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Research Updates

Donald YM Leung,  MD, PhD

Atopic Dermatitis: A Complex Immunopathogenesis

Donald Leung

Wednesday, May 12, 2010

Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects nearly 20% of children and often persists into adulthood.1 New research into the immunopathogenesis of AD suggests that structural defects in the epidermis, combined with immune dysregulation, play an important role in this condition.2 These responses are influenced by genetic abnormalities and environmental exposure.3 Aside from allergen sensitization, patients with AD have a unique predisposition to colonization or infection by a number of infectious organisms.4

Defects in the Skin Barrier

Many studies have demonstrated that patients with AD have significant abnormalities in their epidermal barrier.5 These abnormalities include reduced levels of cornified envelope proteins, such as filaggrin and loricrin, decreased ceramide levels, and increased protease activity contributing to enhanced transepidermal water loss.2 The skin barrier is further damaged by exposure to proteases from house dust mites and S. aureus. Genetic abnormalities in protease inhibitor expression fuel the skin damage seen in eczematoid conditions.3
The importance of skin barrier function in AD is now well established, as multiple reports indicate that null mutations of genes encoding proteins such as filaggrin (FLG) are associated with AD and enhance allergen penetration through the skin, leading to systemic allergen sensitization.6 These patients are at increased risk of developing early-onset, severe AD. However, most patients with AD do not have any of the known FLG mutations, and individuals with FLG-null alleles and icthyosis vulgaris often do not develop inflammatory skin lesions. Indeed, most AD patients with FLG mutations outgrow their childhood skin disease or go into an extended remission. These observations suggest that immunologic responses and environmental factors must also contribute to the expression of clinical AD.7

The Systemic Immune Response

Nearly 80% of AD patients have peripheral blood eosinophilia, as well as increased serum immunoglobulin (Ig)E levels.1 These patients often undergo the so-called atopic march and develop respiratory allergy. Allergen sensitization through the skin may predispose patients with AD to develop food allergies and respiratory disease because epicutanous sensitization has a strong effect on the systemic allergic response.8 Indeed, when mice are sensitized epicutaneously with egg allergen, it induces a local eczematoid skin reaction, elevated serum IgE, eosinophilia, and airway hyper-responsiveness.9
Skin-homing T cells in the peripheral blood of patients with AD express increased levels of interleukin (IL)-4, IL-5, and IL-13, but little interferon (IFN)-γ.10 These immune abnormalities are important because IL-4 and IL-13 promote isotype switching to IgE, whereas IL-5 enhances the development of eosinophils. In contrast, IFN-γ inhibits allergic responses. Clinically, reduced peripheral blood IFN-γ production has been associated with AD skin infections.11,12

The Skin Immune Response

T-cell Response

As shown in Figure 1, the acute AD skin lesion is associated with an influx of T cells and the predominant expression of T helper (Th)2 cytokines (IL-4, IL-13, IL-31). The chronic skin lesion is characterized by Th1 cytokines (IFN-γ and IL-12).13
As pruritus is a key feature of AD, there has been considerable interest in IL-31, which is preferentially expressed by Th2 cells.14 Mice that overexpress IL-31 develop severe pruritus and dermatitis.15 Furthermore, T-cell production of IL-31 is inducible by staphylococcal toxins.16 These findings provide a link between S. aureus colonization (and subsequent T-cell activation) and the induction of pruritus in AD.
Regulatory T cells play an important role in suppressing allergic inflammation. Recently, it has been reported that there is a deficiency of resident regulatory T cells in AD skin.17 In addition, it has been demonstrated that activated CD25-expressing T cells with a phenotype of regulatory T cells promote Th2 immune responses in patients with AD.18 Interestingly, after stimulation with superantigens, regulatory T cells lose their immunosuppressive activity, suggesting a novel mechanism by which superantigens could augment T-cell activation in AD.19
When normal keratinocytes are incubated with IL-17, antimicrobial peptides such as human beta defensin (HBD)-2 are upregulated, suggesting a role for IL-17 in the skin's innate immune response. However, in the presence of IL-4 or IL-13, upregulation of HBD-2 is inhibited.20 Furthermore, Th17 cells appear to have a diminished role in the inflammatory skin lesions of AD when compared with psoriasis. This reduced expression of innate defense genes may contribute to increased skin infections in AD.21

Figure 1.  Atopic dermatitis immunopathogenesis. Reproduced with permission from Elsevier (J Allergy Clin Immunol 2006;118 [July cover image]).

 

Antigen-presenting Cells

Dendritic cells (DCs) play a key role in sensing antigens or invading pathogens via pattern recognition receptors (PRRs), e.g. Toll-like receptors (TLRs). Two subtypes of myeloid DCs have been identified in the epidermis of AD subjects. AD skin contains IgE-bearing Langerhans cells (LCs),22 and binding of IgE to LCs occurs via high-affinity IgE receptors (FcεRI). Higher expression of FcεRI is observed in AD lesions when compared with non-lesional skin of AD patients or epidermal skin of non-atopic individuals. The presence of these IgE-bearing LCs is required to provoke the eczematous skin lesions that occur following epicutaneous application of aeroallergens to non-lesional AD skin. After IgE binding and internalization of allergen, LCs migrate to peripheral lymph nodes, present the processed allergen in a highly efficient manner to naïve T cells, and initiate a Th2 immune response resulting in IgE sensitization to the antigen.
Aggregation of FcεRI on the surface of LCs in vitro promotes the release of chemotactic factors, which contributes to the infiltration of a second population of myeloid DCs - the inflammatory dendritic epidermal cells (IDECs) - into the epidermis.23 IDECs are observed prominently at sites of chronic AD inflammatory skin lesions and produce high levels of proinflammatory cytokines and chemokines after FcεRI cross-linking.24 Stimulation of FcεRI on the surface of IDECs induces the release of IL-12 and IL-18, and enhances the priming of naïve T cells into IFN-γ-producing T cells. These mechanisms may contribute to the biphasic switch from the initial Th2 response in acute AD to Th1 responses in chronic AD.
Human plasmacytoid DCs (PDCs) are the key IFN-producing cells and are important in host defense against viral infections. Human PDCs bear the PRRs TLR7 and TLR9 on their cell surface; furthermore, they express FcεRI.25 FcεRI aggregation induced by allergen challenge of PDCs in AD patients can, however, downregulate the release of IFNs from atopic PDCs following viral challenge. The number of PDCs in lesional epidermal skin of AD is significantly lower than in inflammatory skin lesions from psoriasis or contact dermatitis.26 These factors may enhance the susceptibility of certain AD patients to viral skin infections.

Keratinocytes

Keratinocytes play an important role in the innate immune response and control of the adaptive immune response. They produce filaggrin and other members of the epidermal differentiation complex, resulting in mechanical protection and moisturization of the skin. They also produce antimicrobial proteins and proinflammatory cytokines that protect the host against invading pathogens. AD keratinocytes express high levels of thymic stromal lymphopoietin (TSLP), which activates myeloid DCs in the absence of IL-12 production, to promote Th2 cell development.27 The importance of TSLP is supported by the observation that overexpression of TSLP in a transgenic mouse model resulted in an AD-like phenotype, with the development of eczematoid skin lesions containing inflammatory dermal cellular infiltrates, an increase in skin-infiltrating Th2 CD4+ T cells, and elevated serum levels of IgE.28 Recent studies in animal models suggest that the release of skin-derived TSLP into the systemic circulation may promote the development of asthma, thereby providing a molecular explanation for the atopic march.

Other Factors Contributing to Skin Inflammation

The release of chemokines into the skin as the result of allergen exposure, microbial invasion and trauma from scratching leads to the recruitment of various inflammatory and immune cell subtypes.29 Serum levels of some of these chemokines, e.g. CCL27, correlate directly with the severity of AD skin disease. Increased expression of the CC chemokines RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted)/CCL5, monocyte chemotactic protein-4 (MCP-4/CCL13), and eotaxin/CCL11 promotes chemotaxis of eosinophils and Th2 lymphocytes into AD skin.30 The chemokine receptor CCR3, which is found on eosinophils and Th2 lymphocytes, mediates the action of eotaxin, RANTES, and MCP-4. A role for cutaneous T cell-attracting chemokine (CTACK/CCL27) in the preferential attraction of cutaneous lymphocyte antigen-bearing (CLA+) T cells to the skin has also been reported.31
Chronic AD is linked to the prolonged survival of eosinophils and monocyte-macrophages. IL-5 expression during chronic AD helps to prolong eosinophil survival and enhance their function. In chronic AD, increased expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes the survival and function of monocytes, LCs, and eosinophils.32 Keratinocytes from AD patients have significantly higher levels of RANTES expression following stimulation with tumor necrosis factor (TNF)-α and IFN-γ than do keratinocytes from psoriasis patients. Furthermore, cytokine stimulation during chronic AD enhances the chronicity and severity of eczema.
Another mechanism by which immune dysregulation drives chronic inflammation in AD is via autoimmune skin responses. The itch/scratch cycle in AD can damage epidermal keratinocytes and result in the release of intracellular antigens, which in a subset of AD patients can lead to autoantigen-driven immune activation.33 Serum from a subset of AD patients has shown IgE autoreactivity against cytoplasmic and cell membrane antigens found in epidermal cells. This autoreactivity in AD patients correlates with the severity of the disease. Specific IgE against the stress-inducible enzyme manganese superoxide dismutase (MnSOD) has also been reported in AD. MnSOD has also been found to induce T-cell reactivity in vitro in AD patients sensitized to MnSOD.34 Thus, autoreactivity may contribute to immune activation in AD.

Triggers of AD

Food

Food allergens can induce skin rashes in children with AD.35 Based on double-blind, placebo-controlled food challenges, approximately 40% of infants and young children with moderate to severe AD have a food allergy. Removal of food allergens from the patient's diet can lead to clinical improvement, but requires a great deal of education because most common food allergens, such as egg, milk, wheat, soy, and peanut, contaminate many foods and are difficult to avoid. Immediate skin tests for specific allergens do not always indicate clinical sensitivity in patients, but instead reflect allergen sensitization. Therefore, unlike the patient who has food-induced anaphylaxis, food allergy in AD should be verified by controlled food challenges or careful investigation of the effects of a food elimination diet.

Inhalant Allergens

Pruritus and eczematoid skin lesions can develop after intranasal or bronchial inhalation challenge with inhalant allergens in AD patients producing IgE to aeroallergens.36 Epicutaneous application of aeroallergens by patch test techniques on non-lesional atopic skin elicits eczematoid reactions in 30-50% of patients with AD. Positive reactions have been observed to dust mite, weeds, animal dander, and molds in allergen-sensitized patients. Several studies have also reported that avoidance of aeroallergens can result in clinical improvement of AD. However, the effects of environmental control are highly variable. The observation that certain AD patients can benefit from immunotherapy with specific allergens provides further support that aeroallergens may play a role in AD.37

Microbes

Patients with AD are prone to skin colonization or infection with S. aureus, various viruses and fungi. This propensity to microbial infection may be a result of several innate immune system abnormalities, including a reduction in antimicrobial peptides, diminished recruitment of neutrophils to the skin, TLR defects and epidermal barrier dysfunction.38 Cross-talk between the innate and adaptive immune responses contributes to the infectious complications of AD. As an example, both mobilization of the anti-microbial peptide HBD-3 and killing of S. aureus by keratinocytes from AD patients have been shown to be inhibited significantly by IL-4 and IL-13, whereas neutralization of these cytokines improves these activities.39,40 Furthermore, serum IgE levels in AD patients with herpes simplex virus (HSV) infections correlates inversely with the cathelicidin LL-37.41

S. aureus can contribute to skin inflammation in AD by secreting toxins that activate T cells and other resident and infiltrating cells in the skin.42 Epicutaneous application of staphylococcal enterotoxin B (SEB) to the skin can induce eczematous changes.43 In addition, AD patients make specific IgE antibodies directed against the staphylococcal toxins found on their skin, and basophils from these patients release histamine on exposure to the relevant toxin.44 This suggests that S. aureus-producing superantigens can induce mast cell degranulation and contribute to inflammatory events in the skin. S. aureus isolates from patients with steroid-resistant AD have been shown to produce increased numbers of superantigens compared with isolates from controls.45

The clinical course in patients with AD can also be complicated by both localized and disseminated cutaneous viral infections, most often caused by HSV.46 Compared with AD patients without a history of eczema herpeticum (EH), those with EH have a more Th2-polarized disease with greater allergen sensitization, and are also more likely to develop cutaneous infections with S. aureus. In addition, AD patients of both European and African ancestry who have the R501X mutation in FLG have been found to have an even greater risk for EH, suggesting that a defective skin barrier can also contribute to this serious complication.47 Importantly, patients with AD are also at risk for life-threatening complications from smallpox vaccination (eczema vaccinatum).48,49 When skin biopsies from AD subjects are inoculated with vaccinia virus, viral replication is increased compared with healthy controls.50 In addition, levels of the antimicrobial cathelicidin LL-37 in AD skin are low, whereas expression of IL-4 and IL-13 is elevated; antibodies against Th2 cytokines inhibit vaccinia growth and enhance production of LL-37.

Clinical Implications

The key factors in the management of AD are (i) skin hydration and barrier repair; (ii) use of effective topical anti-inflammatory agents, such as corticosteroids, and calcineurin inhibitors; (iii) avoidance of allergenic triggers; and (iv) treatment of skin infections. In patients whose skin inflammation does not respond to topical therapy, alternative anti-inflammatory approaches should be considered, including phototherapy, cyclosporine, azathioprine, mycophenolate, and methotrexate. With our emerging knowledge of the immunopathogenesis of AD, new therapeutic targets are being identified, including IL-4, IL-13, IL-31 and TSLP.51
Interestingly, vitamin D deficiency is increasingly being recognized in the general population. Vitamin D has been found to increase the expression of antimicrobial peptides (AMPs) in keratinocytes and its deficiency may predispose patients with AD to skin infection.52 A clinical trial found increased expression of the AMP cathelicidin in the skin of AD patients treated with oral vitamin D.53 In addition, children with winter-associated AD showed clinical improvement after treatment with oral vitamin D when compared with placebo.54
These studies suggest that new approaches addressing defects contributing to the innate and adaptive immune defects found in AD may result in more effective treatments for this common skin disease.

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