Contact dermatitis (CD) and Atopic dermatitis (AD)

Contact dermatitis is an inflammatory response of the skin characterized by erythematous and pruritic skin lesions that occur after direct contact with exogenous substances²⁴. Contact dermatitis is frequent and a main cause of occupational dermatitis²⁵. Based on the pathophysiology contact dermatitis is classified in two subtypes: irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD)²⁴. Even though it is possible to differentiate between ICD from ACD at clinical levels, both manifestations can have similar clinical and histological presentations²⁶.

Irritant contact dermatitis (ICD)

Irritant contact dermatitis is considered as the most common type of contact dermatitis²⁶. It is the consequence of an activated innate immune response of skin to various physical and chemical stimuli. It occurs in response of skin injury by foreign particle without prior immunological sensitization of the skin. The

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development of ICD depends on a complex interplay between endo- and exogenous factors²⁷. Intrinsic factors which influence development of ICD include genetic predisposition eg. age, sex and body area, whereas extrinsic factor include the type of the irritant, the irritant concentration and the time of exposure²⁷. An impairment of the skin horny layer and epidermal cell damage are considered to be the main factors in the pathogenesis of ICD. The underlying mechanism of ICD includes an activation of the innate immune response with the release of 1α, IL-1β, TNF-α, GM-CSF and IL-8 (Fig. 3A)²⁸. Consecutively, these cytokines activate Langerhans cells (LC), dDCs and endothelial cells, which further support the cellular recruitment at the site of damage e.g. lymphocytes, macrophages, neutrophilis (Fig.

3A). These cellular infiltrates further promote the inflammatory pathway (Fig. 3A)²⁸. Allergic contact dermatitis (ACD)

Allergic contact dermatitis is a delayed hypersensitivity reaction mediated by antigen-specific T cells²⁹. It occurs only in sensitized patients i.e. individuals who have build an immunological memory response upon a prior contact. The concentration of an allergen is important to initiate an ACD²⁶. ACD is characterized by pruritic papules and vesicles on an erythematous base, in the chronic condition lichenified pruritic plaques can be present. Individuals with a history of ACD develop the symptoms a few days after exposure in the area that was in direct contact with the allergen³⁰. Similar to the scenario in ICD the allergen exposure result in an activation of the innate immune system through a release of proinflammatory cytokines by KC including IL-1α, IL-1β, TNF-α, GM-CSF, IL-8 and IL-18 with in consequence the onset of vasodilation and cellular recruitment (Fig. 3B)²⁸. Upon contact with allergens, LCs and dDCs migrate to the draining lymph nodes, where they activate allergen-specific T cells e.g. Th1, Th2, Th17 and regulatory T (Treg) cells (Fig. 3B)²⁸. Activated T cells further proliferate and enter into the circulation and reach to the site of initial exposure, along with other immune cell such as mast cells and eosinophils (Fig. 3B). Once an individual is re-exposed to an allergen, the allergen-specific T cells, along with other inflammatory cells, enter the site of exposure and release proinflammatory cytokines which consequently stimulate the KCs to induce an inflammatory cascade (Fig. 3B)²⁸.

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Figure 3. Pathogenesis of irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD).

A) In ICD, encounter with an irritant stimulate KCs by activating innate immunity with the release of pronflammatory cytokines such as IL-1α, IL-1β, TNF-α etc. from epidermal KCs. These cytokines further activate inflammatory cells e.g. LCs, dDCs, and endothelial cells, all of which contribute to cellular recruitment to the site of KC damage and further initiate the inflammatory cascade.

B) During sensitization phase of ACD, allergens activate innate immunity through KC activation and proinflammatory cytokines release as well as with vasodilation, cellular recruitment, and infiltration. Upon exposure to allergen, LCs and dDCs migrate to the lymph nodes, where they activate allergen-specific T cells e.g. Th1, Th2, Th17, and regulatory T (Treg) cells. Activated T cells proliferate and reach to the site of infection along with other cell types such as mast cells and eosinophils. Upon re-encountering with allergen, the hapten-specific T cells get activated and along with other inflammatory cells, enter the site of exposure and release proinflammatory cytokines and subsequently stimulate KCs to induce an inflammatory cascade.

Reprinted from Dhingra et al. 2013: Mechanisms of contact sensitization offer insights into the role of barrier defects vs. intrinsic immune abnormalities as drivers of atopic dermatitis, J Invest Dermatol.2311-4. (Oct 1, 2013.). Copyright (2014), with permission from Nature publishing group.

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Atopic dermatitis

AD is a chronic-relapsing, eczematous skin disease clinically characterized by erythema, edema, excoriation, xerosis, intense pruritus and a typical localization pattern³¹. Commonly, AD initiates early in childhood (i.e. early-onset AD)^31,32. Epidemiological studies point towards an increase in AD prevalence in the last decades affecting around 10-20% of children and 1-3% of the adult population worldwide^32-34.

Pathophysiology of atopic dermatitis

AD is a highly complex inflammatory skin disease which depends on the interplay between genetic and environmental factors³⁵. The understanding of AD development is still not completely clear especially at the molecular level³⁶. It is still not certain whether AD is a consequence of an immune dysfunctioning or due to genetic defects or both31,32,36,37. A defect of the skin barrier function plays a crucial role in the pathogenesis of the disease. It leads to an increase of the epidermal water loss and a promotion of an invasion of allergens, microbes or any other irritants (Fig. 4)³⁸. Different studies have shown that a defect of skin barrier promotes skin inflammation in AD patients^34,39. Filaggrin an important skin barrier protein was identified to play a significant role in AD progression. Around 20% of AD patients display a null mutation in the gene encoding for filaggrin^34,35,40. The presence of the filaggrin gene mutation has shown to increase skin dryness in AD patients⁴¹. Different cytokines such as IL-4, IL-13 and TNF-α have been shown to reduce the expression level of filaggrin in AD patients as well⁴². Among filaggrin several other proteins are involved in forming the skin barrier and may be relevant in AD as well. Moreover patients even though carrying filaggrin mutations can outgrow the disease suggesting that breakdown in the skin barrier is not sufficient for the development of AD^43,44.

Various studies have shown that different immune cells are involved in the AD progression apart from the skin barrier. T cell plays a major role in the AD development especially at the early stage of the disease where an increased Th2 response is responsible for the major immune dysbalance⁴⁵. Data from both human 19

and mouse studies show that CD4+ T cells are involved in the development of AD^31,37,46. Specific DCs in the skin including epidermal Langerhans cells and inflammatory dendritic cells activate T cells³⁸. In acute and chronic AD lesions, the expression levels of T cell induced cytokines i.e. IL-4, IL-5 and IL-13 were significantly increased (Fig. 4). Several studies indicate that also the other T-cell types such as T-reg, Th17, Th 9 and Th 22 are involved in the pathogenesis of AD but their exact role in the AD progression is still not clear (Fig. 4)^47,48. Keratinocytes in the skin are regarded to be the key contributors or initiators of the disease. An increased production of TSLP by keratinocytes from atopic skin has been reported to further activate dendritic cells to drive Th2 polarization (Fig. 4)³¹.

Even though T cells which were previously described to be crucial for AD pathogenesis are dispensable under certain conditions and can be “replaced” by innate immune cells which include MCs, eosinophil’s and macrophages (Fig. 4)^49-51. Likewise, AD can develop in the absence of IL-4, signal transducers and activators of transcription 6 (STAT6) and IgE, although the overexpression of IL-4 can trigger AD development in the skin^52,53. Thus, AD seems to have highly superfluous mechanisms which converge furthermore with barrier impairment, xerosis and itch.

Findings showing that AD may be present in of two different immunological forms, the extrinsic AD (atopic eczema) and the intrinsic AD (non-atopic eczema)^34,40 are underlining this complexity of AD. Generally, 20-30% of the patients are affected by intrinsic AD. These patients have no increased levels of allergen specific or total IgE nor eosinophil numbers; yet, the two subtypes are indistinguishable in their clinical presentation. Thus, based on the heterogeneity of AD, it is likely that immune deviations and aberrations in skin cells both can contribute to AD independently and set off its development⁵⁴.

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Figure. 4: Pathogenesis of atopic dermatitis.

In AD, barrier disruption leads to entry of antigens, which encounter langerhans cells, dendritic cells and activating Th2 cells. T cells produces IL-4 and IL-13 which stimulate keratinocytes to produce TSLP. Activated TSLP express OX40 ligand to induce Th2 cells. Cytokines and chemokines, such as IL-4, IL-5 and IL-13 produced by Th2 cells and DCs stimulate skin infiltration by inducing DCs, mast cells, and eosinophils.

Reprinted from Dhingra et al. 2013: Mechanisms of contact sensitization offer insights into the role of barrier defects vs. intrinsic immune abnormalities as drivers of atopic dermatitis, J Invest Dermatol.2311-4. (Oct 1, 2013.). Copyright (2014), with permission from Nature publishing group.