Atopic dermatitis as Th2 disease revisited

Abstract

T helper 1 (Th1) and T helper 2 (Th2) populations are a classical dichotomy to understand the immunological disorders, and this concept remains vital in atopic dermatitis (AD). While IL‐4 and IL‐13 are produced mainly by Th2 cells, mast cells, and basophils, these cytokines target these producers, indicating the presence of autocrine and paracrine stimulation. There are two types of receptors for IL‐4 and IL‐13, type I and type II. IL‐4 binds to both type I and II receptors, while IL‐13 has affinity to type II. Dupilumab is an IL‐4Rα‐antagonist that inhibits IL‐4 and IL‐13 signaling through blockade of the shared IL‐4α subunit. The Th2‐stimulating effect of thymic stromal lymphopoietin (TSLP) is triggered by its binding to TSLP receptor (TSLPR) on Th2 cells. The frequency of TSLPR+CD4+ T cells correlates with disease activity. CD4+ T cells directly interact with TSLP to produce a high amount of IL‐4. Conversely, IL‐4 induces TSLPR expression in T cells. Moreover, TSLP and IL‐4 promote CCR4 expression, which is a chemokine receptor for CCL17/TARC. Langerhans cells initiate epicutaneous sensitization with protein antigens and induce Th2 cell–mediated immune responses via TSLP signaling. Filaggrin deficiency, which cornified layer‐damaged skin allows protein antigens to penetrate through the stratum corneum, leads to allergy where IL‐4 and IL‐13 are overproduced. Subsequently, IL‐4 and IL‐13 further depress filaggrin expression with vicious cycle. AD is generally a Th2 disease, but there exist several exceptional and undeniable facts to be considered, including Th1‐activated intrinsic AD, Th1‐infiltrating chronic AD skin lesions, and Th17 involvement.

Decreased expression of suprabasin induces aberrant differentiation and apoptosis of epidermal keratinocytes: Possible role for atopic dermatitis

“…Th2 cells play a crucial role in AD [19], especially in extrinsic AD [15]. Th2 cytokines down-regulate the expression of differentiation-associated molecules, as represented by filaggrin [20].…”

A medicinal plant Cudrania tricuspidata ameliorates allergic inflammation in mouse

“…In addition, PAR-2 is involved in the generation of ADaggravating factor TSLP (thymic stromal lymphopoietin) by epidermal keratinocytes (Tokura et al, 2018). Current knowledge of PAR-2 has shown a more complicated activities involved in the regulation of epidermal barrier, keratinocyte differentiation, cutaneous tumorigenesis and pigmentation (Henehan and De Benedetto, 2019).…”

“…The level of IFN-γ in the patients increases during the progression of atopic dermatitis from acute to chronic phase (Su et al, 2017). In particular, there still exist some variations due to heterogeneous propeties which needs to be considered, such as Th1-activated intrinsic AD, Th1infiltrating chronic AD, and Th17 involvement (Tokura et al, 2018).…”

Immunological Pathomechanisms of Spongiotic Dermatitis in Skin Lesions of Atopic Dermatitis

“…Atopic dermatitis (AD), a chronic, relapsing eczematous dermatitis that occurs frequently in infants and children, is characterized by a complex pathogenesis and heterogeneous clinical phenotypes [ 1 , 2 ]. AD is a pruritic skin disease that develops and progresses in association with a variety of factors, such as dry skin and epidermal barrier dysfunction due to genetic abnormalities (e.g., filaggrin gene mutations) or non-hereditary chronic inflammation [ 2 , 3 , 4 , 5 ], innate immunity dysregulation [ 6 , 7 ], dominance of T helper (Th) 2 cytokine (i.e., interleukin [IL]-4 and IL-13) immunity [ 2 , 8 , 9 , 10 ], and intractable and diverse itching [ 11 , 12 , 13 ]. The characteristics of AD (e.g., phenotypes and endotypes, clinical course, and disease severity) are associated with several factors, including patient age [ 14 , 15 , 16 ], race [ 15 , 17 ], genetic predisposition [ 18 ], skin dysbiosis involving increased predominance of Staphylococcus aureus ( S. aureus ) [ 19 , 20 ], sex hormones [ 21 ], and environmental stimuli (e.g., allergens, irritants, and chemicals) [ 22 ].…”