Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Basic mechanisms and pathophysiology of allergic contact dermatitis

Anthony Gaspari, MD
Section Editor
Joseph Fowler, MD
Deputy Editor
Rosamaria Corona, MD, DSc


Allergic contact dermatitis (ACD) is a common inflammatory skin disease presenting with pruritic, eczematous lesions. ACD results from a T cell-mediated, delayed type hypersensitivity (DTH) reaction elicited by the contact of the skin with the offending chemical in individuals who have been previously sensitized to the same chemical. ACD is common in the general population and is the most frequent occupational skin disease. Its etiology may be suggested by the body sites of involvement, history of exposure, and morphology and distribution of the skin lesions.

This topic will discuss the immune mechanisms and pathophysiology of ACD. The clinical manifestations, diagnosis, and management of ACD are discussed separately. (See "Clinical features and diagnosis of allergic contact dermatitis" and "Management of allergic contact dermatitis".)


The understanding of the cellular and molecular pathogenesis of allergic contact dermatitis (ACD) has expanded dramatically. In addition to CD4+ and CD8+ T cells, other cell types such as natural killer T (NKT) cells, natural killer cells, innate lymphoid cells, and T regulatory cells have emerged as critical participants (table 1). In the elicitation phase, Langerhans cells appear to play a role in the development of immune tolerance rather than hypersensitivity reaction (as was once thought). B cells also appear to be important during the initiation of ACD by secreting IgM antibody in response to NKT cell-derived interleukin (IL)-4, leading to complement activation and immune cell chemotaxis. As new mechanisms and molecules emerge as a result of advances in the understanding of ACD, new pharmacologic targets will become apparent.


Hapten binding is the initial step in the development of allergic contact dermatitis (ACD). Contact allergens are low molecular weight (<500 Daltons) chemicals called haptens, which are able to penetrate the stratum corneum barrier of the skin. Haptens are not immunogenic by themselves, but they can be efficiently recognized by the immune system after binding to a skin protein carrier. Haptens may be naturally occurring substances such as urushiol found in the resin of poison ivy, synthetic compounds, dyes, fragrances, drugs, or heavy metal salts.

The binding of haptens to skin proteins (protein haptenation) involves the formation of a covalent bond between the electrophilic components of the hapten and the amino acid nucleophilic side chains of the target proteins within the skin [1]. Examples of chemicals containing electrophilic components are aldehydes, ketones, amides, or halogenated compounds. Metal cations (eg, nickel [NIi]2+, one of the most common ACD-associated haptens; and chromium [Cr]3+) are also well-known electrophiles. Some haptens that are not normally electrophilic (prohaptens) can be converted to protein-reactive species via oxidation or metabolic transformation by epidermal keratinocytes and/or dendritic cells [1]. Additional factors influencing the sensitizing ability of haptens include lipophilicity, tridimensional chemical structure, and protein-binding affinity.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Oct 2017. | This topic last updated: Apr 05, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Divkovic M, Pease CK, Gerberick GF, Basketter DA. Hapten-protein binding: from theory to practical application in the in vitro prediction of skin sensitization. Contact Dermatitis 2005; 53:189.
  2. Kaplan DH, Kissenpfennig A, Clausen BE. Insights into Langerhans cell function from Langerhans cell ablation models. Eur J Immunol 2008; 38:2369.
  3. Katz SI, Tamaki K, Sachs DH. Epidermal Langerhans cells are derived from cells originating in bone marrow. Nature 1979; 282:324.
  4. Vocanson M, Hennino A, Rozières A, et al. Effector and regulatory mechanisms in allergic contact dermatitis. Allergy 2009; 64:1699.
  5. Bergstresser PR, Toews GB, Streilein JW. Natural and perturbed distributions of Langerhans cells: responses to ultraviolet light, heterotopic skin grafting, and dinitrofluorobenzene sensitization. J Invest Dermatol 1980; 75:73.
  6. Weinlich G, Heine M, Stössel H, et al. Entry into afferent lymphatics and maturation in situ of migrating murine cutaneous dendritic cells. J Invest Dermatol 1998; 110:441.
  7. Steinbrink K, Kolde G, Sorg C, Macher E. Induction of low zone tolerance to contact allergens in mice does not require functional Langerhans cells. J Invest Dermatol 1996; 107:243.
  8. Larsen CP, Steinman RM, Witmer-Pack M, et al. Migration and maturation of Langerhans cells in skin transplants and explants. J Exp Med 1990; 172:1483.
  9. Lukas M, Stössel H, Hefel L, et al. Human cutaneous dendritic cells migrate through dermal lymphatic vessels in a skin organ culture model. J Invest Dermatol 1996; 106:1293.
  10. Moodycliffe AM, Shreedhar V, Ullrich SE, et al. CD40-CD40 ligand interactions in vivo regulate migration of antigen-bearing dendritic cells from the skin to draining lymph nodes. J Exp Med 2000; 191:2011.
  11. Nuriya S, Yagita H, Okumura K, Azuma M. The differential role of CD86 and CD80 co-stimulatory molecules in the induction and the effector phases of contact hypersensitivity. Int Immunol 1996; 8:917.
  12. Zhou LJ, Tedder TF. A distinct pattern of cytokine gene expression by human CD83+ blood dendritic cells. Blood 1995; 86:3295.
  13. Lehé CL, Jacobs JJ, Hua CM, et al. Subtoxic concentrations of allergenic haptens induce LC migration and maturation in a human organotypic skin explant culture model: a novel method for identifying potential contact allergens. Exp Dermatol 2006; 15:421.
  14. Aiba S, Terunuma A, Manome H, Tagami H. Dendritic cells differently respond to haptens and irritants by their production of cytokines and expression of co-stimulatory molecules. Eur J Immunol 1997; 27:3031.
  15. Toebak MJ, Gibbs S, Bruynzeel DP, et al. Dendritic cells: biology of the skin. Contact Dermatitis 2009; 60:2.
  16. Bennett CL, van Rijn E, Jung S, et al. Inducible ablation of mouse Langerhans cells diminishes but fails to abrogate contact hypersensitivity. J Cell Biol 2005; 169:569.
  17. Poulin LF, Henri S, de Bovis B, et al. The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells. J Exp Med 2007; 204:3119.
  18. Bursch LS, Wang L, Igyarto B, et al. Identification of a novel population of Langerin+ dendritic cells. J Exp Med 2007; 204:3147.
  19. Grabbe S, Steinbrink K, Steinert M, et al. Removal of the majority of epidermal Langerhans cells by topical or systemic steroid application enhances the effector phase of murine contact hypersensitivity. J Immunol 1995; 155:4207.
  20. Grabbe S, Schwarz T. Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol Today 1998; 19:37.
  21. Nakano Y. Antigen-presenting cell function of epidermal cells activated by hapten application. Br J Dermatol 1998; 138:786.
  22. Gaspari AA, Jenkins MK, Katz SI. Class II MHC-bearing keratinocytes induce antigen-specific unresponsiveness in hapten-specific Th1 clones. J Immunol 1988; 141:2216.
  23. Gaspari AA, Katz SI. Induction of in vivo hyporesponsiveness to contact allergens by hapten-modified Ia+ keratinocytes. J Immunol 1991; 147:4155.
  24. Bour H, Peyron E, Gaucherand M, et al. Major histocompatibility complex class I-restricted CD8+ T cells and class II-restricted CD4+ T cells, respectively, mediate and regulate contact sensitivity to dinitrofluorobenzene. Eur J Immunol 1995; 25:3006.
  25. Martin S, Lappin MB, Kohler J, et al. Peptide immunization indicates that CD8+ T cells are the dominant effector cells in trinitrophenyl-specific contact hypersensitivity. J Invest Dermatol 2000; 115:260.
  26. Vocanson M, Hennino A, Cluzel-Tailhardat M, et al. CD8+ T cells are effector cells of contact dermatitis to common skin allergens in mice. J Invest Dermatol 2006; 126:815.
  27. Gocinski BL, Tigelaar RE. Roles of CD4+ and CD8+ T cells in murine contact sensitivity revealed by in vivo monoclonal antibody depletion. J Immunol 1990; 144:4121.
  28. Vocanson M, Hennino A, Chavagnac C, et al. Contribution of CD4(+ )and CD8(+) T-cells in contact hypersensitivity and allergic contact dermatitis. Expert Rev Clin Immunol 2005; 1:75.
  29. Akiba H, Kehren J, Ducluzeau MT, et al. Skin inflammation during contact hypersensitivity is mediated by early recruitment of CD8+ T cytotoxic 1 cells inducing keratinocyte apoptosis. J Immunol 2002; 168:3079.
  30. Kehren J, Desvignes C, Krasteva M, et al. Cytotoxicity is mandatory for CD8(+) T cell-mediated contact hypersensitivity. J Exp Med 1999; 189:779.
  31. Traidl C, Sebastiani S, Albanesi C, et al. Disparate cytotoxic activity of nickel-specific CD8+ and CD4+ T cell subsets against keratinocytes. J Immunol 2000; 165:3058.
  32. Morita H, Moro K, Koyasu S. Innate lymphoid cells in allergic and nonallergic inflammation. J Allergy Clin Immunol 2016; 138:1253.
  33. Dyring-Andersen B, Geisler C, Agerbeck C, et al. Increased number and frequency of group 3 innate lymphoid cells in nonlesional psoriatic skin. Br J Dermatol 2014; 170:609.
  34. Kim HS, Jang JH, Lee MB, et al. A novel IL-10-producing innate lymphoid cells (ILC10) in a contact hypersensitivity mouse model. BMB Rep 2016; 49:293.
  35. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124:783.
  36. Sloane JA, Blitz D, Margolin Z, Vartanian T. A clear and present danger: endogenous ligands of Toll-like receptors. Neuromolecular Med 2010; 12:149.
  37. Martin SF, Dudda JC, Bachtanian E, et al. Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity. J Exp Med 2008; 205:2151.
  38. Martin SF, Esser PR, Weber FC, et al. Mechanisms of chemical-induced innate immunity in allergic contact dermatitis. Allergy 2011; 66:1152.
  39. Scheibner KA, Lutz MA, Boodoo S, et al. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol 2006; 177:1272.
  40. Termeer C, Benedix F, Sleeman J, et al. Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med 2002; 195:99.
  41. Stern R, Kogan G, Jedrzejas MJ, Soltés L. The many ways to cleave hyaluronan. Biotechnol Adv 2007; 25:537.
  42. Schmidt M, Raghavan B, Müller V, et al. Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat Immunol 2010; 11:814.
  43. Rachmawati D, Bontkes HJ, Verstege MI, et al. Transition metal sensing by Toll-like receptor-4: next to nickel, cobalt and palladium are potent human dendritic cell stimulators. Contact Dermatitis 2013; 68:331.
  44. Cavani A, Nasorri F, Ottaviani C, et al. Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals. J Immunol 2003; 171:5760.
  45. Reduta T, Stasiak-Barmuta A, Laudańska H. CD4+CD25+ and CD4+CD2+high regulatory T cells in disseminated and localized forms of allergic contact dermatitis: relation to specific cytokines. Folia Histochem Cytobiol 2011; 49:255.
  46. Honda T, Miyachi Y, Kabashima K. Regulatory T cells in cutaneous immune responses. J Dermatol Sci 2011; 63:75.
  47. Yoshiki R, Kabashima K, Sugita K, et al. IL-10-producing Langerhans cells and regulatory T cells are responsible for depressed contact hypersensitivity in grafted skin. J Invest Dermatol 2009; 129:705.
  48. Ring S, Karakhanova S, Johnson T, et al. Gap junctions between regulatory T cells and dendritic cells prevent sensitization of CD8(+) T cells. J Allergy Clin Immunol 2010; 125:237.
  49. Dubois B, Chapat L, Goubier A, et al. Innate CD4+CD25+ regulatory T cells are required for oral tolerance and inhibition of CD8+ T cells mediating skin inflammation. Blood 2003; 102:3295.
  50. Ring S, Enk AH, Mahnke K. ATP activates regulatory T Cells in vivo during contact hypersensitivity reactions. J Immunol 2010; 184:3408.
  51. Honda T, Otsuka A, Tanizaki H, et al. Enhanced murine contact hypersensitivity by depletion of endogenous regulatory T cells in the sensitization phase. J Dermatol Sci 2011; 61:144.
  52. Ring S, Schäfer SC, Mahnke K, et al. CD4+ CD25+ regulatory T cells suppress contact hypersensitivity reactions by blocking influx of effector T cells into inflamed tissue. Eur J Immunol 2006; 36:2981.
  53. Ring S, Oliver SJ, Cronstein BN, et al. CD4+CD25+ regulatory T cells suppress contact hypersensitivity reactions through a CD39, adenosine-dependent mechanism. J Allergy Clin Immunol 2009; 123:1287.
  54. Tomura M, Honda T, Tanizaki H, et al. Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice. J Clin Invest 2010; 120:883.
  55. Trautmann A, Altznauer F, Akdis M, et al. The differential fate of cadherins during T-cell-induced keratinocyte apoptosis leads to spongiosis in eczematous dermatitis. J Invest Dermatol 2001; 117:927.