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Evolving Concepts of Pathogenesis in Atopic Dermatitis and Other Eczemas

  • Jon M. Hanifin
    Correspondence
    Department of Dermatology, Oregon Health & Science University, 3303 S.W. Bond Avenue, Portland, OR 97239-4501, USA
    Affiliations
    Department of Dermatology, Oregon Health & Science University, 3303 S.W. Bond Avenue, Portland, OR 97239-4501, USA
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      The eczemas represent a common and diverse group of inflammatory skin diseases whose definitions and pathogenic mechanisms have often been confused and controversial. Since the millennium, fresh approaches are providing better insight. Research has focused much more upon the epidermis and the very relevant signaling pathways that contribute to spongiosis, proliferation, generation of proinflammatory factors, and differentiation to form an effective stratum corneum barrier. A major step in understanding has come from the solidly confirmed association between filaggrin null mutations of ichthyosis vulgaris and atopic dermatitis. Similar associations relating to protease and lipid defects have highlighted the role of barrier disruption that allows greater access of environmental toxins, microbes, and allergens. Animal models are beginning to predict mechanisms in which such direct perturbation of keratinocytes may initiate inflammation and condition immune responses in irritant contact dermatitis and atopic dermatitis. These conceptual shifts are nurturing more balanced approaches to understanding eczema and hold the hope for better prevention efforts and more specific molecular targeting for therapy.

      Abbreviations

      ACD
      allergic contact dermatitis
      AD
      atopic dermatitis
      FLG
      filaggrin
      KC
      keratinocyte

      Introduction

      Eczema represents a family of inflammatory skin conditions characterized by pruritic, papulovesicular, sometimes weeping dermatitis. All demonstrate the histological hallmark of spongiosis, which helps to distinguish the eczemas from papulosquamous diseases such as psoriasis. Eczema is probably the most common cutaneous affliction (a partial list of eczemas is shown in Table 1), with few individuals escaping at least occasional irritant contact dermatitis. A large population-based survey in the United States recorded a prevalence of 10.7% for nonspecific eczema and 6% for atopic dermatitis (AD) (
      • Hanifin J.M.
      • Reed M.L.
      A population-based survey of eczema prevalence in the United States.
      ). The term, derived from the Greek, eczeo (“to boil or effervesce”), is nicely descriptive of the acute, spongiotic, sometimes vesicular skin lesions. Eczema and dermatitis are generally used synonymously, though popular use by patients and many physicians implies AD. A variety of etiological and regional variants are included within the eczema family.
      Table 1The eczema family
      Etiologic/morphologic variantsRegional variants
      Atopic dermatitisHand eczema
      Contact dermatitisFace/eyelids
       Irritant (ICD)Lips (cheilitis)
       Allergic (ACD)Scalp
      Nummular eczemaDiaper dermatitis
      Lichen simplex chronicusStasis dermatitis
      Allergic contact dermatitis (ACD), caused by cell-mediated hypersensitivity to chemical haptens, is relatively well-understood mechanistically. In contrast, irritant contact dermatitis (ICD) has received far less basic investigation and, although considerable research has been directed at AD in the past three decades, the complexities of this disease have defied clear understanding, allowing only a general description of pathogenesis. It is an inflammatory skin disease, usually familial, with complex genetic underpinnings. AD is associated with defects of the stratum corneum barrier (
      • Elias P.M.
      Stratum corneum defensive functions: an integrated view.
      ;
      • Elias P.M.
      • Steinhoff M.
      “Outside-to-inside” (and now back to “outside”) pathogenic mechanisms in atopic dermatitis.
      ) and it usually predisposes to IgE reactivity. Th2 cells in lymph nodes and peripheral blood are responsible for elevated serum IgE and increased numbers of eosinophils (
      • Leung D.Y.
      • Boguniewicz M.
      • Howell M.D.
      • Nomura I.
      • Hamid Q.A.
      New insights into atopic dermatitis.
      ). Circulating peripheral blood Th1 cells in AD appear to undergo activation-induced cell death (
      • Akdis M.
      • Trautmann A.
      • Klunker S.
      • Daigle I.
      • Kucuksezer U.C.
      • Deglmann W.
      • et al.
      T helper (Th) 2 predominance in atopic diseases is due to preferential apoptosis of circulating memory/effector Th1 cells.
      ), which, along with increased levels of IL-10 and prostaglandin E2 (
      • Ohmen J.D.
      • Hanifin J.M.
      • Nickoloff B.J.
      • Rea T.H.
      • Wyzykowski R.
      • Kim J.
      • et al.
      Overexpression of IL-10 in atopic dermatitis: contrasting cytokine patterns with delayed-type hypersensitivity reactions.
      ;
      • Chan S.C.
      • Henderson Jr, W.R.
      • Li S.-H.
      • Hanifin J.M.
      Prostaglandin E2 control of T cell cytokine production is functionally related to the reduced lymphocyte proliferation in atopic dermatitis.
      ) might account for the apparent Th2 predominance in AD.
      The T-cell component in AD skin remains somewhat obscure and confused. Early studies assumed that IL-4-producing Th2 cells would predominate, yet an initial study comparing AD, ACD, and tuberculin reactions suggested the opposite, with relatively greater IFN-γ in AD lesional biopsies and more IL-4 in ACD reactions (
      • Ohmen J.D.
      • Hanifin J.M.
      • Nickoloff B.J.
      • Rea T.H.
      • Wyzykowski R.
      • Kim J.
      • et al.
      Overexpression of IL-10 in atopic dermatitis: contrasting cytokine patterns with delayed-type hypersensitivity reactions.
      ). Follow-up studies then, using the aeroallergen patch test as a surrogate for AD, showed Th2 cells in the early 24-hour reactions and IFN-γ-associated Th1 cells later (
      • Grewe M.
      • Walther S.
      • Gyufko K.
      • Czech W.
      • Schopf E.
      • Krutmann J.
      Analysis of the cytokine pattern expressed in situ in inhalant allergen patch test reactions of atopic dermatitis patients.
      ). Other studies attempted to sample lesional “acute” and “chronic” AD lesions, showing Th2 and Th1 features, respectively (
      • Hamid Q.
      • Boguniewicz M.
      • Leung D.Y.
      Differential in situ cytokine gene expression in acute versus chronic dermatitis.
      ), though acute lesions cannot be induced, thus are necessarily poorly and variably defined. Histologically, the two stages can show marked differences in spongiosis and proliferative features, thus are difficult to blind. ACD controls would provide appropriate comparisons but have been lacking from most studies. These technical problems have caused uncertainty as to the role of Th2 in eczematization. Lesional AD skin displays relatively few Th2 cells and clonally expanded T cells isolated from AD skin, or immunohistochemically characterized in situ, display mixed Th0/Th1 and Th2 cytokine profiles producing high quantities of IFN-γ, Fas ligand, tumor necrosis factor-α, IL-5, and IL-13, but not IL-4 (
      • Akdis C.A.
      • Akdis M.
      • Simon D.
      • Dibbert B.
      • Weber M.
      • Gratzl S.
      • et al.
      T cells and T cell-derived cytokines as pathogenic factors in the nonallergic form of atopic dermatitis.
      ;
      • Verhagen J.
      • Akdis M.
      • Traidl-Hoffmann C.
      • Schmid-Grendelmeier P.
      • Hijnen D.
      • Knol E.F.
      • et al.
      Absence of T-regulatory cell expression and function in atopic dermatitis skin.
      ). These studies have helped open the stage to more comprehensive examinations of T cells in AD lesions. Several studies have indicated that CD8 cells may play a role (
      • Akdis C.A.
      • Akdis M.
      • Simon D.
      • Dibbert B.
      • Weber M.
      • Gratzl S.
      • et al.
      T cells and T cell-derived cytokines as pathogenic factors in the nonallergic form of atopic dermatitis.
      ;
      • Hennino A.
      • Vocanson M.
      • Toussaint Y.
      • Rodet K.
      • Benetiere J.
      • Schmitt A.-M.
      • et al.
      Skin-infiltrating CD8+ T cells initiate atopic dermatitis lesions.
      ;
      • Oflazoglu E.
      • Simpson E.L.
      • Takiguchi R.
      • Grewal I.S.
      • Hanifin J.M.
      • Gerber H.P.
      CD30 expression on CD1a+ and CD8+ cells in atopic dermatitis and correlation with disease severity.
      ) and a recent report presents strong evidence for predominance of distinct CD8+ T-cell populations producing IL-13 and IFN-γ in AD lesions (
      • Hijnen D.J.
      • Bruijnzeel-Koomen C.A.
      • Hack I.M.
      • Knol E.F.
      • de-Bruin-Weller M.S.
      • Kupper T.S.
      • et al.
      Interleukin-13 and interferon-gamma producing skin resident CD8+ T cells: a vicious circle of barrier disruption of the skin in atopic dermatitis.
      ). Likewise, studies have suggested increased numbers of IL-17+ cells in some AD lesions (
      • Koga C.
      • Kabashima K.
      • Shiraishi N.
      • Kobayashi M.
      • Tokura Y.
      Possible pathogenic role of Th17 cells for atopic dermatitis.
      ), though decreased IL-17 expression has also been reported (
      • Guttman-Yassky E.
      • Lowes M.
      • Judy F.
      • Irma C.
      • Zaba L.C.
      • Khatcherian A.
      • et al.
      Reduced expression of the IL-23/IL-17 axis in atopic dermatitis skin may impair innate immunity.
      ).
      Clearly, the cell-mediated aspects of AD remain uncertain. Atopic diseases in general appear to be associated with defective cyclic nucleotide regulation of immune and inflammatory cells (
      • Hanifin J.M.
      • Chan S.C.
      Monocyte phosphodiesterase abnormalities and dysregulation of lymphocyte function in atopic dermatitis.
      ), but no unified genetic understanding of the immunological abnormalities has come forth. The clearly evident fact that in about 20% of patients, AD occurs in the absence of IgE reactivity or personal/familial atopy undermines the assumption of a primary immunological defect. Instead, the recent findings of a strongly confirmed association between AD and filaggrin (FLG) null mutations (
      • Palmer C.N.A.
      • Irvine A.D.
      • Terron-Kwiatkowski A.
      • Zhao Y.
      • Liao H.
      • Lee S.P.
      • et al.
      Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.
      ;
      • Sandilands A.
      • Terron-Kwiatkowski A.
      • Hull P.R.
      • O’Regan G.M.
      • Clayton T.H.
      • Watson R.M.
      • et al.
      Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.
      ) suggest the possibility that a barrier defect may be a major factor, or perhaps a primary cause of Th2/IgE abnormalities. Interestingly, similar conclusions are beginning to emerge from research in asthma (
      • Holgate S.T.
      Epithelium dysfunction in asthma.
      ).
      These new findings, along with numerous studies indicating protease, protease inhibitor, and lipid abnormalities in AD stratum corneum (
      • Elias P.M.
      Stratum corneum defensive functions: an integrated view.
      ;
      • Elias P.M.
      • Steinhoff M.
      “Outside-to-inside” (and now back to “outside”) pathogenic mechanisms in atopic dermatitis.
      ), have firmly focused research upon the epidermis in AD. Obviously, barrier defects provide greater access for toxins, microbes, and allergens. A clue to the importance of transepidermal antigen inoculation in amplifying Th2/IgE reactivity derives from murine studies (
      • Wang L.-F.
      • Lin J.-Y.
      • Hsieh K.-H.
      • Lin R.-H.
      Epicutaneous exposure of protein antigen induces a predominant Th2-like response with high IgE production in mice.
      ;
      • Spergel J.M.
      • Mizoguchi E.
      • Brewer J.P.
      • Martin T.R.
      • Bhan A.K.
      • Geha R.S.
      Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice.
      ;
      • Herrick C.A.
      • MacLeod H.
      • Glusac E.
      • Tigelaar R.E.
      • Bottomly K.
      Th2 responses induced by epicutaneous or inhalational protein exposure are differentially dependent on IL-4.
      ) and is supported by clinical observations (
      • Lack G.
      • Fox D.
      • Northstone K.
      • Golding J.
      Factors associated with the development of peanut allergy in childhood.
      ). More recent approaches demonstrate that epidermal structural defects may relate to impaired innate immunity and to vitamin D-enhanced antimicrobial effects (
      • Schauber J.
      • Dorschner R.A.
      • Coda A.B.
      • Buchau A.S.
      • Liu P.T.
      • Kiken D.
      • et al.
      Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism.
      ).
      Another realm of investigation is demonstrating a complex interaction of keratinocyte (KC) signaling events that influence apoptosis, spongiosis, and inflammation in eczema (
      • Trautmann A.
      • Akdis M.
      • Kleemann D.
      • Altznauer F.
      • Simon H.-U.
      • Graeve T.
      • et al.
      T cell-mediated Fas-induced keratinocytes apoptosis plays a key pathogenetic role in eczematous dermatitis.
      ;
      • Pastore S.
      • Mascia F.
      • Mariotti F.
      • Dattilo C.
      • Mariani V.
      • Girolomoni G.
      ERK1/2 regulates epidermal chemokine expression and skin inflammation.
      ;
      • Farley S.M.
      • Dotson A.D.
      • Purdy D.E.
      • Sundholm A.J.
      • Schneider P.
      • Magun B.E.
      • et al.
      Fas ligand elicits a caspase-independent proinflammatory response in human keratinocytes: implications for dermatitis.
      ). Spongiosis is perhaps the earliest physical lesion of AD, and studies suggest it to be the culmination of a varied, multistep epidermal signaling process. An initial report noted Fas-mediated KC apoptosis occurring in AD and ACD (
      • Trautmann A.
      • Akdis M.
      • Kleemann D.
      • Altznauer F.
      • Simon H.-U.
      • Graeve T.
      • et al.
      T cell-mediated Fas-induced keratinocytes apoptosis plays a key pathogenetic role in eczematous dermatitis.
      ), concluding that the process might result in spongiosis. More recent work has demonstrated spongiosis to result from protease-induced lysis of cadherins and probably independently of the apoptosis that leads more prominently to proliferative and proinflammatory signals (
      • Farley S.M.
      • Dotson A.D.
      • Purdy D.E.
      • Sundholm A.J.
      • Schneider P.
      • Magun B.E.
      • et al.
      Fas ligand elicits a caspase-independent proinflammatory response in human keratinocytes: implications for dermatitis.
      ;
      • Proksch E.
      • Folster-Holst R.
      • Jensen J.-M.
      Skin barrier function, epidermal proliferation and differentiation in eczema.
      ). The proliferative features have tended to be overlooked in AD, yet may be of considerable importance and relevance because the lichenification that is so common in AD causes recalcitrance to topical therapies. Proinflammatory factors derived from KCs have received considerable attention in recent years—thymic stromal lymphopoietin, IL-18, RANTES, GM-CSF, and others may contribute to not only the epidermal inflammation but also to mast cell reactivity and T-cell-related type 1 and type 2 immune responses (
      • Soumelis V.
      • Reche P.A.
      • Kanzler H.
      • Yuan W.
      • Edward G.
      • Homey B.
      • et al.
      Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLP.
      ;
      • Li M.
      • Hener P.
      • Zhang Z.
      • Kato S.
      • Metzger D.
      • Chambon P.
      Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis.
      ;
      • Liu Y.-J.
      Thymic stromal lymphopoietin: master switch for allergic inflammation.
      ;
      • Allakhverdi Z.
      • Comeau M.R.
      • Jessup H.K.
      • Yoon B.-R.
      • Brewer A.
      • Chartier S.
      • et al.
      Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells.
      ).
      The genetically conferred epidermal barrier defects that predispose to AD include both Netherton's syndrome and ichthyosis vulgaris. Netherton's is caused by mutations in the serine protease inhibitor Kazal type 5 gene that codes the protease inhibitor, lympho-epithelial Kazal-type-related inhibitor, presumably opening the stratum corneum to destructive intrinsic and microbial proteases (
      • Chavanas S.
      • Bodemer C.
      • Rochat A.
      • Hamel-Teillac D.
      • Ali M.
      • Irvine A.D.
      • et al.
      Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome.
      ). Loss-of-function FLG mutations underlie the development of ichthyosis vulgaris (
      • Palmer C.N.A.
      • Irvine A.D.
      • Terron-Kwiatkowski A.
      • Zhao Y.
      • Liao H.
      • Lee S.P.
      • et al.
      Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.
      ). A number of such mutations have now been described in Europeans and Asians (
      • Sandilands A.
      • Terron-Kwiatkowski A.
      • Hull P.R.
      • O’Regan G.M.
      • Clayton T.H.
      • Watson R.M.
      • et al.
      Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.
      ;
      • Nomura T.
      • Akiyama M.
      • Sandilands A.
      • Nemoto-Hasebe I.
      • Sakai K.
      • Nagasaki A.
      • et al.
      Specific filaggrin mutations cause ichthyosis vulgaris and are significantly associated with atopic dermatitis in Japan.
      ), and multiple reports have confirmed the predisposition of ichthyosis vulgaris to development of AD and allergic respiratory disease (
      • Sandilands A.
      • Smith F.J.
      • Irvine A.D.
      • McLean W.H.
      Filaggrin's fuller figure: a glimpse into the genetic architecture of atopic dermatitis.
      ). These common FLG mutations can also combine with other mutations to uncover subclinical genodermatoses (
      • Liao H.
      • Waters A.J.
      • Goudie D.R.
      • Aitken D.A.
      • Graham G.
      • Smith F.J.
      • et al.
      Filaggrin mutations are genetic modifying factors exacerbating X-linked ichthyosis.
      ) and may well herald future findings of mutations in other important barrier proteins such as involucrin, loricrin, and so on. Such possibilities allow speculation as to whether barrier defects and their downstream immunological effects might theoretically account for all or the majority of AD and asthma (
      • Irvine A.D.
      Fleshing out filaggrin phenotypes.
      ;
      • Sandilands A.
      • Smith F.J.
      • Irvine A.D.
      • McLean W.H.
      Filaggrin's fuller figure: a glimpse into the genetic architecture of atopic dermatitis.
      ).
      There have been many reasons for the long-held assumption of IgE and Th2 primacy in AD, but most are based on correlative information. A prominent correlation is the high serum IgE with more severe AD but severity usually reflects more extreme skin barrier disruption, hence greater inoculation of antigens triggering Th2 and IgE responses. It appears that T cells are important in the pathogenesis of eczemas. A recent study raises the interesting possibility that Th2 cytokines and IFN-γ may affect epidermal differentiation, respectively decreasing or increasing filaggrin expression (
      • Howell M.D.
      • Kim B.E.
      • Gao P.
      • Grant A.V.
      • Boguniewicz M.
      • DeBenedetto A.
      • et al.
      Cytokine modulation of atopic dermatitis filaggrin skin expression.
      ). T cells appear to be the primary response unit in ACD and it is reasonable to surmise that they underlie the allergenic reactivity evident in most AD patients. Alternatively, in AD and irritant dermatitis, they may simply arrive at the behest of KC factors such as thymic stromal lymphopoietin (
      • Li M.
      • Hener P.
      • Zhang Z.
      • Kato S.
      • Metzger D.
      • Chambon P.
      Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis.
      ). Their role in AD could be mainly a factor in chronicity (that is, maintaining inflammation) and in response to infection.
      In summary, the conceptual focus is switching from immunological to epidermal barrier mechanisms that underlie AD. There are now well-established genetic associations between ichthyosis and AD and asthma. Stratum corneum “bricks and mortar,” proteases, their inhibitors, and structural proteins are all being assessed and may lead to further genetic associations. These advances suggest that, in the coming years, genetics may reveal new molecular sites that provide previously unidentified, specific targets for barrier repair and for prevention of AD and allergies.

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