Multipolarity of cytokine axes in the pathogenesis of atopic dermatitis in terms of age, race, species, disease stage and biomarkers

Multipolarity of cytokine axes in the pathogenesis of atopic dermatitis in terms of age, race,... Abstract Atopic dermatitis (AD) is a common T-cell-mediated inflammatory disease of the skin. Signatures of AD are characterized by an impaired skin barrier, aberrant Th2-type cytokine production and intensive pruritus. Transcriptomic analysis, however, has revealed a heterogeneous pathogenesis and the co-existence of multiple cytokine axes of Th17, Th22 and Th1 types, especially in intrinsic (a subtype of AD without skin barrier impairment), pediatric and Asian types of AD. Furthermore, the therapeutic effect of anti-IL-4 receptor α against AD was not as high as that of IL-17 blockage against psoriasis, which implies a modification of the disease spectrum by non-Th2-type cytokine axes in AD. These lines of evidence indicate a need for personalized or precision medicine appropriate for each subtype of AD. animal models, Asian and European AD, extrinsic and intrinsic AD, pediatric AD, psoriasis Introduction Atopic dermatitis (AD) is characterized by persistent and intense pruritus (itching) and relapsing and remitting eczematous lesions. AD is one of the most common skin diseases with a prevalence of 10–20% in developed countries (1–4). Symptoms start in the first year of life in 60% of patients with AD, though they can present at any age (1–4). AD often occurs in conjunction with allergic diseases such as allergic rhinitis, allergic asthma and food allergies (1–4). Allergic symptoms often begin early in life and progress in the typical fashion, which is called the allergic (or atopic) march (5, 6). The pathogenesis of AD is driven by three major pathological factors, namely, disruption of the skin barrier, an altered Th2 cell response and pruritus (itching) (Fig. 1) (1–4). These factors interact in a close relationship with one another. Disruption of the skin barrier allows entry of exogenous stimuli and activates keratinocytes (epithelial cells that form the epidermis), which secrete cytokines such as thymus and activation-regulated chemokine (TARC)/CCL17, thymic stromal lymphopoietin (TSLP), IL-25 and IL-33, which polarize attracted T cells into Th2 cells (1–4). Cytokines such as IL-4 and IL-13 are in turn secreted by Th2 cells, resulting in decreased expression of barrier-related gene products such as filaggrin. Th2 cells also secrete IL-4 and IL-31, both of which cause pruritus (1–4, 7, 8). Expression of a constitutively active form of aryl hydrocarbon receptor (AhR) in keratinocytes induces scratch behavior and hyper-innervation in skin in a mouse model (9). In this model, the neurotrophic factor artemin plays a central role in innervation (9). This finding may explain the relationship between AD and air pollution (a source of various polycyclic aromatic hydrocarbons or ligands for AhR) (9, 10). Pruritus causes patients to scratch persistently, leading to sleep disturbance and exacerbation of AD. The skin barrier defect, altered Th2 cell response and pruritus thus interact to make the pathogenesis of AD more complex and resistant to ordinary treatments (11, 12). Fig. 1. View largeDownload slide Interaction of the three major factors in the pathogenesis of AD. Barrier disruption, Th2 cytokines and pruritus/scratch are the three major factors that play central roles. Barrier disruption is related to repeated/enhanced allergen exposure and cytokine production (TARC, TSLP, IL-25 and IL-33) from irritated keratinocytes, both of which promote activation of Th2 cells (1–4, 7, 8). Th2 cytokines from Th2 cells decrease expression of filaggrin (FLG), a protein maintaining the integrity of the skin barrier (1–4). Activated Th2 cells secrete IL-4 and IL-31, which are itch mediators causing pruritus (1–4, 7, 8). Pruritus induces scratch behavior, which eventually disrupts the skin barrier. Barrier disruption damages keratinocytes and enables them to produce TSLP, artemin, nerve growth factor (NGF) and Sema3A, which mediate pruritus and innervation of the epidermis via the peripheral sensory nerves (1–4, 7, 8). Fig. 1. View largeDownload slide Interaction of the three major factors in the pathogenesis of AD. Barrier disruption, Th2 cytokines and pruritus/scratch are the three major factors that play central roles. Barrier disruption is related to repeated/enhanced allergen exposure and cytokine production (TARC, TSLP, IL-25 and IL-33) from irritated keratinocytes, both of which promote activation of Th2 cells (1–4, 7, 8). Th2 cytokines from Th2 cells decrease expression of filaggrin (FLG), a protein maintaining the integrity of the skin barrier (1–4). Activated Th2 cells secrete IL-4 and IL-31, which are itch mediators causing pruritus (1–4, 7, 8). Pruritus induces scratch behavior, which eventually disrupts the skin barrier. Barrier disruption damages keratinocytes and enables them to produce TSLP, artemin, nerve growth factor (NGF) and Sema3A, which mediate pruritus and innervation of the epidermis via the peripheral sensory nerves (1–4, 7, 8). Although the Th2-type cytokine axis plays a central role in the altered immune response in AD, recent studies indicate the involvement of other cytokine axes in the spectrum of cytokine patterns in skin lesions of patients with AD (13–19). Accordingly, AD manifests with different symptoms in patients of different ages and races, and even at different times in the same patient. This variation in AD challenges physicians to provide a satisfactory regimen for each patient. In this review, we demonstrate the existence of multiple axes of cytokines in the development of AD in patients with various backgrounds. We begin by reviewing the subclasses of AD based on clinical observation and on biomarker patterns. Then we detail the cytokine patterns in patients with AD at different phases as well as in representative animal models for AD. We also interpret the outcomes of current biologics for AD, which corroborate the presence of multiple cytokine axes involved in the background of AD. Stratification of AD and subtype-specific cytokine profiles AD is a heterogenous disease. For decades, dermatologists have noticed that AD can be stratified into several subtypes based on clinical findings and some biomarkers such as serum IgE (20). The complexity of AD has also been confirmed by a set of multiple biomarkers (21). In this section, we summarize the characteristics of the clinical appearances and cytokine spectra of the various subtypes of AD (Fig. 2). Fig. 2. View largeDownload slide Multiple cytokine axes in AD (18). Th2-type cytokines (IL-4, IL-13 and IL-5) mediate barrier disruption and pruritus. IL-22 is a Th22/Tc22 (T22)-type cytokine and is involved in epidermal hyperproliferation that leads to acanthosis (thickening of epidermis). European patients with AD and patients with extrinsic AD tend to exhibit barrier disruption, which causes repeated allergen exposure and B-cell activation resulting in hyper-IgE levels in serum. The cytokine spectrum of patients with intrinsic AD, Asian patients with AD and pediatric patients with AD is further complicated with additional cytokine axes including Th1 (IFN-γ) and Th17 (IL-17, IL-23 and IL-19). Fig. 2. View largeDownload slide Multiple cytokine axes in AD (18). Th2-type cytokines (IL-4, IL-13 and IL-5) mediate barrier disruption and pruritus. IL-22 is a Th22/Tc22 (T22)-type cytokine and is involved in epidermal hyperproliferation that leads to acanthosis (thickening of epidermis). European patients with AD and patients with extrinsic AD tend to exhibit barrier disruption, which causes repeated allergen exposure and B-cell activation resulting in hyper-IgE levels in serum. The cytokine spectrum of patients with intrinsic AD, Asian patients with AD and pediatric patients with AD is further complicated with additional cytokine axes including Th1 (IFN-γ) and Th17 (IL-17, IL-23 and IL-19). Classification by the level of serum IgE Extrinsic and intrinsic types. AD has been categorized as extrinsic type or intrinsic type based on an increased or normal level of serum IgE, respectively, without regarding the age or gender of the patients. This classification is popular and widely accepted (Fig. 3A) (Table 1) (1, 20). Extrinsic or allergic AD includes 80% of patients with AD. It is characterized by high total serum IgE levels and the presence of specific IgE for environmental and food allergens. The extrinsic type is correlated with the presence of filaggrin mutation and accompanied by decreased skin barrier function. Skin barrier dysfunction leads to facilitated/repeated percutaneous sensitization to external stimuli and allergens resulting in high serum IgE. Thus, extrinsic AD is a prototype of skin damage-induced Th2-type dermatitis. Patients with extrinsic AD are at risk for eventual age-dependent progression (atopic march) including the development of other disorders such as food allergies, allergic rhinitis and allergic asthma (20, 22). Table 1. Characteristics of extrinsic and intrinsic AD Characteristic Extrinsic AD Intrinsic AD Frequency 80% 20% Serum IgE Elevated Normal Prevalence of filaggrin mutation High Normal Incidence (male:female) 1:1 1:3–4 Onset Early Relatively late Skin barrier Disrupted Normal Immunological feature Th2 dominant Th1 dominant Metal allergy Not related High prevalence Characteristic Extrinsic AD Intrinsic AD Frequency 80% 20% Serum IgE Elevated Normal Prevalence of filaggrin mutation High Normal Incidence (male:female) 1:1 1:3–4 Onset Early Relatively late Skin barrier Disrupted Normal Immunological feature Th2 dominant Th1 dominant Metal allergy Not related High prevalence View Large Table 1. Characteristics of extrinsic and intrinsic AD Characteristic Extrinsic AD Intrinsic AD Frequency 80% 20% Serum IgE Elevated Normal Prevalence of filaggrin mutation High Normal Incidence (male:female) 1:1 1:3–4 Onset Early Relatively late Skin barrier Disrupted Normal Immunological feature Th2 dominant Th1 dominant Metal allergy Not related High prevalence Characteristic Extrinsic AD Intrinsic AD Frequency 80% 20% Serum IgE Elevated Normal Prevalence of filaggrin mutation High Normal Incidence (male:female) 1:1 1:3–4 Onset Early Relatively late Skin barrier Disrupted Normal Immunological feature Th2 dominant Th1 dominant Metal allergy Not related High prevalence View Large Fig. 3. View largeDownload slide Simplified features of AD subsets. The size of cells indicates relative activity of T cells. (A) Th2 and Th22 cells are highly activated in both extrinsic and intrinsic AD (1, 20). Expression of filaggrin (FLG) is decreased and the barrier is dysfunctional in the extrinsic type, in which repeated allergen exposures lead to secretion of IgE by activated B cells. The barrier is normal in the intrinsic AD, which is characterized by a high frequency of metal allergy and activation of Th17 and Th1 cells. (B) Acute lesions start with IL-22/IL-17-mediated triggers for epidermal hyperplasia in association with epidermal S100 proteins, such as S100A7, S100A8 and S100A9. Activation of Th2/Th22 cytokine axes and a lesser activation of Th1/Th17 cytokines are detected in acute lesions. Chronic lesions are characterized by an intensification of this immune activation without switching to other cytokine axes. (C) Pediatric AD is characterized by acute eczematous lesions on the extensor side of the body (3). Recent transcriptomic analysis revealed multiplex activation of Th2, Th22, Th17, Th1 cells and Th9 cells. IL-4/IL-13 and IL-17 produced by Th2 and Th17 cells, respectively, operate on keratinocytes to induce IL-19, which in turn induces keratinocyte proliferation and skewing toward a Th2-type immune reaction (23). IL-19 is one of the key molecules in the pathogenesis of psoriasis. Thus, the initial phase of pediatric AD seems complex and not just an acute phase of the eczematous reaction (23). In adolescent and adult patients with AD, flexor areas are affected showing significant acanthosis (thickening of epidermis) called lichenification (3). Skin lesions in adults with AD is characterized by Th2/Th22 cytokine axes with a lesser contribution of Th1 and Th17 axes (23). (D) Asian AD shows multiple axes of cytokines provided by activated Th17 and Th1 cells superimposed on the highly activated Th2 and Th22 cells (13). In contrast, Th2 and Th22 cells are the main producers of cytokines in European-American patients with AD (13). In the non-lesional skin in European-American patients, transcripts of Th1-related genes are increased. However, their levels do not change between non-lesional and lesional skin (13). (E) An extensive analysis of serum biomarkers revealed four clusters of AD subtypes (21). Attempts to stratify AD will lead to development of precision medicine. Fig. 3. View largeDownload slide Simplified features of AD subsets. The size of cells indicates relative activity of T cells. (A) Th2 and Th22 cells are highly activated in both extrinsic and intrinsic AD (1, 20). Expression of filaggrin (FLG) is decreased and the barrier is dysfunctional in the extrinsic type, in which repeated allergen exposures lead to secretion of IgE by activated B cells. The barrier is normal in the intrinsic AD, which is characterized by a high frequency of metal allergy and activation of Th17 and Th1 cells. (B) Acute lesions start with IL-22/IL-17-mediated triggers for epidermal hyperplasia in association with epidermal S100 proteins, such as S100A7, S100A8 and S100A9. Activation of Th2/Th22 cytokine axes and a lesser activation of Th1/Th17 cytokines are detected in acute lesions. Chronic lesions are characterized by an intensification of this immune activation without switching to other cytokine axes. (C) Pediatric AD is characterized by acute eczematous lesions on the extensor side of the body (3). Recent transcriptomic analysis revealed multiplex activation of Th2, Th22, Th17, Th1 cells and Th9 cells. IL-4/IL-13 and IL-17 produced by Th2 and Th17 cells, respectively, operate on keratinocytes to induce IL-19, which in turn induces keratinocyte proliferation and skewing toward a Th2-type immune reaction (23). IL-19 is one of the key molecules in the pathogenesis of psoriasis. Thus, the initial phase of pediatric AD seems complex and not just an acute phase of the eczematous reaction (23). In adolescent and adult patients with AD, flexor areas are affected showing significant acanthosis (thickening of epidermis) called lichenification (3). Skin lesions in adults with AD is characterized by Th2/Th22 cytokine axes with a lesser contribution of Th1 and Th17 axes (23). (D) Asian AD shows multiple axes of cytokines provided by activated Th17 and Th1 cells superimposed on the highly activated Th2 and Th22 cells (13). In contrast, Th2 and Th22 cells are the main producers of cytokines in European-American patients with AD (13). In the non-lesional skin in European-American patients, transcripts of Th1-related genes are increased. However, their levels do not change between non-lesional and lesional skin (13). (E) An extensive analysis of serum biomarkers revealed four clusters of AD subtypes (21). Attempts to stratify AD will lead to development of precision medicine. About 20% of AD cases are classified as intrinsic or non-allergic type, which is characterized by normal levels of total IgE, absence of allergen-specific IgE and poor infiltration of eosinophils in the skin (20). It should be noted that the term ‘non-allergic’ does not correctly express the pathogenesis of intrinsic AD (20). ‘Intrinsic’ does not mean that patients of this type are sensitized with endogenous or self-antigens. Rather, the Th2 cells are highly activated by extrinsic stimuli such as metal ions and haptens (small molecules capable of binding to proteins and changing their immunogenicity). Intrinsic AD shows peculiar characteristics such as female predominance, delayed onset and reduced disease severity (20). Barrier function is normal as measured by transepidermal water loss and skin surface hydration. Prevalence of filaggrin mutation is not increased in contrast to the extrinsic type. And the risk of an atopic march is lower in intrinsic AD (20). Instead, there is a high prevalence of metal allergy, indicating that intrinsic AD patients are susceptible to allergic contact dermatitis (ACD) or that intrinsic AD results from chronic metal allergy. Although the intrinsic type shows relatively lower levels of IL-4 and IL-13 in comparison with extrinsic, levels of IL-5 and IL-13 are increased, indicating the presence of Th2-type immune activation (20). Nevertheless, peripheral blood lymphocytes from patients with the intrinsic type contain more IFN-γ+ T cells than those from patients with the extrinsic type. Therefore, dermatitis in the intrinsic type seems to be driven by Th2- and Th1-type cytokine axes (20). Alternative definitions of extrinsic/intrinsic AD. The authenticity of the extrinsic/intrinsic classification has been argued by some investigators. The term ‘atopy’ originally meant a personal or familial tendency to produce IgE antibodies in response to low doses of allergens (24). Accordingly, a condition where (serum) IgE does not increase is technically ‘not atopic’. However, with the current state of art, little is known about the precise role of IgE in the pathogenesis of atopy. To avoid this inconsistency in naming, extrinsic and intrinsic types are classified using other terms, including the following: ‘IgE-associated atopic eczema/dermatitis syndrome (AEDS)’ and ‘T cell-associated AEDS’; ‘allergic AD’ and ‘non-allergic AD’; or ‘atopic eczema’ and ‘non-atopic eczema’ (24). These terms also involve inconsistency in themselves, and may be misleading as well. For example, T cells are associated in the pathogenesis of IgE-associated AEDS. Some propose a term ‘atopiform dermatitis’, which stresses a distinction between different subpopulations, excluding certain conditions from the diagnosis of AD (24). This classification is reasonable because AD is composed of diseases with different pathogenesis. However, it is currently difficult to discriminate the underlying pathogenesis by clinical findings for most of the patients. The problems in diagnosis and classification of AD originate, at least partially, from terminology and lack of criteria to separate subpopulations of the disease. These controversies may reflect that studies of AD are entering a new era. Transcriptomic difference between acute and chronic lesions of AD in adults There are acute and chronic lesions within the same patient. However, the cytokines that govern the onset of new or acute lesions and the maintenance of chronic lesions are not understood well. Gittler et al. (15) investigated intrapersonal sets of transcriptomes from non-lesional skin and from acute and chronic lesions obtained from adult patients with AD [n = 10 (4 men and 6 women), mean age of 43.5 years (range 20–67), race not provided]. In this study, ‘bona fide acute’ lesions were distinguished from ‘acute on chronic’ lesions by the following criteria: (i) new lesions of <72 h duration; (ii) lack of lichenification; and (iii) lack of regenerative hyperplasia as defined by an epidermal thickness of 150 µm or less and basal or confluent supra-basal keratin-16 positivity. Furthermore, no systemic or topical treatments were done for 4 or more weeks before biopsy. For comparison, skin biopsy specimens from healthy volunteers and patients with psoriasis were used. The onset of acute lesions features an abrupt increase of transcription for S100A7, S100A8 and S100A9. These transcripts encode a subset of terminal differentiation proteins of keratinocytes and can be induced by IL-17 and IL-22. Acute lesions were also characterized by transcriptomic increases in Th22 and Th2 cytokines (including itch-inducing IL-31) and a smaller increase in IL-17 levels (15). A lesser but significant induction of Th1-associated genes, such as IL-8, IL-1β and IFN-α, was detected as well (15). The chronic lesions featured progressive activation of Th2 and Th22, as well as Th1, pathways and S100A7, S100A8 and S100A9 transcripts (15). Small increases of the Th1-related genes, such as IFN-γ, CXCL9, CXCL10 and CXCL11, became more evident in the chronic lesions (15). It is not clear if these up-regulated Th1-related transcripts represent a pro-inflammatory stimulus for Th17/Th22 T cells as proposed in psoriasis or counter-regulation against the Th2 and Th17 activation (25–27). Levels of IL-17-related genes were higher than those in non-lesional skin. However, their magnitudes were similar between acute and chronic lesions (15). In summary, acute lesions starts with (i) IL-22/IL-17-mediated triggers for epidermal hyperplasia in association with epidermal S100 proteins, (ii) activation of Th2/Th22 cytokine axes and (iii) a lesser activation of Th1/Th17 cytokines with unknown function. Chronic lesions are characterized by an intensification of this immune activation without a switch of the cytokine axes. In contrast to the patients with psoriasis, the magnitude of Th17/IL-17-induced gene products in patients with AD is much attenuated except for S100 proteins. Differences between pediatric and adult patients with AD Age-dependent transition of skin lesions and peripheral blood phenotype. The morphology and distribution of skin lesions changes depending on patient age (3). In general, the appearance of skin lesions indicates a transition from a state of acute eczematous reaction to the chronic phase (Fig. 3B). Yet analysis of cytokine profiles indicates the presence of a more complex form of dermatitis, which cannot be simply explained by chronicity. Pediatric patients with AD show acute eczematous lesions, which tend to be distributed on the face, trunk and limbs (Fig. 3C, left) (3). Adolescent patients with AD start to show signs of chronicity such as lichenification (thickened epidermis) at flexures (Fig. 3C, right) (3). Adult patients with AD frequently present with extensively itchy papules described as prurigo (3). The transition of these clinical features may take place against a background of changing immunological skewing. For example, a study showed that the immunophenotype of peripheral blood lymphocytes changes from a Th2-dominant pattern in infants with AD [n = 21 (11 girls and 8 boys), mean age of 25 months (range, 5–70), Asian 5, Black 2, White 12] into a state superimposed with Th22/Tc22 (T22) cytokines in adults with AD [n = 42 (18 women and 24 men), mean age of 39 years (range, 19–66), Asian 3, Black 6, White 33] (Fig. 3C, bottom) (28). The complex cytokine spectrum of pediatric patients with AD. As a patient gets older, the cytokine pattern in peripheral blood tends to change from a Th2-dominated type to double-cytokine axes comprising Th2 and T22 types. Here, ‘T22’ means IL-22-producing lymphocytes including CD4+ T (Th22) cells and CD8+ T (Tc22) cells. This transition of the cytokine spectrum from a simple Th2 axis to a Th2/T22 double axes may simply reflect the exaggerated acute responses on the background of chronicity of the disease. However, skin lesions of infants with AD show an unexpectedly complex cytokine patterns that include Th2, Th1, Th17, T22 and Th9 (Fig. 3C, left) (23). A complex phenotype of pediatric AD has been revealed by a comparison between the skin of pediatric [within 6 months of disease onset, n = 19 (8 girls and 11 boys), mean age of 1.3 years (range 0.3–5.0), Asian/Pacific Islander 2, African American 5, Hispanic 4, White 8] and adult [n = 15 (8 women and 7 men), mean age of 51.4 years (range 33–72), White 15] patients with AD (23). As a disease control, lesional skin of adult patients with psoriasis vulgaris [a Th17-centered chronic skin disease, n = 10 (4 women and 6 men), mean age of 51.3 years (range 30–64), White 10] was analyzed in this study (23). On the continuous activation of Th2 (IL-13, IL-31 and CCL17) and T22 (IL-22 and S100As) axes, some Th1 skewing (IFN-γ and CXCL10), induction of cytokines and antimicrobial peptides of the Th17 type (IL-17A, IL-19, CCL20, LL37 and peptidase inhibitor 3/elafin), Th9 (IL-9), IL-33 (an IL-1 family cytokine activating Th2-type responses) and innate markers (IL-1β, IL-8 and IFN-α1) were expressed more highly in children with AD (23). Non-lesional skin in these patients was also abnormal, showing epidermal proliferation and higher levels of IL-17A, IL-19 and LL37 as well as epidermal proliferation markers (keratin 16 and S100As) (23). Increased IL-19 levels indicated a possible link between Th2 and Th17 activation in pediatric AD (23). IL-19, a member of the IL-10 family of cytokines, is induced by both IL-17 and IL-4/IL-13 and amplifies the effects of IL-17 on keratinocytes (29, 30). These findings indicate a state of multipolarity of T-cell skewing in pediatric AD. Filaggrin expression was similar in children with AD and healthy children, indicating a smaller contribution of the skin barrier defect in children with AD (23). The normal skin barrier function is suggestive of intrinsic AD but, unlike the intrinsic type, infantile AD is not correlated with gender or metal allergy. In consistent with low but significant activation of Th17-related genes, pediatric AD showed phenotypic similarities to psoriasis in view of activated inflammatory genes (23). The early phase of pediatric AD is another focus of investigation. Peripheral blood from infants and toddlers aged 0–3 years [n = 29 (11 girls and 18 boys), mean age of 14.5 months (range 4–35), Hispanic 3, Asian 5, African American 5, White 16] was compared with that from 13 children 3–6 years old [n = 13 (6 girls and 7 boys), mean age of 57.1 months (range 37–70), Hispanic 1, Asian 4, African American 3, White 5] (31). This study showed that pediatric AD was characterized by early excessive T-cell activation. A Th2 dominance (lower ratio of IFN-γ+ in CD4+ T cells) was evident in 0- to 3-year-old patients and was intensified by 3–6 years in the CLA+ (skin homing) subset. IL-13+ levels were higher in the younger AD group in both CLA+ and CLA– subsets, supporting the concurrence of non-cutaneous atopic manifestations beginning early in AD (31). Regarding B cells, children with AD [n = 27 (12 girls and 15 boys), mean age of 1.52 years (0.41–4.26), Asian 5, Black 6, White 16] and adults with AD [n = 34 (15 women and 19 men), mean age of 45.55 years (18–81), Asian 1, Black 4, White 30] were examined for their skin and peripheral blood (32). Pediatric AD showed a T-cell predominance in the skin, and lower counts of circulating CD19+CD20+ B cells in peripheral blood in comparison with age-matched children [n = 15 (8 girls and 7 boys), mean age of 2.21 years (0.97–4.93), Black 1, White 14], suggesting an altered differentiation in B cells as well (32). On the other hand, adults with AD showed Th2/Th22-centered cytokine axes with a lesser contribution of Th1 and Th17 axes in the lesional skin (23). IL-9 transcript was increased in non-lesional but, paradoxically, rather decreased in lesional skin in adult patients with AD (23). The numbers of T cells and dendritic cells were similarly increased in pediatric and adult patients with AD (23). What defines the differences in cytokine polarity between pediatric and adult AD is not clear. Neonates have decreased natural killer cell activity, lower percentages of CD4+ and CD8+ IFN-γ+ T cells, a lower proliferative response of T cells and dysregulated cytokine production, all of which may contribute to their increased risk of infection (33). Little is known about how these pediatric characteristics may contribute to pediatric AD. It seems likely, however, that AD begins as a multi-cytokine response at disease onset (31). Differences between races Racial background affects the cytokine pattern in the lesional skin of patients with AD. The prevalence of AD among adults in Japan is estimated at 7 to 10% (34, 35). The exact prevalence of AD in other races is hard to estimate (36). Several studies have shown that the prevalence of AD is increasing and that some races including Asians and Africans may be more prone to develop the disease than Caucasians (36). Furthermore, activation of Th17 cells has been observed in blood and acute AD skin lesions in Asians (Fig. 3D, right) (37). On the contrary, European-American patients with extrinsic AD did not show activation of the IL-23/Th17 axis (Fig. 3D, left) (14, 38, 39). A comparison of extrinsic-type AD between European American [n = 25 (16 men and 9 women), mean age of 45.7 years] and Asian [Japanese and Korean, n = 27 (22 men and 5 women), mean age of 29.6 years] AD patients has revealed that the Asian AD phenotype is a mixed phenotype between the AD and psoriasis vulgaris seen in the European-American population (13). In comparison with European Americans, skin lesions of Asians with AD show parakeratosis and a unique cytokine profile, such as co-activation of the Th2 and Th17 axes (13). Although Th1-related gene transcripts were detected in skin in European-American patients, the degrees of expression levels showed no difference between the non-lesional and lesional skin, suggesting that Th1 cells may not play a central role in European American AD (13). Subtypes revealed by stratification by biomarkers An attempt to stratify adult patients with AD by the serum biological markers has succeeded in identifying four clusters (Fig. 3E) (21). In this study, sera from 193 adult patients with moderate AD [n = 95 (57 women and 38 men), mean age of 30.6 years, race not provided], severe AD [n = 98 [55 women and 43 men], mean age of 31.1 years) and 30 healthy control subjects without AD [n = 30 (15 women and 15 men), mean age of 39.1 years] were analyzed for 147 serum mediators, total IgE levels and 130 allergen-specific IgE levels. A cluster analysis of the 57 largest principal components yielded four distinct clusters of patients with AD. Cluster 1 showed more severe clinical scores and more affected areas enriched with Th2 cytokines with the highest levels of TARC, pulmonary and activation-regulated chemokines (PARC), tissue inhibitor of metalloproteinases 1 (TIMP1) and soluble CD14. Cluster 2 had milder clinical scores with the lowest levels of IFN-α, TIMP1 and vascular endothelial growth factor (VEGF). Regulated on activation normal T cell expressed and secreted (RANTES, CCL5) and tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK, TNFSF12) are also decreased. Cluster 3 had more severe clinical scores with the lowest levels of IFN-β, IL-1 and epithelial cytokines such as TSLP. Cluster 4 had milder clinical scores but the highest levels of the inflammatory markers IL-1, IL-4, IL-13 and TSLP. Multiple cytokine axes in AD and unmet needs for personalized treatment AD has been classified as a Th2-type immune disease (40). However, as we described above, gene expression analyses have revealed an unexpectedly broad spectrum of cytokine profiles attributable to Th1, Th17, T22 and Th9 cells in the skin of AD patients (13–16). This variation in cytokines depends on factors such as disease stage and the age and race of the patient. These findings indicate the contribution to some degree of atypical multi-cytokine axes in the pathogenicity of AD (17, 18). For comparison, we will review psoriasis vulgaris, a Th17-cytokine-driven inflammatory skin disease. As the success of anti-IL-17/IL-23 biologics against this condition indicates, activation of Th17/Tc17 cells plays a major role in the pathogenesis of psoriasis (41–43). For example, let us estimate the efficacy of IL-17A blockade by secukinumab. The severity of psoriasis vulgaris can be measured by the Psoriasis Area and Severity Index (PASI) score in the range of 0 (no disease) to 72 (maximal disease). PASI score is also useful in estimating the efficacy of treatments. If a patient with a PASI score of 50 achieved a reduction in the score <5 (a reduction of the score for >90%) by a treatment, the efficacy of which is defined as PASI-90. By secukinumab, 79.0% of patients with psoriasis vulgaris achieved PASI-90 at week 16 (n = 334) (41). Regarding AD, two phase 3 trials of dupilumab (an anti-IL-4 receptor α) have proven their efficacy in improvement of the symptoms of AD and reduction of the severity as scored using the Eczema Area and Severity Index (EASI) (44). Like in PASI, severity of eczematous lesion can be measured by EASI score in the range of 0 (no disease) to 72 (maximal disease). EASI-90 (a reduction of the score to <10% of the initial) was achieved in 30–36% of dupilumab-treated patients with AD (7–8% of placebo-treated patients) at week 16. These trials confirmed the central role of the Th2 axis in AD. However, the less sharp efficacy of dupilumab is in line with the hypothesis that multiple cytokine axes other than Th2 type may play accompanying roles in their own ways. The degree of contribution by non-Th2 cytokines is not clear, but can be testable by the ongoing clinical trials attempting to treat AD with biologics against non-Th2 cytokines, such as IL-1R1 (anakinra), IL-6 (tocilizumab), IL-22 (ILV-094), IL-23p40 (ustekinumab), TNF-α, IFN-γ, PDE-4 (apremilast) and NK-1R (aprepitant) (45–49). Currently, the efficacy of IL-23p40 blockade against AD is controversial, probably due to the variable composition of the patient groups (50). If the degree of contribution from each cytokine axis differs among patients, especially in Asian patients or infants with AD, personalized treatment may be required. Animal models of AD None of the currently used mouse models of AD represent all aspects of human AD features in the scope of transcriptomic analyses (51). Paradoxically, IL-23-injected mice, a psoriasis model, showed the best similarity to the human AD transcriptomic profile, although the similarity score was only 37% in gene expression (51). Still, mouse models of AD represent most of the clinical features of AD such as hyperplasia of the epidermis, decreased skin barrier function, pruritus, scratching behavior and increased serum IgE. Thus, we must be aware of the discrepancy between the transcriptomic characteristics and phenotypes of mouse models of AD when we utilize these pre-clinical animal models. Here, we summarize characteristics of several mouse models for AD with their possible relevance to human counterparts. Flaky tail mice Flaky tail mice (ma/ma Flgft/ft) have mutations in Flg (Flgft/ft) and Tmem79/Matt (Tmem79ma/ma). The skin barrier integrity is impaired in this model. These mice express a phenotype showing massively entangled or ‘matted’ hair and defective skin barrier (52, 53). Topical application of extracts of Dermatophagoides pteronyssinus (house dust mite) induces AD-like dermatitis and increased serum IgE (53). Expression levels of mRNA for IFN-γ and IL-17 are increased and the absence of IL-17A attenuates the spontaneous development of dermatitis and serum hyper-IgE in these mice (53–56). Skin inflammation is associated with expansion of IL-5-producing group 2 innate lymphoid cells (ILC2s) in skin (57). Thus, flaky tail mice have a mixed cytokine polarity of Th2, Th1 and Th17. Filaggrin-knockout mice Newborn Flg−/− mice exhibit dry scaly skin because of a lack of natural moisturizing factors (the final product of filaggrin) as often seen in patients with AD carrying loss-of-function mutation in FLG (1). In adult Flg−/− mice, however, the epidermis is well hydrated and spontaneous dermatitis did not occur under specific pathogen-free (SPF) conditions (58). Repeated percutaneous application of ovalbumin (OVA) results in exaggerated serum levels of OVA-specific IgG1 and IgE, both of which are markers for Th2-type response (58). The polarity of cytokine profiles in the skin of Flg−/− mice is not known. The epicutaneous OVA exposure model This model mimics multiple (repeated) allergen exposures, which is thought to happen in patients with AD accompanied with the skin barrier defect. Typically, BALB/c mice are epicutaneously exposed to OVA for 3-week long periods separated by 2-week resting periods. This procedure increases total and antigen-specific serum IgE and leads to a form of dermatitis with infiltrating T cells and eosinophils. Levels of mRNA for IL-4, IL-5 and IFN-γ are increased (59–62). Thickening of skin is mediated by IFN-γ, IL-4 and IL-5 (61, 62). Infiltration of T cells and that of eosinophils are primarily dependent on IL-4 and IL-5, respectively (61, 62). Both Th2 and Th1 cytokines seem to play roles in this model. Accordingly, total IgE (a marker of Th2 responses) and IgG2a (a marker of Th1 responses) rise after the second exposure week, followed by a later increase in OVA-specific IgE (62). Other cytokines such as IL-1β, TNF-α, IL-10, IL-13 and IL-12p35 also increase (62). Hapten-challenged mice A hapten is a low-molecular-weight xenobiotic chemical. It penetrates the skin and reacts chemically with self-proteins to form a complex that is recognized as a neo-antigen and that induces antigen-specific T cells in ACD (63). ACD can be simulated by the contact hypersensitivity (CHS) reaction in mice. This reaction is a cell-mediated response to epicutaneously applied haptens or allergens, the whole process of which consists of two phases. The mice are exposed to a hapten (sensitization). Typically following an intermission, mice are subjected to re-exposure (single challenge) to the hapten at a location distal to the site of sensitization (elicitation) (64). In CHS, hapten-specific type 1 CD4+ and CD8+ T cells (Th1 and Tc1 cells, respectively) act as effectors; and Th2 cells function as regulatory elements (65). However, repeated elicitation of CHS with haptens such as oxazolone and 2,4,6-trinitrochlorobenzene (TNCB) results in a different time course of inflammation, i.e. a shift in response from a delayed type to an early type, reflected as a shift in the cutaneous cytokine profile from Th1-like (IL-2, IL-3 and IFN-γ) to a Th2-like (IL-4, IL-10 and TNF-α) (66–68). This shift in reaction is accompanied by epidermal hyperplasia, massive accumulation of CD4+ T cells beneath the epidermis and elevation of antigen-specific serum IgE (66, 67, 69). This model emulates some features of human AD such as pruritus with epidermal hyperplasia and aberrant expression of differentiation proteins, filaggrin, loricrin and involucrin in the epidermis (69). NC/Nga and NC/Tnd mice NC/Nga and NC/Tnd mice spontaneously develop itchy skin lesions resembling those in AD (70, 71). These skin lesions develop between 6 and 8 weeks of age under ‘dirty’ microbiologic conditions but not under SPF conditions (70). Serum IgE levels of NC/Nga increase from 8 weeks of age in correlation with disease severity. Mast cells and IL-4-producing CD4+ T cells are increased in the skin. Th2 chemokines such as TARC and macrophage-derived chemokine (MDC) are increased in the lesions (72). The overproduction of IgE in NC/Nga is explained by defective IFN-γ production by T cells in response to IL-12 and a poor response of B cells to IFN-γ (73). Dust mite antigen-challenged mice AD-like dermatitis can be induced by application of crude extracts of Dermatophagoides farinae at a concentration of 1 or 10 mg ml−1, painted five times at 7-day intervals onto the ears of NC/Nga or BALB/c mice with or without simultaneous tape-stripping (74). The resulting ear swelling is accompanied by increased serum IgE, increased IL-4 mRNA and decreased mRNA levels for IFN-γ. IL-23-injected mice This model was originally developed to analyze the pathogenesis of psoriasis vulgaris. Intradermal injection of IL-23 results in erythema, mixed dermal infiltrates and epidermal hyperplasia associated with parakeratosis in mice (75). IL-23 induces IL-17A, IL-22, IL-19 and IL-24 expression in mouse skin, all of which are elevated in human psoriasis (75, 76). The epidermal hyperplasia is dependent on IL-17A and IL-22, but not on IL-19 and IL-24 (75, 76). The psoriasis-like phenotype of this model requires IL-6, which induces expression of IL-22R1A (77). These data implicate the importance of IL-23 and IL-22 in the pathogenesis of psoriasis. The induction of IL-17, IL-22 and IL-19 may recapitulate some features of AD, especially those seen in infant patients and Asian patients with AD. A caveat regarding mouse models To summarize, investigators should be aware of the differences between the murine AD models and human AD when translating murine data to human skin diseases. Role of regulatory T cells in AD Deficiency of FoxP3 results in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), symptoms of which include AD-like dermatitis (78). Furthermore, genome-wide association studies (GWAS) have revealed a link between allergic sensitization and eczematous traits and LRRC32 encoding the membrane protein also known as GARP (glycoprotein A repetitions predominant), which regulates TGF-β-signaling in regulatory T (Treg) cells (79, 80). However, the contribution of FoxP3+ Treg cells to AD is still controversial. Nevertheless, a study of tumor immunity provides us a clue to solve the controversy on the role of Treg cells in AD. The role of Treg cells has remained controversial in colorectal cancers, in which FoxP3+ T-cell infiltration has been associated with better prognosis in some studies but not in others. This controversy has been addressed by analyzing the subsets of FoxP3+ T cells (81). Human peripheral blood FoxP3+CD4+ T cells can be divided into three functional subpopulations by the expression of FoxP3, CD45RA and CD25 (82). FoxP3lowCD45RA+CD4+ T cells are Treg cells including CD31+ recent thymic emigrants. This population further differentiates to FoxP3highCD45RA−CD4+ Treg cells in response to antigenic stimulation ex vivo (82). These two populations have immune suppressive functions in vitro. FoxP3lowCD45RA−CD4+ T cells, in contrast, are activated effector T cells and can produce pro-inflammatory cytokines including IL-2, IFN-γ and IL-17. And it has been shown that colorectal cancers with predominant infiltration of FoxP3low (non-suppressive) T cells have better prognosis than those with predominantly FoxP3high (suppressive) Treg cell infiltration (81). The development of pro-inflammatory FoxP3low non-Treg cells depends on both the presence of IL-12 and TGF-β and invasion of intestinal bacteria, especially Fusobacterium nucleatum (81). Therefore, we speculate that an analysis of skin surface microbial features and the composition of infiltrating FoxP3+ T cells may solve the controversy over the role of Treg cells in AD. Conclusions As we have shown through the present summary, AD is a heterogenous disease (17, 18, 20, 83, 84). The majority of AD cases are of the extrinsic type, which is characterized by impaired skin barrier function. Extrinsic AD is related to other allergic diseases such as food allergy, allergic asthma and allergic rhinitis. Intrinsic AD, in contrast, is characterized by normal skin barrier function. Biomarkers and other factors such as age and race can be used to stratify AD into multiple subtypes. The massive amounts of information obtained from ‘omics’ studies have confirmed the heterogeneity of AD as previously observed by physicians. The high effectiveness of dupilumab against AD has confirmed the central role of Th2 cytokines in the conditions, but the fact that the efficacy of dupilumab against AD is lower than that of IL-17 blocking against psoriasis corroborates the heterogeneity and complexity of AD. Further study is required to enable precision treatment for AD. We expect the medical community to achieve a clearer understanding of the pathogenesis underlying AD in this era of omics and biologics. Funding This work was supported in part by the Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research (15H05790, 24591649 and 15K09765), Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research on Innovative Areas (15H1155), Japan Society for the Promotion of Science, Grant-in-Aid for challenging Exploratory Research (15K15417), Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO) (16021031300) and Japan Agency for Medical Research and Development (AMED) (16ek0410011h0003 and 16he0902003h0002). Conflicts of interest statement: the authors declared no conflicts of interest. References 1 Kabashima , K. 2013 . New concept of the pathogenesis of atopic dermatitis: interplay among the barrier, allergy, and pruritus as a trinity . J. Dermatol. Sci . 70 : 3 . 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Immunol . 137 : 1347 . Google Scholar CrossRef Search ADS 84 Sokolowska , M. and Akdis , C. A. 2017 . Highlights in immune response, microbiome and precision medicine in allergic disease and asthma . Curr. Opin. Immunol . 48 : iv . Google Scholar CrossRef Search ADS © The Japanese Society for Immunology. 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Immunology Oxford University Press

Multipolarity of cytokine axes in the pathogenesis of atopic dermatitis in terms of age, race, species, disease stage and biomarkers

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Abstract

Abstract Atopic dermatitis (AD) is a common T-cell-mediated inflammatory disease of the skin. Signatures of AD are characterized by an impaired skin barrier, aberrant Th2-type cytokine production and intensive pruritus. Transcriptomic analysis, however, has revealed a heterogeneous pathogenesis and the co-existence of multiple cytokine axes of Th17, Th22 and Th1 types, especially in intrinsic (a subtype of AD without skin barrier impairment), pediatric and Asian types of AD. Furthermore, the therapeutic effect of anti-IL-4 receptor α against AD was not as high as that of IL-17 blockage against psoriasis, which implies a modification of the disease spectrum by non-Th2-type cytokine axes in AD. These lines of evidence indicate a need for personalized or precision medicine appropriate for each subtype of AD. animal models, Asian and European AD, extrinsic and intrinsic AD, pediatric AD, psoriasis Introduction Atopic dermatitis (AD) is characterized by persistent and intense pruritus (itching) and relapsing and remitting eczematous lesions. AD is one of the most common skin diseases with a prevalence of 10–20% in developed countries (1–4). Symptoms start in the first year of life in 60% of patients with AD, though they can present at any age (1–4). AD often occurs in conjunction with allergic diseases such as allergic rhinitis, allergic asthma and food allergies (1–4). Allergic symptoms often begin early in life and progress in the typical fashion, which is called the allergic (or atopic) march (5, 6). The pathogenesis of AD is driven by three major pathological factors, namely, disruption of the skin barrier, an altered Th2 cell response and pruritus (itching) (Fig. 1) (1–4). These factors interact in a close relationship with one another. Disruption of the skin barrier allows entry of exogenous stimuli and activates keratinocytes (epithelial cells that form the epidermis), which secrete cytokines such as thymus and activation-regulated chemokine (TARC)/CCL17, thymic stromal lymphopoietin (TSLP), IL-25 and IL-33, which polarize attracted T cells into Th2 cells (1–4). Cytokines such as IL-4 and IL-13 are in turn secreted by Th2 cells, resulting in decreased expression of barrier-related gene products such as filaggrin. Th2 cells also secrete IL-4 and IL-31, both of which cause pruritus (1–4, 7, 8). Expression of a constitutively active form of aryl hydrocarbon receptor (AhR) in keratinocytes induces scratch behavior and hyper-innervation in skin in a mouse model (9). In this model, the neurotrophic factor artemin plays a central role in innervation (9). This finding may explain the relationship between AD and air pollution (a source of various polycyclic aromatic hydrocarbons or ligands for AhR) (9, 10). Pruritus causes patients to scratch persistently, leading to sleep disturbance and exacerbation of AD. The skin barrier defect, altered Th2 cell response and pruritus thus interact to make the pathogenesis of AD more complex and resistant to ordinary treatments (11, 12). Fig. 1. View largeDownload slide Interaction of the three major factors in the pathogenesis of AD. Barrier disruption, Th2 cytokines and pruritus/scratch are the three major factors that play central roles. Barrier disruption is related to repeated/enhanced allergen exposure and cytokine production (TARC, TSLP, IL-25 and IL-33) from irritated keratinocytes, both of which promote activation of Th2 cells (1–4, 7, 8). Th2 cytokines from Th2 cells decrease expression of filaggrin (FLG), a protein maintaining the integrity of the skin barrier (1–4). Activated Th2 cells secrete IL-4 and IL-31, which are itch mediators causing pruritus (1–4, 7, 8). Pruritus induces scratch behavior, which eventually disrupts the skin barrier. Barrier disruption damages keratinocytes and enables them to produce TSLP, artemin, nerve growth factor (NGF) and Sema3A, which mediate pruritus and innervation of the epidermis via the peripheral sensory nerves (1–4, 7, 8). Fig. 1. View largeDownload slide Interaction of the three major factors in the pathogenesis of AD. Barrier disruption, Th2 cytokines and pruritus/scratch are the three major factors that play central roles. Barrier disruption is related to repeated/enhanced allergen exposure and cytokine production (TARC, TSLP, IL-25 and IL-33) from irritated keratinocytes, both of which promote activation of Th2 cells (1–4, 7, 8). Th2 cytokines from Th2 cells decrease expression of filaggrin (FLG), a protein maintaining the integrity of the skin barrier (1–4). Activated Th2 cells secrete IL-4 and IL-31, which are itch mediators causing pruritus (1–4, 7, 8). Pruritus induces scratch behavior, which eventually disrupts the skin barrier. Barrier disruption damages keratinocytes and enables them to produce TSLP, artemin, nerve growth factor (NGF) and Sema3A, which mediate pruritus and innervation of the epidermis via the peripheral sensory nerves (1–4, 7, 8). Although the Th2-type cytokine axis plays a central role in the altered immune response in AD, recent studies indicate the involvement of other cytokine axes in the spectrum of cytokine patterns in skin lesions of patients with AD (13–19). Accordingly, AD manifests with different symptoms in patients of different ages and races, and even at different times in the same patient. This variation in AD challenges physicians to provide a satisfactory regimen for each patient. In this review, we demonstrate the existence of multiple axes of cytokines in the development of AD in patients with various backgrounds. We begin by reviewing the subclasses of AD based on clinical observation and on biomarker patterns. Then we detail the cytokine patterns in patients with AD at different phases as well as in representative animal models for AD. We also interpret the outcomes of current biologics for AD, which corroborate the presence of multiple cytokine axes involved in the background of AD. Stratification of AD and subtype-specific cytokine profiles AD is a heterogenous disease. For decades, dermatologists have noticed that AD can be stratified into several subtypes based on clinical findings and some biomarkers such as serum IgE (20). The complexity of AD has also been confirmed by a set of multiple biomarkers (21). In this section, we summarize the characteristics of the clinical appearances and cytokine spectra of the various subtypes of AD (Fig. 2). Fig. 2. View largeDownload slide Multiple cytokine axes in AD (18). Th2-type cytokines (IL-4, IL-13 and IL-5) mediate barrier disruption and pruritus. IL-22 is a Th22/Tc22 (T22)-type cytokine and is involved in epidermal hyperproliferation that leads to acanthosis (thickening of epidermis). European patients with AD and patients with extrinsic AD tend to exhibit barrier disruption, which causes repeated allergen exposure and B-cell activation resulting in hyper-IgE levels in serum. The cytokine spectrum of patients with intrinsic AD, Asian patients with AD and pediatric patients with AD is further complicated with additional cytokine axes including Th1 (IFN-γ) and Th17 (IL-17, IL-23 and IL-19). Fig. 2. View largeDownload slide Multiple cytokine axes in AD (18). Th2-type cytokines (IL-4, IL-13 and IL-5) mediate barrier disruption and pruritus. IL-22 is a Th22/Tc22 (T22)-type cytokine and is involved in epidermal hyperproliferation that leads to acanthosis (thickening of epidermis). European patients with AD and patients with extrinsic AD tend to exhibit barrier disruption, which causes repeated allergen exposure and B-cell activation resulting in hyper-IgE levels in serum. The cytokine spectrum of patients with intrinsic AD, Asian patients with AD and pediatric patients with AD is further complicated with additional cytokine axes including Th1 (IFN-γ) and Th17 (IL-17, IL-23 and IL-19). Classification by the level of serum IgE Extrinsic and intrinsic types. AD has been categorized as extrinsic type or intrinsic type based on an increased or normal level of serum IgE, respectively, without regarding the age or gender of the patients. This classification is popular and widely accepted (Fig. 3A) (Table 1) (1, 20). Extrinsic or allergic AD includes 80% of patients with AD. It is characterized by high total serum IgE levels and the presence of specific IgE for environmental and food allergens. The extrinsic type is correlated with the presence of filaggrin mutation and accompanied by decreased skin barrier function. Skin barrier dysfunction leads to facilitated/repeated percutaneous sensitization to external stimuli and allergens resulting in high serum IgE. Thus, extrinsic AD is a prototype of skin damage-induced Th2-type dermatitis. Patients with extrinsic AD are at risk for eventual age-dependent progression (atopic march) including the development of other disorders such as food allergies, allergic rhinitis and allergic asthma (20, 22). Table 1. Characteristics of extrinsic and intrinsic AD Characteristic Extrinsic AD Intrinsic AD Frequency 80% 20% Serum IgE Elevated Normal Prevalence of filaggrin mutation High Normal Incidence (male:female) 1:1 1:3–4 Onset Early Relatively late Skin barrier Disrupted Normal Immunological feature Th2 dominant Th1 dominant Metal allergy Not related High prevalence Characteristic Extrinsic AD Intrinsic AD Frequency 80% 20% Serum IgE Elevated Normal Prevalence of filaggrin mutation High Normal Incidence (male:female) 1:1 1:3–4 Onset Early Relatively late Skin barrier Disrupted Normal Immunological feature Th2 dominant Th1 dominant Metal allergy Not related High prevalence View Large Table 1. Characteristics of extrinsic and intrinsic AD Characteristic Extrinsic AD Intrinsic AD Frequency 80% 20% Serum IgE Elevated Normal Prevalence of filaggrin mutation High Normal Incidence (male:female) 1:1 1:3–4 Onset Early Relatively late Skin barrier Disrupted Normal Immunological feature Th2 dominant Th1 dominant Metal allergy Not related High prevalence Characteristic Extrinsic AD Intrinsic AD Frequency 80% 20% Serum IgE Elevated Normal Prevalence of filaggrin mutation High Normal Incidence (male:female) 1:1 1:3–4 Onset Early Relatively late Skin barrier Disrupted Normal Immunological feature Th2 dominant Th1 dominant Metal allergy Not related High prevalence View Large Fig. 3. View largeDownload slide Simplified features of AD subsets. The size of cells indicates relative activity of T cells. (A) Th2 and Th22 cells are highly activated in both extrinsic and intrinsic AD (1, 20). Expression of filaggrin (FLG) is decreased and the barrier is dysfunctional in the extrinsic type, in which repeated allergen exposures lead to secretion of IgE by activated B cells. The barrier is normal in the intrinsic AD, which is characterized by a high frequency of metal allergy and activation of Th17 and Th1 cells. (B) Acute lesions start with IL-22/IL-17-mediated triggers for epidermal hyperplasia in association with epidermal S100 proteins, such as S100A7, S100A8 and S100A9. Activation of Th2/Th22 cytokine axes and a lesser activation of Th1/Th17 cytokines are detected in acute lesions. Chronic lesions are characterized by an intensification of this immune activation without switching to other cytokine axes. (C) Pediatric AD is characterized by acute eczematous lesions on the extensor side of the body (3). Recent transcriptomic analysis revealed multiplex activation of Th2, Th22, Th17, Th1 cells and Th9 cells. IL-4/IL-13 and IL-17 produced by Th2 and Th17 cells, respectively, operate on keratinocytes to induce IL-19, which in turn induces keratinocyte proliferation and skewing toward a Th2-type immune reaction (23). IL-19 is one of the key molecules in the pathogenesis of psoriasis. Thus, the initial phase of pediatric AD seems complex and not just an acute phase of the eczematous reaction (23). In adolescent and adult patients with AD, flexor areas are affected showing significant acanthosis (thickening of epidermis) called lichenification (3). Skin lesions in adults with AD is characterized by Th2/Th22 cytokine axes with a lesser contribution of Th1 and Th17 axes (23). (D) Asian AD shows multiple axes of cytokines provided by activated Th17 and Th1 cells superimposed on the highly activated Th2 and Th22 cells (13). In contrast, Th2 and Th22 cells are the main producers of cytokines in European-American patients with AD (13). In the non-lesional skin in European-American patients, transcripts of Th1-related genes are increased. However, their levels do not change between non-lesional and lesional skin (13). (E) An extensive analysis of serum biomarkers revealed four clusters of AD subtypes (21). Attempts to stratify AD will lead to development of precision medicine. Fig. 3. View largeDownload slide Simplified features of AD subsets. The size of cells indicates relative activity of T cells. (A) Th2 and Th22 cells are highly activated in both extrinsic and intrinsic AD (1, 20). Expression of filaggrin (FLG) is decreased and the barrier is dysfunctional in the extrinsic type, in which repeated allergen exposures lead to secretion of IgE by activated B cells. The barrier is normal in the intrinsic AD, which is characterized by a high frequency of metal allergy and activation of Th17 and Th1 cells. (B) Acute lesions start with IL-22/IL-17-mediated triggers for epidermal hyperplasia in association with epidermal S100 proteins, such as S100A7, S100A8 and S100A9. Activation of Th2/Th22 cytokine axes and a lesser activation of Th1/Th17 cytokines are detected in acute lesions. Chronic lesions are characterized by an intensification of this immune activation without switching to other cytokine axes. (C) Pediatric AD is characterized by acute eczematous lesions on the extensor side of the body (3). Recent transcriptomic analysis revealed multiplex activation of Th2, Th22, Th17, Th1 cells and Th9 cells. IL-4/IL-13 and IL-17 produced by Th2 and Th17 cells, respectively, operate on keratinocytes to induce IL-19, which in turn induces keratinocyte proliferation and skewing toward a Th2-type immune reaction (23). IL-19 is one of the key molecules in the pathogenesis of psoriasis. Thus, the initial phase of pediatric AD seems complex and not just an acute phase of the eczematous reaction (23). In adolescent and adult patients with AD, flexor areas are affected showing significant acanthosis (thickening of epidermis) called lichenification (3). Skin lesions in adults with AD is characterized by Th2/Th22 cytokine axes with a lesser contribution of Th1 and Th17 axes (23). (D) Asian AD shows multiple axes of cytokines provided by activated Th17 and Th1 cells superimposed on the highly activated Th2 and Th22 cells (13). In contrast, Th2 and Th22 cells are the main producers of cytokines in European-American patients with AD (13). In the non-lesional skin in European-American patients, transcripts of Th1-related genes are increased. However, their levels do not change between non-lesional and lesional skin (13). (E) An extensive analysis of serum biomarkers revealed four clusters of AD subtypes (21). Attempts to stratify AD will lead to development of precision medicine. About 20% of AD cases are classified as intrinsic or non-allergic type, which is characterized by normal levels of total IgE, absence of allergen-specific IgE and poor infiltration of eosinophils in the skin (20). It should be noted that the term ‘non-allergic’ does not correctly express the pathogenesis of intrinsic AD (20). ‘Intrinsic’ does not mean that patients of this type are sensitized with endogenous or self-antigens. Rather, the Th2 cells are highly activated by extrinsic stimuli such as metal ions and haptens (small molecules capable of binding to proteins and changing their immunogenicity). Intrinsic AD shows peculiar characteristics such as female predominance, delayed onset and reduced disease severity (20). Barrier function is normal as measured by transepidermal water loss and skin surface hydration. Prevalence of filaggrin mutation is not increased in contrast to the extrinsic type. And the risk of an atopic march is lower in intrinsic AD (20). Instead, there is a high prevalence of metal allergy, indicating that intrinsic AD patients are susceptible to allergic contact dermatitis (ACD) or that intrinsic AD results from chronic metal allergy. Although the intrinsic type shows relatively lower levels of IL-4 and IL-13 in comparison with extrinsic, levels of IL-5 and IL-13 are increased, indicating the presence of Th2-type immune activation (20). Nevertheless, peripheral blood lymphocytes from patients with the intrinsic type contain more IFN-γ+ T cells than those from patients with the extrinsic type. Therefore, dermatitis in the intrinsic type seems to be driven by Th2- and Th1-type cytokine axes (20). Alternative definitions of extrinsic/intrinsic AD. The authenticity of the extrinsic/intrinsic classification has been argued by some investigators. The term ‘atopy’ originally meant a personal or familial tendency to produce IgE antibodies in response to low doses of allergens (24). Accordingly, a condition where (serum) IgE does not increase is technically ‘not atopic’. However, with the current state of art, little is known about the precise role of IgE in the pathogenesis of atopy. To avoid this inconsistency in naming, extrinsic and intrinsic types are classified using other terms, including the following: ‘IgE-associated atopic eczema/dermatitis syndrome (AEDS)’ and ‘T cell-associated AEDS’; ‘allergic AD’ and ‘non-allergic AD’; or ‘atopic eczema’ and ‘non-atopic eczema’ (24). These terms also involve inconsistency in themselves, and may be misleading as well. For example, T cells are associated in the pathogenesis of IgE-associated AEDS. Some propose a term ‘atopiform dermatitis’, which stresses a distinction between different subpopulations, excluding certain conditions from the diagnosis of AD (24). This classification is reasonable because AD is composed of diseases with different pathogenesis. However, it is currently difficult to discriminate the underlying pathogenesis by clinical findings for most of the patients. The problems in diagnosis and classification of AD originate, at least partially, from terminology and lack of criteria to separate subpopulations of the disease. These controversies may reflect that studies of AD are entering a new era. Transcriptomic difference between acute and chronic lesions of AD in adults There are acute and chronic lesions within the same patient. However, the cytokines that govern the onset of new or acute lesions and the maintenance of chronic lesions are not understood well. Gittler et al. (15) investigated intrapersonal sets of transcriptomes from non-lesional skin and from acute and chronic lesions obtained from adult patients with AD [n = 10 (4 men and 6 women), mean age of 43.5 years (range 20–67), race not provided]. In this study, ‘bona fide acute’ lesions were distinguished from ‘acute on chronic’ lesions by the following criteria: (i) new lesions of <72 h duration; (ii) lack of lichenification; and (iii) lack of regenerative hyperplasia as defined by an epidermal thickness of 150 µm or less and basal or confluent supra-basal keratin-16 positivity. Furthermore, no systemic or topical treatments were done for 4 or more weeks before biopsy. For comparison, skin biopsy specimens from healthy volunteers and patients with psoriasis were used. The onset of acute lesions features an abrupt increase of transcription for S100A7, S100A8 and S100A9. These transcripts encode a subset of terminal differentiation proteins of keratinocytes and can be induced by IL-17 and IL-22. Acute lesions were also characterized by transcriptomic increases in Th22 and Th2 cytokines (including itch-inducing IL-31) and a smaller increase in IL-17 levels (15). A lesser but significant induction of Th1-associated genes, such as IL-8, IL-1β and IFN-α, was detected as well (15). The chronic lesions featured progressive activation of Th2 and Th22, as well as Th1, pathways and S100A7, S100A8 and S100A9 transcripts (15). Small increases of the Th1-related genes, such as IFN-γ, CXCL9, CXCL10 and CXCL11, became more evident in the chronic lesions (15). It is not clear if these up-regulated Th1-related transcripts represent a pro-inflammatory stimulus for Th17/Th22 T cells as proposed in psoriasis or counter-regulation against the Th2 and Th17 activation (25–27). Levels of IL-17-related genes were higher than those in non-lesional skin. However, their magnitudes were similar between acute and chronic lesions (15). In summary, acute lesions starts with (i) IL-22/IL-17-mediated triggers for epidermal hyperplasia in association with epidermal S100 proteins, (ii) activation of Th2/Th22 cytokine axes and (iii) a lesser activation of Th1/Th17 cytokines with unknown function. Chronic lesions are characterized by an intensification of this immune activation without a switch of the cytokine axes. In contrast to the patients with psoriasis, the magnitude of Th17/IL-17-induced gene products in patients with AD is much attenuated except for S100 proteins. Differences between pediatric and adult patients with AD Age-dependent transition of skin lesions and peripheral blood phenotype. The morphology and distribution of skin lesions changes depending on patient age (3). In general, the appearance of skin lesions indicates a transition from a state of acute eczematous reaction to the chronic phase (Fig. 3B). Yet analysis of cytokine profiles indicates the presence of a more complex form of dermatitis, which cannot be simply explained by chronicity. Pediatric patients with AD show acute eczematous lesions, which tend to be distributed on the face, trunk and limbs (Fig. 3C, left) (3). Adolescent patients with AD start to show signs of chronicity such as lichenification (thickened epidermis) at flexures (Fig. 3C, right) (3). Adult patients with AD frequently present with extensively itchy papules described as prurigo (3). The transition of these clinical features may take place against a background of changing immunological skewing. For example, a study showed that the immunophenotype of peripheral blood lymphocytes changes from a Th2-dominant pattern in infants with AD [n = 21 (11 girls and 8 boys), mean age of 25 months (range, 5–70), Asian 5, Black 2, White 12] into a state superimposed with Th22/Tc22 (T22) cytokines in adults with AD [n = 42 (18 women and 24 men), mean age of 39 years (range, 19–66), Asian 3, Black 6, White 33] (Fig. 3C, bottom) (28). The complex cytokine spectrum of pediatric patients with AD. As a patient gets older, the cytokine pattern in peripheral blood tends to change from a Th2-dominated type to double-cytokine axes comprising Th2 and T22 types. Here, ‘T22’ means IL-22-producing lymphocytes including CD4+ T (Th22) cells and CD8+ T (Tc22) cells. This transition of the cytokine spectrum from a simple Th2 axis to a Th2/T22 double axes may simply reflect the exaggerated acute responses on the background of chronicity of the disease. However, skin lesions of infants with AD show an unexpectedly complex cytokine patterns that include Th2, Th1, Th17, T22 and Th9 (Fig. 3C, left) (23). A complex phenotype of pediatric AD has been revealed by a comparison between the skin of pediatric [within 6 months of disease onset, n = 19 (8 girls and 11 boys), mean age of 1.3 years (range 0.3–5.0), Asian/Pacific Islander 2, African American 5, Hispanic 4, White 8] and adult [n = 15 (8 women and 7 men), mean age of 51.4 years (range 33–72), White 15] patients with AD (23). As a disease control, lesional skin of adult patients with psoriasis vulgaris [a Th17-centered chronic skin disease, n = 10 (4 women and 6 men), mean age of 51.3 years (range 30–64), White 10] was analyzed in this study (23). On the continuous activation of Th2 (IL-13, IL-31 and CCL17) and T22 (IL-22 and S100As) axes, some Th1 skewing (IFN-γ and CXCL10), induction of cytokines and antimicrobial peptides of the Th17 type (IL-17A, IL-19, CCL20, LL37 and peptidase inhibitor 3/elafin), Th9 (IL-9), IL-33 (an IL-1 family cytokine activating Th2-type responses) and innate markers (IL-1β, IL-8 and IFN-α1) were expressed more highly in children with AD (23). Non-lesional skin in these patients was also abnormal, showing epidermal proliferation and higher levels of IL-17A, IL-19 and LL37 as well as epidermal proliferation markers (keratin 16 and S100As) (23). Increased IL-19 levels indicated a possible link between Th2 and Th17 activation in pediatric AD (23). IL-19, a member of the IL-10 family of cytokines, is induced by both IL-17 and IL-4/IL-13 and amplifies the effects of IL-17 on keratinocytes (29, 30). These findings indicate a state of multipolarity of T-cell skewing in pediatric AD. Filaggrin expression was similar in children with AD and healthy children, indicating a smaller contribution of the skin barrier defect in children with AD (23). The normal skin barrier function is suggestive of intrinsic AD but, unlike the intrinsic type, infantile AD is not correlated with gender or metal allergy. In consistent with low but significant activation of Th17-related genes, pediatric AD showed phenotypic similarities to psoriasis in view of activated inflammatory genes (23). The early phase of pediatric AD is another focus of investigation. Peripheral blood from infants and toddlers aged 0–3 years [n = 29 (11 girls and 18 boys), mean age of 14.5 months (range 4–35), Hispanic 3, Asian 5, African American 5, White 16] was compared with that from 13 children 3–6 years old [n = 13 (6 girls and 7 boys), mean age of 57.1 months (range 37–70), Hispanic 1, Asian 4, African American 3, White 5] (31). This study showed that pediatric AD was characterized by early excessive T-cell activation. A Th2 dominance (lower ratio of IFN-γ+ in CD4+ T cells) was evident in 0- to 3-year-old patients and was intensified by 3–6 years in the CLA+ (skin homing) subset. IL-13+ levels were higher in the younger AD group in both CLA+ and CLA– subsets, supporting the concurrence of non-cutaneous atopic manifestations beginning early in AD (31). Regarding B cells, children with AD [n = 27 (12 girls and 15 boys), mean age of 1.52 years (0.41–4.26), Asian 5, Black 6, White 16] and adults with AD [n = 34 (15 women and 19 men), mean age of 45.55 years (18–81), Asian 1, Black 4, White 30] were examined for their skin and peripheral blood (32). Pediatric AD showed a T-cell predominance in the skin, and lower counts of circulating CD19+CD20+ B cells in peripheral blood in comparison with age-matched children [n = 15 (8 girls and 7 boys), mean age of 2.21 years (0.97–4.93), Black 1, White 14], suggesting an altered differentiation in B cells as well (32). On the other hand, adults with AD showed Th2/Th22-centered cytokine axes with a lesser contribution of Th1 and Th17 axes in the lesional skin (23). IL-9 transcript was increased in non-lesional but, paradoxically, rather decreased in lesional skin in adult patients with AD (23). The numbers of T cells and dendritic cells were similarly increased in pediatric and adult patients with AD (23). What defines the differences in cytokine polarity between pediatric and adult AD is not clear. Neonates have decreased natural killer cell activity, lower percentages of CD4+ and CD8+ IFN-γ+ T cells, a lower proliferative response of T cells and dysregulated cytokine production, all of which may contribute to their increased risk of infection (33). Little is known about how these pediatric characteristics may contribute to pediatric AD. It seems likely, however, that AD begins as a multi-cytokine response at disease onset (31). Differences between races Racial background affects the cytokine pattern in the lesional skin of patients with AD. The prevalence of AD among adults in Japan is estimated at 7 to 10% (34, 35). The exact prevalence of AD in other races is hard to estimate (36). Several studies have shown that the prevalence of AD is increasing and that some races including Asians and Africans may be more prone to develop the disease than Caucasians (36). Furthermore, activation of Th17 cells has been observed in blood and acute AD skin lesions in Asians (Fig. 3D, right) (37). On the contrary, European-American patients with extrinsic AD did not show activation of the IL-23/Th17 axis (Fig. 3D, left) (14, 38, 39). A comparison of extrinsic-type AD between European American [n = 25 (16 men and 9 women), mean age of 45.7 years] and Asian [Japanese and Korean, n = 27 (22 men and 5 women), mean age of 29.6 years] AD patients has revealed that the Asian AD phenotype is a mixed phenotype between the AD and psoriasis vulgaris seen in the European-American population (13). In comparison with European Americans, skin lesions of Asians with AD show parakeratosis and a unique cytokine profile, such as co-activation of the Th2 and Th17 axes (13). Although Th1-related gene transcripts were detected in skin in European-American patients, the degrees of expression levels showed no difference between the non-lesional and lesional skin, suggesting that Th1 cells may not play a central role in European American AD (13). Subtypes revealed by stratification by biomarkers An attempt to stratify adult patients with AD by the serum biological markers has succeeded in identifying four clusters (Fig. 3E) (21). In this study, sera from 193 adult patients with moderate AD [n = 95 (57 women and 38 men), mean age of 30.6 years, race not provided], severe AD [n = 98 [55 women and 43 men], mean age of 31.1 years) and 30 healthy control subjects without AD [n = 30 (15 women and 15 men), mean age of 39.1 years] were analyzed for 147 serum mediators, total IgE levels and 130 allergen-specific IgE levels. A cluster analysis of the 57 largest principal components yielded four distinct clusters of patients with AD. Cluster 1 showed more severe clinical scores and more affected areas enriched with Th2 cytokines with the highest levels of TARC, pulmonary and activation-regulated chemokines (PARC), tissue inhibitor of metalloproteinases 1 (TIMP1) and soluble CD14. Cluster 2 had milder clinical scores with the lowest levels of IFN-α, TIMP1 and vascular endothelial growth factor (VEGF). Regulated on activation normal T cell expressed and secreted (RANTES, CCL5) and tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK, TNFSF12) are also decreased. Cluster 3 had more severe clinical scores with the lowest levels of IFN-β, IL-1 and epithelial cytokines such as TSLP. Cluster 4 had milder clinical scores but the highest levels of the inflammatory markers IL-1, IL-4, IL-13 and TSLP. Multiple cytokine axes in AD and unmet needs for personalized treatment AD has been classified as a Th2-type immune disease (40). However, as we described above, gene expression analyses have revealed an unexpectedly broad spectrum of cytokine profiles attributable to Th1, Th17, T22 and Th9 cells in the skin of AD patients (13–16). This variation in cytokines depends on factors such as disease stage and the age and race of the patient. These findings indicate the contribution to some degree of atypical multi-cytokine axes in the pathogenicity of AD (17, 18). For comparison, we will review psoriasis vulgaris, a Th17-cytokine-driven inflammatory skin disease. As the success of anti-IL-17/IL-23 biologics against this condition indicates, activation of Th17/Tc17 cells plays a major role in the pathogenesis of psoriasis (41–43). For example, let us estimate the efficacy of IL-17A blockade by secukinumab. The severity of psoriasis vulgaris can be measured by the Psoriasis Area and Severity Index (PASI) score in the range of 0 (no disease) to 72 (maximal disease). PASI score is also useful in estimating the efficacy of treatments. If a patient with a PASI score of 50 achieved a reduction in the score <5 (a reduction of the score for >90%) by a treatment, the efficacy of which is defined as PASI-90. By secukinumab, 79.0% of patients with psoriasis vulgaris achieved PASI-90 at week 16 (n = 334) (41). Regarding AD, two phase 3 trials of dupilumab (an anti-IL-4 receptor α) have proven their efficacy in improvement of the symptoms of AD and reduction of the severity as scored using the Eczema Area and Severity Index (EASI) (44). Like in PASI, severity of eczematous lesion can be measured by EASI score in the range of 0 (no disease) to 72 (maximal disease). EASI-90 (a reduction of the score to <10% of the initial) was achieved in 30–36% of dupilumab-treated patients with AD (7–8% of placebo-treated patients) at week 16. These trials confirmed the central role of the Th2 axis in AD. However, the less sharp efficacy of dupilumab is in line with the hypothesis that multiple cytokine axes other than Th2 type may play accompanying roles in their own ways. The degree of contribution by non-Th2 cytokines is not clear, but can be testable by the ongoing clinical trials attempting to treat AD with biologics against non-Th2 cytokines, such as IL-1R1 (anakinra), IL-6 (tocilizumab), IL-22 (ILV-094), IL-23p40 (ustekinumab), TNF-α, IFN-γ, PDE-4 (apremilast) and NK-1R (aprepitant) (45–49). Currently, the efficacy of IL-23p40 blockade against AD is controversial, probably due to the variable composition of the patient groups (50). If the degree of contribution from each cytokine axis differs among patients, especially in Asian patients or infants with AD, personalized treatment may be required. Animal models of AD None of the currently used mouse models of AD represent all aspects of human AD features in the scope of transcriptomic analyses (51). Paradoxically, IL-23-injected mice, a psoriasis model, showed the best similarity to the human AD transcriptomic profile, although the similarity score was only 37% in gene expression (51). Still, mouse models of AD represent most of the clinical features of AD such as hyperplasia of the epidermis, decreased skin barrier function, pruritus, scratching behavior and increased serum IgE. Thus, we must be aware of the discrepancy between the transcriptomic characteristics and phenotypes of mouse models of AD when we utilize these pre-clinical animal models. Here, we summarize characteristics of several mouse models for AD with their possible relevance to human counterparts. Flaky tail mice Flaky tail mice (ma/ma Flgft/ft) have mutations in Flg (Flgft/ft) and Tmem79/Matt (Tmem79ma/ma). The skin barrier integrity is impaired in this model. These mice express a phenotype showing massively entangled or ‘matted’ hair and defective skin barrier (52, 53). Topical application of extracts of Dermatophagoides pteronyssinus (house dust mite) induces AD-like dermatitis and increased serum IgE (53). Expression levels of mRNA for IFN-γ and IL-17 are increased and the absence of IL-17A attenuates the spontaneous development of dermatitis and serum hyper-IgE in these mice (53–56). Skin inflammation is associated with expansion of IL-5-producing group 2 innate lymphoid cells (ILC2s) in skin (57). Thus, flaky tail mice have a mixed cytokine polarity of Th2, Th1 and Th17. Filaggrin-knockout mice Newborn Flg−/− mice exhibit dry scaly skin because of a lack of natural moisturizing factors (the final product of filaggrin) as often seen in patients with AD carrying loss-of-function mutation in FLG (1). In adult Flg−/− mice, however, the epidermis is well hydrated and spontaneous dermatitis did not occur under specific pathogen-free (SPF) conditions (58). Repeated percutaneous application of ovalbumin (OVA) results in exaggerated serum levels of OVA-specific IgG1 and IgE, both of which are markers for Th2-type response (58). The polarity of cytokine profiles in the skin of Flg−/− mice is not known. The epicutaneous OVA exposure model This model mimics multiple (repeated) allergen exposures, which is thought to happen in patients with AD accompanied with the skin barrier defect. Typically, BALB/c mice are epicutaneously exposed to OVA for 3-week long periods separated by 2-week resting periods. This procedure increases total and antigen-specific serum IgE and leads to a form of dermatitis with infiltrating T cells and eosinophils. Levels of mRNA for IL-4, IL-5 and IFN-γ are increased (59–62). Thickening of skin is mediated by IFN-γ, IL-4 and IL-5 (61, 62). Infiltration of T cells and that of eosinophils are primarily dependent on IL-4 and IL-5, respectively (61, 62). Both Th2 and Th1 cytokines seem to play roles in this model. Accordingly, total IgE (a marker of Th2 responses) and IgG2a (a marker of Th1 responses) rise after the second exposure week, followed by a later increase in OVA-specific IgE (62). Other cytokines such as IL-1β, TNF-α, IL-10, IL-13 and IL-12p35 also increase (62). Hapten-challenged mice A hapten is a low-molecular-weight xenobiotic chemical. It penetrates the skin and reacts chemically with self-proteins to form a complex that is recognized as a neo-antigen and that induces antigen-specific T cells in ACD (63). ACD can be simulated by the contact hypersensitivity (CHS) reaction in mice. This reaction is a cell-mediated response to epicutaneously applied haptens or allergens, the whole process of which consists of two phases. The mice are exposed to a hapten (sensitization). Typically following an intermission, mice are subjected to re-exposure (single challenge) to the hapten at a location distal to the site of sensitization (elicitation) (64). In CHS, hapten-specific type 1 CD4+ and CD8+ T cells (Th1 and Tc1 cells, respectively) act as effectors; and Th2 cells function as regulatory elements (65). However, repeated elicitation of CHS with haptens such as oxazolone and 2,4,6-trinitrochlorobenzene (TNCB) results in a different time course of inflammation, i.e. a shift in response from a delayed type to an early type, reflected as a shift in the cutaneous cytokine profile from Th1-like (IL-2, IL-3 and IFN-γ) to a Th2-like (IL-4, IL-10 and TNF-α) (66–68). This shift in reaction is accompanied by epidermal hyperplasia, massive accumulation of CD4+ T cells beneath the epidermis and elevation of antigen-specific serum IgE (66, 67, 69). This model emulates some features of human AD such as pruritus with epidermal hyperplasia and aberrant expression of differentiation proteins, filaggrin, loricrin and involucrin in the epidermis (69). NC/Nga and NC/Tnd mice NC/Nga and NC/Tnd mice spontaneously develop itchy skin lesions resembling those in AD (70, 71). These skin lesions develop between 6 and 8 weeks of age under ‘dirty’ microbiologic conditions but not under SPF conditions (70). Serum IgE levels of NC/Nga increase from 8 weeks of age in correlation with disease severity. Mast cells and IL-4-producing CD4+ T cells are increased in the skin. Th2 chemokines such as TARC and macrophage-derived chemokine (MDC) are increased in the lesions (72). The overproduction of IgE in NC/Nga is explained by defective IFN-γ production by T cells in response to IL-12 and a poor response of B cells to IFN-γ (73). Dust mite antigen-challenged mice AD-like dermatitis can be induced by application of crude extracts of Dermatophagoides farinae at a concentration of 1 or 10 mg ml−1, painted five times at 7-day intervals onto the ears of NC/Nga or BALB/c mice with or without simultaneous tape-stripping (74). The resulting ear swelling is accompanied by increased serum IgE, increased IL-4 mRNA and decreased mRNA levels for IFN-γ. IL-23-injected mice This model was originally developed to analyze the pathogenesis of psoriasis vulgaris. Intradermal injection of IL-23 results in erythema, mixed dermal infiltrates and epidermal hyperplasia associated with parakeratosis in mice (75). IL-23 induces IL-17A, IL-22, IL-19 and IL-24 expression in mouse skin, all of which are elevated in human psoriasis (75, 76). The epidermal hyperplasia is dependent on IL-17A and IL-22, but not on IL-19 and IL-24 (75, 76). The psoriasis-like phenotype of this model requires IL-6, which induces expression of IL-22R1A (77). These data implicate the importance of IL-23 and IL-22 in the pathogenesis of psoriasis. The induction of IL-17, IL-22 and IL-19 may recapitulate some features of AD, especially those seen in infant patients and Asian patients with AD. A caveat regarding mouse models To summarize, investigators should be aware of the differences between the murine AD models and human AD when translating murine data to human skin diseases. Role of regulatory T cells in AD Deficiency of FoxP3 results in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), symptoms of which include AD-like dermatitis (78). Furthermore, genome-wide association studies (GWAS) have revealed a link between allergic sensitization and eczematous traits and LRRC32 encoding the membrane protein also known as GARP (glycoprotein A repetitions predominant), which regulates TGF-β-signaling in regulatory T (Treg) cells (79, 80). However, the contribution of FoxP3+ Treg cells to AD is still controversial. Nevertheless, a study of tumor immunity provides us a clue to solve the controversy on the role of Treg cells in AD. The role of Treg cells has remained controversial in colorectal cancers, in which FoxP3+ T-cell infiltration has been associated with better prognosis in some studies but not in others. This controversy has been addressed by analyzing the subsets of FoxP3+ T cells (81). Human peripheral blood FoxP3+CD4+ T cells can be divided into three functional subpopulations by the expression of FoxP3, CD45RA and CD25 (82). FoxP3lowCD45RA+CD4+ T cells are Treg cells including CD31+ recent thymic emigrants. This population further differentiates to FoxP3highCD45RA−CD4+ Treg cells in response to antigenic stimulation ex vivo (82). These two populations have immune suppressive functions in vitro. FoxP3lowCD45RA−CD4+ T cells, in contrast, are activated effector T cells and can produce pro-inflammatory cytokines including IL-2, IFN-γ and IL-17. And it has been shown that colorectal cancers with predominant infiltration of FoxP3low (non-suppressive) T cells have better prognosis than those with predominantly FoxP3high (suppressive) Treg cell infiltration (81). The development of pro-inflammatory FoxP3low non-Treg cells depends on both the presence of IL-12 and TGF-β and invasion of intestinal bacteria, especially Fusobacterium nucleatum (81). Therefore, we speculate that an analysis of skin surface microbial features and the composition of infiltrating FoxP3+ T cells may solve the controversy over the role of Treg cells in AD. Conclusions As we have shown through the present summary, AD is a heterogenous disease (17, 18, 20, 83, 84). The majority of AD cases are of the extrinsic type, which is characterized by impaired skin barrier function. Extrinsic AD is related to other allergic diseases such as food allergy, allergic asthma and allergic rhinitis. Intrinsic AD, in contrast, is characterized by normal skin barrier function. Biomarkers and other factors such as age and race can be used to stratify AD into multiple subtypes. The massive amounts of information obtained from ‘omics’ studies have confirmed the heterogeneity of AD as previously observed by physicians. The high effectiveness of dupilumab against AD has confirmed the central role of Th2 cytokines in the conditions, but the fact that the efficacy of dupilumab against AD is lower than that of IL-17 blocking against psoriasis corroborates the heterogeneity and complexity of AD. Further study is required to enable precision treatment for AD. We expect the medical community to achieve a clearer understanding of the pathogenesis underlying AD in this era of omics and biologics. Funding This work was supported in part by the Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research (15H05790, 24591649 and 15K09765), Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research on Innovative Areas (15H1155), Japan Society for the Promotion of Science, Grant-in-Aid for challenging Exploratory Research (15K15417), Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO) (16021031300) and Japan Agency for Medical Research and Development (AMED) (16ek0410011h0003 and 16he0902003h0002). Conflicts of interest statement: the authors declared no conflicts of interest. References 1 Kabashima , K. 2013 . New concept of the pathogenesis of atopic dermatitis: interplay among the barrier, allergy, and pruritus as a trinity . J. Dermatol. Sci . 70 : 3 . 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International ImmunologyOxford University Press

Published: Mar 17, 2018

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