In atopic dermatitis

Atopic Dermatitis. The mechanism of itching associated with atopic dermatitis remains unknown, but histamine is almost certainly involved to some extent as histamine concentrations are increased in the skin and in the plasma of patients with this disorder (39,42). Second-generation H receptor antagonists, unlike first-generation H receptor antagonists, have not been uniformly found to be effective in relieving itching in atopic dermatitis, which may be related to the absence of a sedative effect (43). 

Vestergaard C, Deleuran M, Gesser B, Gronhoj Larsen C. Expression of the T-helper 2-specific chemokine receptor CCR4 on CCRIO-positive lymphocytes in atopic dermatitis skin but not in psoriasis skin. Br J Dermatol 2003 149 457-463. 

Beside the well-established role of Th2 cells in allergy, it also became clear that not only Th2, but also Thl cells can contribute to allergic pathology, specifically in atopic dermatitis such as in acute lesional skin [10], where IFN-y is known to induce cell death in keratinocytes causing the spongiform pathology observed in atopic dermatitis [11]. 

Akdis M, Akdis CA, Weig IL, Disch R, Blaser K Skin homing, CLA-F memory T cells are activated in atopic dermatitis and regulate IgE by an IL-13-dominated cytokine pattern. IgG4 counter-regulation byCLA+ memory T cells. J Immunol 1997 159 4611-4619. 

Akdis M, Simon HU, Weigl L, Kreyden O, Blaser K, Akdis AC Skin homing CLA-F CD8+ T cells respond to superantigen and contribute to eosinophilia and IgE production in atopic dermatitis. J Immunol 1999 163 466-475. 

Clinically unaffected skin in atopic dermatitis differs from normal skin the underlying barrier defect associated in more than 30% with filaggrin loss of function mutations first published in 2006 [4] leads to dry skin associated with a greater irritant skin response than in normal healthy skin. Microscopic studies revealed a sparse perivascular T cell infiltrate in unaffected atopic dermatitis skin that is not seen in normal healthy skin. 

Role of Adaptive Immune Responses in Atopic Dermatitis Involving IgE Responses In about 80% of adult patients with atopic dermatitis, the disease is associated with increased serum IgE levels, sensitization against aeroallergens... 

Food-Specific T Cells Are Involved in Allergic Responses in Atopic Dermatitis in Children and Adults... 

Patients sensitized to pollen allergens often develop an IgE response to cross-reactive food allergens. Birch pollen-related food may lead to an exacerbation of eczema in a subpopulation of patients with atopic dermatitis and sensitization to birch pollen allergens. A birch pollen-specific T-cell response could be detected in lesional skin of these responding patients. T-cell cross-reactivity between Bet v 1 and related food allergens can occur independently of IgE cross-reactivity in vitro and in vivo. This has been shown in atopic dermatitis patients who developed late eczematous skin reactions to cooked food which was shown to elicit T-cell but not IgE-mediated responses [11]. 

T Cells May Contribute to the Defects in Innate Immune Response in Atopic Dermatitis Most patients with atopic dermatitis are colonized with S. aureus and experience exacerbation of their skin disease after infection with this organism [2]. In patients with S. aureus infection, treatment with anti-staphylococcal substances can result in the reduction of skin disease. Binding of S. aureus to the epidermis is enhanced by atopic skin inflammation. This is supported by clinical studies demonstrating that treatment with topical corticosteroids or tacrolimus reduces S. aureus counts in atopic dermatitis. 

Microorganism Activate T Lymphocytes and Bystander Cells in the Skin in Atopic Dermatitis An important strategy by which S. aureus exacerbates atopic dermatitis is by secreting exotoxins. Some of them function as superantigens, which stimulate activation of T cells and major histocompatibility (MHC) class II + APC or keratinocytes, which express MHC class II upon activation. Many effects on T lymphocytes and other cells are elicited by superantigens (table 1). 

Are T Cells Involved in Specific Immune Responses to Autoantigens in Atopic Dermatitis Autoimmune phenomena to human self-proteins may also contribute to the pathophysiology of atopic dermatitis. IgE against autoantigens such as Horn SI-4 have been shown to stimulate type 1 hypersensitivity reactions which in turn may contribute to the clinical cutaneous reactions in atopic dermatitis [15]. Autoallergens induce the proliferation of CLA+ autoreactive T cells derived... 

Cellular and Molecular Interactions of T Cells in Atopic Dermatitis... 

The role of CD8-I- T cells in atopic skin inflammation is still not well defined. It has been shown that CLA-I-CD8-I- T cells isolated from the circulation are as potent as CLA+CD4-I- T cells in the induction of IgE and enhancement of eosinophil survival. This suggests that these cells have more than bystander functions in atopic dermatitis. Recent data from a mouse model indicate that allergen-primed CD8+ T cells are required for the development of atopic dermati-tis-like lesions in vivo [19]. 

T Cells Secrete Different Cytokines at Different Stages in Atopic Dermatitis The onset of acute atopic dermatitis is strongly associated with the production ofTh-2 cytokines, notably IL-4, IL-13 and IL-31, levels of which are significantly higher in atopic dermatitis individuals compared with control subjects [2]. 

IL-23 has recently been shown to be produced by dendritic cells and by human cultured keratinocytes in healthy skin and in psoriasis - its role in atopic dermatitis has to be defined [22]. Interaction of keratinocytes with activated T cells via CD40-CD40L may enhance IL-23 production and subsequently the IFN-y production by memory T cells [23]. 

Th-2 Cytokines Have Numerous Effects on Cutaneous Cells in Atopic Dermatitis In acute eczema, IL-4 and IL-13 induce a variety of local responses such as the induction of the adhesion molecules on endothelial cells, of chemokines or of Fc receptors on eosinophils [1]. Recent findings point to direct effects of IL-4 and... 

As mentioned above, a subgroup of patients with atopic dermatitis has a filaggrin loss-of-function mutation Recently, it was shown that filaggrin expression is reduced in atopic dermatitis even in the absence of any mutation [29]. Keratinocytes differentiated in the presence of IL-4 and IL-13 exhibited significantly reduced filaggrin gene expression and neutralization of IL-4 and IL-13 improves skin barrier integrity [30]. This indicates that Th-2 lymphocytes directly contribute to the skin barrier defect in atopic dermatitis. 

Th-17 cells appear to be involved in protection against bacterial pathogens. In addition, Th-17 cells may also be crucial in the pathogenesis of various chronic inflammatory diseases that were formerly categorized as Th-1-mediated disorders. Whereas IL-17 may play an important role in the pathogenesis of psoriasis and contact hypersensitivity, its role in atopic dermatitis is still unclear [36]. In skin biopsy specimens recovered from acute and chronic skin lesions from patients with atopic dermatitis, IL-17 was preferentially associated with acute lesions [37]. 

As outlined above, SIT, which has been shown to involve adaptive and natural Tregs in respiratory allergy and insect venom allergy [46], appears to work in atopic dermatitis as well. During SIT the... 

Keratinocytes secrete a unique profile of chemo-kines and cytokines after exposure to proinflam-matory cytokines. Keratinocyte-derived thymic stromal lymphopoietin (TSLP) may be of particular importance in atopic dermatitis This protein is undetectable in normal skin or non-lesional skin in patients with atopic dermatitis, but is highly expressed in acute and chronic atopic dermatitis lesions [18]. TSLP instructs human dendritic cells to create a Th-2-permissive microenvironment by inducing the expression of OX40L which triggers the differentiation of inflammatory Th-2 cells [48]. 

It has been shown that IFN-y induces Fas on keratinocytes which renders them susceptible to apoptosis induction by infiltrating FasL+ T cells. This has been interpreted as an important event in eczema, mainly in atopic dermatitis. There is further evidence that cleavage of E-cadherin and sustained desmosomal cadherin contacts between keratinocytes that are undergoing apoptosis result in spon-gioform morphology in the epidermis as a hallmark of eczematous lesions. Suppression of keratinocyte activation and apoptosis thus remains a potential target for the treatment of atopic dermatitis [2]. 

Werfel T, Breuer K Role of food allergy in atopic dermatitis. Curr Opin Allergy Clin Immunol 2004 4 379-385. 

---