The etiopathogenesis of atopic dermatitis: barrier disruption, immunological derangement, and pruritus

Abstract

Atopic dermatitis (AD) is a common chronic skin inflammatory disorder characterized by recurrent eczema accompanied by an intractable itch that leads to an impaired quality of life. Extensive recent studies have shed light on the multifaceted pathogenesis of the disease. The complex interplay among skin barrier deficiency, immunological derangement, and pruritus contributes to the development, progression, and chronicity of the disease. Abnormalities in filaggrin, other stratum corneum constituents, and tight junctions induce and/or promote skin inflammation. This inflammation, in turn, can further deteriorate the barrier function by downregulating a myriad of essential barrier-maintaining molecules. Pruritus in AD, which may be due to hyperinnervation of the epidermis, increases pruritogens, and central sensitization compromises the skin integrity and promotes inflammation. There are unmet needs in the treatment of AD. Based on the detailed evidence available to date, certain disease mechanisms can be chosen as treatment targets. Numerous clinical trials of biological agents are currently being conducted and are expected to provide treatments for patients suffering from AD in the future. This review summarizes the etiopathogenesis of the disease and provides a rationale for choosing the novel targeted therapy that will be available in the future.

Keywords: Adaptive; Atopic dermatitis; Filaggrin; Immunology; Innate; Pathogenesis.

Fig. 1

Immunologic modulation of filaggrin (FLG) in the development of atopic dermatitis. Decreased FLG exacerbates skin inflammation in many ways. Th2 phenotype skewing occurs because of barrier disruption and keratinocyte injuries that stimulate thymic stromal lymphopoietin (TSLP), Th2, and eosinophil-recruiting chemokines together with IL-33 and IL-25 released from keratinocytes. Moreover, the loss of the acid mantle in the epidermis also promotes TSLP secretion via protease-activated receptor type 2 (PAR-2) activation by increased serine proteases. Enhanced allergen penetration and microbial colonization activate inflammasomes and the Th17 pathway that complicate the pathogenesis of AD in a later state

Fig. 2

Interplay among the barrier dysfunction, innate lymphoid cell (ILC)2, basophils, eosinophils, and mast cells. Barrier disruption leads to the production and release of epithelial-derived cytokines, namely, thymic stromal lymphopoietin (TSLP), IL-25, and IL-33. Upon ligation with the corresponding receptors on ILC2, TSLP receptor (TSLPR), IL-25 receptor (IL-25R, also known as IL17RB), and IL-33 receptor (IL-33R or ST2), ILC2 is activated to release Th2 cytokines, e.g., IL-5 and IL-13. In addition, IL-4 from basophils which are found in proximity to ILC2 in AD skin lesions can directly activate ILC2. PGD2, presumably from mast cell degranulation, also contributes to the recruitment of ILC2 into the skin as well as the induction of ILC2 Th2 cytokine production. In contrast, cell adhesion molecules, E-cadherin, on keratinocytes, are known to have an inhibitory effect on ILC2. Nevertheless, loss of E-cadherin is observed in FLG-deficient individuals. Therefore, skin inflammation is enhanced as there is an increase in stimulatory but a decrease in inhibitory stimuli

Fig. 3

The relationship among itch, barrier disruption and an immunologic aberration. Scratching resulting from itch can worsen a breach in the skin. Dry skin promotes itch by increasing the density of epidermal nerve fibers. Scratching also promotes Th2 chemokines, eosinophil-recruiting chemokines, and thymic stromal lymphopoietin (TSLP). Conversely, immune responses can induce itch via the secretion of a myriad of cytokines that can act as pruritogens