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Filaggrin pp 9–21Cite as

Morphology of Filaggrin-Depleted Epidermis

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Abstract

Depletion of filaggrin results in dose-dependent impairment of epidermal permeability barrier function, which is characterized by distinctive morphological changes best detectable in ichthyosis vulgaris. In addition to increased skin surface pH, epidermal hyperplasia, augmented number of stratum corneum (SC) cell layers, and decreased SC hydration, the keratinocytes of the stratum granulosum show an absence to near-absence of F-type keratohyalin granules and perinuclear halos resulting from retraction of keratin intermediate filaments. Although filaggrin is an intracellular protein, filaggrin-deficient corneocytes display only a slightly reduced integrity and increased permeation verifiable by elevated transepidermal water loss (TEWL) that occurs solely via a paracellular route. This goes together with an abnormal extracellular lamellar bilayer architecture due to impaired loading of secretory cargo within lamellar bodies and nonuniform extracellular post-secretory dispersion of secreted organelle contents. Furthermore, filaggrin-depleted epidermis features defective corneocyte cohesion based on decreased corneodesmosome density and length and impaired tight junction (TJ) formation pointed by abnormal expression and localization of TJ proteins.

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References

  1. Gruber R, Elias PM, Crumrine D, Lin TK, Brandner JM, Hachem JP, et al. Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function. Am J Pathol. 2011;178(5):2252–63.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Traupe H, Happle R. Clinical features and genetics of the ichthyosis vulgaris group. Fortschr Med. 1980;98(46):1809–15.

    CAS  PubMed  Google Scholar 

  3. Uehara M, Hayashi S. Hyperlinear palms: association with ichthyosis and atopic dermatitis. Arch Dermatol. 1981;117(8):490–1.

    Article  CAS  PubMed  Google Scholar 

  4. Oji V, Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Soreze 2009. J Am Acad Dermatol. 2010;63(4):607–41.

    Article  PubMed  Google Scholar 

  5. Schmuth M, Martinz V, Janecke AR, Fauth C, Schossig A, Zschocke J, et al. Inherited ichthyoses/generalized Mendelian disorders of cornification. Eur J Hum Genet. 2013;21(2):123–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Brown SJ, Relton CL, Liao H, Zhao Y, Sandilands A, Wilson IJ, et al. Filaggrin null mutations and childhood atopic eczema: a population-based case-control study. J Allergy Clin Immunol. 2008;121(4):940–46.e3.

    Article  CAS  PubMed  Google Scholar 

  7. Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006;38(3):337–42.

    Article  CAS  PubMed  Google Scholar 

  8. Sandilands A, Terron-Kwiatkowski A, Hull PR, O'Regan GM, Clayton TH, Watson RM, et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet. 2007;39(5):650–4.

    Article  CAS  PubMed  Google Scholar 

  9. Sandilands A, O’Regan GM, Liao H, Zhao Y, Terron-Kwiatkowski A, Watson RM, et al. Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis. J Invest Dermatol. 2006;126(8):1770–5.

    Article  CAS  PubMed  Google Scholar 

  10. Gruber R, Janecke AR, Fauth C, Utermann G, Fritsch PO, Schmuth M. Filaggrin mutations p.R501X and c.2282del4 in ichthyosis vulgaris. Eur J Hum Genet. 2007;15(2):179–84.

    Article  CAS  PubMed  Google Scholar 

  11. Thyssen JP, Linneberg A, Johansen JD, Carlsen BC, Zachariae C, Meldgaard M, et al. Atopic diseases by filaggrin mutations and birth year. Allergy. 2012;67(5):705–8.

    Article  CAS  PubMed  Google Scholar 

  12. 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(4):441–6.

    Article  CAS  PubMed  Google Scholar 

  13. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011;365(14):1315–27.

    Article  CAS  PubMed  Google Scholar 

  14. Angelova-Fischer I, Mannheimer AC, Hinder A, Ruether A, Franke A, Neubert RH, et al. Distinct barrier integrity phenotypes in filaggrin-related atopic eczema following sequential tape stripping and lipid profiling. Exp Dermatol. 2011;20(4):351–6.

    Article  PubMed  Google Scholar 

  15. 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(6):1337–43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Proksch E, Brandner JM, Jensen JM. The skin: an indispensable barrier. Exp Dermatol. 2008;17(12):1063–72.

    Article  PubMed  Google Scholar 

  17. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007;120(1):150–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. 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(2):266–78.

    Article  CAS  PubMed  Google Scholar 

  19. Kawasaki H, Nagao K, Kubo A, Hata T, Shimizu A, Mizuno H, et al. Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice. J Allergy Clin Immunol. 2012;129(6):1538–46.e6.

    Article  CAS  PubMed  Google Scholar 

  20. Presland RB, Boggess D, Lewis SP, Hull C, Fleckman P, Sundberg JP. Loss of normal pro-filaggrin and filaggrin in flaky tail (ft/ft) mice: an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris. J Invest Dermatol. 2000;115(6):1072–81.

    Article  CAS  PubMed  Google Scholar 

  21. Saunders SP, et al. Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects. J Allergy Clin Immunol. 2013;132(5):1121–9. (PMID 24084074).

    Google Scholar 

  22. Brown SJ, McLean WH. One remarkable molecule: filaggrin. J Invest Dermatol. 2012;132(3 Pt 2):751–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol. 2005;6(4):328–40.

    Article  CAS  PubMed  Google Scholar 

  24. 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(30):17702–11.

    Article  CAS  PubMed  Google Scholar 

  25. Simon M, Haftek M, Sebbag M, Montezin M, Girbal-Neuhauser E, Schmitt D, et al. Evidence that filaggrin is a component of cornified cell envelopes in human plantar epidermis. Biochem J. 1996;317(Pt 1):173–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Elias PM, et al. Formation and functions of the corneocyte lipid envelope (CLE). Biochim Biophys Acta. 2014;1841(3):314–18. (PMID 24076475).

    Google Scholar 

  27. Zheng Y, Yin H, Boeglin WE, Elias PM, Crumrine D, Beier DR, et al. Lipoxygenases mediate the effect of essential fatty acid in skin barrier formation: a proposed role in releasing omega-hydroxyceramide for construction of the corneocyte lipid envelope. J Biol Chem. 2011;286(27):24046–56.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Feingold KR, Schmuth M, Elias PM. The regulation of permeability barrier homeostasis. J Invest Dermatol. 2007;127(7):1574–6.

    Article  CAS  PubMed  Google Scholar 

  29. Elias PM. Stratum corneum defensive functions: an integrated view. J Invest Dermatol. 2005;125(2):183–200.

    CAS  PubMed  Google Scholar 

  30. 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(1):84–92.

    Article  CAS  PubMed  Google Scholar 

  31. Krien PM, Kermici M. Evidence for the existence of a self-regulated enzymatic process within the human stratum corneum -an unexpected role for urocanic acid. J Invest Dermatol. 2000;115(3):414–20.

    Article  CAS  PubMed  Google Scholar 

  32. Fluhr JW, Elias PM, Man MQ, Hupe M, Selden C, Sundberg JP, et al. Is the filaggrin-histidine-urocanic acid pathway essential for stratum corneum acidification? J Invest Dermatol. 2010;130(8):2141–4.

    Article  CAS  PubMed  Google Scholar 

  33. Perusquia-Ortiz AM, Oji V, Sauerland MC, Tarinski T, Zaraeva I, Seller N, et al. Complete filaggrin deficiency in ichthyosis vulgaris is associated with only moderate changes in epidermal permeability barrier function profile. J Eur Acad Dermatol Venereol. 2013;27(12):1552–8.

    Article  CAS  PubMed  Google Scholar 

  34. Denda M, Sato J, Tsuchiya T, Elias PM, Feingold KR. Low humidity stimulates epidermal DNA synthesis and amplifies the hyperproliferative response to barrier disruption: implication for seasonal exacerbations of inflammatory dermatoses. J Invest Dermatol. 1998;111(5):873–8.

    Article  CAS  PubMed  Google Scholar 

  35. Ohman H, Vahlquist A. The pH gradient over the stratum corneum differs in X-linked recessive and autosomal dominant ichthyosis: a clue to the molecular origin of the “acid skin mantle”? J Invest Dermatol. 1998;111(4):674–7.

    Article  CAS  PubMed  Google Scholar 

  36. Nachat R, Mechin MC, Takahara H, Chavanas S, Charveron M, Serre G, et al. Peptidylarginine deiminase isoforms 1–3 are expressed in the epidermis and involved in the deimination of K1 and filaggrin. J Invest Dermatol. 2005;124(2):384–93.

    Article  CAS  PubMed  Google Scholar 

  37. Scott IR, Harding CR, Barrett JG. Histidine-rich protein of the keratohyalin granules. Source of the free amino acids, urocanic acid and pyrrolidone carboxylic acid in the stratum corneum. Biochim Biophys Acta. 1982;719(1):110–7.

    Article  CAS  PubMed  Google Scholar 

  38. Erickson L, Kahn G. The granular layer thickness in atopy and ichthyosis vulgaris. J Invest Dermatol. 1970;54(1):11–2.

    Article  CAS  PubMed  Google Scholar 

  39. Sybert VP, Dale BA, Holbrook KA. Ichthyosis vulgaris: identification of a defect in synthesis of filaggrin correlated with an absence of keratohyaline granules. J Invest Dermatol. 1985;84(3):191–4.

    Article  CAS  PubMed  Google Scholar 

  40. Fleckman P, Holbrook KA, Dale BA, Sybert VP. Keratinocytes cultured from subjects with ichthyosis vulgaris are phenotypically abnormal. J Invest Dermatol. 1987;88(5):640–5.

    Article  CAS  PubMed  Google Scholar 

  41. Anton-Lamprecht I, Hofbauer M. Ultrastructural distinction of autosomal dominant ichthyosis vulgaris and X-linked recessive ichthyosis. Humangenetik. 1972;15(3):261–4.

    CAS  PubMed  Google Scholar 

  42. Fleckman P, Brumbaugh S. Absence of the granular layer and keratohyalin define a morphologically distinct subset of individuals with ichthyosis vulgaris. Exp Dermatol. 2002;11(4):327–36.

    Article  PubMed  Google Scholar 

  43. Ziprkowski L, Feinstein A. A survey of ichthyosis vulgaris in Israel. Br J Dermatol. 1972;86(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  44. Rice RH, Crumrine D, Uchida Y, Gruber R, Elias PM. Structural changes in epidermal scale and appendages as indicators of defective TGM1 activity. Arch Dermatol Res. 2005;297(3):127–33.

    Article  CAS  PubMed  Google Scholar 

  45. Winge MC, Hoppe T, Berne B, Vahlquist A, Nordenskjold M, Bradley M, et al. Filaggrin genotype determines functional and molecular alterations in skin of patients with atopic dermatitis and ichthyosis vulgaris. PLoS One. 2011;6(12):e28254.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Schmuth M, Gruber R, Elias PM, Williams ML. Ichthyosis update: towards a function-driven model of pathogenesis of the disorders of cornification and the role of corneocyte proteins in these disorders. Adv Dermatol. 2007;23:231–56.

    Article  PubMed Central  PubMed  Google Scholar 

  47. Mildner M, Jin J, Eckhart L, Kezic S, Gruber F, Barresi C, et al. Knockdown of filaggrin impairs diffusion barrier function and increases UV sensitivity in a human skin model. J Invest Dermatol. 2010;130(9):2286–94.

    Article  CAS  PubMed  Google Scholar 

  48. Fallon PG, Sasaki T, Sandilands A, Campbell LE, Saunders SP, Mangan NE, et al. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet. 2009;41(5):602–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Scharschmidt TC, Man MQ, Hatano Y, Crumrine D, Gunathilake R, Sundberg JP, et al. Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens. J Allergy Clin Immunol. 2009;124(3):496–506, e1–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. 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(1):214–9.

    Article  CAS  PubMed  Google Scholar 

  51. Thyssen JP, Johansen JD, Linneberg A, Menné T, Nielsen NH, Meldgaard M, et al. The association between null mutations in the filaggrin gene and contact sensitization to nickel and other chemicals in the general population. Br J Dermatol. 2010;162(6):1278–85.

    Google Scholar 

  52. Menon GK, Price LF, Bommannan B, Elias PM, Feingold KR. Selective obliteration of the epidermal calcium gradient leads to enhanced lamellar body secretion. J Invest Dermatol. 1994;102(5):789–95.

    Article  CAS  PubMed  Google Scholar 

  53. Hachem JP, Man MQ, Crumrine D, Uchida Y, Brown BE, Rogiers V, et al. Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity. J Invest Dermatol. 2005;125(3):510–20.

    Article  CAS  PubMed  Google Scholar 

  54. Hachem JP, Wagberg F, Schmuth M, Crumrine D, Lissens W, Jayakumar A, et al. Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome. J Invest Dermatol. 2006;126(7):1609–21.

    Article  CAS  PubMed  Google Scholar 

  55. Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, Moustafa M, et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol. 2009;129(8):1892–908.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Dermatology and Venereology, Innsbruck Medical University, Anichstraße 35, Innsbruck, 6020, Austria

    Robert Gruber MD

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  1. Robert Gruber MD
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Correspondence to Robert Gruber MD .

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  1. Department of Dermato-Allergology, National Allergy Research Centre, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark

    Jacob P. Thyssen

  2. Department of Dermatology, University of California, San Francisco, California, USA

    Howard I. Maibach

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Gruber, R. (2014). Morphology of Filaggrin-Depleted Epidermis. In: Thyssen, J., Maibach, H. (eds) Filaggrin. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-54379-1_2

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  • DOI: https://doi.org/10.1007/978-3-642-54379-1_2

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