. Clin. Immunol. 1, 75–86 (2005).
Martin, S. F. et al. Fas-mediated inhibition of CD4+ T cell priming results in dominance of type 1 CD8+ T cells in the immune response to the contact sensitizer trinitrophenyl. J. Immunol. 173, 3178–3185 (2004).
Watanabe, H., Unger, M., Tuvel, B., Wang, B. & Sauder, D. N. Contact hypersensitivity: the mechanism of immune responses and T cell balance. J. Interferon Cytokine Res. 22, 407–412 (2002).
Landsteiner, K. & Jacobs, J. Studies on the sensitization of animals with simple chemical compounds. III. Anaphylaxis induced by arsphenamine. J. Exp. Med. 64, 717–721 (1936). This article first proposed the idea that the formation of the hapten–self complex is a crucial early event in allergic contact dermatitis. Seventy-five years later, this hypothesis has been supported by the work of many investigators, and remains a core concept of allergic contact dermatitis.
Aptula, A. O. & Roberts, D. W. Mechanistic applicability domains for nonanimal-based prediction of toxicological end points: general principles and application to reactive toxicity. Chem. Res. Toxicol. 19, 1097–1105 (2006).
Roberts, D. W. & Aptula, A. O. Determinants of skin sensitisation potential. J. Appl. Toxicol. 28, 377–387 (2008).
Divkovic, M., Pease, C. K., Gerberick, G. F. & Basketter, D. A. Hapten–protein binding: from theory to practical application in the in vitro prediction of skin sensitization. Contact Dermatitis 53, 189–200 (2005).
Aptula, A. O., Roberts, D. W. & Pease, C. K. Haptens, prohaptens and prehaptens, or electrophiles and proelectrophiles. Contact Dermatitis 56, 54–56 (2007).
Smith, C. K. & Hotchkiss, S. A. M. Allergic Contact Dermatitis: Chemical and Metabolic Mechanisms 119–205 (Taylor and Francis, London, 2001).
Smith, C. K. & Hotchkiss, S. A. M. Allergic Contact Dermatitis: Chemical and Metabolic Mechanisms 89–117 (Taylor and Francis, London, 2001).
Kalgutkar, A. S. et al. A comprehensive listing of bioactivation pathways of organic functional groups. Curr. Drug Metab. 6, 161–225 (2005).
Lepoittevin, J. P. Metabolism versus chemical transformation or pro- versus prehaptens? Contact Dermatitis 54, 73–74 (2006).
Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).
Sloane, J. A., Blitz, D., Margolin, Z. & Vartanian, T. A clear and present danger: endogenous ligands of Toll-like receptors. Neuromolecular Med. 12, 149–163 (2010).
Martin, S. F. et al. Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity. J. Exp. Med. 205, 2151–2162 (2008). This is the first article to suggest that innate immune receptors, in the form of TLRs, play an important part in contact hypersensitivity.
Martin, S. F. et al. Mechanisms of chemical-induced innate immunity in allergic contact dermatitis. Allergy 66, 1152–1163 (2011).
Scheibner, K. A. et al. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J. Immunol. 177, 1272–1281 (2006).
Termeer, C. et al. Oligosaccharides of hyaluronan activate dendritic cells via Toll-like receptor 4. J. Exp. Med. 195, 99–111 (2002).
Stern, R., Kogan, G., Jedrzejas, M. J. & Soltes, L. The many ways to cleave hyaluronan. Biotechnol. Adv. 25, 537–557 (2007).
Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).
Sutterwala, F. S. et al. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24, 317–327 (2006).
Watanabe, H. et al. Activation of the IL-1β-processing inflammasome is involved in contact hypersensitivity. J. Invest. Dermatol. 127, 1956–1963 (2007).
Antonopoulos, C. et al. Functional caspase-1 is required for Langerhans cell migration and optimal contact sensitization in mice. J. Immunol. 166, 3672–3677 (2001).
Weber, F. C. et al. Lack of the purinergic receptor P2X7 results in resistance to contact hypersensitivity. J. Exp. Med. 207, 2609–2619 (2010). This study demonstrated that self molecules (such as ATP) released as a result of cellular damage by haptens activate the inflammasome.
Watanabe, H. et al. Danger signaling through the inflammasome acts as a master switch between tolerance and sensitization. J. Immunol. 180, 5826–5832 (2008).
Steinbrink, K., Sorg, C. & Macher, E. Low zone tolerance to contact allergens in mice: a functional role for CD8+ T helper type 2 cells. J. Exp. Med. 183, 759–768 (1996).
Schmidt, M. et al. Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nature Immunol. 11, 814–819 (2010). This study demonstrated how the world's most common contact allergen, nickel, activates TLR4, resulting in human APC activation following exposure to this ubiquitous chemical.
Beltrani, V. S. The role of house dust mites and other aeroallergens in atopic dermatitis. Clin. Dermatol. 21, 177–182 (2003).
Trompette, A. et al. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature 457, 585–588 (2009).
Palmer, C. N. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nature Genet. 38, 441–446 (2006).
Novak, N. et al. Loss-of-function mutations in the filaggrin gene and allergic contact sensitization to nickel. J. Invest. Dermatol. 128, 1430–1435 (2008).
Fallon, P. G. et al. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nature Genet. 41, 602–608 (2009).
Oyoshi, M. K., Murphy, G. F. & Geha, R. S. Filaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen. J. Allergy Clin. Immunol. 124, 485–493 (2009).
Scharschmidt, T. C. et al. Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens. J. Allergy Clin. Immunol. 124, 496–506 (2009).
Lebre, M. C. et al. Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9. J. Invest. Dermatol. 127, 331–341 (2007).
Uchi, H., Terao, H., Koga, T. & Furue, M. Cytokines and chemokines in the epidermis. J. Dermatol. Sci. 24, S29–S38 (2000).
Corsini, E. & Galli, C. L. Epidermal cytokines in experimental contact dermatitis. Toxicology 142, 203–211 (2000).
Nishibu, A., Ward, B. R., Boes, M. & Takashima, A. Roles for IL-1 and TNFα in dynamic behavioral responses of Langerhans cells to topical hapten application. J. Dermatol. Sci. 45, 23–30 (2007).
Cumberbatch, M., Griffiths, C. E., Tucker, S. C., Dearman, R. J. & Kimber, I. Tumour necrosis factor-α induces Langerhans cell migration in humans. Br. J. Dermatol. 141, 192–200 (1999).
Cumberbatch, M., Dearman, R. J. & Kimber, I. Langerhans cells require signals from both tumour necrosis factor-α and interleukin-1 β for migration. Immunology 92, 388–395 (1997).
Pasparakis, M., Alexopoulou, L., Episkopou, V. & Kollias, G. Immune and inflammatory responses in TNFα-deficient mice: a critical requirement for TNFα in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J. Exp. Med. 184, 1397–1411 (1996).
Liu, Y. J. et al. TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu. Rev. Immunol. 25, 193–219 (2007).
Soumelis, V. et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nature Immunol. 3, 673–680 (2002).
Ebner, S. et al. Thymic stromal lymphopoietin converts human epidermal Langerhans cells into antigen-presenting cells that induce proallergic T cells. J. Allergy Clin. Immunol. 119, 982–990 (2007).
Larson, R. P. et al. Dibutyl phthalate-induced thymic stromal lymphopoietin is required for Th2 contact hypersensitivity responses. J. Immunol. 184, 2974–2984 (2010).
Loser, K. et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nature Med. 12, 1372–1379 (2006).
Loser, K. & Beissert, S. Regulation of cutaneous immunity by the environment: an important role for UV irradiation and vitamin D. Int. Immunopharmacol. 9, 587–589 (2009).
Ghoreishi, M. et al. Expansion of antigen-specific regulatory T cells with the topical vitamin D analog calcipotriol. J. Immunol. 182, 6071–6078 (2009).
Hanneman, K. K., Scull, H. M., Cooper, K. D. & Baron, E. D. Effect of topical vitamin D analogue on in vivo contact sensitization. Arch. Dermatol. 142, 1332–1334 (2006).
Morioka, Y., Yamasaki, K., Leung, D. & Gallo, R. L. Cathelicidin antimicrobial peptides inhibit hyaluronan-induced cytokine release and modulate chronic allergic dermatitis. J. Immunol. 181, 3915–3922 (2008).
Nasir, A., Ferbel, B., Salminen, W., Barth, R. K. & Gaspari, A. A. Exaggerated and persistent cutaneous delayed-type hypersensitivity in transgenic mice whose epidermal keratinocytes constitutively express B7–1 antigen. J. Clin. Invest. 94, 892–898 (1994).
Williams, I. R., Ort, R. J. & Kupper, T. S. Keratinocyte expression of B7–1 in transgenic mice amplifies the primary immune response to cutaneous antigens. Proc. Natl Acad. Sci. USA 91, 12780–12784 (1994).
Ferguson, T. A., Dube, P. & Griffith, T. S. Regulation of contact hypersensitivity by interleukin 10. J. Exp. Med. 179, 1597–1604 (1994).
Forster, R. et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999).
Itano, A. A. et al. Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity. Immunity 19, 47–57 (2003). This study demonstrated that a productive immune response requires the transport of antigens to regional lymph nodes by skin-resident DCs.
Allenspach, E. J., Lemos, M. P., Porrett, P. M., Turka, L. A. & Laufer, T. M. Migratory and lymphoid-resident dendritic cells cooperate to efficiently prime naive CD4 T cells. Immunity 29, 795–806 (2008).
Ohl, L. et al. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21, 279–288 (2004).
Chorro, L. et al. Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network. J. Exp. Med. 206, 3089–3100 (2009).
Merad, M. et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nature Immunol. 3, 1135–1141 (2002).
Romani, N., Clausen, B. E. & Stoitzner, P. Langerhans cells and more: langerin-expressing dendritic cell subsets in the skin. Immunol. Rev. 234, 120–141 (2010).
Henri, S. et al. The dendritic cell populations of mouse lymph nodes. J. Immunol. 167, 741–748 (2001).
Bursch, L. S. et al. Identification of a novel population of langerin+ dendritic cells. J. Exp. Med. 204, 3147–3156 (2007).
Ginhoux, F. et al. Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state. J. Exp. Med. 204, 3133–3146 (2007).
Poulin, L. F. et al. The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells. J. Exp. Med. 204, 3119–3131 (2007).
Shklovskaya, E., Roediger, B. & Fazekas de St. Groth, B. Epidermal and dermal dendritic cells display differential activation and migratory behavior while sharing the ability to stimulate CD4+ T cell proliferation in vivo. J. Immunol. 181, 418–430 (2008).
Ginhoux, F. et al. The origin and development of nonlymphoid tissue CD103+ DCs. J. Exp. Med. 206, 3115–3130 (2009).
Henri, S. et al. CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells. J. Exp. Med. 207, 189–206 (2010).
Edelson, B. T. et al. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells. J. Exp. Med. 207, 823–836 (2010).
Merad, M., Ginhoux, F. & Collin, M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nature Rev. Immunol. 8, 935–947 (2008).
Le Borgne, M. et al. Dendritic cells rapidly recruited into epithelial tissues via CCR6/CCL20 are responsible for CD8+ T cell crosspriming in vivo. Immunity 24, 191–201 (2006).
Ginhoux, F. et al. Langerhans cells arise from monocytes in vivo. Nature Immunol. 7, 265–273 (2006).
Kaplan, D. H., Jenison, M. C., Saeland, S., Shlomchik, W. D. & Shlomchik, M. J. Epidermal Langerhans cell-deficient mice develop enhanced contact hypersensitivity. Immunity 23, 611–620 (2005).
Bobr, A. et al. Acute ablation of Langerhans cells enhances skin immune responses. J. Immunol. 185, 4724–4728 (2010).
Igyarto, B. Z. et al. Langerhans cells suppress contact hypersensitivity responses via cognate CD4 interaction and Langerhans cell-derived IL-10. J. Immunol. 183, 5085–5093 (2009).
Yoshiki, R. et al. IL-10-producing Langerhans cells and regulatory T cells are responsible for depressed contact hypersensitivity in grafted skin. J. Invest. Dermatol. 129, 705–713 (2009).
Obhrai, J. S. et al. Langerhans cells are not required for efficient skin graft rejection. J. Invest. Dermatol. 128, 1950–1955 (2008).
Kautz-Neu, K. et al. Langerhans cells are negative regulators of the anti-Leishmania response. J. Exp. Med. 208, 885–891 (2011).
Schwarz, A. et al. Langerhans cells are required for UVR-induced immunosuppression. J. Invest. Dermatol. 130, 1419–1427 (2010).
Fukunaga, A. et al. Langerhans cells serve as immunoregulatory cells by activating NKT cells. J. Immunol. 185, 4633–4640 (2010).
Kissenpfennig, A. et al. Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells. Immunity 22, 643–654 (2005).
Bennett, C. L. et al. Inducible ablation of mouse Langerhans cells diminishes but fails to abrogate contact hypersensitivity. J. Cell Biol. 169, 569–576 (2005).
Bennett, C. L., Noordegraaf, M., Martina, C. A. & Clausen, B. E. Langerhans cells are required for efficient presentation of topically applied hapten to T cells. J. Immunol. 179, 6830–6835 (2007).
Wang, L. et al. Langerin expressing cells promote skin immune responses under defined conditions. J. Immunol. 180, 4722–4727 (2008).
Kumamoto, Y., Denda-Nagai, K., Aida, S., Higashi, N. & Irimura, T. MGL2+ dermal dendritic cells are sufficient to initiate contact hypersensitivity in vivo. PLoS ONE 4, e5619 (2009).
Honda, T. et al. Compensatory role of Langerhans cells and langerin-positive dermal dendritic cells in the sensitization phase of murine contact hypersensitivity. J. Allergy Clin. Immunol. 125, 1154–1156 (2010).
Noordegraaf, M., Flacher, V., Stoitzner, P. & Clausen, B. E. Functional redundancy of Langerhans cells and langerin+ dermal dendritic cells in contact hypersensitivity. J. Invest. Dermatol. 130, 2752–2759 (2010).
Bedoui, S. et al. Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nature Immunol. 10, 488–495 (2009).
Igyarto, B. Z. et al. Skin-resident murine dendritic cell subsets promote distinct and opposing antigen-specific T helper cell responses. Immunity 35, 260–272 (2011).
Marshall, J. S., King, C. A. & McCurdy, J. D. Mast cell cytokine and chemokine responses to bacterial and viral infection. Curr. Pharm. Des. 9, 11–24 (2003).
Abraham, S. N. & St. John, A. L. Mast cell-orchestrated immunity to pathogens. Nature Rev. Immunol. 10, 440–452 (2010).
Askenase, P. W. et al. Defective elicitation of delayed-type hypersensitivity in W/Wv and SI/SId mast cell-deficient mice. J. Immunol. 131, 2687–2694 (1983).
Galli, S. J. & Hammel, I. Unequivocal delayed hypersensitivity in mast cell-deficient and beige mice. Science 226, 710–713 (1984).
Tsuji, R. F. et al. B cell-dependent T cell responses: IgM antibodies are required to elicit contact sensitivity. J. Exp. Med. 196, 1277–1290 (2002).
Jawdat, D. M., Albert, E. J., Rowden, G., Haidl, I. D. & Marshall, J. S. IgE-mediated mast cell activation induces Langerhans cell migration in vivo. J. Immunol. 173, 5275–5282 (2004).
McLachlan, J. B., Catron, D. M., Moon, J. J. & Jenkins, M. K. Dendritic cell antigen presentation drives simultaneous cytokine production by effector and regulatory T cells in inflamed skin. Immunity 30, 277–288 (2009).
Kalesnikoff, J. & Galli, S. J. New developments in mast cell biology. Nature Immunol. 9, 1215–1223 (2008).
Suto, H. et al. Mast cell-associated TNF promotes dendritic cell migration. J. Immunol. 176, 4102–4112 (2006).
Bryce, P. J. et al. Immune sensitization in the skin is enhanced by antigen-independent effects of IgE. Immunity 20, 381–392 (2004).
Grimbaldeston, M. A., Nakae, S., Kalesnikoff, J., Tsai, M. & Galli, S. J. Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B. Nature Immunol. 8, 1095–1104 (2007).
Galli, S. J., Grimbaldeston, M. & Tsai, M. Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nature Rev. Immunol. 8, 478–486 (2008).
Scholten, J. et al. Mast cell-specific Cre/loxP-mediated recombination in vivo. Transgenic Res. 17, 307–315 (2008).
Dudeck, A. et al. Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens. Immunity 34, 973–984 (2011). This study demonstrated that the adjuvant effects of haptens require mast cells and histamine. Mast cells are also required for hapten-induced DC migration to regional lymph nodes and for contact hypersensitivity.
Strid, J. et al. Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis. Nature Immunol. 9, 146–154 (2008).
Macleod, A. S. & Havran, W. L. Functions of skin-resident γδ T cells. Cell. Mol. Life Sci. 68, 2399–2408 (2011).
Girardi, M. et al. Resident skin-specific γδ T cells provide local, nonredundant regulation of cutaneous inflammation. J. Exp. Med. 195, 855–867 (2002).
Lewis, J. M. et al. Selection of the cutaneous intraepithelial γδ+ T cell repertoire by a thymic stromal determinant. Nature Immunol. 7, 843–850 (2006).
Toulon, A. et al. A role for human skin-resident T cells in wound healing. J. Exp. Med. 206, 743–750 (2009).
DeGroot, A. Patch Testing: Test Concentrations and Vehicles for 2800 Allergens (Elsevier, New York, USA, 1986).
Vocanson, M., Hennino, A., Rozieres, A., Poyet, G. & Nicolas, J. F. Effector and regulatory mechanisms in allergic contact dermatitis. Allergy 64, 1699–1714 (2009).
Kupper, T. S. & Fuhlbrigge, R. C. Immune surveillance in the skin: mechanisms and clinical consequences. Nature Rev. Immunol. 4, 211–222 (2004).
Akiba, H. et al. Skin inflammation during contact hypersensitivity is mediated by early recruitment of CD8+ T cytotoxic 1 cells inducing keratinocyte apoptosis. J. Immunol. 168, 3079–3087 (2002).
Cavani, A. et al. Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals. J. Immunol. 171, 5760–5768 (2003).
Vocanson, M. et al. Inducible costimulator (ICOS) is a marker for highly suppressive antigen-specific T cells sharing features of TH17/TH1 and regulatory T cells. J. Allergy Clin. Immunol. 126, 280–289 (2010).
O'Leary, J. G., Goodarzi, M., Drayton, D. L. & von Andrian, U. H. T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nature Immunol. 7, 507–516 (2006).
von Bubnoff, D. et al. Natural killer cells in atopic and autoimmune diseases of the skin. J. Allergy Clin. Immunol. 125, 60–68 (2010).
Carbone, T. et al. CD56highCD16−CD62L− NK cells accumulate in allergic contact dermatitis and contribute to the expression of allergic responses. J. Immunol. 184, 1102–1110 (2010).
Balato, A., Unutmaz, D. & Gaspari, A. A. Natural killer T cells: an unconventional T-cell subset with diverse effector and regulatory functions. J. Invest. Dermatol. 129, 1628–1642 (2009).
Nieuwenhuis, E. E. et al. CD1d and CD1d-restricted iNKT-cells play a pivotal role in contact hypersensitivity. Exp. Dermatol. 14, 250–258 (2005).
Campos, R. A. et al. Cutaneous immunization rapidly activates liver invariant Vα14 NKT cells stimulating B-1 B cells to initiate T cell recruitment for elicitation of contact sensitivity. J. Exp. Med. 198, 1785–1796 (2003).
Yusuf, N. et al. Protective role of Toll-like receptor 4 during the initiation stage of cutaneous chemical carcinogenesis. Cancer Res. 68, 615–622 (2008).
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).
The authors declare no competing financial interests.
- 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.
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.
(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.
About this article
Cite this article
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
Nature Reviews Disease Primers (2021)
Molecular Biology Reports (2021)
Current Dermatology Reports (2021)
Histopathologic Spectrum of Intraoral Irritant and Contact Hypersensitivity Reactions: A Series of 12 cases
Head and Neck Pathology (2021)