Our evolving understanding of the functional role of filaggrin in atopic dermatitis
2009; Elsevier BV; Volume: 124; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2009.07.041
ISSN1097-6825
Autores Tópico(s)Food Allergy and Anaphylaxis Research
ResumoOver the past few years, skin barrier dysfunction has emerged as a critical driving force in the development and progression of atopic dermatitis (AD). Identification of loss-of-function mutations in the gene encoding epidermal structural protein filaggrin (FLG) as a major risk factor for AD has shed new light on disease mechanisms in AD.1O'Regan G.M. Sandilands A. McLean W.H.I. Irvine A.D. Filaggrin in atopic dermatitis.J Allergy Clin Immunol. 2008; 122: 689-693Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar It has been widely replicated that FLG gene mutations are associated with more severe AD, early onset of this skin disease, enhanced systemic allergen sensitization, and an increased risk of asthma in patients with a previous history of eczema (ie, the so-called atopic march).2Baurecht H. Irvine A.D. Novak N. Illig T. Bühler B. Ring J. et al.Toward a major risk factor for atopic eczema: meta-analysis of filaggrin polymorphism data.J Allergy Clin Immunol. 2007; 120: 1406-1412Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 3Rodríguez E. Baurecht H. Herberich E. Wagenpfeil S. Brown S.J. Cordell H.J. et al.Meta-analysis of filaggrin polymorphisms in eczema and asthma: Robust risk factors in atopic disease.J Allergy Clin Immunol. 2009; 123 (e7): 1361-1370Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar The critical link between abnormal skin barrier in FLG-deficient patients with AD and TH2 polarization might be explained in part by enhanced allergen penetration through the skin accompanied by increased production of thymic stromal lymphopoietin. Insults from allergens or microbes can trigger keratinocytes to produce thymic stromal lymphopoietin, an IL-7–like cytokine that is overexpressed in epidermis of patients with AD, and signal immature myeloid dendritic cells to induce development of TH2 cells by inducing upregulation of OX40 ligand in the absence of IL-12 production.4Liu Y.J. Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation.J Allergy Clin Immunol. 2007; 120: 238-244Abstract Full Text Full Text PDF PubMed Scopus (216) Google ScholarRecent articles published in the Journal have provided further evidence that FLG mutations can contribute to AD disease severity and infection. In animal models of AD and eczema vaccinatum, allergen sensitization has also been associated with disseminated vaccinia viral infection.5Scott J.E. ElKhal A. Freyschmidt E.-J. MacArthur D.H. McDonald D. Howell M.D. et al.Impaired immune response to vaccinia virus inoculated at the site of cutaneous allergic inflammation.J Allergy Clin Immunol. 2007; 120: 1382-1388Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar As part of the National Institutes of Health/National Institute of Allergy and Infectious Diseases–sponsored Atopic Dermatitis and Vaccinia Network to dissect mechanisms increasing susceptibility of patients with AD to disseminated viral skin infections, Beck et al6Beck L.A. Boguniewicz M. Hata T. Schneider L.C. Hanifin J. Gallo R. et al.Phenotype of subjects with atopic dermatitis with a history of eczema herpeticum.J Allergy Clin Immunol. 2009; 124: 260-269Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar reported that AD with a history of eczema herpeticum (ADEH) primarily affects patients with severe AD, an earlier age of onset, more frequent history of other allergic disorders (eg, asthma or food allergy), increased serum IgE levels, and high levels of allergen sensitization. Patients with ADEH also had an increased prevalence of skin infections with Staphylococcus aureus compared with that seen in patients without a history of eczema herpeticum.In a parallel Atopic Dermatitis and Vaccinia Network study published this month, Gao et al7Gao P.-S. Rafaels N.M. Hand T. Murray T. Boguniewicz M. Hata T. et al.Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticum.J Allergy Clin Immunol. 2009; 124: 507-513Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar sought to determine whether FLG gene mutations conferred a risk of ADEH. Significant associations were observed for both the R501X and 2282del4 mutations and AD among European Americans, but the frequency of the R501X mutation was 3 times higher for patients with ADEH compared with that seen in patients with AD without EH. Associations with the R501X mutation were replicated in the African American population. These data indicate that the R501X mutation in the gene encoding FLG confers a significant risk for ADEH in both populations of European and populations of African ancestry, suggesting a role for a defective skin barrier in this devastating condition.Because ADEH manifests as a severe form of AD, it is tempting to attribute the role of the R501X mutation to ADEH susceptibility because it relates to disease severity. Indeed, among both European American and African American patients with ADEH, total serum IgE levels were significantly higher compared with those seen in patients with AD without EH, as was severity of skin disease. Disseminated viral skin infection could also result from skin barrier dysfunction independent of serum IgE and skin severity. Defects in barrier function might predispose to increased viral penetration and spread in the skin. However, the increased serum IgE levels and increased allergen sensitization observed in patients with FLG mutations might also be due to greater allergen penetration through the skin. Because TH2 responses diminish the skin barrier and innate immune response,8Howell M.D. Kim B.E. Gao P. Grant A.V. Boguniewicz M. Debenedetto A. et al.Cytokine modulation of atopic dermatitis filaggrin skin expression.J Allergy Clin Immunol. 2007; 120: 150-155Abstract Full Text Full Text PDF PubMed Scopus (577) Google Scholar FLG mutations might play a dual role in allowing increased spread of viruses in AD skin and establishing TH2 immune responses that subvert host defense.Despite the enormous effect of finding strong associations between FLG null mutations and persistent AD, it should be noted that the same FLG mutations were first reported to occur in ichthyosis vulgaris, a dry scaling skin condition not associated with significant skin inflammation.9Smith F.J. Irvine A.D. Terron-Kwiatkowsk A. Sandilands A. Campbell E. Zhao Y. et al.Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.Nat Genet. 2006; 38: 337-442Crossref PubMed Scopus (795) Google Scholar Furthermore, a substantial number of patients with severe AD do not have FLG null mutations. Conversely, there are healthy subjects with FLG null mutations who have no evidence of skin disease. This suggests that additional factors are important in the development of clinical AD. These might include exposure to allergens, microbes, and other genes that predispose to atopy, including thymic stromal lymphopoietin polymorphisms, and cutaneous allergic responses. In a genetically complex disease, it is difficult to sort out the relative importance of these many factors. The recent report by Fallon et al10Fallon P.G. Sasaki T. Sandilands A. Campbell L.E. Saunders S.P. Mangan N.E. et al.A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming.Nat Genet. 2009; 41: 602-608Crossref PubMed Scopus (373) Google Scholar that the flaky-tail (ft/ft) mouse, which lacks processed FLG because of a homozygous frameshift mutation in profilaggrin that is analogous to the human null mutations in filaggrin has the potential to address some of the questions that remain about the relative importance of FLG compared with other factors involved in the pathobiology of AD. Indeed, the Fallon et al study found an increased uptake of intact allergens through flg-deficient mouse skin. This defect in the skin barrier contributed to increased IgE sensitization and facilitated the initiation of atopic skin inflammation.In a study by Scharschmidt et al11Scharschmidt T.C. Man M.-Q. Hatano Y. Crumrine D. Gunathilake R. Sundberg J.P. et al.Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens.J Allergy Clin Immunol. 2009; 124: 496-506Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar published in the current issue of the Journal, skin barrier function of the ft/ft mice was characterized, and thresholds to irritant and hapten-induced dermatitis were assessed. The investigators observed accelerated paracellular water loss in ft/ft mice. Normal stratum corneum does not allow entry of water-soluble xenobiotes. However, they found that epicutaneously applied, water-soluble tracers did rapidly enter the stratum corneum of flg-deficient mice. Moreover, when exposed repeatedly to topical haptens at doses that produce no inflammation in control mice, ft/ft mice had a severe AD-like dermatosis with a further deterioration in barrier function and features of a TH2 immune response.In another study in this month's Journal, Oyoshi et al12Oyoshi M.K. Murphy G.F. Geha R.S. Filaggrin deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen.J Allergy Clin Immunol. 2009; 124: 485-493Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar have also performed a study examining the phenotype and immune responses of ft/ft mice. No visible skin lesions were observed in ft/ft mice at 4, 8, and 16 weeks of age. Eczematous skin lesions, however, appeared after age 28 weeks. They also found increased skin expression of mRNA for IL-17 and the IL-17–promoting cytokines IL-6 and IL-23. Ovalbumin application to the skin of ft/ft mice resulted in increased skin inflammation with expression of TH1, TH2, and TH17 cytokines. The skin of ft/ft mice was permissive to epicutaneous sensitization of nonstripped skin with ovalbumin, a protein antigen normally excluded from penetrating the skin. The link of IL-17 expression in ft/ft mice to the emergence of skin inflammation is interesting because of recent reports that AD skin is associated with increased IL-17 levels.13Nograles K.E. Zaba L.C. Shemer A. Fuentes-Duculan J. Cardinale I. Kikuchi T. et al.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 (e2): 1244-1252Abstract Full Text Full Text PDF PubMed Scopus (493) Google ScholarThese data suggests that FLG deficiency alone can provoke a barrier abnormality in the epidermis and predispose to the development of dermatitis by enhancing allergen absorption through the skin. Further studies are required to better understand additional environmental, immune, and genetic factors that predispose such individuals to disseminated skin infection. Interestingly, the majority of patients with AD with FLG mutations eventually outgrow their AD, suggesting there is much more to be learned in this exciting area of allergy.14Henderson J. Northstone K. Lee S.P. Liao H. Zhao Y. Pembrey M. et al.The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study.J Allergy Clin Immunol. 2008; 121: 872-877Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar Over the past few years, skin barrier dysfunction has emerged as a critical driving force in the development and progression of atopic dermatitis (AD). Identification of loss-of-function mutations in the gene encoding epidermal structural protein filaggrin (FLG) as a major risk factor for AD has shed new light on disease mechanisms in AD.1O'Regan G.M. Sandilands A. McLean W.H.I. Irvine A.D. Filaggrin in atopic dermatitis.J Allergy Clin Immunol. 2008; 122: 689-693Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar It has been widely replicated that FLG gene mutations are associated with more severe AD, early onset of this skin disease, enhanced systemic allergen sensitization, and an increased risk of asthma in patients with a previous history of eczema (ie, the so-called atopic march).2Baurecht H. Irvine A.D. Novak N. Illig T. Bühler B. Ring J. et al.Toward a major risk factor for atopic eczema: meta-analysis of filaggrin polymorphism data.J Allergy Clin Immunol. 2007; 120: 1406-1412Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 3Rodríguez E. Baurecht H. Herberich E. Wagenpfeil S. Brown S.J. Cordell H.J. et al.Meta-analysis of filaggrin polymorphisms in eczema and asthma: Robust risk factors in atopic disease.J Allergy Clin Immunol. 2009; 123 (e7): 1361-1370Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar The critical link between abnormal skin barrier in FLG-deficient patients with AD and TH2 polarization might be explained in part by enhanced allergen penetration through the skin accompanied by increased production of thymic stromal lymphopoietin. Insults from allergens or microbes can trigger keratinocytes to produce thymic stromal lymphopoietin, an IL-7–like cytokine that is overexpressed in epidermis of patients with AD, and signal immature myeloid dendritic cells to induce development of TH2 cells by inducing upregulation of OX40 ligand in the absence of IL-12 production.4Liu Y.J. Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation.J Allergy Clin Immunol. 2007; 120: 238-244Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar Recent articles published in the Journal have provided further evidence that FLG mutations can contribute to AD disease severity and infection. In animal models of AD and eczema vaccinatum, allergen sensitization has also been associated with disseminated vaccinia viral infection.5Scott J.E. ElKhal A. Freyschmidt E.-J. MacArthur D.H. McDonald D. Howell M.D. et al.Impaired immune response to vaccinia virus inoculated at the site of cutaneous allergic inflammation.J Allergy Clin Immunol. 2007; 120: 1382-1388Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar As part of the National Institutes of Health/National Institute of Allergy and Infectious Diseases–sponsored Atopic Dermatitis and Vaccinia Network to dissect mechanisms increasing susceptibility of patients with AD to disseminated viral skin infections, Beck et al6Beck L.A. Boguniewicz M. Hata T. Schneider L.C. Hanifin J. Gallo R. et al.Phenotype of subjects with atopic dermatitis with a history of eczema herpeticum.J Allergy Clin Immunol. 2009; 124: 260-269Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar reported that AD with a history of eczema herpeticum (ADEH) primarily affects patients with severe AD, an earlier age of onset, more frequent history of other allergic disorders (eg, asthma or food allergy), increased serum IgE levels, and high levels of allergen sensitization. Patients with ADEH also had an increased prevalence of skin infections with Staphylococcus aureus compared with that seen in patients without a history of eczema herpeticum. In a parallel Atopic Dermatitis and Vaccinia Network study published this month, Gao et al7Gao P.-S. Rafaels N.M. Hand T. Murray T. Boguniewicz M. Hata T. et al.Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticum.J Allergy Clin Immunol. 2009; 124: 507-513Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar sought to determine whether FLG gene mutations conferred a risk of ADEH. Significant associations were observed for both the R501X and 2282del4 mutations and AD among European Americans, but the frequency of the R501X mutation was 3 times higher for patients with ADEH compared with that seen in patients with AD without EH. Associations with the R501X mutation were replicated in the African American population. These data indicate that the R501X mutation in the gene encoding FLG confers a significant risk for ADEH in both populations of European and populations of African ancestry, suggesting a role for a defective skin barrier in this devastating condition. Because ADEH manifests as a severe form of AD, it is tempting to attribute the role of the R501X mutation to ADEH susceptibility because it relates to disease severity. Indeed, among both European American and African American patients with ADEH, total serum IgE levels were significantly higher compared with those seen in patients with AD without EH, as was severity of skin disease. Disseminated viral skin infection could also result from skin barrier dysfunction independent of serum IgE and skin severity. Defects in barrier function might predispose to increased viral penetration and spread in the skin. However, the increased serum IgE levels and increased allergen sensitization observed in patients with FLG mutations might also be due to greater allergen penetration through the skin. Because TH2 responses diminish the skin barrier and innate immune response,8Howell M.D. Kim B.E. Gao P. Grant A.V. Boguniewicz M. Debenedetto A. et al.Cytokine modulation of atopic dermatitis filaggrin skin expression.J Allergy Clin Immunol. 2007; 120: 150-155Abstract Full Text Full Text PDF PubMed Scopus (577) Google Scholar FLG mutations might play a dual role in allowing increased spread of viruses in AD skin and establishing TH2 immune responses that subvert host defense. Despite the enormous effect of finding strong associations between FLG null mutations and persistent AD, it should be noted that the same FLG mutations were first reported to occur in ichthyosis vulgaris, a dry scaling skin condition not associated with significant skin inflammation.9Smith F.J. Irvine A.D. Terron-Kwiatkowsk A. Sandilands A. Campbell E. Zhao Y. et al.Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.Nat Genet. 2006; 38: 337-442Crossref PubMed Scopus (795) Google Scholar Furthermore, a substantial number of patients with severe AD do not have FLG null mutations. Conversely, there are healthy subjects with FLG null mutations who have no evidence of skin disease. This suggests that additional factors are important in the development of clinical AD. These might include exposure to allergens, microbes, and other genes that predispose to atopy, including thymic stromal lymphopoietin polymorphisms, and cutaneous allergic responses. In a genetically complex disease, it is difficult to sort out the relative importance of these many factors. The recent report by Fallon et al10Fallon P.G. Sasaki T. Sandilands A. Campbell L.E. Saunders S.P. Mangan N.E. et al.A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming.Nat Genet. 2009; 41: 602-608Crossref PubMed Scopus (373) Google Scholar that the flaky-tail (ft/ft) mouse, which lacks processed FLG because of a homozygous frameshift mutation in profilaggrin that is analogous to the human null mutations in filaggrin has the potential to address some of the questions that remain about the relative importance of FLG compared with other factors involved in the pathobiology of AD. Indeed, the Fallon et al study found an increased uptake of intact allergens through flg-deficient mouse skin. This defect in the skin barrier contributed to increased IgE sensitization and facilitated the initiation of atopic skin inflammation. In a study by Scharschmidt et al11Scharschmidt T.C. Man M.-Q. Hatano Y. Crumrine D. Gunathilake R. Sundberg J.P. et al.Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens.J Allergy Clin Immunol. 2009; 124: 496-506Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar published in the current issue of the Journal, skin barrier function of the ft/ft mice was characterized, and thresholds to irritant and hapten-induced dermatitis were assessed. The investigators observed accelerated paracellular water loss in ft/ft mice. Normal stratum corneum does not allow entry of water-soluble xenobiotes. However, they found that epicutaneously applied, water-soluble tracers did rapidly enter the stratum corneum of flg-deficient mice. Moreover, when exposed repeatedly to topical haptens at doses that produce no inflammation in control mice, ft/ft mice had a severe AD-like dermatosis with a further deterioration in barrier function and features of a TH2 immune response. In another study in this month's Journal, Oyoshi et al12Oyoshi M.K. Murphy G.F. Geha R.S. Filaggrin deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen.J Allergy Clin Immunol. 2009; 124: 485-493Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar have also performed a study examining the phenotype and immune responses of ft/ft mice. No visible skin lesions were observed in ft/ft mice at 4, 8, and 16 weeks of age. Eczematous skin lesions, however, appeared after age 28 weeks. They also found increased skin expression of mRNA for IL-17 and the IL-17–promoting cytokines IL-6 and IL-23. Ovalbumin application to the skin of ft/ft mice resulted in increased skin inflammation with expression of TH1, TH2, and TH17 cytokines. The skin of ft/ft mice was permissive to epicutaneous sensitization of nonstripped skin with ovalbumin, a protein antigen normally excluded from penetrating the skin. The link of IL-17 expression in ft/ft mice to the emergence of skin inflammation is interesting because of recent reports that AD skin is associated with increased IL-17 levels.13Nograles K.E. Zaba L.C. Shemer A. Fuentes-Duculan J. Cardinale I. Kikuchi T. et al.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 (e2): 1244-1252Abstract Full Text Full Text PDF PubMed Scopus (493) Google Scholar These data suggests that FLG deficiency alone can provoke a barrier abnormality in the epidermis and predispose to the development of dermatitis by enhancing allergen absorption through the skin. Further studies are required to better understand additional environmental, immune, and genetic factors that predispose such individuals to disseminated skin infection. Interestingly, the majority of patients with AD with FLG mutations eventually outgrow their AD, suggesting there is much more to be learned in this exciting area of allergy.14Henderson J. Northstone K. Lee S.P. Liao H. Zhao Y. Pembrey M. et al.The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study.J Allergy Clin Immunol. 2008; 121: 872-877Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar Filaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigenJournal of Allergy and Clinical ImmunologyVol. 124Issue 3PreviewFilaggrin is important for skin barrier function and is mutated in 15% to 20% of patients with atopic dermatitis. Full-Text PDF Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticumJournal of Allergy and Clinical ImmunologyVol. 124Issue 3PreviewLoss-of-function null mutations R501X and 2282del4 in the skin barrier gene, filaggrin (FLG), represent the most replicated genetic risk factors for atopic dermatitis (AD). Associations have not been reported in African ancestry populations. Atopic dermatitis eczema herpeticum (ADEH) is a rare but serious complication of AD resulting from disseminated cutaneous herpes simplex virus infections. Full-Text PDF
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