Atopic Dermatitis Knowledge Centre
Pathophysiology
Immune system dysfunction
The immune system plays a crucial role in atopic dermatitis and a schematic representation of the immunological processes involved is shown below. Several immunoregulatory defects have been identified, each of which contribute to the overall disease pathogenesis.
- T-cell responses
At birth, predominant T-cell effector responses to infection are driven by Th-2 cells. As unaffected individuals age, this is superseded by a predominantly Th-1-driven response. In acute atopic dermatitis episodes, Th-2 cells remain the principle response to antigen exposure. Elevated levels of Th-2 cells are present in both lesional and non-lesional skin of atopic dermatitis patients, strongly suggesting that even uninvolved skin is primed towards a hypersensitive response to allergens. Th-2 cells produce the cytokines interleukin (IL)-4, IL-5 and IL-13, which induce differentiation of Th-2 cells from naïve CD4+ precursors, enhance the production of IgE from B-cells and suppress the production of specific antimicrobial peptides (AMP) by keratinocytes. AMPs, including the beta-defensins and the cathelicidin LL-37, represent an ancient and efficient innate defence mechanism which protects skin from infection with pathogenic microorganisms.40
The failure of the immune system to shift from Th-2 to Th-1 responses, termed the missing immune deviation, was the first biological mechanism to account for the enhanced Th-2 cell responses observed in acute atopic dermatitis and is associated with reduced microbial burden early in life (the hygiene hypothesis). More recently, it has been suggested that polarisation towards a Th-2-mediated immune response is the result of reduced numbers of regulatory T-cells due to defects in antigen presenting cell (APC) stimulation.41
- Antigen presenting cells
APCs, such as Langerhans cells (LC) and dendritic cells (DC), interact with antigens and present them to T-cells. In both lesional and non-lesional atopic dermatitis skin, APCs express significantly greater numbers of high-affinity IgE receptors than observed in non-atopic skin.25 After IgE binding, Langerhans cells present the antigen to naïve T-cells, stimulating their differentiation into Th-2 effector cells and inducing sensitisation to the antigen. Similarly, when antigens bind to IgE motifs on the surface of dendritic cells, large amounts of proinflammatory cytokines are released, stimulating T-cells and amplifying the allergic inflammatory immune response.
- Keratinocytes
Presently, there are two recognised mechanisms by which keratinocytes influence the progression and severity of atopic dermatitis. Firstly, epidermal keratinocytes from atopic dermatitis patients produce a unique profile of chemokines and cytokines following mechanical damage or interaction with inflammatory cytokines. The increased expression of GM-CSF, IL-1, IL-18 and TNF-α by keratinocytes promotes differentiation of dendritic cells from monocyte precursors and stimulates the activation of T-cells thus contributing significantly to the release of more proinflammatory cytokines, B-cell activation and histamine release.42 Secondly, keratinocytes of atopic dermatitis patients express significantly lower amounts of AMPs than in unaffected people.40 This allows increased colonisation of the skin by microbes, particularly Staphylococcus aureus and is associated with the recurrent skin infections frequently observed in atopic dermatitis patients.43
Immune Response Dysfunction In Atopic Dermatitis
It is becoming increasingly apparent that the uninvolved skin of atopic dermatitis patients exhibits many of the same characteristics as involved, lesional skin, albeit to a lesser extent.
Indeed, studies that profile the cells present in the different types of skin in patients with atopic dermatitis have identified markers of an underlying inflammatory reaction in normal-appearing, non-lesional skin. For example, an analysis of Langerhan’s cells in normal skin (i.e. from patients without an inflammatory condition) compared with the skin of patients with atopic dermatitis revealed an upregulation of FCεR1β (a cell-surface marker that correlates with serum IgE levels).44 This upregulation was evident in skin samples taken from non-lesional skin as well as lesional skin as shown in the graph below.
Analysis of inflammatory cell surface markers (FCεR1β) in the skin of patients with atopic dermatitis
Reproduced from Wollenberg et al. Cytometry 1999; 37:147–55 with the permission of the publisher John Wiley and Sons. ©1999 Wiley-Liss, Inc
The observation that non-lesional skin in atopic dermatitis sufferers contains elevated number of Th-2 cells, antigen presenting cells and mast cells suggests that, although there is no outward clinical manifestation of atopic dermatitis, there are constant, subclinical inflammatory processes taking place within the tissues, which predispose the skin to repeated acute flare episodes.
References:
40. Schittek B, Paulmann M, Senyurek I, et al. The role of antimicrobial peptides in human skin and in skin infectious diseases. Infect Disord Drug Targets 2008; 8: 135-43.
41. Romagnani S. The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both? Immunology 2004; 112: 352-63.
25. Maintz L, Novak N. Getting more and more complex: the pathophysiology of atopic eczema. Eur J Dermatol 2007; 17: 267-83.
42. Pastore S, Mascia F, Girolomoni G. The contribution of keratinocytes to the pathogenesis of atopic dermatitis. Eur J Dermatol 2006; 16: 125-31.
43. Baker BS. The role of microorganisms in atopic dermatitis. Clin Exp Immunol 2006; 144: 1-9.
44. Wollenberg A, Wen S, Bieber T. Phenotyping of epidermal dendritic cells: clinical applications of a flow cytometric micromethod. Cytometry 1999; 37: 147-55.
© February 2010 Astellas Pharma Europe LTD.
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