Fig. 21.1
AD spectrum based on extrinsic and intrinsic AD dichotomy. AD can be divided into barrier-disrupted high-IgE extrinsic type and barrier-nondisrupted normal IgE intrinsic type. Some of the patients with extrinsic AD have FLG mutations and exhibit ichthyosis vulgaris and palmar hyperlinearity. Intrinsic AD affects mainly women and shows metal allergy in a considerable percentage of patients
In AD, the extrinsic and intrinsic types began to be adopted in the late 1980s [72]. They are also called several different series of names: mixed AD versus pure AD, allergic AD versus nonallergic AD, and classical AD versus atopiform dermatitis. Historically, the intrinsic and extrinsic types appear to correspond to “pure” and “mixed” types, and the latter has concomitant respiratory allergies [9]. Because there is still no sufficient consensus whether the intrinsic type is a distinct entity, some researchers denominate it atopiform dermatitis [2]. However, the classification into the extrinsic and intrinsic AD has been widely used especially since the millennium. Recently, various kinds of clinical studies have been performed under this dichotomy in many countries, including Germany [11, 36, 56], the Netherlands [2], Hungary [47], Italy [22, 28], and other European countries and Asian countries such as Korea [45, 50] and Japan [19, 30].
The original concept of “intrinsic” type represents the nonallergic nature [36], however, the intrinsic type may also show eosinophilia. More fundamentally, both types represent eczematous dermatitis, a manifestation of the delayed-type or late-phase reaction. Therefore, the intrinsic type AD is not a simple nonallergic type, but is induced via some immunological mechanism. This chapter focuses on the differences between intrinsic and extrinsic AD to represent heterogeneous causes and barrier states in AD patients.
21.2 Definition of Extrinsic and Intrinsic AD
Extrinsic AD and intrinsic AD are defined according to IgE-mediated sensitization, namely the presence or absence of specific IgE for environmental allergens and food allergens [30, 45, 71]. Based on this fundamental concept, intrinsic AD has different features from extrinsic AD as described throughout this Chapter (Box 21.1). According to the EAACI nomenclature task force, the term “atopic eczema/dermatitis syndrome” can be used to cover the different subtypes of AD. In this nomenclature, the intrinsic type is termed nonallergic atopic eczema/dermatitis syndrome, which shows normal IgE levels, no specific IgE, no association with respiratory diseases (bronchial asthma or allergic rhinitis), and negative skin-prick tests to common aeroallergens or food allergens [73]. Inasmuch as total serum IgE values are significantly associated with the allergen-specific IgE status [40], total IgE can be regarded as a clinically useful parameter to differentiate between the extrinsic and intrinsic types in both adults [11, 30] and children [40]. The reported mean values of total serum IgE in the intrinsic type are from 22.2 to 134 kU/L, or alternatively, IgE values less than 150 or 200 kU/L have been used for an indication of intrinsic AD [60]. Our study of Japanese patients also showed that the mean value of total serum IgE was 110.5 kU/L [30] or 125 kU/L [19]. Considering the relatively higher serum IgE levels in Japanese than westerners, these mean values are very low.
Among specific IgE antibodies, infantile AD patients are more allergic to food [45], whereas environmental antigens are common in adults. It should be noted that some allergens may not be useful to discriminate the two types. For example, IgE to Malassezia sympodialis was found in patients with the intrinsic type as well as the extrinsic type [3]. IgE levels of Dermatophagoides (D) pteronyssinus (DP) and D. farinae (DF) can be used for categorization of extrinsic and intrinsic AD as well as total IgE levels [74]. Serum IgE specific to these mites is graded into seven classes (class 0–6). Intrinsic AD can be defined as serum IgE levels ≤200 kU/L or 200<IgE≤400 plus class 0 or 1 of IgE specific to DP or DF, and extrinsic AD defined as 400<IgE levels or 200<IgE≤400 plus class 2 or more of the specific IgE [74].
21.3 Box 21.1 Characteristics of Intrinsic AD
1.
Definition
Normal total serum IgE. Absence of specific IgE for environmental and food allergens
2.
Incidence
Percentage of intrinsic AD in total AD: 10–45 %
Female predominance (70–80 %)
3.
Clinical features
Dennie–Morgan fold
No ichthyosis vulgris or palmar hyperlinearity
No nonspecific hand or foot eczema
Lower colonization of Staphylococcus aureus
Relative late onset
Milder severity
4.
Skin barrier
No markedly disturbed barrier function
No high incidence of FLG mutations
5.
Immunological features
High percentage of IFN-γ–producing T cells
6.
Contact allergens
High prevalence of metal allergy (Ni and Co)
21.4 Prevalence of Extrinsic and Intrinsic AD
21.4.1 Incidence
Because extrinsic AD is the prototype of AD, dermatologists know its prevalence at their daily clinics. On the other hand, the frequency of intrinsic AD has been a matter of investigation. Schmid–Grendelmeier et al. [60] summarized the 12 reports that had been published from 1990 to 2000 and documented the clinical features of extrinsic and intrinsic AD. According to their review paper, the frequency of intrinsic AD was 10–45 %. More recently, the incidence of extrinsic AD and intrinsic AD were reported as follows: 73 % versus 27 % [40] and 63 % versus37 % [41] in German children, 88 % versus 12 % in Hungarian adults [47], 78.2 % versus 21.8 % in Dutch patients from 13 to 37 years of age [2], and approximately 80 % versus 20 % in Koreans [5]. These data are in accordance with the empirical knowledge that about 20 % of AD patients show normal IgE levels and lack of sensitization towards environmental allergens. Intrinsic AD is seen in various countries, but the prevalence may depend on local areas, as it was reported that intrinsic AD was higher in incidence in East Germany than West Germany, although the exact reason remains unclear [56].
21.4.2 Female Predominance of Intrinsic AD
Although extrinsic AD equally affects both males and females, the female predominance in intrinsic AD is well known and has been observed by a number of studies [2, 19, 28, 36, 37]. Our observation disclosed that 76.5 % of AD patients were female [30]. More extremely, 14 intrinsic AD patients enrolled in a study were all female [37].
21.4.3 Adults and Children
Extrinsic AD starts at infancy or early childhood and persists at adulthood with or without transient remission. The clinical course of intrinsic AD is an issue to be clarified. Several reports may provide an implication that the intrinsic type is seen at higher frequencies in children than adults [19]. A Korean group of AD investigators showed that the intrinsic type is more prevalent in infancy, and even the third group of the indeterminate type between the intrinsic and extrinsic ones can be identified in this younger generation [45]. A prospective birth cohort study followed for 5 years by a German group demonstrated that one third of child AD was the intrinsic one, and more common in females [24]. Another German group indicated the low prevalence of the intrinsic AD among adult patients [11]. They showed 6.9 % patients fulfilled the criteria of intrinsic AD, and after follow-up, the incidence was declined to 5.4 % because some patients developed respiratory allergies or IgE-mediated sensitizations. These observations may suggest that the intrinsic type is more prevalent in children than adults.
However, it should be noted that a considerable number of the above infantile or juvenile intrinsic AD patients possibly develop the extrinsic type as they grow and show high levels of serum IgE. Furthermore, the later onset was reported to be a feature of intrinsic AD [2]. It is tempting to speculate that the juvenile IgE-normal AD group contains two types, the genuine intrinsic AD and the IgE level-normal stage of extrinsic AD. In addition, it appears that a part of adult intrinsic AD may occur or deteriorate after high school age in Japan.
21.5 Clinical Features of Extrinsic and Intrinsic AD
The skin manifestations of the two types of AD are indistinguishable. As described below, however, a part of extrinsic AD patients have filaggrin (FLG) gene mutations; they may exhibit ichthyosis vulgaris (or severe dry skin) and palmar hyperlinearity (Fig. 21.1). Keratosis pilaris, pityriasis alba, and nonspecific hand or foot eczema are the features of extrinsic AD.
Intrinsic AD shares the vast majority of features with extrinsic AD. However, Brenninkmeijer et al. extensively studied the clinical features of intrinsic AD [2] and found that the Dennie–Morgan fold is significantly more often present in the intrinsic type. The later onset of disease and milder disease severity are also characteristics of intrinsic AD. The features that are negatively associated with intrinsic AD include personal or family history of atopy, recurrent conjunctivitis, palmar hyperlinearity, keratosis pilaris, pityriasis alba, nonspecific hand or foot eczema, and influence of emotional or environmental factors [6]. As mentioned below, some of these nonassociated features are considered to stem from the lack of barrier disruption and/or filaggrin gene mutations in intrinsic AD.
21.6 Skin Barrier Function in Extrinsic and Intrinsic AD
21.6.1 Barrier Function of Stratum Corneum and Pruritus Perception
The barrier function is usually assessed by transepidermal water loss (TEWL) and skin surface hydration (capacitance). Extrinsic AD patients have increased TEWL and lower skin surface hydration, whereas intrinsic AD patients have comparable levels of TEWL and skin surface hydration to those of healthy subjects [5]. On the antecubital fossae, both types of AD patients have higher TEWL and decreased capacitance. We examined the skin surface hydration and TEWL at the nonlesional forearm and lower leg of patients and normal volunteers in a comparison between the extrinsic and intrinsic types [30]. The level of skin surface hydration was significantly lower in extrinsic AD than in normal control subjects. On the other hand, there was no significant difference in the hydration level between intrinsic AD and healthy control. The extrinsic type tended to be lower than the intrinsic type at both sites. Thus, the skin barrier function was impaired in extrinsic AD and relatively preserved in intrinsic AD. The barrier impairment induces allergic responses to external antigen in extrinsic AD (Fig. 21.2).
Fig, 21.2
Basic concept of extrinsic AD. In extrinsic AD, barrier impairment, which is typically associated with FLG mutations, induces allergic responses to external antigens, especially protein allergens. Langerhans cells (LCs) serve as antigen-presenting cells to protein antigens, and serum IgE is elevated as a result of Th2 responses
The skin perception threshold of electric current stimuli is one of the indices of itch. The electric current perception threshold significantly correlates with the skin surface hydration and inversely with TEWL in intrinsic AD patients as well as healthy individuals. In contrast, extrinsic AD patients do not exhibit such a correlation. Therefore, intrinsic AD patients retain the normal barrier function and sensory reactivity to external pruritic stimuli [73].
21.6.2 High and Low Frequencies of FLG Mutations in Extrinsic and Intrinsic AD, Respectively
The recent identification of loss-of-function mutations in FLG as a widely replicated major risk factor for eczema sheds new light on the mechanisms of AD [43]. These mutations also represent a strong genetic predisposing factor for atopic eczema, asthma, and allergies in various countries [35]. Profilaggrin is the major component of the keratohyalin granules within epidermal granular cells. During epidermal terminal differentiation, the profilaggrin polyprotein is dephosphorylated and rapidly cleaved by serine proteases, such as kallikrein-5 [54], to form monomeric FLG, which is further degradated into natural moisturizing factor (Fig. 21.3). Perturbation of the skin barrier function as a result of reduction or complete loss of FLG expression leads to enhanced percutaneous transfer of allergens (Fig. 21.2). The association of the FLG mutations in particular with the extrinsic type of AD was observed [19, 69].
Fig. 21.3
Profilaggrin processing. FLG gene product profilaggrin is cleaved by processing enzymes at the linker site [28] and then degraded into FLG monomer, which is further converted to NMF
Furthermore, FLG mutations are significantly associated with palmar hyperlinearity in patients with AD (Fig. 21.1), which represents a shared feature of AD and ichthyosis vulgaris (Fig. 21.1). This is in accordance with the finding that palmar hyperlinearity is negatively associated in the intrinsic type [2, 19]. We investigated FLG mutations in IgE-high and IgE-normal Japanese AD patients. Although 5–9 % of IgE-normal AD cases had FLG mutations, about 33–44 % IgE-high patients possessed FLG mutations [19, 74], suggesting that FLG mutations are less prevalent in the IgE-normal group (normal controls, 3.7 %). In the IgE-high patients, there was no statistical difference in SCORAD or IgE level between the FLG mutation-bearing and FLG mutation-lacking patients. It has also been reported that FLG mutations predispose to early-onset and extrinsic AD [70].
21.7 Characteristics of T Cells, Cytokines/Chemokines, and Dendritic Cells (DCs) in Extrinsic and Intrinsic AD
21.7.1 Th1 and Th2 Cells
AD is well known as a Th2-polarized disease. However, some differences in systemic cytokine polarization between the two types of AD have been reported. As expected with elevated total serum IgE, extrinsic AD patients show high levels of Th2 cytokines, such as IL -4, IL-5, and IL-13, and intrinsic AD is linked with much lower levels of IL-4 and IL-13 [28]. Along with the elevation of IL-5 [33, 48], eosinophil counts [45] and eosinophil cationic protein levels [41] are increased in extrinsic AD. On the other hand, there was a report demonstrating that both extrinsic and intrinsic patients showed increased production of IL-5 and IL-13 [61]. In that study, however, when peripheral blood mononuclear cells were stimulated with anti-CD3 antibody, extrinsic AD patients had a decreased capacity to produce interferon -γ (IFN-γ) and GM-CSF as compared to the intrinsic AD [61]. The apoptosis of circulating memory/effector Th1 cells is confined to extrinsic AD patients, whereas intrinsic AD patients show no evidence for enhanced T-cell apoptosis in vivo [1].
Circulating IFN-γ+ T cell frequency was higher in intrinsic than extrinsic AD in our study [19]. In addition, although not statistically significant, there was a tendency that the frequencies of circulating IL-4+ or IL-5+ Th2 cells were higher in extrinsic AD than in intrinsic AD. Intrinsic AD may have a less Th2-skewing state and rather shows a high expression level of IFN-γ (Fig. 21.4). The overproduction of IFN-γ may further downregulate IgE production in intrinsic AD, as suggested by our in vitro study [19].
Fig. 21.4
Differences between extrinsic and intrinsic AD in the barrier status and immune responses. In extrinsic AD, the impaired stratum corneum barrier allows protein antigen to penetrate through the skin. The external stimuli via the impaired barrier also stimulate keratinocytes to produce TSLP, which subsequently renders LCs to serve as antigen-presenting cells to Th2 cells. In intrinsic AD, nonprotein antigens, such as metals and haptens, can penetrate and function as antigen through the unimpaired barrier
In the skin lesions, eosinophils infiltrate the dermis more markedly in the extrinsic than the intrinsic type, and the extrinsic type exhibits more prominent deposition of eosinophil granular protein and higher staining for eotaxin [23, 50]. Although the levels of mRNA expression for IL-5, IL-13, and IL-1β are higher in both types of AD patients than nonatopic subjects, extrinsic AD shows even higher levels than intrinsic AD [23]. The expression of IFN-γ, IL-12, and GM-CSF, IL-4, and IL-10 are elevated without differences between extrinsic and intrinsic AD [1]. However, a recent study using lesional skin showed that higher activation of all inflammatory axes, including Th2, was seen in patients with intrinsic AD [62], suggesting an important role of Th2 cells in the development of intrinsic AD lesions as well as extrinsic AD lesions.
21.7.2 Th17 Cells
We found that Th17 cells, producing IL -17A and IL-22, were increased in the peripheral blood of AD, and Th17 cells infiltrated the acute skin lesions more markedly than in the chronic lesions [20]. There was a tendency that the frequency of circulating Th17 cells was higher in intrinsic AD than in extrinsic AD [19]. In the lesional skin, another group of investigators reported that positive correlations between Th17-related molecules and SCORAD scores were only found in patients with intrinsic AD, whereas only patients with extrinsic AD showed positive correlations between SCORAD scores and Th2 cytokine (IL-4 and IL-5) levels [62]. In AD, the acute skin lesion corresponds to the late phase reaction evoked by Th2 cells and eosinophils, whereas the chronic skin lesion corresponds to the delayed-type hypersensitivity induced by Th1/Tc1 cells [42]. Because Th17 cells already exist in the Th2-associated acute lesions, they seem to disappear gradually in the progression to the chronic lesion where Th1/Tc1 cells infiltrate.
21.7.3 Chemokines and Others
With regard to chemokines, patients of both types showed high serum amounts of CCL 17/TARC and CCL22/MDC and high peripheral blood mononuclear cell expression of CCL17 and CCL22 at comparable levels [44]. We investigated serum CCL17/TARC levels in extrinsic and intrinsic patients. Both groups had higher levels of serum CCL17 than healthy controls. However, its value was significantly higher in extrinsic than intrinsic AD [19, 42]. The blood levels of soluble receptors derived from lymphocytes correlate to the activity in various diseases. There is no significant difference in the elevated amounts of sCD23, sCD25, and sCD30 between the two types [68].
21.7.4 Dendritic Cells (DCs) and Langerhans Cells (LCs)
DCs as well as CD4+ and CD8+ T cells are comparably increased in both extrinsic and intrinsic AD. The extrinsic type is characterized by a significantly high level of the expression of IgE high-affinity receptor (FCεR) on the CD1a+ DCs compared to the intrinsic type [36, 39]. When the high-affinity/low-affinity expression ratio was used as a disease marker for AD, the values for intrinsic AD fell below the diagnostic cut-off level, suggesting that intrinsic AD can be distinguished by phenotyping of epidermal LCs [36, 39]. In accordance with these data from the lesional skin, the surface expression of the high- and low-affinity receptor for IgE and the IL-4Rα chain are significantly elevated in circulating monocytes from extrinsic AD patients [52].
As described below, it is possible that epidermal LCs in the barrier-disrupted skin produce high amounts of Th2 and eosinophil chemokines. Recent accumulating evidence indicates that upon external stimulation, epidermal keratinocytes produce thymic stromal lymphopoietin (TSLP) , which stimulates LCs possessing TSLP receptors (Fig. 21.4) [18]. Protein antigen is more essential than hapten as the cause of extrinsic AD. Upon the epicutaneous application of ovalalbumin (OVA), conditional LC depletion attenuated the development of clinical manifestations as well as serum OVA-specific IgE increase, OVA-specific T-cell proliferation, and IL-4 mRNA expression in the draining lymph nodes [32]. Consistently, even in the steady state, permanent LC depletion resulted in decreased serum IgE levels, suggesting that LCs mediate the Th2 local environment. In addition, mice deficient in TSLP receptors on LCs abrogated the induction of OVA-specific IgE levels upon epicutaneous OVA sensitization [32]. Thus, LCs initiate epicutaneous sensitization with protein antigens and induce Th2-type immune responses via TSLP signaling, further suggesting that LCs play a mandatory role in extrinsic AD.
21.8 Relationship Between Barrier Status and Skin Immune Responses in Extrinsic AD
21.8.1 Epidermal Cytokine Production in Barrier-Disrupted Skin
The skin immune status is closely associated with the disordered condition of the skin barrier (Fig. 21.4). Studies using a mouse model of contact hypersensitivity (CHS) have shown that CHS responses to hapten are increased when a hapten is applied to the barrier-damaged skin [34]. Barrier disruption of the skin is experimentally performed by extraction of epidermal lipids with acetone or removal of corneocytes by tape stripping. Both procedures can induce elevated CHS responses. Not only increased permeability of hapten through the epidermis but also altered immune functions of epidermal cells potentiate T-cell activation in acute barrier disruption [34]. Such augmentation of immune reactivity may be critical to elimination of environmental noxious agents that penetrate easily into the barrier-disrupted epidermis, and it is also closely related to the mechanism underlying extrinsic AD.
21.8.2 Epidermal Chemokine Production in Barrier-Disrupted Skin
Regarding epidermal chemokines of the barrier-disrupted skin, the mRNA expression levels of Th1 chemokines (CXCL10, CXCL9, and CXCL11), Th2 chemokines (CCL17 and CCL22), and eosinophil chemoattractant (CCL5) are high in the epidermal cells from Th2 response-prone mice. In particular, we found that CCL17, CCL22, and CCL5 were remarkably elevated in BALB⁄c mice [38]. Tape stripping induced dermal infiltration of eosinophils in BALB⁄c mice, and the late-phase reaction was increased with infiltration of Th2 cells as well as eosinophils, when challenged via the tape-stripped skin. Notably, Th1 chemokines (CXCL9 and CXCL10) and Th2 chemokines (CCL17 and CCL22) are derived mainly from keratinocytes and LC, respectively [31]. Therefore, it is likely that LCs serve not only as protein antigen-presenting cells [32] but also as a Th2-attracting chemokine source [31].
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