Pathophysiology of atopic eczema

The pathophysiology of atopic eczema involves genetic predisposition, disturbed skin barrier function, defects in the antimicrobial immune defence and frequent allergic responses against allergens [19,20].

A high familial association has been described for atopic eczema. Genetic research was fo-cussed on specific atopic eczema alleles, as well as identifying overlapping genes associ-ated with other allergic disorders. Genetic polymorphisms have been assigned for a cluster of T_H2 cytokine genes located on chromosome 5q22-23, the IL-13 coding region and the IL-4Rα subunit (16q12) [20,21,24]. Heritable epidermal barrier defect has been shown to be connected to the filaggrin (filament-aggregating protein) gene (FLG). FLG mutations are a major risk factor for eczema associated asthma [21,24].

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Atopic eczema is characterised by dry skin with increased transepidermal water loss. The disturbed barrier function results from a reduced activity of acid ceramidase and decreased ceramides content, the most important water retaining molecules in the extracellular space.

Additionally, this dysfunction causes a reduction of sphingosine levels in the stratum corneum. Since sphingosines are potent antimicrobials, the colonisation with Staphylococcus aureus (S. aureus) is supported. Diminished levels of additional antimicrobial peptides, e.g.

β-defensine 2 and cathelicidin, promote the ongoing colonisation of inflamed skin by various microorganisms [20,21].

The T_H2 predominance in atopic eczema patients, resulting from an increased frequency of allergen specific TH2 cells and a decrease of interferon (IFN) γ producing cells, favours IgE production and peripheral eosinophilia. Disturbed cellular immunity, humoral factors like in-creased IgE synthesis and high production of related cytokines contribute to development of skin lesions [18,20].

Clinically unaffected skin in atopic eczema is characterised by sparse perivascular T cell infil-trate, increased number of TH2 cells expressing IL-4 and IL-13, but not IFNγ [25] (Figure 5).

Initially, allergens penetrate into damaged skin and activate DC by cross linking FcεRI bound IgE molecules leading to an enhanced antigen presentation capacity. In this phase naive T cells are polarised into T_H2 cells producing associated cytokines. Additionally, MC are acti-vated via antigen specific IgE and contribute to induction of the inflammatory response [22].

Very early events initiating atopic skin inflammation are not completely elucidated. Environ-mental allergens, scratching or microbial toxins cause skin injury thereby activating keratino-cytes, MC and DC to release proinflammatory cytokines and chemokines, like IL-1, thymic stromal lymphopoietin (TSLP) and TNFα. Local proinflammatory mediator expression or-chestrates adhesion to the endothelium and subsequent extravasation of cells and thus de-fining the nature of the inflammatory infiltrate. These mediators enhance the expression of adhesion molecules on vascular endothelium and facilitate the extravasation of inflammatory cells into the skin. In the tissue these cells respond to chemotactic gradients established by cytokines and chemokines originated from sites of injury or infection [20,26]. Cutaneous T cell attracting chemokine (CCL27) is pivotal in mediating the migration of CLA⁺ T cells. Addi-tionally, macrophage derived chemokine and activation regulated cytokine are increased in patients with atopic eczema. These molecules selectively recruit CCR4 expressing TH2 cells.

Dimension of thymus and activation regulated cytokine levels have been linked to severity of atopic eczema [20].

Figure 5: Immunological processes in the skin involved in the pathogenesis of atopic eczema [20]. Circulating CLA expressing T_H2 cells lead to elevated serum IgE and eosinophil numbers. These T cells recirculate through unaffected skin where they can en-gage allergen triggered IgE⁺ LC and MC supporting T_H2 cell pattern. Skin injury provokes keratinocytes to release proinflammatory cytokines and chemokines thereby enhancing the expression of adhesion molecules on vascular endothelium and facilitating extravasation of inflammatory cells into skin. Keratinocyte derived TSLP and MC originated IL-4 enhance T_H2 cell differentiation. In acute skin lesions, TH2 cell numbers are increased, but chronic eczema results in the infiltration of inflammatory dendritic epidermal cells (IDEC), macrophages (MΦ) and eosinophils. IL-12 production provokes the switch to a TH1 cytokine milieu associated with increased IFNγ expression. Ag, antigen; SAg, superantigen; AICD, activation induced cell death. Reprinted from Akdis CA et al.: Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report, J Allergy Clin Immunol 2006;118(1): 152-69, Copyright (2006), with permission from Elsevier.

Acute eczematous skin lesions are clinically designated by extremely pruritic, erythematous papules associated with excoriation and serious exudation. Memory CD4⁺ cells infiltrate into the dermis. Compared to unaffected skin, acute skin lesions show a significantly larger

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ber of T_H2 cells, but only few T_H1 cells. Importantly, LC, IDEC and macrophages in lesional and, to a lesser extent, in non-lesional skin bear IgE [20,25].

Due to ongoing inflammation, chronic lichenified skin lesions have undergone tissue remod-elling. The clinical criteria are thickened plaques with increased markings (lichenification) and dry, fibrotic papules. Collagen deposition during chronic atopic eczema results from in-creased expression of the profibrotic cytokine, IL-11. While T cells remain present, although in smaller numbers than seen in acute atopic eczema, macrophages dominate the dermal mononuclear cell infiltrate. Increased number of IgE bearing LC and IDEC are found in the epidermis. Inflammatory response is also supported by eosinophils. The late phase switch to TH1 depicts the chronicity of the atopic lesions, characterised by an increased production of the related cytokines, such as IFNγ and IL-18 [20,27].