Skip to main content

Extrinsic and Intrinsic Atopic Dermatitis

  • Chapter
  • First Online:
Evolution of Atopic Dermatitis in the 21st Century

Abstract

Atopic dermatitis (AD) can be categorized into extrinsic and intrinsic types. The serum levels of IgE are high in extrinsic AD and normal in intrinsic AD. This dichotomy also corresponds to the following terminology: mixed AD vs pure AD, allergic AD vs non-allergic AD, and classical AD vs atopiform dermatitis. While extrinsic AD is the common type with high prevalence, intrinsic AD is approximately 20% in incidence and shows apparent female predominance. Extrinsic AD is closely associated with barrier perturbation and Th2-skewing immunological condition, but the causes and mechanisms of intrinsic AD remain elusive. In extrinsic AD, antigens can penetrate through disrupted barrier, and epidermal Langerhans cells serve as antigen-presenting cells to Th2 cells. In intrinsic AD, nonprotein antigens, such as metals and haptens, and Th1/Th17 cells participate as well as Th2 cells. Notably, intrinsic AD shows significantly higher percentages of positive patch test to nickel and cobalt than extrinsic AD, indicating high frequency of metal allergy in intrinsic AD.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Institutional subscriptions

Similar content being viewed by others

References

  1. Novak N, Bieber T. Allergic and nonallergic forms of atopic diseases. J Allergy Clin Immunol. 2003;112:252–62.

    Article  PubMed  Google Scholar 

  2. Tokura Y. Extrinsic and intrinsic types of atopic dermatitis. J Dermatol Sci. 2010;58:1–7.

    Article  CAS  PubMed  Google Scholar 

  3. Romanet-Manent S, Charpin D, Magnan A, Lanteaume A, Vervloet D. Allergic vs nonallergic asthma: what makes the difference? Allergy. 2002;57:607–13.

    Article  PubMed  Google Scholar 

  4. Wuthrich B. Atopic dermatitis. Ther Umsch. 1989;46:633–40.

    CAS  PubMed  Google Scholar 

  5. Diepgen TL, Fartasch M. Recent epidemiological and genetic studies in atopic dermatitis. Acta Derm Venereol. 1992;176:13–8.

    CAS  Google Scholar 

  6. Brenninkmeijer EE, Spuls PI, Legierse CM, Lindeboom R, Smitt JH, Bos JD. Clinical differences between atopic and atopiform dermatitis. J Am Acad Dermatol. 2008;58:407–14.

    Article  PubMed  Google Scholar 

  7. Folster-Holst R, Pape M, Buss YL, Christophers E, Weichenthal M. Low prevalence of the intrinsic form of atopic dermatitis among adult patients. Allergy. 2006;61:629–32.

    Article  CAS  PubMed  Google Scholar 

  8. Schafer T, Kramer U, Vieluf D, Abeck D, Behrendt H, Ring J. The excess of atopic eczema in east germany is related to the intrinsic type. Br J Dermatol. 2000;143:992–8.

    Article  CAS  PubMed  Google Scholar 

  9. Ponyai G, Hidvegi B, Nemeth I, Sas A, Temesvari E, Karpati S. Contact and aeroallergens in adulthood atopic dermatitis. J Eur Acad Dermatol Venereol. 2008;22:1346–55.

    Article  CAS  PubMed  Google Scholar 

  10. Miraglia del Giudice M, Decimo F, Leonardi S, Maioello N, Amelio R, Capasso A, et al. Immune dysregulation in atopic dermatitis. Allergy Asthma Proc. 2006;27:451–5.

    Article  CAS  PubMed  Google Scholar 

  11. Ingordo V, D'Andria G, D'Andria C, Tortora A. Results of atopy patch tests with house dust mites in adults with ‘intrinsic’ and ‘extrinsic’ atopic dermatitis. J Eur Acad Dermatol Venereol. 2002;16:450–4.

    Article  CAS  PubMed  Google Scholar 

  12. Rho NK, Kim WS, Lee DY, Lee JH, Lee ES, Yang JM. Immunophenotyping of inflammatory cells in lesional skin of the extrinsic and intrinsic types of atopic dermatitis. Br J Dermatol. 2004;151:119–25.

    Article  PubMed  Google Scholar 

  13. Park JH, Choi YL, Namkung JH, Kim WS, Lee JH, Park HJ, et al. Characteristics of extrinsic vs. intrinsic atopic dermatitis in infancy: correlations with laboratory variables. Br J Dermatol. 2006;155:778–83.

    Article  PubMed  Google Scholar 

  14. Mori T, Ishida K, Mukumoto S, Yamada Y, Imokawa G, Kabashima K, et al. Comparison of skin barrier function and sensory nerve electric current perception threshold between ige-high extrinsic and ige-normal intrinsic types of atopic dermatitis. Br J Dermatol. 2009;162(1):83–90.

    Article  PubMed  Google Scholar 

  15. Kabashima-Kubo R, Nakamura M, Sakabe JI, Sugita K, Hino R, Mori T, Kobayashi M, Bito T, Kabashima K, Ogasawara K, Nomura Y, Nomura T, Akiyama M, Shimizu H, Tokura Y. A group of atopic dermatitis without IgE elevation or barrier impairment shows a high Th1 frequency: possible immunological state of the intrinsic type. J Dermatol Sci. 2012;67:37–43.

    Article  CAS  PubMed  Google Scholar 

  16. Wollenberg A, Kraft S, Oppel T, Bieber T. Atopic dermatitis: pathogenetic mechanisms. Clin Exp Dermatol. 2000;25:530–4.

    Article  CAS  PubMed  Google Scholar 

  17. Wuthrich B, Schmid-Grendelmeier P. The atopic eczema/dermatitis syndrome. Epidemiology, natural course, and immunology of the IgE-associated (“extrinsic”) and the nonallergic (“intrinsic”) AEDS. J Investig Allergol Clin Immunol. 2003;13:1–5.

    CAS  PubMed  Google Scholar 

  18. Ott H, Stanzel S, Ocklenburg C, Merk HF, Baron JM, Lehmann S. Total serum ige as a parameter to differentiate between intrinsic and extrinsic atopic dermatitis in children. Acta Derm Venereol. 2009;89:257–61.

    Article  PubMed  Google Scholar 

  19. Schmid-Grendelmeier P, Simon D, Simon HU, Akdis CA, Wuthrich B. Epidemiology, clinical features, and immunology of the “intrinsic” (non-IgE-mediated) type of atopic dermatitis (constitutional dermatitis). Allergy. 2001;56:841–9.

    Article  CAS  PubMed  Google Scholar 

  20. Casagrande BF, Fluckiger S, Linder MT, Johansson C, Scheynius A, Crameri R, et al. Sensitization to the yeast malassezia sympodialis is specific for extrinsic and intrinsic atopic eczema. J Invest Dermatol. 2006;126:2414–21.

    Article  PubMed  Google Scholar 

  21. Yamaguchi H, Kabashima-Kubo R, Bito T, Sakabe J-I, Shimauchi T, Ito T, Hirakawa S, Hirasawa N, Ogasawara K, Tokura Y. High frequencies of positive nickel/cobalt patch tests and high sweat nickel concentration in patients with intrinsic atopic dermatitis. J Dermatol Sci. 2013;72(3):240–5. (in press)

    Article  CAS  PubMed  Google Scholar 

  22. Ott H, Wilke J, Baron JM, Hoger PH, Folster-Holst R. Soluble immune receptor serum levels are associated with age, but not with clinical phenotype or disease severity in childhood atopic dermatitis. J Eur Acad Dermatol Venereol. 2009;24(4):395–402.

    Article  PubMed  Google Scholar 

  23. Choi SJ, Song MG, Sung WT, Lee DY, Lee JH, Lee ES, et al. Comparison of transepidermal water loss, capacitance and pH values in the skin between intrinsic and extrinsic atopic dermatitis patients. J Korean Med Sci. 2003;18:93–6.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Novak N, Kruse S, Kraft S, Geiger E, Kluken H, Fimmers R, et al. Dichotomic nature of atopic dermatitis reflected by combined analysis of monocyte immunophenotyping and single nucleotide polymorphisms of the interleukin-4/interleukin-13 receptor gene: the dichotomy of extrinsic and intrinsic atopic dermatitis. J Invest Dermatol. 2002;119:870–5.

    Article  CAS  PubMed  Google Scholar 

  25. Kusel MM, Holt PG, de Klerk N, Sly PD. Support for 2 variants of eczema. J Allergy Clin Immunol. 2005;116:1067–72.

    Article  PubMed  Google Scholar 

  26. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38:441–6.

    Article  CAS  PubMed  Google Scholar 

  27. Nomura T, Akiyama M, Sandilands A, Nemoto-Hasebe I, Sakai K, Nagasaki A, et al. Specific filaggrin mutations cause ichthyosis vulgaris and are significantly associated with atopic dermatitis in japan. J Invest Dermatol. 2008;128:1436–41.

    Article  CAS  PubMed  Google Scholar 

  28. Sakabe J, Yamamoto M, Hirakawa S, Motoyama A, Ohta I, Tatsuno K, Ito T, Kabashima K, Hibino T, Tokura Y. Kallikrein-related peptidase 5 functions in proteolytic processing of profilaggrin in cultured human keratinocytes. J Biol Chem. 2013;288:17179–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol. 2006;118:214–9.

    Article  CAS  PubMed  Google Scholar 

  30. Weidinger S, Rodriguez E, Stahl C, et al. Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis. J Invest Dermatol. 2007;127:724–6.

    Article  CAS  PubMed  Google Scholar 

  31. Sakabe J, Kamiya K, Yamaguchi H, Ikeya S, Suzuki T, Aoshima M, Tatsuno K, Fujiyama T, Suzuki M, Yatagai T, Ito T, Ojima T, Tokura Y. Proteome analysis of stratum corneum from atopic dermatitis patients by hybrid quadrupole-orbitrap mass spectrometer. J Allergy Clin Immunol. 2014;134:957–60.

    Article  CAS  PubMed  Google Scholar 

  32. Namkung JH, Lee JE, Kim E, Cho HJ, Kim S, Shin ES, et al. IL-5 and IL-5 receptor alpha polymorphisms are associated with atopic dermatitis in koreans. Allergy. 2007;62:934–42.

    Article  CAS  PubMed  Google Scholar 

  33. Raap U, Werfel T, Goltz C, Deneka N, Langer K, Bruder M, et al. Circulating levels of brain-derived neurotrophic factor correlate with disease severity in the intrinsic type of atopic dermatitis. Allergy. 2006;61:1416–8.

    Article  CAS  PubMed  Google Scholar 

  34. Simon D, Von Gunten S, Borelli S, Braathen LR, Simon HU. The interleukin-13 production by peripheral blood T cells from atopic dermatitis patients does not require CD2 costimulation. Int Arch Allergy Immunol. 2003;132:148–55.

    Article  CAS  PubMed  Google Scholar 

  35. Akdis M, Trautmann A, Klunker S, Daigle I, Kucuksezer UC, Deglmann W, Disch R, Blaser K, Akdis CA. T helper (Th) 2 predominance in atopic diseases is due to preferential apoptosis of circulating memory/effector Th1 cells. FASEB J. 2003;17:1026–35.

    Article  CAS  PubMed  Google Scholar 

  36. Jeong CW, Ahn KS, Rho NK, Park YD, Lee DY, Lee JH, et al. Differential in vivo cytokine mrna expression in lesional skin of intrinsic vs. extrinsic atopic dermatitis patients using semiquantitative rt-pcr. Clin Exp Allergy. 2003;33:1717–24.

    Article  CAS  PubMed  Google Scholar 

  37. Suárez-Fariñas M, Dhingra N, Gittler J, Shemer A, Cardinale I, de Guzman Strong C, Krueger JG, Guttman-Yassky E. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J Allergy Clin Immunol. 2013;132:361–70.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Koga C, Kabashima K, Shiraishi N, Kobayashi M, Tokura Y. Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol. 2008;128:2625–30.

    Article  CAS  PubMed  Google Scholar 

  39. Oyoshi MK, He R, Kumar L, Yoon J, Geha RS. Cellular and molecular mechanisms in atopic dermatitis. Adv Immunol. 2009;102:135–226.

    Article  CAS  PubMed  Google Scholar 

  40. Park CO, Lee HJ, Lee JH, Wu WH, Chang NS, Hua L, et al. Increased expression of cc chemokine ligand 18 in extrinsic atopic dermatitis patients. Exp Dermatol. 2008;17:24–9.

    Article  CAS  PubMed  Google Scholar 

  41. Wang IJ, Hsieh WS, Guo YL, Jee SH, Hsieh CJ, Hwang YH, et al. Neuro-mediators as predictors of paediatric atopic dermatitis. Clin Exp Allergy. 2008;38:1302–8.

    Article  CAS  PubMed  Google Scholar 

  42. Oppel T, Schuller E, Gunther S, Moderer M, Haberstok J, Bieber T, et al. Phenotyping of epidermal dendritic cells allows the differentiation between extrinsic and intrinsic forms of atopic dermatitis. Br J Dermatol. 2000;143:1193–8.

    Article  CAS  PubMed  Google Scholar 

  43. Kabashima K. New concept of the pathogenesis of atopic dermatitis: interplay among the barrier, allergy, and pruritus as a trinity. J Dermatol Sci. 2013;70:3–11.

    Article  PubMed  Google Scholar 

  44. Tatsuno K, Fujiyama T, Yamaguchi H, Waki M, Tokura Y. TSLP directly interacts with skin-homing Th2 cells highly expressing its receptor to enhance IL-4 production in atopic dermatitis. J Invest Dermatol. 2015;135:3017–24.

    Article  CAS  PubMed  Google Scholar 

  45. Nakajima S, Igyártó BZ, Honda T, Egawa G, Otsuka A, Hara-Chikuma M, Watanabe N, Ziegler SF, Tomura M, Inaba K, Miyachi Y, Kaplan DH, Kabashima K. Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling. J Allergy Clin Immunol. 2013;129:1048–55.

    Article  Google Scholar 

  46. Nishijima T, Tokura Y, Imokawa G, Seo N, Furukawa F, Takigawa M. Altered permeability and disordered cutaneous immunoregulatory function in mice with acute barrier disruption. J Invest Dermatol. 1997;109:175–82.

    Article  CAS  PubMed  Google Scholar 

  47. Onoue A, Kabashima K, Kobayashi M, Mori T, Tokura Y. Induction of eosinophil- and th2-attracting epidermal chemokines and cutaneous late-phase reaction in tape-stripped skin. Exp Dermatol. 2009;18:1036–43.

    Article  CAS  PubMed  Google Scholar 

  48. Mori T, Kabashima K, Yoshiki R, Sugita K, Shiraishi N, Onoue A, et al. Cutaneous hypersensitivities to hapten are controlled by ifn-gamma-upregulated keratinocyte th1 chemokines and ifn-gamma-downregulated langerhans cell th2 chemokines. J Invest Dermatol. 2008;128:1719–27.

    Article  CAS  PubMed  Google Scholar 

  49. Hatano Y, Terashi H, Arakawa S, Katagiri K. Interleukin-4 suppresses the enhancement of ceramide synthesis and cutaneous permeability barrier functions induced by tumor necrosis factor-alpha and interferon-gamma in human epidermis. J Invest Dermatol. 2005;124:786–92.

    Article  CAS  PubMed  Google Scholar 

  50. Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol. 2009;9:437–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hachem JP, Roelandt T, Schurer N, Pu X, Fluhr J, Giddelo C, et al. Acute acidification of stratum corneum membrane domains using polyhydroxyl acids improves lipid processing and inhibits degradation of corneodesmosomes. J Invest Dermatol. 2010;130:500–10.

    Article  CAS  PubMed  Google Scholar 

  52. Giordano-Labadie F, Rance F, Pellegrin F, Bazex J, Dutau G, Schwarze HP. Frequency of contact allergy in children with atopic dermatitis: results of a prospective study of 137 cases. Contact Dermatitis. 1999;40:192–5.

    Article  CAS  PubMed  Google Scholar 

  53. Shanon J. Pseudo-atopic dermatitis. Contact dermatitis due to chrome sensitivity simulating atopic dermatitis. Dermatologica. 1965;131:176–90.

    Article  CAS  PubMed  Google Scholar 

  54. De CP, Decock PA, Shanon J. Pseudo-atopic dermatitis. An example of pseudo-nomenclature. Dermatologica. 1966;133:236–7.

    Article  Google Scholar 

  55. Ruff CA, Belsito DV. The impact of various patients factors on contact allergy to nickel, cobalt, and chrome. J Am Acad Dermatol. 2006;55:32–9.

    Article  PubMed  Google Scholar 

  56. Dena M, Donald VB. Cutaneous delayed-type hypersensitivity in patients with atopic dermatitis. J Am Acad Dermatol. 2013;70(1):102–7.

    Google Scholar 

  57. Jensen CS, Menné T, Lisby S, Kristiansen J, Veien NK. Experimental systemic contact dermatitis from nickel: a dose-response study. Contact Dermatitis. 2003;49:124–32.

    Article  CAS  PubMed  Google Scholar 

  58. Lammintausta K, Pitkänen OP, Kalimo K, et al. Interrelationship of nickel and cobalt contact sensitization. Contact Dermatitis. 1985;13:148–52.

    Article  CAS  PubMed  Google Scholar 

  59. Schmidt M, Raghavan B, Müller V, Vogl T, Fejer G, Tchaptchet S, et al. Crucial role for human toll-like receptor 4 in the development of contact allergy to nickel. Nat Immunol. 2010;11:814–9.

    Article  CAS  PubMed  Google Scholar 

  60. Raghavan B, Martin SF, Esser PR, Goebeler M, Schmidt M. Metal allergens nickel and cobalt facilitate TLR4 homodimerization independently of MD2. EMBO Rep. 2012;13:1109–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Schram SE, Warshaw EM. Genetics of nickel allergic contact dermatitis. Dermatitis. 2007;18:125–33.

    Article  CAS  PubMed  Google Scholar 

  62. Minang JT, Areström I, Troye-Blomberg M, Lundeberg L, Ahlborg N. Nickel, cobalt, chromium, palladium and gold induce a mixed Th1- and Th2-type cytokine response in vitro in subjects with contact allergy to the respective metals. Clin Exp Immunol. 2006;146:417–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Thyssen JP. Nickel and cobalt allergy before and after nickel regulation: evaluation of a public health intervention. Contact Dermatitis. 2011;65(Suppl. 1):1–68.

    Article  Google Scholar 

  64. Darsow U, Fedorov M, Schwegler U, Twardella D, Schaller KH, Habernegg R, et al. Influence of dietary factors, age and nickel contact dermatitis on nickel excretion. Contact Dermatitis. 2012;67:351–8.

    Article  CAS  PubMed  Google Scholar 

  65. Martin SF, Esser PR, Weber FC, Jakob T, Freudenberg MA, Scmidt M, et al. Mechanisms of chemical-induced innate immunity in allergic contact dermatitis. Allergy. 2011;66:1152–63.

    Article  CAS  PubMed  Google Scholar 

  66. Thyssen JP, Linneberg A, Engkidle K, Menne ́ T, Johansen JD. Contact sensitization to common haptens is associated with atopic dermatitis: new insight. Br J Dermatol. 2012;166:1255–61.

    Article  CAS  PubMed  Google Scholar 

  67. Sharma AD. Relationship between nickel and diet. Indian J Dermatol. 2007;73:307–12.

    Google Scholar 

  68. Veien NK, Andersen MR. Nickel in Danish food. Acta Derm Venereol. 1986;66:502–9.

    CAS  PubMed  Google Scholar 

  69. Christensen JM, Kristiansen J, Nielsen NH, Menne ́ T, Byrialsen K. Nickel concentrations in serum and urine of patients with nickel eczema. Toxicol Lett. 1999;108:185–9.

    Article  CAS  PubMed  Google Scholar 

  70. Yamaguchi H, Hirasawa N, Asakawa S, Okita K, Tokura Y. Intrinsic atopic dermatitis shows high serum nickel concentration. Allergol Int. 2015;64:282–4.

    Article  CAS  PubMed  Google Scholar 

  71. Howell MD, Boguniewicz M, Pastore S, Novak N, Bieber T, Girolomoni G, et al. Mechanism of HBD-3 deficiency in atopic dermatitis. Clin Immunol. 2006;121:332–8.

    Article  CAS  PubMed  Google Scholar 

  72. Ricci G, Patrizi A, Neri I, Bendandi B, Masi M. Frequency and clinical role of staphylococcus aureus overinfection in atopic dermatitis in children. Pediatr Dermatol. 2003;20:389–92.

    Article  PubMed  Google Scholar 

  73. Pavlovic S, Liezmann C, Blois SM, Joachim R, Kruse J, Romani N, Klapp BF, Peters EM. Substance P is a key mediator of stress-induced protection from allergic sensitization via modified antigen presentation. J Immunol. 2011;186:848–55.

    Article  CAS  PubMed  Google Scholar 

  74. Jin H, He R, Oyoshi M, Geha RS. Animal models of atopic dermatitis. J Invest Dermatol. 2009;129:31–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chen L, Overbergh L, Mathieu C, Chan LS. The development of atopic dermatitis is independent of immunoglobulin E up-regulation in the K14-IL-4 skh1 transgenic mouse model. Clin Exp Allergy. 2008;38:1367–80.

    Article  CAS  PubMed  Google Scholar 

  76. Konishi H, Tsutsui H, Murakami T, Yumikura-Futatsugi S, Yamanaka K, Tanaka M, et al. IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of ige/stat6 under specific pathogen-free conditions. Proc Natl Acad Sci U S A. 2002;99:11340–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Terada M, Tsutsui H, Imai Y, Yasuda K, Mizutani H, Yamanishi K, et al. Contribution of IL-18 to atopic-dermatitis-like skin inflammation induced by staphylococcus aureus product in mice. Proc Natl Acad Sci U S A. 2006;103:8816–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yoshiki Tokura M.D., Ph.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

Tokura, Y. (2018). Extrinsic and Intrinsic Atopic Dermatitis. In: Katayama, I., Murota, H., Satoh, T. (eds) Evolution of Atopic Dermatitis in the 21st Century. Springer, Singapore. https://doi.org/10.1007/978-981-10-5541-6_15

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-5541-6_15

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-5540-9

  • Online ISBN: 978-981-10-5541-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics