Update on the pathogenesis of atopic dermatitis

Abstract

Atopic dermatitis is a chronic, recurrent, and multifactorial skin-mucosal manifestation resulting from the interaction between elements mainly associated with the skin barrier deficit, the homeostasis of the immune response, neurological aspects, and patterns of reactivity to environmental antigens, which are established in genetically predisposed individuals. In addition to the skin, atopic diathesis involves other organs such as the airways (upper and lower), eyes, digestive tract, and neuropsychiatric aspects, which inflict additional morbidity on the dermatological patient. The different phenotypes of the disease fundamentally depend on the participation of each of these factors, in different life circumstances, such as age groups, occupational exposure patterns, physical activity, pollution, genetic load, and climatic factors. A better understanding of the complexity of its pathogenesis allows not only the understanding of therapeutic targets but also how to identify preponderant elements that mediate disease activity in each circumstance, for selecting the best treatment strategies and mitigation of triggering factors. This narrative review presents an update on the pathogenesis of atopic dermatitis, especially aimed at understanding the clinical manifestations, the main disease phenotypes and the context of available therapeutic strategies.

Keywords: Atopic dermatitis; Cytokines; Dermatopathies; Eczema; Homeopathic pathogenesis; Immunity.

Fig. 1

Histopathology of atopic dermatitis (subacute lesion). (A) Epidermis with irregular acanthosis, hyperkeratosis and focal parakeratosis, associated with mild spongiosis (Hematoxylin & eosin, ×200). (B) Inflammatory lymphocytic infiltrate of the superficial dermis, predominantly perivascular, with sparse eosinophils (Hematoxylin & eosin, ×400).

Fig. 2

Production of alarmins resulting from stressors on keratinocytes and subsequent events in innate and adaptive immunity.

Fig. 3

Representation of the differentiation process of keratinocytes in the epidermis, from the basal layer to the corneocyte, with epidermal barrier dysfunction due to the action of gene mutations with loss of function (LOF) and protein suppression due to the action of atopic inflammation cytokines. During this differentiation process, the lipid envelope, the filaggrin/keratin network, and the cornified envelope are formed, with the desmosomes differentiating into corneodesmosomes. Together these components form a compact barrier preventing the permeation of harmful substances or pathogens into the epidermis, as well as irradiation and irritants. Additionally, this barrier prevents transepidermal water loss (TEWL) and loss of associated solutes. The “bricks and mortar” model that occurs in the architecture of the corneal layer is comprised of the protein-lipid envelope that surrounds the corneocyte (proteins made up of loricrin, involucrin, small proteins rich in proline and filaggrin) and the lipid envelope made up of a monolayer of lipids, which function as the basis for the organization of intercellular lamellar lipids (consisting of 25% cholesterol, 10% to 15% free fatty acids, 5% of cholesterol sulfate and triacylglycerol and 45% to 50% of ceramides in the stratum corneum). These extracellular lipids are stored within lamellar bodies in keratinocytes of the upper spinous and granulosa layers, consisting of glucosylceramides, sphingomyelin and phospholipids. The “intercellular cement” is a matrix consisting of ω-hydroxyceramides, cholesterol and free fatty acids modified by enzymes from the stratum corneum, in addition to antimicrobial peptides. Free amino acids resulting from the degradation of filaggrin form the majority of the so-called “Natural moisturizing factor” (NMF) in the stratum corneum, representing an exceptional capacity to retain water and contributing to the acidic pH of this layer. Thus, the inter-corneocyte lipid-protein matrix and protein-rich corneocytes are crucial for the formation of the functional epidermal barrier. Genetic defects in genes that control the synthesis of these proteins can contribute to atopic dermatitis, as well as the suppression of the function of these genes by inflammatory cytokines, as observed in this diagram. The corneodesmosin (CDSN) gene is suppressed in atopic dermatitis, but the integrity of the corneodesmosomes can also be negatively modulated by type 2 cytokines: IL-4, IL-13, IL-31, IL-25, IL-22. IL-4 promotes filaggrin deficiency in AD. IL-33 suppresses claudin expression in keratinocytes. TSLP decreases the synthesis of antimicrobial peptides, such as human β-defensin via the JAK-STAT system and cathelicidin (LL-37), allowing greater vulnerability to eczema herpeticum and bacterial infections.

Fig. 4

Pathways of pruritus, their mediators and receptors in atopic dermatitis. Prurigogenic agents produced by keratinocytes (substance P, SP; Acetylcholine, ACOL; endothelin-1, ET-1; and alarmins, such as thymic stromal lymphopoietin, TSLP and IL-33) bind to specific receptors in the membrane of slow conduction unmyelinated type C sensory nerves, respectively neurokinin-1 receptor, NK-1; muscarinic receptor, M3; endothelin 1 receptor, ETA (Endothelin A receptor); TSLP receptor, TSLPR; IL-33 STL2 receptor. The TSLP produced by keratinocytes under stress induces macrophages to differentiate into an M2 phenotype, which contributes to the production of interleukin 31 (IL-31). Undifferentiated macrophages produce tumor necrosis factor alpha (TNF-α), which binds to its receptor TNFR, anandamide (AEA) which binds to cannabinoid 1/2 (CB1/CB2) receptors, enkephalin, ENK, which binds to kappa (KOR) and mu (MOR) opioid receptors, in addition to producing nerve growth factor (NGF), which binds to the tropomyosin kinase A (TrkA) receptor. Eosinophils produce leukotrienes (LT), which bind to the LTR receptor, NGF and proteases that bind to the protease receptor (PAR2/PAR4). Mast cells release serotonin (5-hydroxy-tryptophan, 5-HT) activating its 5HTR receptor, histamine that binds to H1/H4 receptors, tryptase that binds to the PAR2/4 receptor, and substance P. Basophils are also a producing source of histamine and type 2 inflammation cytokines, such as IL-31, IL-4 and IL-13, which bind to their respective receptors in nerve endings, which have the JAK-STAT enzyme system as their intracellular signaling pathway. Th2 lymphocytes produce the same cytokines and Th22 lymphocytes produce IL-22, which also has its specific receptor on sensory nerve endings. All of them together work to produce acute and chronic pruritus in atopic dermatitis. The sensory neural fibers have transient potential receptors (TRP) V1 (valinoid transient potential receptor 1) and TRPA1 (ankyrin transient potential receptor 1), which are nonspecific cation channels. Once the nerve endings have been stimulated by the cytokines IL-4, IL-13, IL-22, IL-33, IL-31 and their specific receptors, the activation of TRVP1 and/or TRPA1 induces calcium influx, which eventually induces the release of action potentials via Na_v1.7 and Na_v1.8 or Na_v1.9 sodium channels. TRPV1 and TRPA1 must be present for these pruritogens to induce pruritus or sensitize sensory nerves to other pruritogens.

Fig. 5

Main cytokines involved in the pathogenesis of atopic dermatitis, intracellular signaling of the JAK-STAT system, biologicals and small molecules used in the treatment of atopic dermatitis.