Abstract
The majority of patients with eczema have a filaggrin defect, most commonly mutations R501X and 2282del4, both of which relate to skin barrier function. The truest expression of filaggrin deficiency is ichthyosis vulgaris, and patients who have both ichthyosis vulgaris and eczema have profound itching. Patients with other types of ichthyosis may also have eczema though the causative genes are dissimilar. The common link in these differing genes is their role in making a faulty stratum corneum, preventing it from serving as a barrier to protect the human organism from outside substances. The hypothesis is that biofilm-producing staphylococci that are normal flora under the influence of sweating and occlusion produce biofilms. These biofilms obstruct the sweat ducts and lead to the activation of Toll-like receptor 2, which triggers the production of many mediators, including tumor necrosis factor α, which leads to epidermal spongiosis, and protease-activating receptor 2 (PAR2), which in turn leads to itching. Therefore in this “double-hit” (genetic and environmental) phenomenon, the environmental hit is staphylococci and their biofilms and the genetic hit is filaggrin.
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References
Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011;365(14):1315–27. A “mechanisms of disease” review article from the New England Journal of Medicine discussing extensively the discovery, genomic variations, and clinical manifestations associated with filaggrin mutations. Although attention focuses on ichthyosis vulgaris, atopic dermatitis, asthma, allergic rhinitis, and food allergies, this article offers a comprehensive, multiorgan, and genetic overview of the ramifications associated with these mutations.
Sandilands A, Terron-Kwiatkowski A, Hull PR, 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.
Sandilands A, O’Regan GM, Liao H, 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.
Smith FJ, Irvine AD, Terron-Kwiatkowski A, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006;38(3):337–42. A series of articles based around a study of European school children, confirming the genetic basis of ichthyosis vulgaris. In addition, certain physical characteristics such as hyperlinear palms are specifically linked to genetic mutations. The authors also describe a process for evaluating the gene sequence of filaggrin. Fifteen separate mutations of the filaggrin gene were discovered using these methods. The authors also comment on both the prevalence and European geographic distribution of these mutations.
Yosipovitch G, Papoiu AD. What causes itch in atopic dermatitis? Curr Allergy Asthma Rep. 2008;8(4):306–11. Yosipovitch and Papoiu provide an excellent commentary on the pathophysiologic basis of itch in atopic dermatitis. The abnormal barrier function, in conjunction with cytokines and inflammatory mediators, contributes to the scratch–itch cycle. Atopic dermatitis is also contrasted with other diseases displaying filaggrin mutations.
Hoffjan S, Stemmler S. On the role of the epidermal differentiation complex in ichthyosis vulgaris, atopic dermatitis and psoriasis. Br J Dermatol. 2007;157(3):441–9. Hoffjan and Stemmler discuss the importance and function of the epidermal differentiation complex, a collection of genes located on the long arm of chromosome 1 (1q21). A number of proteins, such as filaggrin, loricrin, and S100, are encoded within this area. The role of these proteins, and the diseases associated with their absence, are discussed in detail.
Spitz JL. Genodermatoses: a full color clinical guide to genetic skin disorders. 2nd ed. New York: Williams & Wilkins; 2005. p. 2–28; 262–3. The seminal text in the field of genodermatoses, this reference offers a comprehensive overview of many genetic diseases. The spectrum of disease includes disorders of cornification, pigmentation, hair and nails, vascularization, connective tissue, immunodeficiency, metabolism, malignancy, photosensitivity, and frank chromosomal abnormalities.
Elias PM, Williams ML, Maloney ME, et al. Stratum corneum lipids in disorders of cornification. Steroid sulfatase and cholesterol sulfate in normal desquamation and the pathogenesis of recessive X-linked ichthyosis. J Clin Invest. 1984;74(4):1414–21. Elias et al. demonstrate that the scale associated with X-linked ichthyosis is related to the accumulation of cholesterol sulfate in the stratum corneum. They also establish a direct link between the absence of steroid sulfatase (arylsulfatase C) and the manifestations of X-linked ichthyosis.
Cork MJ, Danby SG, Vasilopoulos Y, et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol. 2009;129(8):1892–908. Cork et al. review the role of genetic and environmental factors in the pathogenesis and pathophysiology of atopic dermatitis. The authors conclude that a disruption of the epidermal barrier is the primary event in regards to developing atopic dermatitis.
Elias PM. Epidermal lipids, barrier function, and desquamation. J Invest Dermatol. 1983;80(1 Suppl):44s–9. Elias proposes a two-compartment model of the stratum corneum, comparing keratinocytes and intercellular lipids to bricks and mortar, respectively.
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. Schmuth et al. explore how specific genetic mutations result in the various ichthyotic phenotypes. The authors thoroughly discuss specific molecular components of the stratum corneum, as well as the resultant phenotypes associated with varying mutations.
Knudson Jr AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971;68(4):820–3. Knudson’s original article outlines the concept that has become known as the “double-hit” phenomenon. Although Knudson’s article refers to retinoblastoma, his concept elegantly describes a process that occurs in many other clinical entities.
Takeuchi O, Akira S. Toll-like receptors; their physiological role and signal transduction system. Int Immunopharmacol. 2001;1(4):625–35.
Ozato K, Tsujimura H, Tamura T. Toll-like receptor signaling and regulation of cytokine gene expression in the immune system. Biotechniques. 2002;Suppl:66–68, 70, 72. Ozato et al. discuss the discovery of the signal transduction system involving TLRs. Activation of MyD88 and the eventual production of NF-κB and TNFα play key roles in the pathogenesis of eczema. TLRs are important parts of the innate immune system, especially with regards to recognizing the cell membranes of bacteria. TLRs also play a role in the adaptive immune system by generating cytokines that stimulate macrophages and dendritic cells.
Bitoun E, Chavanas S, Irvine AD, et al. Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. J Invest Dermatol. 2002;118(2):352–61. Netherton syndrome is a disorder of keratinzation marked by atopy, erythroderma, trichorrhexis invaginata (“bamboo hair”), and ichthyosis linearis circumflexa. This disease is associated with mutations in the serine protease inhibitor Kazal-type 5 protein (SPINK-5). Bitoun et al. delineate various types of mutations of this protein. There is no clear correlation between individual mutation and severity of condition.
Rizzo WB, Craft DA. Sjögren-Larsson syndrome. Deficient activity of the fatty aldehyde dehydrogenase component of fatty alcohol:NAD+ oxidoreductase in cultured fibroblasts. J Clin Invest. 1991;88(5):1643–8. Sjögren-Larsson syndrome is a disorder involving the decreased production of fatty aldehydes from fatty alcohol. Rizzo and Craft used cultured fibroblasts from patients with Sjögren-Larsson syndrome to conclusively demonstrate that it is the FALDH enzymatic subunit of the fatty alcohol NAD+ oxidoreductase complex that is abnormal in this syndrome.
Richard G, Rouan F, Willoughby CE, et al. Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. Am J Hum Genet. 2002;70(5):1341–8. Keratitis-ichthyosis-deafness (KID) syndrome is caused by a mutation in the connexin-26 gene. Richard et al. describe 10 cases of KID syndrome, each with a point missense mutation in the connexin-26 gene. Connexin-26, which encodes for GJB2, is important in epidermal differentiation as well as in immune response.
Vandecasteele SJ, Peetermans WE, Merckx R, Van Eldere J. Expression of biofilm-associated genes in Staphylococcus epidermidis during in vitro and in vivo foreign body infections. J Infect Dis. 2003;188(5):730–7. These authors discuss the genes in terms of initializing and persistence capabilities with regards to infections.
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Allen, H.B. (2015). Genetics. In: The Etiology of Atopic Dermatitis. Springer, London. https://doi.org/10.1007/978-1-4471-6545-3_5
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DOI: https://doi.org/10.1007/978-1-4471-6545-3_5
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