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The New Concept of Pathogenesis of Atopic Dermatitis

Widodo Judarwanto, Allergy Clinic Online

Atopic dermatitis (AD) is a paradigmatic skin disease in which multiple gene-gene and gene-environment interactions play a pivotal role. Although the complex pathophysiologic network of AD explains the large spectrum of risk and trigger factors, it is far from being comprehensively understood. Genetic modifications underlying the dysfunction of the epidermal skin barrier as well as the close interaction of innate and adaptive immune mechanisms were the focus of intensive research studies. The pathogenesis of AD remains to be studied but generally includes abnormal skin barrier and aberrant cutaneous immune responses.

Atopic dermatitis (AD) is a pruritic inflammatory skin disease associated with a personal or family history of allergy. The prevalence of AD is on the rise and estimated at approximately 17% in the USA. Atopic dermatitis (AD) is a common allergic disease and constitutes a huge social and economic burden for the whole country. AD usually heralds other allergic diseases, such as asthma and allergic rhinitis. The fundamental lesion in AD is a defective skin barrier that results in dry itchy skin, and is aggravated by mechanical injury inflicted by scratching. This allows entry of antigens via the skin and creates a milieu that shapes the immune response to these antigens.

Atopic eczema/dermatitis syndrome is a term that covers different subtypes of atopic dermatitis. The “intrinsic” type of atopic dermatitis is non-IgE-associated, and the “extrinsic” type is IgE-associated atopic eczema/dermatitis syndrome. In the etiopathogenesis of atopic dermatitis there are well known interactions among genetic, environmental, skin barrier, immune factors, and stress. Genetic factors determine the expression of atopic dermatitis as pure or mixed with concomitant respiratory or intestinal allergy, depending on genetic susceptibility.

Atopic dermatitis (AD), a skin disease characterized by pruritus and chronic inflammation, results from a complex interplay between environmental and genetic factors. Atopic dermatitis (AD) is a common skin condition, characterized by a complex, heterogeneous pathogenesis, including skin barrier dysfunctions, allergy/immunology, and pruritus. When the skin barrier is disrupted by, for example, the filaggrin gene mutation and/or environmental factors, the skin is predisposed to being penetrated by external stimuli. Foreign antigens can be subdivided into two subsets by size: haptens (including metals) and protein antigens. It is known that a single hapten challenge provokes Th1 initially, but that repeated elicitation with haptens results in a shift toward Th2-dominated responses. On the other hand, exposure to protein antigens directly induces Th2-dominant conditions via the thymic stromal lymphopoietin (TSLP) receptor on Langerhans cells. Recently, it has been revealed that Th2 cells produce IL-31, which provokes pruritus, and that Th2 cytokines decrease filaggrin expressions by keratinocytes. These findings suggest that Th2 conditions lead to pruritus and barrier dysfunctions. The highly complex interplay among skin barrier abnormality, allergy/immunology, and pruritus as a trinity in the development of AD.

Immunologic abnormalities of type I and type IV reactions have been described in patients with atopic dermatitis. Immunologic triggers are aeroallergens, food allergens, microbial products, autoallergens and contact allergens. Immune reactions determine many features of atopic dermatitis.

The discovery of mutations in the filaggrin gene, a key protein for stratum corneum maturation, have refocused attention on the skin and operated a Copernican revolution in our understanding of this group of disorders. AD has become a prototype of inflammatory epithelial barrier diseases. The epidermal barrier has three major elements: the stratum corneum, which provides an air-liquid barrier, tight junctions in the granular layer (liquid-liquid barrier), and Langerhans cells that capture antigens (immunological barrier). Better knowledge of the molecular events underlying epidermal barrier function and its dysfunction in AD should lead to ways of preventing and eventually curing this group of disorders.

Immunological Responses

Langerhans cells and inflammatory dendritic epidermal cells (IDECs) play a predominant role in the initiation of the allergic immune response through the conversion of prime naive T cells into the T cell of the Th2 type; IL-4 plays an important role in this process as it stimulates both the conversion of naive T cells to Th2 cells, and is produced in high quantities by the Th2 subsets. Langerhans cells may possess high-affinity receptors for IgE on their surface, which avidly bind allergens, such as food, aeroallergens and microbial superantigens. Such linkage induces the release of chemotactic signals and recruitment of IDECs and T cells. Stimulation of high-affinity IgE receptor (FcεRI) on IDECs leads to the release of high amounts of proinflammatory signals, which contribute to allergic immune response.

Cytokines and chemokines are key factors in the elaboration of AD. As previously mentioned, Th2 cytokines (IL-4, -5 and -13) mediate isotype switching to IgE synthesis and upregulate expression of adhesion molecules on endothelial cells.[39] The eosinophilic cationic protein and IL-16 are also elevated in the acute AD phase. In chronic AD skin, Th2 cytokine IL-5, which is involved in eosinophil development and survival, predominates as well as the Th1-dependent expressions of IL-12 and -18, GM-CSF, IFN-γ[40] and several remodeling-associated cytokines, such as IL-11, IL-17 and TGF-ß1.

Other cytokines shown to be involved in acute and chronic AD skin lesions include increased expression of the novel eosinophil chemoattractants, eotaxin, monocyte chemotactic protein-4 and fractalkine, a chemokine expressed on activated vascular endothelial cells stimulated with IL-1, TNF-α or IFN-γ.

This imbalance of Th1 and Th2 in AD may depend on polymorphisms in the IL-18 gene on peripheral mononuclear cells, which react after stimulation with superantigens through the upregulation of IL-18 and the downregulation of IL-12.

A variety of pharmacophysiologic abnormalities have also been described. Leukocytes, and especially monocytes, from atopic patients demonstrate elevated phosphodiesterase activity, leading to decreased levels of cAMP and increased production of prostaglandin and IL-10, which inhibit Th1 function and enhance IgE production

The immunological hallmark of atopic dermatitis (AD) is a Th1/Th2 dysbalance. The reaction to high molecular weight environmental allergens (e.g. pollen, house dust mites), production of IgE and activation of eosinophil granulocytes result from Th2 dominance. The Th2-cytokine interleukin-4 (IL-4) is necessary for IgE synthesis. Additionally, IL-4 inhibits the generation of Th1-cells. The marker cytokine of Th1-cells, interferon gamma (IFN gamma), exhibits reciprocal effects. It inhibits IgE synthesis and Th2 expansion, but supports Th1-cell growth. Beside the well known mechanisms of IgE-mediated immediate type reactions, the relevance of IgE for the pathogenesis of AD seems to be likely since the discovery of IgE-receptors upon Langerhans cell surfaces. Langerhans cell-bound IgE may be possibly necessary for the presentation of high molecular weight aero-allergens. Analyses of Th subsets at different intervals after allergen challenge showed, that Th2-cells play an important role in the initial phase of inflammatory reactions whereas in later stages Th1-cells can be detected in greater numbers.

These immune reactions also include cell mediated or delayed hypersensitivity. The currently accepted model proposes a predominant Th2 cytokine milieu in the initiating stages of acute atopic dermatitis lesions, and a mixed Th1 and Th2 pattern in chronic lesions. A two-phase model includes Th2 initiation with attraction of macrophages and eosinophils, which in turn produce interleukin 12 that is the activator of Th1 type response. Atopic dermatitis skin contains an increased number of IgE-bearing Langerhans cells which bind allergens via the high-affinity IgE receptor (FcepsilonRI). Langerhans cells play an important role in cutaneous allergen presentation to Th2 cells via major histocompatibility molecules. Eosinophilia and IgE production are influenced by type 2 cytokines. Degranulation of eosinophils occurs in the dermis with the release of toxic proteins such as major basic protein and could account for much of the inflammation. Mast cells are increased in number and produce mediators other than histamine that induce pruritus and may have an effect on interferon gamma expression. Mast cells produce a number of proinflammatory cytokines. There is an elevated production of prostaglandin E2 by peripheral monocytes. Prostaglandin E2 has at least two potential roles in the initiation of atopic dermatitis. Firstly, it reduces interferon-gamma production by T helper cells, thereby favoring the initial, dominant Th2 immune response; and secondly, it directly enhances IgE production by B lymphocytes with an increased secretion of interleukin 4, interleukin 5 and interleukin 13. Many lesions of atopic dermatitis result from scratching, thus it is tempting to speculate that immune perturbations in genetically predisposed individuals provoke the release of local pruritogens and keratinocyte-derived cytokines, which then further exacerbate the previously described immune response.

Thymic stromal lymphopoietin (TSLP), an IL-7-like cytokine, is believed to propagate AD lesions through T helper 2 (Th2) polarization. This paper describes the immunologic mechanisms involving TSLP in the generation of allergic disease. Specifically in AD, TSLP has been shown to be an inducer of myeloid dendritic cells, Th2 responses, mast cells, and natural killer T cells, thereby leading to cytokine secretion and the development of AD. We hope that further understanding of the TSLP pathway and its role in the pathogenesis of AD will lead to improved clinical management of AD in the future.

Role of IgE in atopic dermatitis.

Atopic dermatitis is a chronic inflammatory skin disease associated with elevated serum IgE levels and sensitization to a variety of inhalant, food and microbial allergens. Controlled challenges have provided substantial evidence that allergens can trigger acute IgE-mediated mast-cell dependent exacerbations of eczema in these patients.

However, the sustained chronic skin inflammation that characterizes atopic dermatitis is likely to result from a local expansion of allergen-specific T helper type 2 cells that produce interleukin-4 and interleukin-5 and the concomitant infiltration of eosinophils. An important role for IgE in allergen presentation to T helper type 2 cells by Langerhans cells has been proposed. These observations may have important implications for the development of new approaches for the treatment of this increasingly common allergic disorder.

Increased total and specific serum immunoglobulin E (IgE) levels are common characteristics of atopic diseases and their basal production is proposed to be under strong genetic control. Interleukin 13 (IL13) variants have been consistently associated with total serum IgE levels in white populations with a strongest association in non-atopics. The aim of this study was to test the IL13 p.R130Q and c.1-1111C>T variants in children with atopic dermatitis (AD) for associations with total serum IgE and early sensitization to common food and inhalant allergens and with asthma. We included 453 children with AD [participants of the Early Treatment of the Atopic Child (ETAC) study] that were followed from the age of 12-24 months for 3 yr. Total and specific IgE were determined at four time points. We genotyped the IL13 p.R130Q and c.1-1111C>T variants by melting curve analysis. In children up to 4 yr of age, the 130Q allele was related to slightly higher total IgE levels compared to heterozygotes and 130R homozygotes. More importantly, both IL13 variants were significantly associated with sensitization to food allergens, with most significant results for sensitization to egg (p = 0.0001). Although early sensitization to hen’s egg represents a strong risk factor for subsequent sensitization to inhalant allergens and asthma, the investigated IL13 variants were not associated with these phenotypes at the age of 48-60 months.

IL13 variants contribute to elevated levels of total serum IgE in young atopic children and are strongly associated with sensitization to food allergens, particularly to hen’s egg. These findings suggest that IL13 variants play a major role not only in non-cognate but also in allergen specific IgE synthesis.

Biomarkers for itch and disease severity in atopic dermatitis.

Biomarkers are important in monitoring disease severity, prognosis and treatment responses. With the investigation and robust knowledge on AD pathophysiology, more and more biomarkers are being explored. Aberrant cutaneous inflammation is associated with Th2 polarization, chemokine upregulation in Langerhans cells and keratinocytes, IgE production by B cells, and degranulation of mast cells and eosinophils, subsequently leading to changes in the levels of cell-specific biomarkers in blood or urine.

Furthermore, skin barrier abnormalities, including increased transepidermal water loss and decreased skin hydration, are biomarkers for severity and itch intensity in AD. Cross-talk between skin barrier abnormalities and aberrant immune responses is evidenced by epidermal abnormalities enhancing the release of keratinocyte-derived cytokines and chemokines, including CC chemokine ligand (CCL) 17, CCL27 and thymic stromal lymphopoietin, resulting in modulation of skin immune responses. The pathophysiology of itch in AD remains unclear. The subjective nature of itch makes biomarkers to estimate its intensity crucial in AD patients. Pruritus results from the activation of small nerve endings in the skin by noxious mediators, including neuropeptides, proinflammatory cytokines and prostaglandins, all of which might serve as potential biomarkers for itch.

Recently, IL-31 and gastrin-releasing peptide have been reported to be involved in the development of itch, making the estimation of itch intensity a future reality. With the enormous amount of research in immunology, skin physiology and neurology in AD, more biomarkers in AD and its itch will be found in the near future.

Cellular and molecular mechanisms in atopic dermatitis.

The abnormal skin barrier in AD, namely abnormalities in epidermal structural proteins, such as filaggrin, mutated in approximately 15% of patients with AD, epidermal lipids, and epidermal proteases and protease inhibitors. The review also dissects, based on information from mouse models of AD, the contributions of the innate and adaptive immune system to the pathogenesis of AD, including the effect of mechanical skin injury on the polarization of skin dendritic cells, mediated by keratinocyte-derived cytokines such as thymic stromal lymphopoietin (TSLP), IL-6, and IL-1, that results in a Th2-dominated immune response with a Th17 component in acute AD skin lesions and the progressive conversion to a Th1-dominated response in chronic AD skin lesions. Finally, we discuss the mechanisms of susceptibility of AD skin lesions to microbial infections and the role of microbial products in exacerbating skin inflammation in AD. Based on this information, we discuss current and future therapy of this common disease.

References

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IL13 variants are associated with total serum IgE and early sensitization to food allergens in children with atopic dermatitis. Zitnik SE, et al. Pediatr Allergy Immunol. 2009 Sep;20(6):551-5. doi: 10.1111/j.1399-3038.2008.00815.x. Epub 2009 Jun 10.

Jariwala SP, et al. The role of thymic stromal lymphopoietin in the immunopathogenesis of atopic dermatitis. Clin Exp Allergy. 2011 Nov;41(11):1515-20.

Biomarkers for itch and disease severity in atopic dermatitis. Lee CH, et al. Curr Probl Dermatol. 2011;41:136-48.

Oyoshi MK, et al. Cellular and molecular mechanisms in atopic dermatitis. Adv Immunol. 2009;102:135-226.

Cookson W: The immunogenetics of asthma and eczema: a new focus on the epithelium. Nat Rev Immunol 2004, 4:978–988.

Vasilopoulos Y, Cork MJ, Murphy R, et al.: Genetic association between an AACC insertion in the 3’UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis. J Invest Dermatol 2004, 123:62–66.

De Benedetto A, Latchney LE, McGirt LS, et al.: The tight junction protein Claudin-1 is dysregulated in atopic dermatitis. J Allergy Clin Immunol 2008, 121:S32.

Soderhall C, Marenholz I, Kerscher T, et al.: Variants in a novel epidermal collagen gene (COL29A1) are associated with atopic dermatitis. PLoS Biol 2007, 5:e242

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