Atopic dermatitis: Scratching through the complexity of barrier dysfunction
2013; Elsevier BV; Volume: 132; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2013.09.026
ISSN1097-6825
AutoresEli Sprecher, Donald Y.M. Leung,
Tópico(s)Food Allergy and Anaphylaxis Research
ResumoThe prevalence of atopic dermatitis (AD) has been steadily increasing for reasons that remain largely elusive. In parallel, the therapeutic arsenal presently available to treat AD has not significantly evolved over the past few years, with the possible exception of the forthcoming introduction of novel targeted immunobiological drugs. One explanation for this paradoxical observation is that the notion that atopy results from a primary dysfunction of the immune system has prevailed for decades, limiting the development of novel treatment strategies to therapies mostly aimed at attenuating immune system activity. Recent studies demonstrating an equally important role for epidermal dysfunction in patients with AD might lead to new strategies in the treatment of this common skin disease. The current issue of the Journal features a new gene involved in epidermal function that contributes to the clinical onset of AD (see the cover image).Shifting paradigms in the landscape of allergic skin diseasesThe finding that immunologic abnormalities found in patients with allergic skin diseases occur as the direct consequence of primary defects residing within the epidermis suggests intricate relationships between skin barrier dysfunction and immune abnormalities that were previously unrecognized. This barrier is located in the uppermost layers of the epidermis (the stratum corneum) and comprises 3 major elements: intracellular keratin filaments, intercellular lipids, and, between these, a cornified cell envelope that progressively replaces the plasma cell membrane of epidermal cells while they differentiate. The epidermal barrier plays a vital role in all terrestrial forms of life. It functions by avoiding loss of fluids and essential elements while preventing unwanted intruders, including allergens, from gaining access to the circulation and tissues.Recent findings have substantiated the notion that allergy can result from a primary isolated epidermal defect. Netherton syndrome manifesting with hair defects and atopic diathesis was shown to result from defective function of a natural inhibitor of serine proteases in the epidermis, leading to increased proteolytic activity within the epidermis and abnormal epidermal differentiation. Mutations in the gene encoding filaggrin (FLG), an essential component of the skin barrier, were later found to underlie both ichthyosis vulgaris and AD.1McAleer M.A. Irvine A.D. The multifunctional role of filaggrin in allergic skin disease.J Allergy Clin Immunol. 2013; 131: 280-291Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar More recently, deficient expression of desmoglein 1 in the epidermis was found to destabilize intercellular adhesion within the epidermis, leading to a life-threatening condition characterized by impaired barrier function and multiple allergies.2Samuelov L. Sarig O. Harmon R.M. Rapaport D. Ishida-Yamamoto A. Isakov O. et al.Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting.Nat Genet. 2013; ([Epub ahead of print])PubMed Google ScholarNot only is the functional lack of epidermal enzymes and structural skin cytoplasmic or membrane proteins sufficient to compromise the skin barrier integrity, several studies have shown that these deficiencies can even induce local changes in the expression of various mediators of inflammation by epidermal cells,2Samuelov L. Sarig O. Harmon R.M. Rapaport D. Ishida-Yamamoto A. Isakov O. et al.Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting.Nat Genet. 2013; ([Epub ahead of print])PubMed Google Scholar, 3Kezic S. O'Regan G.M. Lutter R. Jakasa I. Koster E.S. Saunders S. et al.Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency.J Allergy Clin Immunol. 2012; 129: 1031-1039.e1Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 4Lee K.H. Cho K.A. Kim J.Y. Kim J.Y. Baek J.H. Woo S.Y. et al.Filaggrin knockdown and Toll-like receptor 3 (TLR3) stimulation enhanced the production of thymic stromal lymphopoietin (TSLP) from epidermal layers.Exp Dermatol. 2011; 20: 149-151Crossref PubMed Scopus (63) Google Scholar thus pointing to a direct immunologic role of the epidermis in the pathogenesis of allergic skin diseases.Traffic jams in the epidermisIn 2 articles published in this month's issue of the Journal, Sasaki et al5Sasaki T. Shiohama A. Kubo A. Kawasaki H. Ishida-Yamamoto A. Yamada T. et al.A homozygous nonsense mutation in the gene for Tmem79, a component for lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 1111-1120Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar and Saunders et al6Saunders S.P. Goh C.S. Brown S.J. Palmer C.N. Porter R.M. Cole C. et al.Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in humans.J Allergy Clin Immunol. 2013; 132: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar report successful delineation of the genetic basis of the flaky tail mouse phenotype. Flaky tail mice display a matted hair phenotype and have spontaneous dermatitis under pathogen-free conditions; therefore they have been used over the years as a model for AD.7Moniaga C.S. Egawa G. Kawasaki H. Hara-Chikuma M. Honda T. Tanizaki H. et al.Flaky tail mouse denotes human atopic dermatitis in the steady state and by topical application with Dermatophagoides pteronyssinus extract.Am J Pathol. 2010; 176: 2385-2393Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar These mice arose spontaneously as the result of crosses between mice carrying a recessive mutation named matted (ma) and have been since maintained as double mutants (maft). Flaky tail mice were recently found to carry a deletion in the mouse filaggrin gene (Flg),8Fallon 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 (372) Google Scholar suggesting that filaggrin deficiency might explain the propensity of those mice to have dermatitis in analogy with the situation in human subjects affected with AD. Quite surprisingly, genetically engineered filaggrin-deficient mice were found to display impaired barrier function but to lack the propensity of flaky tail mice to spontaneously have skin inflammation.9Kawasaki 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: 1538-1546.e6Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar In the 2 studies published in the present issue, both groups used a mouse genetics approach to separate the Flg from the ma mutations. The matted phenotype in flaky tail mice was found to be due to a loss-of-function mutation in Tmem79. Unexpectedly, the Tmem79 mutation, rather than the deletion in Flg, was found to be associated with the development of dermatitis in mice. Moreover, exogenous Tmem79 expression was able to rescue both the hair and the dermatitis phenotype in flaky tail mice. Tmem79 is mainly expressed in the granular layers of the epidermis, where its absence correlates with abnormal function of lamellar granules. Those lamellar granules are Golgi-derived specialized organelles, which are responsible for transferring lipids and proteases to the upper part of the epidermis.10Ishida-Yamamoto A. Igawa S. Kishibe M. Order and disorder in corneocyte adhesion.J Dermatol. 2011; 38: 645-654Crossref PubMed Scopus (54) Google ScholarMore data, better questions, arousing prospectsAs usual, these new data raise a large number of questions. First, although abnormal lamellar granule trafficking has been implicated in the past in the setting of several monogenic conditions, their dysfunction has not been invariably found to result in atopy-related phenotypes. Premature secretion of lamellar granules has been observed in patients with Netherton syndrome.11Fartasch M. Williams M.L. Elias P.M. Altered lamellar body secretion and stratum corneum membrane structure in Netherton syndrome: differentiation from other infantile erythrodermas and pathogenic implications.Arch Dermatol. 1999; 135: 823-832Crossref PubMed Scopus (102) Google Scholar In contrast, decreased secretion of lamellar granules, as observed in the study by Sasaki et al,5Sasaki T. Shiohama A. Kubo A. Kawasaki H. Ishida-Yamamoto A. Yamada T. et al.A homozygous nonsense mutation in the gene for Tmem79, a component for lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 1111-1120Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar has been reported in patients with several other noninflammatory disorders of cornification.12Hershkovitz D. Mandel H. Ishida-Yamamoto A. Chefetz I. Hino B. Luder A. et al.Defective lamellar granule secretion in arthrogryposis, renal dysfunction, and cholestasis syndrome caused by a mutation in VPS33B.Arch Dermatol. 2008; 144: 334-340Crossref PubMed Scopus (37) Google Scholar, 13Sprecher E. Ishida-Yamamoto A. Mizrahi-Koren M. Rapaport D. Goldsher D. Indelman M. et al.A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma.Am J Hum Genet. 2005; 77: 242-251Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar These conflicting observations remain to be explained. Meanwhile, they indicate that abnormal trafficking of lamellar granules might be contributory but is certainly not sufficient to induce cutaneous allergic responses.More intriguing is the fact that FLG mutations have been shown to be strongly associated with AD in human subjects,1McAleer M.A. Irvine A.D. The multifunctional role of filaggrin in allergic skin disease.J Allergy Clin Immunol. 2013; 131: 280-291Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar whereas filaggrin deficiency seems not to be sufficient to induce dermatitis in the mouse. Interactions with environmental agents, the effect of inherited modifier traits, or both in human subjects might explain this discrepancy. Of direct relevance to this issue is the fact that a single nucleotide polymorphism in the human TMEM79 gene was found by Saunders et al6Saunders S.P. Goh C.S. Brown S.J. Palmer C.N. Porter R.M. Cole C. et al.Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in humans.J Allergy Clin Immunol. 2013; 132: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar to confer a significant risk for AD in human subjects, even when controlling for the effect of FLG mutations, suggesting that both gene products can play a role in the pathogenesis of the disease. Further expanding the spectrum of proteins possibly involved in the chain of events leading to atopy is a recent study demonstrating a wide range of defects in numerous filaggrin-related molecules.14Pellerin L. Henry J. Hsu C.Y. Balica S. Jean-Decoster C. Mechin M.C. et al.Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin.J Allergy Clin Immunol. 2013; 131: 1094-1102Abstract Full Text Full Text PDF PubMed Scopus (168) Google ScholarTaken together, the 2 studies published in this issue of the Journal not only shed new light on the pathogenesis of AD but also and more importantly underscore the fact that the skin barrier represents an often neglected but nonetheless clinically critical (and most accessible) target for old and novel therapeutic approaches in the treatment of AD. The prevalence of atopic dermatitis (AD) has been steadily increasing for reasons that remain largely elusive. In parallel, the therapeutic arsenal presently available to treat AD has not significantly evolved over the past few years, with the possible exception of the forthcoming introduction of novel targeted immunobiological drugs. One explanation for this paradoxical observation is that the notion that atopy results from a primary dysfunction of the immune system has prevailed for decades, limiting the development of novel treatment strategies to therapies mostly aimed at attenuating immune system activity. Recent studies demonstrating an equally important role for epidermal dysfunction in patients with AD might lead to new strategies in the treatment of this common skin disease. The current issue of the Journal features a new gene involved in epidermal function that contributes to the clinical onset of AD (see the cover image). Shifting paradigms in the landscape of allergic skin diseasesThe finding that immunologic abnormalities found in patients with allergic skin diseases occur as the direct consequence of primary defects residing within the epidermis suggests intricate relationships between skin barrier dysfunction and immune abnormalities that were previously unrecognized. This barrier is located in the uppermost layers of the epidermis (the stratum corneum) and comprises 3 major elements: intracellular keratin filaments, intercellular lipids, and, between these, a cornified cell envelope that progressively replaces the plasma cell membrane of epidermal cells while they differentiate. The epidermal barrier plays a vital role in all terrestrial forms of life. It functions by avoiding loss of fluids and essential elements while preventing unwanted intruders, including allergens, from gaining access to the circulation and tissues.Recent findings have substantiated the notion that allergy can result from a primary isolated epidermal defect. Netherton syndrome manifesting with hair defects and atopic diathesis was shown to result from defective function of a natural inhibitor of serine proteases in the epidermis, leading to increased proteolytic activity within the epidermis and abnormal epidermal differentiation. Mutations in the gene encoding filaggrin (FLG), an essential component of the skin barrier, were later found to underlie both ichthyosis vulgaris and AD.1McAleer M.A. Irvine A.D. The multifunctional role of filaggrin in allergic skin disease.J Allergy Clin Immunol. 2013; 131: 280-291Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar More recently, deficient expression of desmoglein 1 in the epidermis was found to destabilize intercellular adhesion within the epidermis, leading to a life-threatening condition characterized by impaired barrier function and multiple allergies.2Samuelov L. Sarig O. Harmon R.M. Rapaport D. Ishida-Yamamoto A. Isakov O. et al.Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting.Nat Genet. 2013; ([Epub ahead of print])PubMed Google ScholarNot only is the functional lack of epidermal enzymes and structural skin cytoplasmic or membrane proteins sufficient to compromise the skin barrier integrity, several studies have shown that these deficiencies can even induce local changes in the expression of various mediators of inflammation by epidermal cells,2Samuelov L. Sarig O. Harmon R.M. Rapaport D. Ishida-Yamamoto A. Isakov O. et al.Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting.Nat Genet. 2013; ([Epub ahead of print])PubMed Google Scholar, 3Kezic S. O'Regan G.M. Lutter R. Jakasa I. Koster E.S. Saunders S. et al.Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency.J Allergy Clin Immunol. 2012; 129: 1031-1039.e1Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 4Lee K.H. Cho K.A. Kim J.Y. Kim J.Y. Baek J.H. Woo S.Y. et al.Filaggrin knockdown and Toll-like receptor 3 (TLR3) stimulation enhanced the production of thymic stromal lymphopoietin (TSLP) from epidermal layers.Exp Dermatol. 2011; 20: 149-151Crossref PubMed Scopus (63) Google Scholar thus pointing to a direct immunologic role of the epidermis in the pathogenesis of allergic skin diseases. The finding that immunologic abnormalities found in patients with allergic skin diseases occur as the direct consequence of primary defects residing within the epidermis suggests intricate relationships between skin barrier dysfunction and immune abnormalities that were previously unrecognized. This barrier is located in the uppermost layers of the epidermis (the stratum corneum) and comprises 3 major elements: intracellular keratin filaments, intercellular lipids, and, between these, a cornified cell envelope that progressively replaces the plasma cell membrane of epidermal cells while they differentiate. The epidermal barrier plays a vital role in all terrestrial forms of life. It functions by avoiding loss of fluids and essential elements while preventing unwanted intruders, including allergens, from gaining access to the circulation and tissues. Recent findings have substantiated the notion that allergy can result from a primary isolated epidermal defect. Netherton syndrome manifesting with hair defects and atopic diathesis was shown to result from defective function of a natural inhibitor of serine proteases in the epidermis, leading to increased proteolytic activity within the epidermis and abnormal epidermal differentiation. Mutations in the gene encoding filaggrin (FLG), an essential component of the skin barrier, were later found to underlie both ichthyosis vulgaris and AD.1McAleer M.A. Irvine A.D. The multifunctional role of filaggrin in allergic skin disease.J Allergy Clin Immunol. 2013; 131: 280-291Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar More recently, deficient expression of desmoglein 1 in the epidermis was found to destabilize intercellular adhesion within the epidermis, leading to a life-threatening condition characterized by impaired barrier function and multiple allergies.2Samuelov L. Sarig O. Harmon R.M. Rapaport D. Ishida-Yamamoto A. Isakov O. et al.Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting.Nat Genet. 2013; ([Epub ahead of print])PubMed Google Scholar Not only is the functional lack of epidermal enzymes and structural skin cytoplasmic or membrane proteins sufficient to compromise the skin barrier integrity, several studies have shown that these deficiencies can even induce local changes in the expression of various mediators of inflammation by epidermal cells,2Samuelov L. Sarig O. Harmon R.M. Rapaport D. Ishida-Yamamoto A. Isakov O. et al.Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting.Nat Genet. 2013; ([Epub ahead of print])PubMed Google Scholar, 3Kezic S. O'Regan G.M. Lutter R. Jakasa I. Koster E.S. Saunders S. et al.Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency.J Allergy Clin Immunol. 2012; 129: 1031-1039.e1Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 4Lee K.H. Cho K.A. Kim J.Y. Kim J.Y. Baek J.H. Woo S.Y. et al.Filaggrin knockdown and Toll-like receptor 3 (TLR3) stimulation enhanced the production of thymic stromal lymphopoietin (TSLP) from epidermal layers.Exp Dermatol. 2011; 20: 149-151Crossref PubMed Scopus (63) Google Scholar thus pointing to a direct immunologic role of the epidermis in the pathogenesis of allergic skin diseases. Traffic jams in the epidermisIn 2 articles published in this month's issue of the Journal, Sasaki et al5Sasaki T. Shiohama A. Kubo A. Kawasaki H. Ishida-Yamamoto A. Yamada T. et al.A homozygous nonsense mutation in the gene for Tmem79, a component for lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 1111-1120Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar and Saunders et al6Saunders S.P. Goh C.S. Brown S.J. Palmer C.N. Porter R.M. Cole C. et al.Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in humans.J Allergy Clin Immunol. 2013; 132: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar report successful delineation of the genetic basis of the flaky tail mouse phenotype. Flaky tail mice display a matted hair phenotype and have spontaneous dermatitis under pathogen-free conditions; therefore they have been used over the years as a model for AD.7Moniaga C.S. Egawa G. Kawasaki H. Hara-Chikuma M. Honda T. Tanizaki H. et al.Flaky tail mouse denotes human atopic dermatitis in the steady state and by topical application with Dermatophagoides pteronyssinus extract.Am J Pathol. 2010; 176: 2385-2393Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar These mice arose spontaneously as the result of crosses between mice carrying a recessive mutation named matted (ma) and have been since maintained as double mutants (maft). Flaky tail mice were recently found to carry a deletion in the mouse filaggrin gene (Flg),8Fallon 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 (372) Google Scholar suggesting that filaggrin deficiency might explain the propensity of those mice to have dermatitis in analogy with the situation in human subjects affected with AD. Quite surprisingly, genetically engineered filaggrin-deficient mice were found to display impaired barrier function but to lack the propensity of flaky tail mice to spontaneously have skin inflammation.9Kawasaki 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: 1538-1546.e6Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar In the 2 studies published in the present issue, both groups used a mouse genetics approach to separate the Flg from the ma mutations. The matted phenotype in flaky tail mice was found to be due to a loss-of-function mutation in Tmem79. Unexpectedly, the Tmem79 mutation, rather than the deletion in Flg, was found to be associated with the development of dermatitis in mice. Moreover, exogenous Tmem79 expression was able to rescue both the hair and the dermatitis phenotype in flaky tail mice. Tmem79 is mainly expressed in the granular layers of the epidermis, where its absence correlates with abnormal function of lamellar granules. Those lamellar granules are Golgi-derived specialized organelles, which are responsible for transferring lipids and proteases to the upper part of the epidermis.10Ishida-Yamamoto A. Igawa S. Kishibe M. Order and disorder in corneocyte adhesion.J Dermatol. 2011; 38: 645-654Crossref PubMed Scopus (54) Google Scholar In 2 articles published in this month's issue of the Journal, Sasaki et al5Sasaki T. Shiohama A. Kubo A. Kawasaki H. Ishida-Yamamoto A. Yamada T. et al.A homozygous nonsense mutation in the gene for Tmem79, a component for lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 1111-1120Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar and Saunders et al6Saunders S.P. Goh C.S. Brown S.J. Palmer C.N. Porter R.M. Cole C. et al.Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in humans.J Allergy Clin Immunol. 2013; 132: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar report successful delineation of the genetic basis of the flaky tail mouse phenotype. Flaky tail mice display a matted hair phenotype and have spontaneous dermatitis under pathogen-free conditions; therefore they have been used over the years as a model for AD.7Moniaga C.S. Egawa G. Kawasaki H. Hara-Chikuma M. Honda T. Tanizaki H. et al.Flaky tail mouse denotes human atopic dermatitis in the steady state and by topical application with Dermatophagoides pteronyssinus extract.Am J Pathol. 2010; 176: 2385-2393Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar These mice arose spontaneously as the result of crosses between mice carrying a recessive mutation named matted (ma) and have been since maintained as double mutants (maft). Flaky tail mice were recently found to carry a deletion in the mouse filaggrin gene (Flg),8Fallon 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 (372) Google Scholar suggesting that filaggrin deficiency might explain the propensity of those mice to have dermatitis in analogy with the situation in human subjects affected with AD. Quite surprisingly, genetically engineered filaggrin-deficient mice were found to display impaired barrier function but to lack the propensity of flaky tail mice to spontaneously have skin inflammation.9Kawasaki 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: 1538-1546.e6Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar In the 2 studies published in the present issue, both groups used a mouse genetics approach to separate the Flg from the ma mutations. The matted phenotype in flaky tail mice was found to be due to a loss-of-function mutation in Tmem79. Unexpectedly, the Tmem79 mutation, rather than the deletion in Flg, was found to be associated with the development of dermatitis in mice. Moreover, exogenous Tmem79 expression was able to rescue both the hair and the dermatitis phenotype in flaky tail mice. Tmem79 is mainly expressed in the granular layers of the epidermis, where its absence correlates with abnormal function of lamellar granules. Those lamellar granules are Golgi-derived specialized organelles, which are responsible for transferring lipids and proteases to the upper part of the epidermis.10Ishida-Yamamoto A. Igawa S. Kishibe M. Order and disorder in corneocyte adhesion.J Dermatol. 2011; 38: 645-654Crossref PubMed Scopus (54) Google Scholar More data, better questions, arousing prospectsAs usual, these new data raise a large number of questions. First, although abnormal lamellar granule trafficking has been implicated in the past in the setting of several monogenic conditions, their dysfunction has not been invariably found to result in atopy-related phenotypes. Premature secretion of lamellar granules has been observed in patients with Netherton syndrome.11Fartasch M. Williams M.L. Elias P.M. Altered lamellar body secretion and stratum corneum membrane structure in Netherton syndrome: differentiation from other infantile erythrodermas and pathogenic implications.Arch Dermatol. 1999; 135: 823-832Crossref PubMed Scopus (102) Google Scholar In contrast, decreased secretion of lamellar granules, as observed in the study by Sasaki et al,5Sasaki T. Shiohama A. Kubo A. Kawasaki H. Ishida-Yamamoto A. Yamada T. et al.A homozygous nonsense mutation in the gene for Tmem79, a component for lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 1111-1120Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar has been reported in patients with several other noninflammatory disorders of cornification.12Hershkovitz D. Mandel H. Ishida-Yamamoto A. Chefetz I. Hino B. Luder A. et al.Defective lamellar granule secretion in arthrogryposis, renal dysfunction, and cholestasis syndrome caused by a mutation in VPS33B.Arch Dermatol. 2008; 144: 334-340Crossref PubMed Scopus (37) Google Scholar, 13Sprecher E. Ishida-Yamamoto A. Mizrahi-Koren M. Rapaport D. Goldsher D. Indelman M. et al.A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma.Am J Hum Genet. 2005; 77: 242-251Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar These conflicting observations remain to be explained. Meanwhile, they indicate that abnormal trafficking of lamellar granules might be contributory but is certainly not sufficient to induce cutaneous allergic responses.More intriguing is the fact that FLG mutations have been shown to be strongly associated with AD in human subjects,1McAleer M.A. Irvine A.D. The multifunctional role of filaggrin in allergic skin disease.J Allergy Clin Immunol. 2013; 131: 280-291Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar whereas filaggrin deficiency seems not to be sufficient to induce dermatitis in the mouse. Interactions with environmental agents, the effect of inherited modifier traits, or both in human subjects might explain this discrepancy. Of direct relevance to this issue is the fact that a single nucleotide polymorphism in the human TMEM79 gene was found by Saunders et al6Saunders S.P. Goh C.S. Brown S.J. Palmer C.N. Porter R.M. Cole C. et al.Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in humans.J Allergy Clin Immunol. 2013; 132: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar to confer a significant risk for AD in human subjects, even when controlling for the effect of FLG mutations, suggesting that both gene products can play a role in the pathogenesis of the disease. Further expanding the spectrum of proteins possibly involved in the chain of events leading to atopy is a recent study demonstrating a wide range of defects in numerous filaggrin-related molecules.14Pellerin L. Henry J. Hsu C.Y. Balica S. Jean-Decoster C. Mechin M.C. et al.Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin.J Allergy Clin Immunol. 2013; 131: 1094-1102Abstract Full Text Full Text PDF PubMed Scopus (168) Google ScholarTaken together, the 2 studies published in this issue of the Journal not only shed new light on the pathogenesis of AD but also and more importantly underscore the fact that the skin barrier represents an often neglected but nonetheless clinically critical (and most accessible) target for old and novel therapeutic approaches in the treatment of AD. As usual, these new data raise a large number of questions. First, although abnormal lamellar granule trafficking has been implicated in the past in the setting of several monogenic conditions, their dysfunction has not been invariably found to result in atopy-related phenotypes. Premature secretion of lamellar granules has been observed in patients with Netherton syndrome.11Fartasch M. Williams M.L. Elias P.M. Altered lamellar body secretion and stratum corneum membrane structure in Netherton syndrome: differentiation from other infantile erythrodermas and pathogenic implications.Arch Dermatol. 1999; 135: 823-832Crossref PubMed Scopus (102) Google Scholar In contrast, decreased secretion of lamellar granules, as observed in the study by Sasaki et al,5Sasaki T. Shiohama A. Kubo A. Kawasaki H. Ishida-Yamamoto A. Yamada T. et al.A homozygous nonsense mutation in the gene for Tmem79, a component for lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 1111-1120Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar has been reported in patients with several other noninflammatory disorders of cornification.12Hershkovitz D. Mandel H. Ishida-Yamamoto A. Chefetz I. Hino B. Luder A. et al.Defective lamellar granule secretion in arthrogryposis, renal dysfunction, and cholestasis syndrome caused by a mutation in VPS33B.Arch Dermatol. 2008; 144: 334-340Crossref PubMed Scopus (37) Google Scholar, 13Sprecher E. Ishida-Yamamoto A. Mizrahi-Koren M. Rapaport D. Goldsher D. Indelman M. et al.A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma.Am J Hum Genet. 2005; 77: 242-251Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar These conflicting observations remain to be explained. Meanwhile, they indicate that abnormal trafficking of lamellar granules might be contributory but is certainly not sufficient to induce cutaneous allergic responses. More intriguing is the fact that FLG mutations have been shown to be strongly associated with AD in human subjects,1McAleer M.A. Irvine A.D. The multifunctional role of filaggrin in allergic skin disease.J Allergy Clin Immunol. 2013; 131: 280-291Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar whereas filaggrin deficiency seems not to be sufficient to induce dermatitis in the mouse. Interactions with environmental agents, the effect of inherited modifier traits, or both in human subjects might explain this discrepancy. Of direct relevance to this issue is the fact that a single nucleotide polymorphism in the human TMEM79 gene was found by Saunders et al6Saunders S.P. Goh C.S. Brown S.J. Palmer C.N. Porter R.M. Cole C. et al.Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in humans.J Allergy Clin Immunol. 2013; 132: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar to confer a significant risk for AD in human subjects, even when controlling for the effect of FLG mutations, suggesting that both gene products can play a role in the pathogenesis of the disease. Further expanding the spectrum of proteins possibly involved in the chain of events leading to atopy is a recent study demonstrating a wide range of defects in numerous filaggrin-related molecules.14Pellerin L. Henry J. Hsu C.Y. Balica S. Jean-Decoster C. Mechin M.C. et al.Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin.J Allergy Clin Immunol. 2013; 131: 1094-1102Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar Taken together, the 2 studies published in this issue of the Journal not only shed new light on the pathogenesis of AD but also and more importantly underscore the fact that the skin barrier represents an often neglected but nonetheless clinically critical (and most accessible) target for old and novel therapeutic approaches in the treatment of AD. Dr Leung wishes to acknowledge the Edelstein Family Foundation for their generous support of his work and to thank Shih-Yun Lyman for her assistance in the preparation of this article. A homozygous nonsense mutation in the gene for Tmem79, a component for the lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitisJournal of Allergy and Clinical ImmunologyVol. 132Issue 5PreviewFlaky tail (ma/ma Flgft/ft) mice have a frameshift mutation in the filaggrin (Flgft) gene and are widely used as a model of human atopic dermatitis associated with FLG mutations. These mice possess another recessive hair mutation, matted (ma), and develop spontaneous dermatitis under specific pathogen-free conditions, whereas genetically engineered Flg−/− mice do not. Full-Text PDF Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjectsJournal of Allergy and Clinical ImmunologyVol. 132Issue 5PreviewAtopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted, causing a matted hair phenotype. Full-Text PDF Open Access
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