Evolving Concepts of Pathogenesis in Atopic Dermatitis and Other Eczemas

REVIEW

Evolving Concepts of Pathogenesis in Atopic Dermatitis and Other Eczemas Jon M. Hanifin1 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. Journal of Investigative Dermatology (2009) 129, 320–322; doi:10.1038/jid.2008.252; published online 21 August 2008

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. 1

Department of Dermatology, Oregon Health & Science University, 3303 S.W. Bond Avenue, Portland, OR 97239-4501, USA

Presented at the 56th Annual Montagna Symposium, 11–15 October 2007, Gleneden Beach, Portland, Oregon, USA. Correspondence: Dr Jon M. Hanifin, Department of Dermatology, Oregon Health & Science University, 3303 S.W. Bond Avenue, Portland, OR 972394501, USA. E-mail: [email protected] Abbreviations: ACD, allergic contact dermatitis; AD, atopic dermatitis; FLG, filaggrin; KC, keratinocyte Received 7 March 2008; revised 1 July 2008; accepted 8 July 2008; published online 21 August 2008

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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 and Reed, 2007). 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. 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, 2005; Elias and Steinhoff, 2008) 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 et al., 2004). Circulating peripheral blood Th1 cells in AD appear to undergo activation-induced cell death (Akdis et al., 2003), which, along with increased levels of IL-10 and prostaglandin E2 (Ohmen et al., 1995; Chan et al., 1996) 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-g in AD lesional biopsies and more IL-4 in ACD reactions (Ohmen et al., 1995). 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-g-associated Th1 cells later (Grewe et al., 1995). Other studies attempted to sample lesional ‘‘acute’’ and ‘‘chronic’’ AD lesions, showing Th2 and Th1 features, respectively (Hamid et al., 1994), 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 & 2009 The Society for Investigative Dermatology

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Table 1. The eczema family Etiologic/morphologic variants

Regional variants

Atopic dermatitis

Hand eczema

Contact dermatitis

Face/eyelids

Irritant (ICD)

Lips (cheilitis)

Allergic (ACD)

Scalp

Nummular eczema

Diaper dermatitis

Lichen simplex chronicus

Stasis dermatitis

IFN-g, Fas ligand, tumor necrosis factor-a, IL-5, and IL-13, but not IL-4 (Akdis et al., 1999; Verhagen et al., 2006). 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 et al., 1999; Hennino et al., 2007; Oflazoglu et al., 2008) and a recent report presents strong evidence for predominance of distinct CD8 þ T-cell populations producing IL-13 and IFN-g in AD lesions (Hijnen et al., 2008). Likewise, studies have suggested increased numbers of IL-17 þ cells in some AD lesions (Koga et al., 2008), though decreased IL-17 expression has also been reported (Guttman-Yassky et al., 2008). 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 and Chan, 1995), 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 et al., 2006; Sandilands et al., 2007b) 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, 2007). These new findings, along with numerous studies indicating protease, protease inhibitor, and lipid abnormalities in AD stratum corneum (Elias, 2005; Elias and Steinhoff, 2008), 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 et al., 1996; Spergel et al., 1998; Herrick et al., 2000) and is supported by clinical observations (Lack et al., 2003). More recent approaches demonstrate that epidermal structural defects may relate to impaired innate immunity and to vitamin D-enhanced antimicrobial effects (Schauber et al., 2007). Another realm of investigation is demonstrating a complex interaction of keratinocyte (KC) signaling events that influence apoptosis, spongiosis, and inflammation in eczema (Trautmann et al., 2000; Pastore et al., 2005; Farley et al., 2006). 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 et al., 2000), 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 et al., 2006; Proksch et al., 2006). 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 et al., 2002; Li et al., 2006; Liu, 2006; Allakhverdi et al., 2007). 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 et al., 2000). Lossof-function FLG mutations underlie the development of ichthyosis vulgaris (Palmer et al., 2006). A number of such mutations have now been described in Europeans and Asians (Sandilands et al., 2007b; Nomura et al., 2008), and multiple reports have confirmed the predisposition of ichthyosis vulgaris to development of AD and allergic respiratory disease (Sandilands et al., 2007a). These common FLG mutations can also combine with other mutations to uncover subclinical genodermatoses (Liao et al., 2007) 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, 2007; Sandilands et al., 2007a). 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-g may affect epidermal differentiation, respectively decreasing or increasing filaggrin expression (Howell et al., 2007). 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 et al., 2006). 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 www.jidonline.org

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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. CONFLICT OF INTEREST The author states no conflict of interest.

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