J Korean Med Assoc.  2014 Mar;57(3):218-225. 10.5124/jkma.2014.57.3.218.

Pathogenesis of atopic dermatitis

Affiliations
  • 1Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Korea. choieh@yonsei.ac.kr

Abstract

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease with severe pruritus, and the first step of atopic march since it often precedes asthma or allergic rhinitis. Since its etiology or pathogenesis is very complex and frequently changing, physicians cannot easily understand it in entirety. New insights into the genetics and pathophysiology of AD emphasize the crucial function of the skin barrier as well as abnormal immune response. In this review, the pathogenesis of AD is explained as the combined features of impaired skin barrier and abnormal immune response rather than each independent concept. Understanding the whole pathogenesis of AD may lead to early intervention and prevention of atopic march as well as proper clinical treatment.

Keyword

Atopic dermatitis; Skin barrier; Hypersensitivity; Filaggrin; Thymic stromal lymphopoietin

MeSH Terms

Asthma
Dermatitis, Atopic*
Early Intervention (Education)
Genetics
Hypersensitivity
Pruritus
Rhinitis
Skin
Skin Diseases

Figure

  • Figure 1 Life cycle of filaggrin. Filaggrin exists as profilaggrin within keratohyaline granules in the granular layer of epidermis. It is degraded to filaggrin during the terminal differentiation process. Then, going up to the upper part of stratum corneum (SC), filaggrin degrades into amino acids and plays a crucial role in maintaining SC hydration and pH by forming natural moisturizing factor including pyrrolidone carboxylic acid or urocanic acid (From Choi EH, et al. J Skin Barrier Res 2013;15:13-23, with permission from Korean Society for Skin Barrier Research) [4].

  • Figure 2 Two main pathogenesis of dry skin in atopic dermatitis. First pathway is a reduced natural moisturizing factor (NMF) in the stratum corneum (SC) due to filaggrin deficiency which caused by inherited FLG mutation or lesional Th2 inflammation. Second is a decreased SC hydration as well as increased transepidermal water loss (TEWL) and epidermal proliferation due to disrupted SC intercellular lamellae which caused by deficiency of ceramide (esp, ceramide 1 having long chain) in SC. KC, keratinocytes.

  • Figure 3 Complex interaction among skin pH, filaggrin, serine protease and serine protease inhibitor in skin inflammation of atopic dermatitis (AD) patients. Acute barrier disruption in non-atopy healthy people induces serine protease (SP) activation transiently, but inhibited immediately with serine protease inhibitor (SPI), therefore reaches to barrier recovery (top blue dotted box). On the other hand, in the case of AD patients with SPINK5 or FLG gene mutation, uncontrolled SP activity could induce the activation of protease-activated receptor-2 (PAR-2), in turn thymic stromal lymphopoietin (TSLP) followed by aggravation cycle to skin allergic inflammation (bottom red dotted box). LB, lamellar body, LC, Langerhans cell.

  • Figure 4 Combined pathogenesis of atopic dermatitis including dysfunctions of skin barrier and immune response. Skin barrier is composed of corneocytes (brick), intercellular lipid lamellae (mortar) and corneodesmosomes (rivet) in stratum corneum and tight junctions in upper stratum granulosum. If these structures have inherited or acquired defect, exogenous allergens, microbes, or pollutants can easily penetrate skin barrier. And then abnormal responses of innate immune and adaptive system induce allergic inflammation in the patients with atopic dermatitis.


Reference

1. Yu JS, Lee CJ, Lee HS, Kim J, Han Y, Ahn K, Lee SI. Prevalence of atopic dermatitis in Korea: analysis by using national statistics. J Korean Med Sci. 2012; 27:681–685.
Article
2. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Ser-geant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006; 38:441–446.
Article
3. Elias PM, Steinhoff M. "Outside-to-inside" (and now back to "outside") pathogenic mechanisms in atopic dermatitis. J Invest Dermatol. 2008; 128:1067–1070.
Article
4. Choi EH, Yoon NY, Kim DH, Jung M. Barrier related biomarkers of atopic dermatitis. J Skin Barrier Res. 2013; 15:13–23.
5. Irvine AD, McLean WH. Breaking the (un)sound barrier: filaggrin is a major gene for atopic dermatitis. J Invest Dermatol. 2006; 126:1200–1202.
Article
6. Melnik B, Hollmann J, Plewig G. Decreased stratum corneum ceramides in atopic individuals: a pathobiochemical factor in xerosis? Br J Dermatol. 1988; 119:547–549.
Article
7. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, Gallo RL, Leung DY. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002; 347:1151–1160.
Article
8. Kato A, Fukai K, Oiso N, Hosomi N, Murakami T, Ishii M. Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. Br J Dermatol. 2003; 148:665–669.
Article
9. De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, Berger AE, Zhang K, Vidyasagar S, Yoshida T, Boguniewicz M, Hata T, Schneider LC, Hanifin JM, Gallo RL, Novak N, Weidinger S, Beaty TH, Leung DY, Barnes KC, Beck LA. Tight junction defects in patients with atopic dermatitis. J Allergy Clin Immunol. 2011; 127:773–786e7.
Article
10. Seguchi T, Cui CY, Kusuda S, Takahashi M, Aisu K, Tezuka T. Decreased expression of filaggrin in atopic skin. Arch Dermatol Res. 1996; 288:442–446.
Article
11. Choi EH, Yoon NY. Skin barrier related pathogenesis of atopic dermatitis. J Skin Barrier Res. 2012; 14:70–76.
12. Morar N, Cookson WO, Harper JI, Moffatt MF. Filaggrin mutations in children with severe atopic dermatitis. J Invest Dermatol. 2007; 127:1667–1672.
Article
13. Nomura T, Akiyama M, Sandilands A, Nemoto-Hasebe I, Sakai K, Nagasaki A, Ota M, Hata H, Evans AT, Palmer CN, Shimizu H, McLean WH. Specific filaggrin mutations cause ichthyosis vulgaris and are significantly associated with atopic dermatitis in Japan. J Invest Dermatol. 2008; 128:1436–1441.
Article
14. Li M, Liu Q, Liu J, Cheng R, Zhang H, Xue H, Bao Y, Yao Z. Mutations analysis in filaggrin gene in northern China patients with atopic dermatitis. J Eur Acad Dermatol Venereol. 2013; 27:169–174.
Article
15. Greisenegger E, Novak N, Maintz L, Bieber T, Zimprich F, Haubenberger D, Gleiss A, Stingl G, Kopp T, Zimprich A. Analysis of four prevalent filaggrin mutations (R501X, 2282del4, R2447X and S3247X) in Austrian and German patients with atopic dermatitis. J Eur Acad Dermatol Venereol. 2010; 24:607–610.
Article
16. Barker JN, Palmer CN, Zhao Y, Liao H, Hull PR, Lee SP, Allen MH, Meggitt SJ, Reynolds NJ, Trembath RC, McLean WH. Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood. J Invest Dermatol. 2007; 127:564–567.
Article
17. Kezic S, O'Regan GM, Yau N, Sandilands A, Chen H, Campbell LE, Kroboth K, Watson R, Rowland M, McLean WH, Irvine AD. Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity. Allergy. 2011; 66:934–940.
Article
18. Imokawa G, Abe A, Jin K, Higaki Y, Kawashima M, Hidano A. Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol. 1991; 96:523–526.
Article
19. Jeong SK, Kim HJ, Youm JK, Ahn SK, Choi EH, Sohn MH, Kim KE, Hong JH, Shin DM, Lee SH. Mite and cockroach allergens activate protease-activated receptor 2 and delay epidermal permeability barrier recovery. J Invest Dermatol. 2008; 128:1930–1939.
Article
20. Zhao LP, Di Z, Zhang L, Wang L, Ma L, Lv Y, Hong Y, Wei H, Chen HD, Gao XH. Association of SPINK5 gene polymorphisms with atopic dermatitis in Northeast China. J Eur Acad Dermatol Venereol. 2012; 26:572–577.
Article
21. Baek JH, Lee SE, Choi KJ, Choi EH, Lee SH. Acute modulations in stratum corneum permeability barrier function affect claudin expression and epidermal tight junction function via changes of epidermal calcium gradient. Yonsei Med J. 2013; 54:523–528.
Article
22. Kubo A, Nagao K, Amagai M. Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases. J Clin Invest. 2012; 122:440–447.
Article
23. De Benedetto A, Slifka MK, Rafaels NM, Kuo IH, Georas SN, Boguniewicz M, Hata T, Schneider LC, Hanifin JM, Gallo RL, Johnson DC, Barnes KC, Leung DY, Beck LA. Reductions in claudin-1 may enhance susceptibility to herpes simplex virus 1 infections in atopic dermatitis. J Allergy Clin Immunol. 2011; 128:242–246e5.
Article
24. Boguniewicz M, Leung DY. Recent insights into atopic dermatitis and implications for management of infectious complications. J Allergy Clin Immunol. 2010; 125:4–13.
Article
25. Valenta R, Natter S, Seiberler S, Roschanak M, Mothes N, Mahler V, Eibensteiner P. Autoallergy: a pathogenetic factor in atopic dermatitis? Curr Probl Dermatol. 1999; 28:45–50.
Article
26. Liu FT, Goodarzi H, Chen HY. IgE, mast cells, and eosinophils in atopic dermatitis. Clin Rev Allergy Immunol. 2011; 41:298–310.
Article
27. Kuo IH, Yoshida T, De Benedetto A, Beck LA. The cutaneous innate immune response in patients with atopic dermatitis. J Allergy Clin Immunol. 2013; 131:266–278.
Article
28. Leung DY. New insights into atopic dermatitis: role of skin barrier and immune dysregulation. Allergol Int. 2013; 62:151–161.
Article
29. Mamessier E, Magnan A. Cytokines in atopic diseases: revisiting the Th2 dogma. Eur J Dermatol. 2006; 16:103–113.
30. Howell MD, Boguniewicz M, Pastore S, Novak N, Bieber T, Girolomoni G, Leung DY. Mechanism of HBD-3 deficiency in atopic dermatitis. Clin Immunol. 2006; 121:332–338.
Article
31. He JQ, Chan-Yeung M, Becker AB, Dimich-Ward H, Ferguson AC, Manfreda J, Watson WT, Sandford AJ. Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children. Genes Immun. 2003; 4:385–389.
Article
32. Beghe B, Barton S, Rorke S, Peng Q, Sayers I, Gaunt T, Keith TP, Clough JB, Holgate ST, Holloway JW. Polymorphisms in the interleukin-4 and interleukin-4 receptor alpha chain genes confer susceptibility to asthma and atopy in a Caucasian population. Clin Exp Allergy. 2003; 33:1111–1117.
33. Hummelshoj T, Bodtger U, Datta P, Malling HJ, Oturai A, Poulsen LK, Ryder LP, Sorensen PS, Svejgaard E, Svejgaard A. Association between an interleukin-13 promoter polymorphism and atopy. Eur J Immunogenet. 2003; 30:355–359.
Article
34. Koga C, Kabashima K, Shiraishi N, Kobayashi M, Tokura Y. Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol. 2008; 128:2625–2630.
Article
35. Nograles KE, Zaba LC, Shemer A, Fuentes-Duculan J, Cardinale I, Kikuchi T, Ramon M, Bergman R, Krueger JG, Guttman-Yassky E. IL-22-producing "T22" T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin Immunol. 2009; 123:1244–1252e2.
Article
36. Ziegler SF, Artis D. Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol. 2010; 11:289–293.
Article
37. Lee EB, Kim KW, Hong JY, Jee HM, Sohn MH, Kim KE. Increased serum thymic stromal lymphopoietin in children with atopic dermatitis. Pediatr Allergy Immunol. 2010; 21:e457–e460.
Article
38. Wu WH, Park CO, Oh SH, Kim HJ, Kwon YS, Bae BG, Noh JY, Lee KH. Thymic stromal lymphopoietin-activated invariant natural killer T cells trigger an innate allergic immune response in atopic dermatitis. J Allergy Clin Immunol. 2010; 126:290–299e4.
Article
39. Harada M, Hirota T, Jodo AI, Hitomi Y, Sakashita M, Tsunoda T, Miyagawa T, Doi S, Kameda M, Fujita K, Miyatake A, Enomoto T, Noguchi E, Masuko H, Sakamoto T, Hizawa N, Suzuki Y, Yoshihara S, Adachi M, Ebisawa M, Saito H, Matsumoto K, Nakajima T, Mathias RA, Rafaels N, Barnes KC, Himes BE, Duan QL, Tantisira KG, Weiss ST, Nakamura Y, Ziegler SF, Tamari M. Thymic stromal lymphopoietin gene promoter polymorphisms are associated with susceptibility to bronchial asthma. Am J Respir Cell Mol Biol. 2011; 44:787–793.
Article
40. Zhang Z, Hener P, Frossard N, Kato S, Metzger D, Li M, Chambon P. Thymic stromal lymphopoietin overproduced by keratinocytes in mouse skin aggravates experimental asthma. Proc Natl Acad Sci U S A. 2009; 106:1536–1541.
Article
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