Atopic dermatitis: A tale of two distinct pathomechanisms that make you itch

Abstract

Atopic dermatitis (AD) or eczema is the most common chronic inflammatory skin disease, with an incidence of more than 10% in children [1], decreasing to about 3% in the adult population [2]. AD is a chronic disease that can be difficult to control, both due to patient treatment compliance, as well as the unremitting underlying inflammatory process. Moisturizing ointments and topical corticosteroids are the main treatments to minimize dryness and limit inflammation and itchiness in these patients. Recently, the biological dupilumab, an antibody which blocks the receptor for IL-4 and IL-13, has been demonstrated to be a very potent treatment modality in AD. The use of dupilumab has been a breakthrough in the implementation of more targeted treatment of AD [3].Correspondence: Dr. Edward F. Knol e-mail: e.f.knol@umcutrecht.nl It is clear that AD is the result of local, as well as systemic, pathomechanisms. However, AD is considered mainly a Th2-driven systemic disease due to the fact that it is strongly associated with other atopic diseases, i.e. allergic rhinoconjunctivitis, allergic asthma, and food allergy [4].The local skin response in AD Filaggrin (FLG) is an important structural protein required for epidermal barrier function through its role in the form and function of the stratum corneum [5]. Reduced FLG favors transepidermal water loss, allergen penetration and skin bacterial colonization [6]. Recently, it was demonstrated that FLG inhibits neo-antigen formation by the house-dust mite enzyme phospholipase [7]. It has been already known for some years that functional effects of profilaggrin and FLG loss in flaky tail mice results in a dry and flaky skin, resembling the skin of patients with ichthyosis vulgaris [8]. FLG-deficient mice displayed an increased permissiveness to epicutaneous sensitization with protein antigens such as ovalbumin [9]. FLG loss-of-function mutations are the strongest genetic risk factor in AD. It is estimated that up to 50% of patients with AD in diverse populations carry one or more FLG loss-of-function mutations [6]. It is also important to realize that, although null mutations in the FLG gene are the strongest and most reproducible genetic risk factors in AD in human, 60% of the carriers do not develop AD. In addition, more than half of the AD patients do not carry FLG mutations [6]. Therefore, other factors must also be involved in the pathogenesis of AD.The reduction in the integrity of the skin barrier results in increased penetration of allergens in the upper layers of the epidermis [9]. Subsequently, allergens are taken up by Langerhans cells, especially those that carry allergen-specific IgE on the high affinity Fc receptor for IgE (FcεRI), and then presented to T cells [10,11] (Fig. 1). The latter finding has frustrated the implication of rodent models for AD, because the FcεRI expression on antigen-presenting cells is much more difficult to establish in rodents [12]. Systemic immune responses in ADThere are marked immune responses in AD both within the innate and adaptiv...

Associations between T cells and attention problems in the general pediatric population: The Generation R study

“…In contrast with previous studies that suggested increased Th2 cells because of the association of attention problems with atopic disease, we did not observe an association between attention problems and Th2 cell numbers (Cortese et al., 2018 ; Pelsser et al., 2009 ; Verlaet et al., 2019 ). Previously, it has been shown that in chronic atopic dermatitis immunological inflammation could cause a shift towards increased Th1 and CD8 + T cell numbers (Hijnen et al., 2013 ; Knol and Hijnen, 2016 ). This might explain the association of attention problems with both Th1 and Th2‐mediated disease as well as our study results with increased Th1, CD8 + cells, but not Th2 cells.…”

Investigation of Immune-Regulatory Effects of Mageumsan Hot Spring via Protein Microarray In Vitro

“…These mediators may also have a direct bearing on characteristic symptoms; studies have revealed that in AD-associated intractable pruritus-where the receptors involved are often not entirely histaminic 13 -proinflammatory cytokines are prime target suspects that instigate it 14 15 . Naturally brought along with this paradigmatic shift was revamping in management scheme; systemic immunomodulators and biologics have taken a center-stage as an important arsenal against the immunological leg of AD patho-mechanism 16 . The authors, having experienced an apparent, skin barrier-reparative effect with an HS water after 4 weeks of bathing in a tub 17 , were prompted with the question of whether HS water brings upon beneficial effects on cellular and molecular level with certain immune-mediating action.…”

Treatment for moderate to severe atopic dermatitis in alpine and moderate maritime climates differentially affects helper T cells and memory B cells in children

“…Still, it has been shown that dupilumab, an antibody blocking IL‐4/IL‐13 receptors, has equal potency in treatment of either extrinsic AD (with increased IgE levels) or intrinsic AD (without increased IgE levels). This can be explained by data showing that Th2 cytokines diminish the expression of barrier proteins such as filaggrin, loricrin, involucrin and antimicrobial peptides . Hence, this illustrates the clinical and immunological diversity of the disease.…”

“…This can be explained by data showing that Th2 cytokines diminish the expression of barrier proteins such as filaggrin, loricrin, involucrin and antimicrobial peptides. 34 Hence, this illustrates the clinical and immunological diversity of the disease.…”