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Skin manifestations of elderly AD: extrinsic form, Cases 1–3; intrinsic form, Case 4 (a) Lichenified eczema on the upper back (Case 1). (b) Facial erythema (atopic red face) with Hertogh’s sign (loss of lateral eyebrows) and Dennie-Morgan infraorbital folds (Case 2). (c) Dirty neck (Case 2). (d) Lichenified eczema around the scarcely involved elbow fold (reverse sign) (Case 2). (e) Eczematous erythroderma (Case 3). (f) Eczematous lesions mostly disappeared after successful treatment and the cured skin shows a normal appearance (Case 3). (g) Lichenified eczema of erythroderma on the trunk and neck (Case 4).
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Background/Objectives
Atopic dermatitis (AD) in the elderly is gradually increasing in industrialized countries in association with the aging of society. We report herein four cases of elderly AD {three extrinsic [immunoglobulin (Ig)E-mediated allergy]; one intrinsic (non-IgE-allergy)} in which we investigated the presence of IgE+ cells in lesional...
Contexts in source publication
Context 1
... 1 A 79-year-old man with hypertension, chronic kidney disease and senile depression complained of chronic eczema for 3 years. He showed mild eczematous dermatitis on the face and upper extremities and significant lichenified eczema on the nape and upper back (Fig. 1a). He also showed symptomatic allergic conjunctivitis, but had no family history of atopic ...
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... associated with allergic rhino-conjunctivitis was referred to our department with generalized erythroderma. He had a history of chronic eczema until 5 years old that matched the classic course of childhood AD, but no family history of atopic disorders was apparent. He showed facial erythema with Hertogh's sign and Dennie-Morgan infraorbital folds (Fig. 1b), dirty neck (Fig. 1c) and diffuse lichenified eczema on the trunk and extremities. Liche- nified eczema at the flexural sites of the upper extremities was mainly observed around the unaffected elbow folds (reverse sign) 1,2 (Fig. ...
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... rhino-conjunctivitis was referred to our department with generalized erythroderma. He had a history of chronic eczema until 5 years old that matched the classic course of childhood AD, but no family history of atopic disorders was apparent. He showed facial erythema with Hertogh's sign and Dennie-Morgan infraorbital folds (Fig. 1b), dirty neck (Fig. 1c) and diffuse lichenified eczema on the trunk and extremities. Liche- nified eczema at the flexural sites of the upper extremities was mainly observed around the unaffected elbow folds (reverse sign) 1,2 (Fig. ...
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... atopic disorders was apparent. He showed facial erythema with Hertogh's sign and Dennie-Morgan infraorbital folds (Fig. 1b), dirty neck (Fig. 1c) and diffuse lichenified eczema on the trunk and extremities. Liche- nified eczema at the flexural sites of the upper extremities was mainly observed around the unaffected elbow folds (reverse sign) 1,2 (Fig. ...
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... man with chronic eczema lasting 7 months was admitted to our department for erythrodemic eczematous rash. He had occasionally experienced chronic eczema since 29 years old, but had no personal or family history of atopic disor- ders. He showed facial erythema with Hertogh's sign, and diffuse lichenified eczema on the trunk and extremities (Fig. 1e). He was treated with topical corticosteroids and moisturizer, and antihista- mines, a T-helper (Th)2 cytokine inhibitor (suplatast tosi- late,150 mg ⁄ day) and systemic corticosteroids (prednisolone, 15 mg ⁄ day) were administered. After 2 years of treatment, oral corticosteroids and Th2 cytokine inhibitor were discontinued after ...
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... tosi- late,150 mg ⁄ day) and systemic corticosteroids (prednisolone, 15 mg ⁄ day) were administered. After 2 years of treatment, oral corticosteroids and Th2 cytokine inhibitor were discontinued after tapering of therapeutic doses. After 10 years of therapeutic man- agement, most of the lesions had disappeared, replaced by nor- mal-appearing skin (Fig. 1f). At this time, serum total IgE levels had decreased to within normal ranges and specific IgE was unde- ...
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... 4 An 81-year-old woman with a 7-year history of chronic eczema was referred to our departments with severe generalized erythroderma (Fig. 1g). She also showed facial pallor and the reverse sign of lichenification around the folds of the elbows and knees. She had experienced intrinsic asthma since she was 68 years old and reported family histories of asthma in her mother and aspirin-related urticaria in her ...
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... However, the contribution of IgE-positive cells in skin lesions of elderly AD allergen-specific IgE to the eczematous lesion remains controver- sial. 10 The present study used immunohistochemical and double immunofluorescence studies to demonstrate numerous IgE- bearing cells in the inflammatory infiltrate of lichenified lesions in the extrinsic (IgE-allergic) form of elderly AD (Cases 1-3). The majority of infiltrating IgE+ cells were either mast cells or CD11c+ dermal dendritic cells. ...
Citations
... In mast cells and basophils, allergen-induced crosslinking of bound IgE elicits release of pre-formed inflammatory mediators, e.g., histamine [7]. Dendritic cells expressing FcεRI are increased in AD patients [41,42], and dendritic cells in lesional skin of both humans and canines bind IgE [43,44]. Activation of FcεRI-expressing dendritic cells stimulates newly activated naive T H cells along the T H 2 differentiation pathway, amplifying the T H 2 response [45]. ...
Atopic dermatitis is a chronic relapsing dermatopathology involving IgE against allergenic materials present on mammalian epithelial surfaces. Allergens are as diverse as pet danders, and polypeptides expressed by microbes of the mammalian microbiome, e.g., Malassezia spp. The Acari Hypothesis posits that the mammalian innate immune system utilizes pathogen-bound acarian immune effectors to protect against the vectorial threat posed by mites and ticks. Per The Hypothesis, IgE-mediated allergic disease is a specious consequence of the pairing of acarian gastrointestinal materials, e.g., allergenic foodstuffs, with acarian innate immune effectors that have interspecies operability. In keeping with The Hypothesis, the IgE profile of atopic patients should include both anti-acarian antibodies and specious antibodies responsible for specific allergy. Further, the profile should inform on the diet and/or environment of the acarian vector. In this regard, the prevalence of Demodex and Dermatophagoides on the skin of persons suffering from atopic dermatitis is increased. Importantly, the diets of these mites correspond well with the allergens of affected patients. In this report, roles for these specific acarians in the pathogenesis of atopic dermatitis are proposed and elaborated.
... In addition, these IgE-expressing LCs in the epidermis are not specific to patients with IgEallergic AD, but are also found in patients with other inflammatory skin diseases involving serum hyper-IgE [57,86]. Non-lesioned skin of IgE-allergic AD patients usually exhibits no IDECs in the epidermis and no or few infiltrating IgE+ inflammatory DCs in the dermis (Figure 3a) [86,88]. In addition, histopathological analysis of non-lesioned skin revealed almost no HDM antigens captured by IgE+ LCs in the epidermis and IgE+ infiltrating cells in the upper dermis (Figure 3b) [86,89]. ...
... As mentioned above, in non-lesioned skin, IgE+ LCs are regularly arranged in preparation for allergen/antigen invasion in the epidermis, and an increase in the number of T cells expressing IL-13, IL-4, and INF-γ is observed in the dermis (Figure 4a: left-side part). In addition, IgE expression on MCs in the dermis is also increased [86,88]. These findings may be related to systemic molecular immune activation originating from the cytokine milieu of lesioned skin that feeds back to non-lesioned skin [45,79] (Figure 4b). ...
Atopic dermatitis (AD) is a chronic pruritic skin disease with a complex pathogenesis underlying its heterogeneous clinical phenotypes and endotypes. The skin manifestation of AD reflects the cytokine milieu of a type-2-dominant immunity axis induced by genetic predisposition, innate immunity dysregulation, epidermal barrier defects, and allergic inflammation. However, the detailed pathomechanism of eczematous dermatitis, which is the principal characteristic of AD, remains unclear. This review examines previous studies demonstrating research progress in this area and considers the immunological pathomechanism of "spongiotic dermatitis", which is the histopathological hallmark of eczematous dermatitis. Studies in this field have revealed the importance of IgE-mediated delayed-type hypersensitivity, the Fas/Fas-ligand system, and cell-mediated cytotoxicity in inducing the apoptosis of keratinocytes in spongiotic dermatitis. Recent studies have demonstrated that, together with infiltrating CD4 T cells, IgE-expressing dendritic cells (i.e., inflammatory dendritic epidermal cells and Langerhans cells) that capture specific allergens (i.e., house dust mites) are present in the spongiotic epidermis of lichenified eczema in patients with IgE-allergic AD. These findings suggest that IgE-mediated delayed-type hypersensitivity plays a pivotal role in the pathogenesis of spongiotic dermatitis in the skin lesions of AD.
... Moreover, the increasing predisposition of late AD development in older adults is due to exposure-induced epidermal barrier malfunction and immunosenescence-caused chronic itch in advanced age. The core of AD is skin inflammation involving IgE produced by B cells and inflammatory mediators of T-cell origin, while Th2 cytokines dominate in the inflammation milieu (Tanei, and Hasegawa, 2016;Tanei, et al., 2013). Th2/Th22 cytokines in skin increase during aging in healthy individuals, while the opposite phenomenon is observed in older AD patients (Bocheva, et al., 2021;Gittler, et al., 2012). ...
Skin-resident stromal cells, including keratinocytes, fibroblasts, adipocytes, and immune cells including Langerhans cells, dendritic cells, T cells, and innate lymphoid cells, and their functional products work in concert to ensure the realization of skin barrier immunity. However, aging-induced immunosenescence predisposes the elderly to pruritic dermatoses, including type 2 inflammation-mediated. Inflammaging, characterized by chronic low level of pro-inflammatory cytokines released from senescent cells with the senescence-associated secretory phenotype (SASP), may drive immunosenescence and tangle with type 2 inflammatory dermatoses. The present mini-review summarizes current evidence on immunosenescence and type 2 inflammation in the skin and further focuses on future needs from an inflammaging perspective to clarify their complexity.
... Frozen 7-µm-thick sections were used for double-immunofluorescence staining. The single-immunohistochemical staining and doubleimmunofluorescence staining were performed with the same procedure used in our previous studies [13,14]. ...
... In the present immunohistopathological studies with double-immunofluorescence staining techniques for adult and elderly patients with IgE-allergic AD and HDM allergy, we confirmed that along with T-cell infiltration, IgE-bearing IDECs (CD11c+ and CD206+ cells) infiltrated and aggregated in the central area of the spongiotic epidermis in active lesions of chronic AD [25] in all of the AD patients [13]. However, in the non-spongiotic epidermis, they were scattered in the middle to lower epidermis [13,14]. In addition, we demonstrated the presence of IgE-bearing IDECs coexisting with HDM antigens (i.e., Der f1 and/or Mite Extract antigens) gathered in the spongiotic epidermis of skin lesions in four of the six (66.7%) ...
The immunopathogenic role of house dust mite (HDM) allergens in the development of skin lesions in atopic dermatitis (AD) has not yet been precisely clarified. We immunohistopathologically evaluated the localization of immunoglobulin E (IgE)-positive epidermal dendritic cells with HDM antigens in the skin lesions of patients with IgE-allergic AD. Using double-immunofluorescence and single-immunochemical staining methods, we analyzed biopsy specimens from the skin lesions of six patients with IgE-allergic AD and HDM allergy and 11 control subjects with inflammatory skin disorders. Inflammatory dendritic epidermal cells (IDECs; CD11c+ and CD206+ cells) were markedly observed in the central area of the spongiotic epidermis of skin lesions in all AD patients. Furthermore, IgE-positive IDECs with HDM antigens in the central areas of the spongiosis were found in four of the six (66.7%) AD patients. Langerhans cells (LCs; CD207+ cells) with HDM antigens were also observed in the peripheral areas of the spongiosis. Infiltration of CD4+ and CD8+ T cells in association with IgE-positive IDECs and LCs with HDM antigens was seen in the spongiotic epidermis. An IgE-mediated delayed-type hypersensitivity reaction, in combination with IgE-bearing dendritic cells, specific T cells, keratinocytes, and HDM antigens, may lead to spongiotic tissue formation in eczematous dermatitis in AD.
... Another study indicated that IgE plasma cells (CD19 + CD38 hi ) and IgE memory cells (CD19 + CD38 low ) were increased in the blood of children suffering from atopic diseases [93]. Furthermore, studies have shown that most of the immune cells infiltrating the lesioned AD skin are positive for IgE or its high-affinity receptor FcεRI [18,94]. The expression of B cell-intrinsic transcription factor STAT6 is needed during type 2 immune responses for class switch to IgG1 and IgE as well as for GC formation [95,96]. ...
Atopic dermatitis (AD) is one of the most prevalent inflammatory disease among non-fatal skin diseases, affecting up to one fifth of the population in developed countries. AD is characterized by recurrent pruritic and localized eczema with seasonal fluctuations. AD initializes the phenomenon of atopic march, during which infant AD patients are predisposed to progressive secondary allergies such as allergic rhinitis, asthma, and food allergies. The pathophysiology of AD is complex; onset of the disease is caused by several factors, including strong genetic predisposition, disrupted epidermal barrier, and immune dysregulation. AD was initially characterized by defects in the innate immune system and a vigorous skewed adaptive Th2 response to environmental agents; there are compelling evidences that the disorder involves multiple immune pathways. Symptomatic palliative treatment is the only strategy to manage the disease and restore skin integrity. Researchers are trying to more precisely define the contribution of different AD genotypes and elucidate the role of various immune axes. In this review, we have summarized the current knowledge about the roles of innate and adaptive immune responsive cells in AD. In addition, current and novel treatment strategies for the management of AD are comprehensively described, including some ongoing clinical trials and promising therapeutic agents. This information will provide an asset towards identifying personalized targets for better therapeutic outcomes.
... [9] A monozyotic twin of an affected person has a sevenfold risk of developing AD compared with a threefold increased risk in dizygotic twin. [9] Intrinsic IgE-mediated allergic inflammation may play an important role in the pathobiology of elderly AD, similar to other age groups of AD. [10] About 5-15% of cases have intrinsic non-IgE-allergic eczema. [4] Most of the adult AD patients have sensitivity to aeroallergens such as cat epithet, dog epithel and housedusthouse dust mites [11] while common food allergies affect only few. ...
... Three clinical patterns have been described by Heli et al. [130] 1. Chronic, persistent AD 2. Relapsing course 3. Adult-onset AD Some classify the clinical features into (a) adult-onset AD, and (b) persistent AD and AD with relapsing course grouped together as persistent/recurring infantile or childhood AD. [131] In the elderly, AD can occur as geriatric onset AD, geriatric recurrence of typical childhood AD, and geriatric recurrence and /or continuation of adult AD. [10] Persistent ADrefers to childhood AD running a chronic recurrent course up to and even in adulthood; occurs in 20-30% childhood cases. [131] Presentations are similar to children with flexural involvement (flexor surface of extremities) in majority of patients with pre-adult-onset. ...
Atopic dermatitis (AD) is an itchy chronic relapsing inflammatory skin condition mostly affecting children than adults. Eczematous conditions are common worldwide with increase in the prevalence in both developed and developing countries. AD in adults is of two types – the first type starts as AD in childhood and gradually progresses to adulthood (Persistent AD) and the second type results from AD developing in adulthood (Adult-onset AD). The article reviews and discusses this condition in adults considering the epidemiology, risk factors, pathogenesis, diagnostic criteria, and management of this condition.
... [5][6][7]125 As in adult-type AD, lichenified lesions are common, but tend to be localized to the cubital and popliteal extensor areas rather than the flexural areas, as is typical of adult-type AD. 5,126,127 Three forms of elderly-type AD are apparent -elderly onset, relapsing, and continuous -and are subdivided by age at onset. [126][127][128][129][130][131][132] A comparison of studies carried out in various geographic locations indicates that the prevalence of AD in those aged >60 years is relatively stable at 2-5%. 127,130,133 Immune system changes due to aging (immunosenescence), such as increased type 2 cytokine production [mainly interleukin (IL)-4 and IL-13], may play a key role in the pathogenesis of elderlyonset AD, 127,134 as they do in chronic idiopathic pruritus of the elderly. ...
Atopic dermatitis is a heterogeneous disease and resists classification. In this review, we discuss atopic dermatitis nomenclature and identify morphologic phenotypes, which will facilitate correct diagnoses and development of treatment strategies. We support using the term ‘atopic dermatitis’ rather than eczema, because it describes the allergic background and inflammation (‘itis’) as drivers of the disease. Atopic dermatitis has many morphologic manifestations that vary by topographic area affected, age, or race and require consideration in differential diagnosis. Different phenotypes based on morphology and topographic location, ethnicity, and age are discussed. A better-defined phenotype identification for atopic dermatitis will facilitate earlier and correct diagnosis of this complex condition and inform selection of the most appropriate treatment choice in an era in which targeted therapies may generate more individualized patient care.
... [5] Evidence from a study by Mocsai et al. showed that skin barrier functions were related to total immunoglobulin E (IgE) levels. [25] Furthermore, Tanei and his colleagues showed that allergic inflammation, mediated by the level of IgE, was crucial in the pathobiology of AD. [26] Recently, Hubiche et al. ...
Background:
This study aimed to investigate the role of serine protease inhibitor Kazal-type 5 (SPINK5) polymorphisms (Asn368Ser, Asp386Asn and Glu420Lys) and the risk of atopic dermatitis (AD).
Methods:
Studies associated with SPINK5 mutations and AD risk were searched from three databases, including PubMed, Embase, and Cochrane library, with a retrieval deadline of April 22, 2019. An odds ratio (OR) with a 95% confidence interval (95% CI) was chosen as the effect size. Egger's linear regression test was enrolled to assess the level of publication bias.
Results:
Overall, 6 studies met the inclusion criteria for meta-analysis. Significantly statistical differences were calculated between patients with AD and healthy individuals on Asn368Ser polymorphism in the allele model (G vs A: OR = 1.2643, 95% CI = 1.0666-1.4987, P = .0069), co-dominant model (GG vs AA: OR = 1.6609, 95% CI = 1.1736-2.3505, P = .0042; GA vs AA: OR = 1.5448, 95% CI = 1.1263-2.1189, P = .0070), and dominant model (GG+GA vs AA: OR = 1.5700, 95% CI = 1.1656-2.1146, P = .0030). However, no statistically significant difference was found in the recessive model for Asn368Ser and other genetic models for Asp386Asn and Glu420Lys (all P > .05). No significant publication bias was found.
Conclusion:
The SPINK5 Asn368Ser polymorphism may be a risk factor for AD.
... However, the paradigm has recently changed. The number of cases of AD remaining or first appearing in adulthood [4,5], and even in older adults [3,6], have increased and the characteristics of elderly AD have become apparent [7][8][9][10]. Hence, this newly defined subgroup of elderly AD (age > 60 R. Tanei or ≥ 60 years) was recently added into the classification of AD as a fourth subtype [11,12]. ...
... In a recent study on age-specific changes in the molecular phenotype of patients with AD, serum total IgE levels and eosinophil counts were negatively correlated with age in patients with AD, and patients with elderly AD tended to show immune skewing with decreased Th2 and Th22 cytokines and increased Th1 cytokines in lesional skin compared with patients with adult AD [9]. The participation and role of allergen-specific IgEs in the development of skin lesions of AD has been controversial [26], but immunohistopathological analysis in our previous studies indicated that, at least in patients with IgE-allergic elderly AD, IgE-mediated allergic inflammation (composed of IgE-bearing cells, including mast cells, dermal dendritic cells, inflammatory dendritic epidermal cells, and Langerhans cells) accompanied by specific allergens (e.g., HDMs) play a critical role in the features of skin lesions [7,16,21]. ...
Atopic dermatitis (AD) in older adults (elderly AD) has recently emerged as a newly defined subgroup of AD. When selecting treatment options, clinical characteristics of elderly AD and age-specific factors of older patients must be considered. As in other age groups, regular application of moisturizers in combination with topical corticosteroids and calcineurin inhibitors, adjunctive administration of oral antihistamines/anti-allergic drugs, and avoidance of exacerbating factors comprise basic treatments for elderly AD. For moderate-to-severe cases and/or in those with a decreased ability to use topical treatments, powerful anti-inflammatory treatments may become necessary as additional treatment options. While low-dose oral corticosteroids may be useful for cases of elderly AD, careful attention should be paid to adverse effects. Oral cyclosporine (ciclosporin) is less commonly used due to the increased risk of malignancy and organ toxicity in older patients with AD. Narrow-band ultraviolet B phototherapy may also be useful for older patients, although the necessity of frequent hospital visits for irradiation therapy may become a burden of disease for such patients. As a biologic, dupilumab therapy markedly improves skin lesions and itch in older patients with AD, with a rapid response and non-serious adverse effects. Nevertheless, injection pain, expensive medical care, and regular follow-up every 2 weeks are disadvantages of dupilumab therapy. Therefore, clinicians must prioritize individualized treatment options that will reduce the burden of disease for cases of elderly AD.
... A compromised T helper function and defects of the isotype switching leading to impaired immunologic memory and lower response to vaccines have been observed in the elderly [24]. Conversely, the IgE isotype is less compromised by aging [25]. In particular, immunosenescence does not influence IgE levels in aged patients with atopy, suggesting the persistence of allergy propensity into advanced age [14,26]. ...
... Dryness and hyperkeratosis, with consequent itching and increased risk of skin infections, are dermatologic manifestations that often mimic and/or mask the symptoms of an allergy. Cutaneous symptoms, such as atopic dermatitis and urticaria, could also represent manifestations of FAs in the elderly [25]. However, in addition to FAs, even drugs and systemic diseases, mainly hematologic and immune dysfunctions, can also induce urticaria in the elderly. ...
All over the world, there is an increase in the overall survival of the population and the number of elderly people. The incidence of allergic reactions is also rising worldwide. Until recently, allergies, and in particular food allergies (FAs), was regarded as a pediatric problem, since some of them start in early childhood and may spontaneously disappear in adulthood. It is being discovered that, on the contrary, these problems are increasingly affecting even the elderly. Along with other diseases that are considered characteristics of advanced age, such as cardiovascular, dysmetabolic, autoimmune, neurodegenerative, and oncological diseases, even FAs are increasingly frequent in the elderly. An FA is a pleiomorphic and multifactorial disease, characterized by an abnormal immune response and an impaired gut barrier function. The elderly exhibit distinct FA phenotypes, and diagnosis is difficult due to frequent co-morbidities and uncertainty in the interpretation of in vitro and in vivo tests. Several factors render the elderly susceptible to FAs, including the physiological changes of aging, a decline in gut barrier function, the skewing of adaptive immunity to a Th2 response, dysregulation of innate immune cells, and age-related changes of gut microbiota. Aging is accompanied by a progressive remodeling of immune system functions, leading to an increased pro-inflammatory status where type 1 cytokines are quantitatively dominant. However, serum Immunoglobulin E (IgE) levels and T helper type 2 (Th2 cytokine production have also been found to be increased in the elderly, suggesting that the type 2 cytokine pattern is not necessarily defective in older age. Dysfunctional dendritic cells in the gut, defects in secretory IgA, and decreased T regulatory function in the elderly also play important roles in FA development. We address herein the main immunologic aspects of aging according to the presence of FAs.
