Allergy Asthma Immunol Res.  2012 Jan;4(1):12-16. 10.4168/aair.2012.4.1.12.

Epidermal Barrier in Atopic Dermatitis

• Kim BE
• Leung DY

• KMID: 2130373
• DOI: http://doi.org/10.4168/aair.2012.4.1.12

Abstract

Atopic dermatitis (AD) is a complex disease that affects up to 20% of children and impacts the quality of patients and families in a significant manner. New insights into the pathophysiology of AD point to an important role of structural abnormalities in the epidermis combined with immune dysregulation. Filaggrin (FLG) is synthesized as a large precursor, profilaggrin, and is expressed in the upper layers of the epidermis. FLG plays a critical role in the epidermal barrier, and FLG mutations cause abnormal epidermal function. FLG mutations are strongly associated with early-onset, and persistent severe AD. In addition, FLG deficiency in the epidermis is related to allergic sensitization and asthma. The basic skin care including repair and protection of the skin barrier with proper hydration and topical anti-inflammatory therapy is important to control the severity of skin disease in patients with AD.

Keyword

Atopic dermatitis; epidermal barrier; filaggrin

MeSH Terms

Asthma
Child
Dermatitis, Atopic
Epidermis
Humans
Intermediate Filament Proteins
Skin
Skin Care
Skin Diseases
Intermediate Filament Proteins

Figure

• 

  Figure Filaggrin (FLG) expression and functions in the epidermal skin barrier. FLG is expressed in the granular layer of epidermis. Profilaggrin is dephosphorylated and cleaved by several endoproteases including caspase-14 to generate FLG, and then FLG is degraded into free amino acids (NMF) by caspase-14.

Reference

1. Odhiambo JA, Williams HC, Clayton TO, Robertson CF, Asher MI. Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three. J Allergy Clin Immunol. 2009. 124:1251–1258.e23.

2. Bieber T. Atopic dermatitis. Ann Dermatol. 2010. 22:125–137.

3. Boguniewicz M, Leung DY. Recent insights into atopic dermatitis and implications for management of infectious complications. J Allergy Clin Immunol. 2010. 125:4–13.

4. Kay J, Gawkrodger DJ, Mortimer MJ, Jaron AG. The prevalence of childhood atopic eczema in a general population. J Am Acad Dermatol. 1994. 30:35–39.

5. Spergel JM. Atopic march: link to upper airways. Curr Opin Allergy Clin Immunol. 2005. 5:17–21.

6. Zheng T, Yu J, Oh MH, Zhu Z. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. Allergy Asthma Immunol Res. 2011. 3:67–73.

7. Beattie PE, Lewis-Jones MS. A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br J Dermatol. 2006. 155:145–151.

8. Boguniewicz M, Abramovits W, Paller A, Whitaker-Worth DL, Prendergast M, Cheng JW, Wang P, Tong KB. A multiple-domain framework of clinical, economic, and patient-reported outcomes for evaluating benefits of intervention in atopic dermatitis. J Drugs Dermatol. 2007. 6:416–423.

9. Mancini AJ, Kaulback K, Chamlin SL. The socioeconomic impact of atopic dermatitis in the United States: a systematic review. Pediatr Dermatol. 2008. 25:1–6.

10. Guttman-Yassky E, Suárez-Fariñas M, Chiricozzi A, Nograles KE, Shemer A, Fuentes-Duculan J, Cardinale I, Lin P, Bergman R, Bowcock AM, Krueger JG. Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis. J Allergy Clin Immunol. 2009. 124:1235–1244.e58.

11. Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol. 2009. 9:437–446.

12. Elias PM, Hatano Y, Williams ML. Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms. J Allergy Clin Immunol. 2008. 121:1337–1343.

13. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol. 2005. 6:328–340.

14. Kalinin A, Marekov LN, Steinert PM. Assembly of the epidermal cornified cell envelope. J Cell Sci. 2001. 114:3069–3070.

15. Oyoshi MK, Murphy GF, Geha RS. Filaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen. J Allergy Clin Immunol. 2009. 124:485–493. 493.e1

16. Potten CS. Cell replacement in epidermis (keratopoiesis) via discrete units of proliferation. Int Rev Cytol. 1981. 69:271–318.

17. Denecker G, Hoste E, Gilbert B, Hochepied T, Ovaere P, Lippens S, Van den Broecke C, Van Damme P, D'Herde K, Hachem JP, Borgonie G, Presland RB, Schoonjans L, Libert C, Vandekerckhove J, Gevaert K, Vandenabeele P, Declercq W. Caspase-14 protects against epidermal UVB photodamage and water loss. Nat Cell Biol. 2007. 9:666–674.

18. Nicotera P, Melino G. Caspase-14 and epidermis maturation. Nat Cell Biol. 2007. 9:621–622.

19. Scott IR, Harding CR. Filaggrin breakdown to water binding compounds during development of the rat stratum corneum is controlled by the water activity of the environment. Dev Biol. 1986. 115:84–92.

20. Steven AC, Bisher ME, Roop DR, Steinert PM. Biosynthetic pathways of filaggrin and loricrin--two major proteins expressed by terminally differentiated epidermal keratinocytes. J Struct Biol. 1990. 104:150–162.

21. Steinert PM, Marekov LN. The proteins elafin, filaggrin, keratin intermediate filaments, loricrin, and small proline-rich proteins 1 and 2 are isodipeptide cross-linked components of the human epidermal cornified cell envelope. J Biol Chem. 1995. 270:17702–17711.

22. Rice RH, Green H. The cornified envelope of terminally differentiated human epidermal keratinocytes consists of cross-linked protein. Cell. 1977. 11:417–422.

23. O'Regan GM, Sandilands A, McLean WH, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol. 2009. 124:R2–R6.

24. Guttman-Yassky E, Nograles KE, Krueger JG. Contrasting pathogenesis of atopic dermatitis and psoriasis--part I: clinical and pathologic concepts. J Allergy Clin Immunol. 2011. 127:1110–1118.

25. Harding CR. The stratum corneum: structure and function in health and disease. Dermatol Ther. 2004. 17:Suppl 1. 6–15.

26. Proksch E, Brandner JM, Jensen JM. The skin: an indispensable barrier. Exp Dermatol. 2008. 17:1063–1072.

27. Spergel JM, Mizoguchi E, Brewer JP, Martin TR, Bhan AK, Geha RS. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J Clin Invest. 1998. 101:1614–1622.

28. 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. 127:773–786.e1-7.

29. Jarnik M, de Viragh PA, Schärer E, Bundman D, Simon MN, Roop DR, Steven AC. Quasi-normal cornified cell envelopes in loricrin knockout mice imply the existence of a loricrin backup system. J Invest Dermatol. 2002. 118:102–109.

30. Koch PJ, de Viragh PA, Scharer E, Bundman D, Longley MA, Bickenbach J, Kawachi Y, Suga Y, Zhou Z, Huber M, Hohl D, Kartasova T, Jarnik M, Steven AC, Roop DR. Lessons from loricrin-deficient mice: compensatory mechanisms maintaining skin barrier function in the absence of a major cornified envelope protein. J Cell Biol. 2000. 151:389–400.

31. Rodríguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown SJ, Cordell HJ, Irvine AD, Weidinger S. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J Allergy Clin Immunol. 2009. 123:1361–1370.e7.

32. Jungersted JM, Scheer H, Mempel M, Baurecht H, Cifuentes L, Høgh JK, Hellgren LI, Jemec GB, Agner T, Weidinger S. Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema. Allergy. 2010. 65:911–918.

33. Morar N, Willis-Owen SA, Moffatt MF, Cookson WO. The genetics of atopic dermatitis. J Allergy Clin Immunol. 2006. 118:24–34.

34. Leung DY. Our evolving understanding of the functional role of filaggrin in atopic dermatitis. J Allergy Clin Immunol. 2009. 124:494–495.

35. Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, Klopp N, Wagenpfeil S, Zhao Y, Liao H, Lee SP, Palmer CN, Jenneck C, Maintz L, Hagemann T, Behrendt H, Ring J, Nothen MM, McLean WH, Novak N. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol. 2006. 118:214–219.

36. Sandilands A, Smith FJ, Irvine AD, McLean WH. Filaggrin's fuller figure: a glimpse into the genetic architecture of atopic dermatitis. J Invest Dermatol. 2007. 127:1282–1284.

37. O'Regan GM, Sandilands A, McLean WH, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol. 2008. 122:689–693.

38. Stemmler S, Parwez Q, Petrasch-Parwez E, Epplen JT, Hoffjan S. Two common loss-of-function mutations within the filaggrin gene predispose for early onset of atopic dermatitis. J Invest Dermatol. 2007. 127:722–724.

39. Brown SJ, Sandilands A, Zhao Y, Liao H, Relton CL, Meggitt SJ, Trembath RC, Barker JN, Reynolds NJ, Cordell HJ, McLean WH. Prevalent and low-frequency null mutations in the filaggrin gene are associated with early-onset and persistent atopic eczema. J Invest Dermatol. 2008. 128:1591–1594.

40. Nomura T, Sandilands A, Akiyama M, Liao H, Evans AT, Sakai K, Ota M, Sugiura H, Yamamoto K, Sato H, Palmer CN, Smith FJ, McLean WH, Shimizu H. Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis. J Allergy Clin Immunol. 2007. 119:434–440.

41. Zhang H, Guo Y, Wang W, Shi M, Chen X, Yao Z. Mutations in the filaggrin gene in Han Chinese patients with atopic dermatitis. Allergy. 2011. 66:420–427.

42. Henderson J, Northstone K, Lee SP, Liao H, Zhao Y, Pembrey M, Mukhopadhyay S, Smith GD, Palmer CN, McLean WH, Irvine AD. The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study. J Allergy Clin Immunol. 2008. 121:872–877.e9.

43. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, ORegan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant 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.

44. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007. 120:150–155.

45. Kim BE, Leung DY, Boguniewicz M, Howell MD. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008. 126:332–337.

46. Gao PS, Rafaels NM, Hand T, Murray T, Boguniewicz M, Hata T, Schneider L, Hanifin JM, Gallo RL, Gao L, Beaty TH, Beck LA, Barnes KC, Leung DY. Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticum. J Allergy Clin Immunol. 2009. 124:507–513. 513.e1–513.e7.

47. McLean WH, Palmer CN, Henderson J, Kabesch M, Weidinger S, Irvine AD. Filaggrin variants confer susceptibility to asthma. J Allergy Clin Immunol. 2008. 121:1294–1295. author reply 1295-6.

48. Hudson TJ. Skin barrier function and allergic risk. Nat Genet. 2006. 38:399–400.

49. Beck LA, Boguniewicz M, Hata T, Schneider LC, Hanifin J, Gallo R, Paller AS, Lieff S, Reese J, Zaccaro D, Milgrom H, Barnes KC, Leung DY. Phenotype of atopic dermatitis subjects with a history of eczema herpeticum. J Allergy Clin Immunol. 2009. 124:260–269. 269.e1–269.e7.

50. Howell MD, Fairchild HR, Kim BE, Bin L, Boguniewicz M, Redzic JS, Hansen KC, Leung DY. Th2 cytokines act on S100/A11 to down-regulate keratinocyte differentiation. J Invest Dermatol. 2008. 128:2248–2258.

51. Jung T, Stingl G. Atopic dermatitis: therapeutic concepts evolving from new pathophysiologic insights. J Allergy Clin Immunol. 2008. 122:1074–1081.

52. Gupta J, Grube E, Ericksen MB, Stevenson MD, Lucky AW, Sheth AP, Assa'ad AH, Khurana Hershey GK. Intrinsically defective skin barrier function in children with atopic dermatitis correlates with disease severity. J Allergy Clin Immunol. 2008. 121:725–730.e2.

53. Jensen JM, Pfeiffer S, Witt M, Bräutigam M, Neumann C, Weichenthal M, Schwarz T, Fölster-Holst R, Proksch E. Different effects of pimecrolimus and betamethasone on the skin barrier in patients with atopic dermatitis. J Allergy Clin Immunol. 2009. 124:R19–R28.

54. Akdis CA, Akdis M, Bieber T, Bindslev-Jensen C, Boguniewicz M, Eigenmann P, Hamid Q, Kapp A, Leung DY, Lipozencic J, Luger TA, Muraro A, Novak N, Platts-Mills TA, Rosenwasser L, Scheynius A, Simons FE, Spergel J, Turjanmaa K, Wahn U, Weidinger S, Werfel T, Zuberbier T. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/ PRACTALL Consensus Report. J Allergy Clin Immunol. 2006. 118:152–169.