References

1 Bieber T. Atopic dermatitis. N Engl J Med 2008;358:1483–94.

2 Leung DY, Bieber T. Atopic dermatitis. Lancet 2003;361:151–60.

The Systemic Immune Response (see Box 24.1)

Atopy may be considered a systemic illness with AD as the cutaneous manifestation [1] of this condition. The majority of children with AD undergo the so-called atopic march, developing asthma and allergic rhinitis later in life. In murine models, epicutaneous sensitization has been shown to increase serum IgE levels and induce eosinophilia and airway hyper-reactivity characteristic of asthma [2]. That said, many children develop asthma in the absence of a history of AD, and children can outgrow AD without developing respiratory allergy. Therefore, different genes probably drive systemic atopy versus local barrier dysfunction [3–5].

Serum IgE levels are elevated in the majority of patients with AD [6,7]. Approximately 80% of patients have positive immediate skin tests or serum IgE antibody directed to a variety of foods, aeroallergens, microbial allergens and skin autoantigens. It has been proposed that AD patients should be segregated into two groups: those with elevated serum IgE (so-called extrinsic AD) and those with normal serum IgE (so-called intrinsic AD). The potential problem with this approach is that it ignores the primary defect in skin barrier that characterizes AD [4] and most physicians only focus on IgE directed to foods and aeroallergens. However, several studies have found the presence of IgE to microbial antigens and autoantigens in patients originally characterized as intrinsic AD [8,9].

The majority of patients with AD also have peripheral blood eosinophilia. Unlike eosinophils from normal donors, peripheral blood eosinophils from AD patients are primed for chemotaxis and transendothelial transmigration [10,11]. Furthermore, serum levels of eosinophil cationic protein and urinary eosinophil protein X are elevated in AD and levels of these markers of eosinophil activation correlate with the severity of skin disease [12]. These findings probably reflect a systemic T helper type 2 (Th2) immune response in AD. Importantly, the peripheral blood skin homing CLA⁺ T cells in AD spontaneously secrete interleukin (IL)-5 and IL-13, which functionally prolong eosinophil survival and induce IgE synthesis.

Peripheral blood mononuclear cells (PBMC) from AD patients have a decreased capacity to produce interferons (IFN) [13]. IFN-γ generation ex vivo is inversely correlated with serum IgE levels in AD. The peripheral blood of AD also has an increased frequency of allergen-specific T cells producing increased IL-4, IL-5 and IL-13, but low levels of IFN-γ. These immunological alterations are important because IL-4 and IL-13 promote isotype switching to IgE, downregulate T helper type 1 (Th1) cell function and induce the expression of vascular adhesion molecules involved in eosinophil infiltration. In contrast, IFN-γ inhibits IgE synthesis as well as the proliferation of Th2 cells.

Peripheral blood monocytes from AD patients are activated and have an abnormally low incidence of spontaneous apoptosis. The likely cause of this low level of apoptosis is increased production of granulocyte macrophage-colony stimulating factor (GM-CSF) by circulating monocytes of AD patients [14]. Cytokine production in AD patient-derived monocytes has also been demonstrated to be impaired in response to bacterial and viral insult. The decreased inflammatory cytokine response by AD monocytes may be due to impairment of toll-like receptors (TLRs) [15,16].

References

1 Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest 2004;113:651–7.

2 Spergel JM, Mizoguchi E, Brewer JP et al. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J Clin Invest 1998;101:1614–22.

3 Cookson WO, Ubhi B, Lawrence R et al. Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat Genet 2001;27:372–3.

4 Baurecht H, Irvine AD, Novak N et al. Toward a major risk factor for atopic eczema: meta-analysis of filaggrin polymorphism data. J Allergy Clin Immunol 2007;120:1406–12.

5 Rogers AJ, Celedon JC, Lasky-Su JA, Weiss ST, Raby BA. Filaggrin mutations confer susceptibility to atopic dermatitis but not to asthma. J Allergy Clin Immunol 2007;120:1332–7.

6 Bieber T. Atopic dermatitis. N Engl J Med 2008;358:1483–94.

7 Leung DY, Bieber T. Atopic dermatitis. Lancet 2003;361:151–60.

8 Novak N, Allam JP, Bieber T. Allergic hyperreactivity to microbial components: a trigger factor of “intrinsic” atopic dermatitis? J Allergy Clin Immunol 2003;112:215–16.

9 Altrichter S, Kriehuber E, Moser J et al. Serum IgE autoantibodies target keratinocytes in patients with atopic dermatitis. J Invest Dermatol 2008;128:2232–9.

10 Gleich GJ. Mechanisms of eosinophil-associated inflammation. J Allergy Clin Immunol 2000;105:651–63.

11 Simon D, Braathen LR, Simon HU. Eosinophils and atopic dermatitis. Allergy 2004;59:561–70.

12 Taniuchi S, Chihara J, Kojima T et al. Serum eosinophil derived neurotoxin may reflect more strongly disease severity in childhood atopic dermatitis than eosinophil cationic protein. J Dermatol Sci 2001;26:79–82.

13 Akdis M, Trautmann A, Klunker S et al. T helper (Th) 2 predominance in atopic diseases is due to preferential apoptosis of circulating memory/effector Th1 cells. FASEB J 2003;17:1026–35.

14 Bratton DL, Hamid Q, Boguniewicz M et al. Granulocyte macrophage colony-stimulating factor contributes to enhanced monocyte survival in chronic atopic dermatitis. J Clin Invest 1995;95:211–18.

15 Hasannejad H, Takahashi R, Kimishima M, Hayakawa K, Shiohara T. Selective impairment of Toll-like receptor 2-mediated proinflammatory cytokine production by monocytes from patients with atopic dermatitis. J Allergy Clin Immunol 2007;120:69–75.

16 Niebuhr M, Langnickel J, Draing C et al. Dysregulation of toll-like receptor-2 (TLR-2)-induced effects in monocytes from patients with atopic dermatitis: impact of the TLR-2 R753Q polymorphism. Allergy 2008;63:728–34.

Histopathological Skin Reaction Patterns

Several skin reaction patterns are seen in AD. Clinically unaffected skin of AD patients exhibits mild epidermal hyperplasia and a sparse perivascular T cell infiltrate [1]. Acute AD skin lesions are characterized by intensely pruritic, erythematous papules associated with excoriation, vesicles over erythematous skin and marked intercellular edema (spongiosis) of the epidermis. In the dermis of the acute lesion, there is a marked perivenular T cell infiltrate with occasional monocyte-macrophages.

Chronic lichenified AD lesions are characterized by a hyperplastic epidermis with elongation of the rete ridges, prominent hyperkeratosis and minimal spongiosis. There are an increased number of dendritic cells in the epidermis and macrophages dominate the dermal mononuclear cell infiltrate. Mast cells are increased in number but are generally fully granulated. Increased numbers of eosinophils are observed. These eosinophils undergo cytolysis with release of granule protein contents into the upper dermis of lesional skin.

In patients with established AD, all three stages of skin reactions frequently co-exist in the same individual. At all stages of AD, patients usually have dry, lacklustre skin. Pruritus is an important feature of AD and is thought to be induced by various products of inflammatory effector cells including histamine, neuropeptides, leukotrienes, proteolytic enzymes and the Th2 cytokine, IL-31 [2,3].

References

1 Hamid Q, Boguniewicz M, Leung DY. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest 1994;94:870–6.

2 Bilsborough J, Leung DY, Maurer M et al. IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis. J Allergy Clin Immunol 2006;117:418–25.

3 Raap U, Wichmann K, Bruder M et al. Correlation of IL-31 serum levels with severity of atopic dermatitis. J Allergy Clin Immunol 2008;122:421–3.

Immune Response in Atopic Dermatitis Skin

Role of Cytokines

The onset of atopic skin inflammation is orchestrated by the local expression of proinflammatory cytokines and chemokines [1]. Physical or chemical damage to the epithelial barrier triggers the release of preformed cytokines such as tumour necrosis factor-α (TNF-α), IL-1 and GM-CSF from resident cells (keratinocytes, mast cells, dendritic cells). Allergens can also directly trigger inflammatory cytokine production. Proteolytic activity of dust mites upregulates GM-CSF and IL-8 release from keratinocytes [2]. These cytokines in turn bind to receptors on the vascular endothelium, activating cellular signalling pathways which lead to the induction of vascular endothelial cell adhesion molecules.

These events initiate the process of tethering, activation and adhesion to vascular endothelium followed by extravasation of inflammatory cells into the skin. Th2- and Th1-type cytokine expression varies in AD with chronicity of the skin lesion (Box 24.2). As compared with the skin of normal controls, the unaffected skin of AD patients has an increased number of cells expressing IL-4 and IL-13 [3] but not IL-5, IL-12 or IFN-γ [4,5]. Acute and chronic skin lesions, when compared to normal skin or uninvolved skin of AD patients, have a significantly greater numbers of cells that are positive for IL-4, IL-5 and IL-13. However, acute AD does not contain significant numbers of cells expressing IFN-γ or IL-12. The lymphocytic infiltrate consists predominantly of activated memory T cells bearing CD3, CD4 and CD45 RO (suggesting previous encounter with antigen).

Chronic AD has significantly fewer cells expressing IL-4 and IL-13 but increased numbers of cells expressing IL-5, GM-CSF, IL-12 and IFN-γ than does acute AD. Thus, acute T cell infiltration in AD is associated with a predominance of IL-4 and IL-13 expression, whereas maintenance of chronic inflammation is associated with increased IL-5, GM-CSF, IL-12 and IFN-γ expression, and is accompanied by the infiltration of eosinophils and macrophages. The increased expression of IL-12 in chronic AD skin lesions is of interest as that cytokine plays a key role in Th1 cell development and its expression in eosinophils and/or macrophages may initiate the switch to Th1 or Th0 cell development in chronic AD.

Interleukin-31 is a newly characterized cytokine, produced by activated T cells preferentially skewed toward a Th2 type phenotype [6]. Its receptor is a member of the IL-6R group and is constitutively expressed on epithelial cells including keratinocytes. IL-31 has recently been implicated as a major factor in the origin of pruritus in AD. Overexpression of IL-31 in lymphocytes induces severe pruritus and dermatitis in mice. IL-31 mRNA levels are increased in AD skin and this increase correlates with IL-4 and IL-13 levels [7].

It has also been recognized that AD skin lesions have increased expression of IL-17 [8]. IL-17 stimulates keratinocytes to produce GM-CSF, TNF-α, IL-8 and antimicrobial peptides [9]. Recent studies suggest that the source of IL-17 in AD skin lesions is CD4+ Th17+ cells. However, the level of IL-17 expression in AD skin is significantly lower than that observed in psoriasis [10].

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