Acute Phase Of Atopic Dermatitis Research Articles

Exploratory analyses of biomarkers in blood and stratum corneum in patients with atopic dermatitis.

Background:The pathogenesis of atopic dermatitis (AD) involves various mediators, including cytokines and chemokines, which are produced by immune cells, such as dendritic cells and lymphocytes, and non-immune cells, such as epidermal cells. Several mediators, including thymus and activation-regulated chemokine (TARC), are used as biomarkers for AD severity and activity. However, additional local and systemic biomarkers of AD are required.Methods:This study will include 10 male patients with AD and 5 healthy adult males (age range: 20–80 years). The Eczema Area and Severity Index will be used to objectively evaluate the clinical findings. In addition, the severity of eruptions will be assessed on a 5-point scale by scoring symptoms (erythema, edema/papules, oozing/crusting, excoriation, lichenification, and xerosis), and the total intensity will be calculated by adding the symptom scores together. Subjective symptoms will be assessed using a peak pruritus numerical rating scale. Laboratory tests, including measurements of peripheral eosinophil count and serum total immunoglobulin E, TARC, and lactate dehydrogenase levels, will be performed. Using blood samples and extracts of stratum corneum samples obtained by tape stripping, we will conduct an exploratory analysis of protein expression using an antibody array to identify mediators whose levels are significantly altered in patients with AD. After 4 to 8 weeks, blood samples and stratum corneum samples will be collected again from AD patients. Moreover, we will examine whether the candidate proteins can be quantified using enzyme-linked immunosorbent assays.Discussion:This is an important study exploring potential local and systemic biomarkers of AD. The results of this study will be clinically meaningful for the discovery of new biomarkers for diagnosing and assessing the severity of AD.

The role of cytokines in atopic dermatitis: a breakthrough in immunopathogenesis and treatment

Atopic dermatitis is a multifactorial inflammatory skin disease with a complex immunopathogenesis that is characterized by an underlying imbalance of T-cell subsets. Although cytokines of type 2 immunity consistently predominate in the acute phase of atopic dermatitis, there is strong evidence supporting the contribution of cytokines of type 1 immunity, type 3 immunity, and other cytokines in the development and progression of the disease. This review explores the cytokine network in atopic dermatitis, and it highlights areas and causes of controversy in the immunopathogenesis of the disease. In addition, it presents the current therapeutic targets currently being investigated, including monoclonal antibodies and small molecules that inhibit cytokines and downstream signaling molecules in atopic dermatitis. We conclude that atopic dermatitis has a complex and controversial cytokine profile. Understanding the role of cytokines in the immunopathogenesis of the disease is essential for identifying personalized targets for better management and disease control.

3,3'-Diindolylmethane alleviates acute atopic dermatitis by regulating T cell differentiation in a mouse model

Atopic dermatitis is a severe, chronic relapsing inflammatory disease of the skin with family clustering. It is characterized into acute phase, which is dominated by T helper 2-type immune responses, and chronic phase, which is dominated by T helper 1-type immune responses. Studies have shown that 3,3′-diindolylmethane not only has antitumor effects but also can relieve symptoms of inflammatory diseases by inhibiting the nuclear factor-κB signaling pathway and regulating T cell differentiation. To study the effect of 3,3′-diindolylmethane on atopic dermatitis and the underlying mechanism, a mouse model of acute atopic dermatitis was established using 2,4-dinitrofluorobenzene. After intraperitoneal injection of 3,3′-diindolylmethane, skin erythema and edema in mice were significantly alleviated. Furthermore, 3,3′-diindolylmethane reduced immune activation, probably by inhibiting the secretion of thymic stromal lymphopoietin by keratinocytes. 3,3′-Diindolylmethane also promoted the differentiation of regulatory T cells and inhibited the activation of T helper 2 and T helper 17 cells to reduce atopic dermatitis-related immune responses. However, it showed no significant effect on the differentiation of T helper 1 cells. These results indicate that 3,3′-diindolylmethane has a significant inhibitory effect on T helper 2 cells in the acute phase of atopic dermatitis. Our findings may provide not only more insights into the pathological mechanism of AD, but also a new candidate medicine for it.

Novel topical agent containing superoxide dismutase 100000IU and 4% of plant extracts as a mono-therapy for atopic dermatitis.

Corticosteroids are the mainstay of treatment for the acute phase of atopic dermatitis (AD), whereas topical emollients are mainly used for maintenance of remission. A topical agent that combines emollient and anti-inflammatory properties would achieve control of all phases of AD, without the need for chronic corticosteroid use. To assess the efficacy of a novel topical agent containing superoxide dismutase (SOD) 100000IU and 4% of a combination of plant extracts (blackcurrant seed oil, sunflower oil concentrate, balloon vine extract). Twenty patients (age range from 8months to 72years old) with mild-to-moderate atopic dermatitis were assessed. The product was used as mono-therapy, applied to the affected skin areas twice daily. Patients were evaluated before and after a 30-day course using the SCORAD and the Visual Analog Scale for assessment of pruritus intensity. Primary endpoint was improvement of AD according to SCORAD and clinical assessment. Secondary endpoint was patient satisfaction and improvement of pruritus. Mean SCORAD on day 0 was 32.61(range=16.0-46.9) and decreased to 10.55 (range=0-17.0) on day 30, reflecting a reduction of 67.6%. On day 30, all patients described significant improvement in pruritus and quality of sleep. The application of the study product cream resulted in significant improvement of AD, as reflected by the objective SCORAD measurement, and the subjective assessment of pruritus and quality of life. This novel anti-inflammatory emollient product may emerge as a safe and effective therapeutic tool for all phases of AD without the adverse effects of chronic use of corticosteroids.

The potential of the non-pharmacological methods for the rehabilitation and prophylaxis in the patients suffering from with atopic dermatitis

This article was designed to discuss the therapeutic potential of various non-pharmacological and physiotherapeutic methods for the treatment and rehabilitation of the patients presenting with atopic dermatitis (AD) during the inter-recurrence period of the disease. The particular emphasis is placed on the physical agents most frequently used for the purpose with special reference to the combined therapy of atopic dermatitis in the adults and children and to their rehabilitation in the inter-exacerbation periods. In addition, the data on the prospects for the use of various medications intended for tissue- and organotherapy of the patients suffering from atopic dermatitis are presented. The main traditional approaches to the management of the patients with atopic dermatitis under conditions of the spa and health resort facilities are considered based on the original experience of the authors including the application of various modes of ozone therapy regarded as a physiotherapeutic procedure for the treatment of atopic dermatitis in the children and adult patients, their rehabilitation, and the prevention of exacerbations of the pathological process based on the external and/or systemic application of the ozone-oxygen gaseous mixture. The selected modalities of ozone therapy used to treat various clinical forms and stages of the atopic dermatitis differing in severity are described in detail. The data on the influence of ozone therapy on a variety of pathogenetic factors of atopic dermatitis are presented as obtained by the investigations into dynamics of the characteristics of immunity, microcirculation, and the levels of free radical metabolites. The results of the study give evidence of the high effectiveness of ozone therapy as a method of physiotherapeutic treatment both in the capacity of a component of combined therapy during the acute phase of atopic dermatitis and as the means of secondary (post-exposure) prophylaxis of the exacerbations and relapses of this condition based at the medical and preventive treatment facilities of various specialization.

Pruni Cortex Extract Accelerates Wound Healing in a Mouse Model of Atopic Dermatitis

The crude drug Pruni Cortex (PC) is a component of Jumihaidokuto, which is a Chinese herbal medicine used for the treatment of skin diseases including atopic dermatitis (AD). To understand the role of PC in the mechanism of action of Jumihaidokuto on the skin, PC was administered to AD model mice. NC/Nga mice were induced to exhibit AD lesions by treating them with Dermatophagoides farina extract for 2 weeks and PC was orally administered for a further 4 weeks. The dermatitis score and histopathologic parameters were observed from 1 week after AD induction (the acute phase of AD) to 4 weeks after AD induction (the chronic phase of AD). At 4 weeks, the dermatitis score was significantly lower in the PC-treated group than in the untreated group. However, in the histopathological analysis conducted 1 week after AD induction, the PC-treated mice did not show fewer inflammatory cells in the dermis, but showed more fibroblasts in comparison with the untreated mice. At 4 weeks after AD induction, the PCtreated mice showed fewer inflammatory cells and fibroblasts than the untreated mice. PC may accelerate wound healing by increasing the number of fibroblasts in the dermis from the acute phase of atopic dermatitis.

Expression proteaseinhibitors receptor PAR-2 on neutrophils peripheral blood of patients with atopic dermatitis and their relation with heat shock proteins HSP90

Expression ofprotease-activated receptors PAR-2 has been investigated on neutrophils isolated from atopic dermatitis patient peripheral blood and has been analyzed with index SCORAD. The simultaneous expression of both, PAR-2 receptors and heat shock protein 90 (HSP90) was measured on neutrophils at the first week of acute phase of atopic dermatitis. Methods. Peripheral blood neutrophils were isolated on the Percoll gradient. Cells were stained with antibodies to PAR-2 receptor and HSP90 followed by the flow cytometry. Results. The PAR-2 receptors have been shown to be expressed on the plasma membrane of neutrophils obtained from patients with atopic dermatitis. The percentage of PAR-2+ neutrophils was positive correlated with diseases severity. HSP90 was found to be elevated simultaneously with PAR-2 receptors on neutrophils at the acute phase of atopic relapse. Conclusions. Atopic dermatitis patients have the higher level of PAR-2 receptor expression compared with healthy donors. Percentage of PAR-2+ neutrophils is elevated with the increasing of disease severity. Simultaneous elevation of PAR-2 receptors and HSP90 was found at the first week of acute atopic dermatitis.

Mutant interleukin-4/13 signaling blockade successfully suppresses acute phase inflammation

Atopic dermatitis (AD) is a chronic disease with Th2-type-cytokine dominant profile. Several cytokines and related peptides had been tried for the treatment of AD but with unsuccessful results; a part of the reason is the limitation of their biological half time. We have recently developed a highly efficient mouse dominant negative IL-4/IL-13 DNA vaccine, which blocks both IL-4 and IL-13 signal transductions, resulting in the amelioration of atopic reaction. At the next step, the further consistent protein supplementation system is required for stable suppression of allergic reaction. To examine the effects of mutant IL-4/13 protein supplementation from skin, a keratinocyte-specific dominant negative IL-4-transgenic mouse line (IL-4DM) was established. The anti-inflammatory function was evaluated measuring ear thickness and analyzing histological change in mice AD model induced by repeated elicitation of oxazolone. In IL-4DM, ear thickness was suppressed significantly in the early phase of the elicitation schedule of contact hypersensitivity response. We next transplanted IL-4DM skin to normal control mice, and investigated effects in inflammatory reactions. In IL-4DM-skin-grafted mice, the inflammatory response was suppressed significantly similarly in the early phase accompanied with lesional suppressed Th2-type-cytokine signaling transduction. IL-4DM skin has the anti-inflammatory function especially in the acute phase of AD. Although there are several issues to be addressed for human application, the present results implicated that the gene manipulated skin transplantation is a potent therapeutic strategy to control allergic reactions.

Regulation of immunological balance by sustained interferon-γ gene transfer for acute phase of atopic dermatitis in mice

Interferon (IFN)-γ, a potent T helper 1 (Th1) cell cytokine, is suggested to suppress Th2 cell responses. Here, we aimed to investigate whether pCpG-Muγ, a plasmid continuously expressing murine IFN-γ, is an effective treatment of atopic dermatitis, a Th2-dominant skin disease. Nishiki-nezumi Cinnamon/Nagoya (NC/Nga) atopic mice with early dermatitis were transfected with pCpG-Muγ by a hydrodynamic tail vein injection at a dose of 0.05 or 0.2 pmol per mouse. The skin lesions improved only in mice receiving the high dose of pCpG-Muγ. IFN-γ gene transfer resulted in a high mRNA expression of IFN-γ and interleukin (IL)-12 and regulatory T cell (Treg) related cytokines, such as IL-10 and transforming growth factor-β, in the spleen, whereas it reduced the IL-4 mRNA expression, and serum levels of immunoglobulin (Ig) G1 and IgE. In addition, the gene transfer markedly inhibited the epidermal thickening, infiltration of inflammatory cells into the skin, the occurrence of dry skin and pruritus. No exacerbating effect on the Th1-mediated contact dermatitis was observed after IFN-γ gene transfer. Taken together, these results indicate that sustained IFN-γ gene transfer induced polarized Th1 immunity under Th2-dominant conditions in NC/Nga mice, leading to an improvement in the symptoms of acute atopic dermatitis without adverse side effects.

IL-33 and ST2 in Atopic Dermatitis: Expression Profiles and Modulation by Triggering Factors

In the acute phase of atopic dermatitis (AD), T-helper type 2 (Th2) cytokines characterize the inflammatory response in the skin. IL-33 is a new tissue-derived cytokine, which is mainly expressed by cells of barrier tissues, and is known to activate Th2 lymphocytes, mast cells, and eosinophils. IL-33 signals through a receptor complex consisting of IL-33-specific receptor ST2 and a co-receptor IL-1RAcP. As IL-33 is known to promote Th2-type immunity, we examined expression profiles of IL-33 and its receptor components in human AD skin, in the murine model of AD, and in various cell models. We found increased expression of IL-33 and ST2 in AD skin after allergen or staphylococcal enterotoxin B (SEB) exposure, as well as in the skin of 22-week-old filaggrin-deficient mice. In addition, skin fibroblasts, HaCaT keratinocytes, primary macrophages, and HUVEC endothelial cells efficiently produced IL-33 in response to the combined stimulation of tumor necrosis factor-α and IFN-γ, which was further enhanced by a mimetic of double-stranded RNA. Finally, the increased expression of IL-33 and ST2 caused by irritant, allergen, or SEB challenge was suppressed by topical tacrolimus treatment. These results suggest an important role for IL-33-ST2 interaction in AD and highlight the fact that bacterial and viral infections may increase the production of IL-33.

Expression of chemokines and chemokine receptors in lesional and nonlesional upper skin of patients with atopic dermatitis

Trafficking of dendritic cell (DC) subtypes to and from the skin plays a pivotal role in atopic dermatitis (AD). We sought to determine the CCR pattern of epidermal DC subtypes and CCL expression in relation to the state of AD. Shave biopsy specimens were taken from patients with AD before and after 24 and 72 hours of atopy patch testing and from the skin of patients with chronic AD, skin of patients with psoriasis, and healthy skin. CCR expression of epidermal DCs was studied by using flow cytometry, and chemokine mRNA levels in the skin were quantified by means of real-time PCR. The total number of CD1a(+) epidermal DCs increased and the proportion of Langerin-positive CD1a(+) DCs decreased whereas the percentage of Langerin-negative CD1a(+) DCs increased after allergen application. Expression of CCR5 and CCR6 of Langerin-negative CD1a(+) DCs was characteristic for acute AD. Expression of CCL1, CCL3, CCL4, and CCL11 mRNA was greater in patients with acute AD versus that seen in patients with chronic AD. Only a strong increase of CCLs, in particular CCL1, CCL17, and CCL18, went along with eczema development, and increased CCL1, CCL13, CCL17 and CCL18 expression was specific for patients with chronic AD compared with those with psoriasis. Modified recruitment and differentiation of DCs from their dermal and blood precursors occurs in the acute phase of AD. A boost in the amplitude of CCLs after allergen application goes along with eczema development.

Rebound phenomenon to systemic corticosteroid in atopic dermatitis

Three patients with atopic dermatitis, one boy and two girls, aged between 6 and 17 years, presented eczematous skin, pruritus, scarifications, lichenification and a family history of atopy. During exacerbations, the patients sought emergency care and were prescribed oral corticosteroids for a period of approximately 15 days. Initially, the patients improved but after cessation of therapy or dose reduction, marked worsening occurred with the development of lesions with extreme pruritus, several confluent lesions, scarification and intense exudates, as well as fever and dehydration. The patients’ condition was so severe that two were admitted to the allergy unit. The medication was withdrawn and intravenous hydration was administered, together with hydrating skin creams and antihistamine therapy. In addition, weak topical corticosteroids were applied on the most severely affected areas. All three patients progressively improved. We conclude that the patients with atopic dermatitis described herein presented a rebound phenomenon after the use of corticosteroids. We believe that systemic corticosteroids may exacerbate the acute phase of atopic dermatitis, mediated by IgE, accentuating the Th2 pattern in these patients.

Pathogenesis of canine atopic dermatitis: 2004 hypothesis

The exact pathogenesis of canine atopic dermatitis (AD) remains elusive at this time. However, information on selected aspects of the immunological mechanisms of canine AD can be derived from the results of static (fixed‐point) and dynamic studies. Static studies yield data from samples collected at single time points and are thus fraught with imprecision dependent on the immunological stage of the lesions. In contrast, dynamic investigations provide information from sequential samples collected after immune cell activation with or without allergens. Examples of dynamic studies include stimulation of normal and atopic canine skin with intradermal injections of anti‐IgE antibodies, epicutaneous application (e.g. patch tests) with house dust mite allergens on sensitized dogs, and environmental challenges of sensitized dogs with house dust mites. This lecture will review results from selected static studies investigating epidermal lipids, epidermotropic and dermal immune cells, and cytokines detected in the skin of dogs with AD. Cellular inflammatory infiltrates and cytokines released during dynamic experiments will be reviewed subsequently. The information collated from various studies enables the generation of a working hypothesis for the pathogenesis of canine AD. In the acute phase of AD, a putative epidermal barrier defect could facilitate the contact of environmental allergens and microbes with epidermal immune cells at skin sites of friction and trauma. Epidermal Langerhans cells capture allergens with antigen‐specific IgE and migrate to the dermis and regional lymph nodes. Keratinocytes release chemokines that include thymus and activation‐regulated chemokine (TARC/CCL17). Allergen‐specific IgE‐coated dermal mast cells release histamine, proteases including chymase and tryptase, chemokines, and cytokines including TNFα and stem cell factor. There is an early influx of granulocytes (neutrophils and eosinophils), allergen‐specific Th2 lymphocytes and dermal dendritic cells. Eosinophils degranulate upon allergen challenge and release proteins that induce dermal and epidermal damage and inflammation. Th2 lymphocytes release cytokines promoting IgE synthesis (IL‐4 and IL‐13) and eosinophil survival (IL‐5). In chronic canine AD, microbes, self‐trauma and neuromediators are suspected to contribute to chronic inflammation. Chemokines are released in a continuous allergen‐dependent and ‐independent cycle, with subsequent influx and activation of leucocytes and further release of chemokines and other mediators. There is infiltration of T lymphocytes expressing type‐2 and type‐1 cytokines (IL‐12 and IFNγ). The failure to down‐regulate proinflammatory mechanisms leads to self‐perpetuating cutaneous inflammation.