Mechanisms Of Atopic Dermatitis Research Articles

Patho-immunological mechanisms of atopic dermatitis: The role of the three major human microbiomes.

Atopic dermatitis (AD) is a genetically predisposed allergic inflammatory dermatosis with chronic, pruritic, and recurrent features. Patients with AD have dry and itchy skin, often accompanied by chronic eczematous lesions, allergic rhinitis, or asthma, which has a considerable impact on their daily lives. With advances in genome sequencing technology, it has been demonstrated that microorganisms are involved in this disease, and the microorganisms associated with AD are attracting considerable research attention. An increasing number of studies conducted in recent years have demonstrated that an imbalanced microbiome in AD patients has substantial impact on disease prognosis, and the causes are closely tied to various immune mechanisms. However, the involvement of microorganisms in the pathogenesis of AD remains poorly understood. In this paper, we review the advances in research on the immunological mechanisms of the skin microbiome, intestinal microbiome, and lung microbiome that are related to AD prognosis and immunotherapy protocols. It is hoped that this approach will lay the foundation for exploring the pathogenesis of and emerging treatments for AD.

Clinical Characterization and Underlying Pathophysiological Mechanisms in Atopic Dermatitis: A Comprehensive Exploration of its Clinical Presentation and Emerging Therapeutic Perspectives

Atopic dermatitis, a chronic inflammatory skin disease of a predominantly genetic nature, has attracted continued interest in the field of dermatology and immunology due to its pathophysiological complexity and its significant impact on patients' quality of life. In this article, we present a comprehensive review of the current literature on atopic dermatitis, addressing its clinical characterization from a holistic perspective and the underlying pathophysiologic mechanisms that define it. From a clinical point of view, the heterogeneity of cutaneous manifestations in atopic dermatitis is highlighted, including erythema, intense pruritus, lichenification and exudation. In addition, the variability of clinical presentations throughout the different stages of life is explored, focusing on early childhood and adulthood, which underlines the need for a multidisciplinary and personalized approach to its management. In terms of pathophysiological mechanisms, the dysfunction of the skin barrier, the dysregulated immune response and the involvement of key cytokines in the perpetuation of the inflammatory process are examined in detail. The interaction between genetic and environmental factors in the development and exacerbation of the disease is discussed, as well as the connection between atopic dermatitis and other atopic conditions, such as asthma and allergic rhinitis. In addition, conventional and emerging therapies for atopic dermatitis, including topical corticosteroids, calcineurin inhibitors, biologic therapies, and approaches aimed at modulating the skin microbiota, are discussed. The importance of patient education, skin care strategies and a comprehensive approach to achieve effective symptom control and prevent recurrences is emphasized. In summary, this article provides a comprehensive view of atopic dermatitis, merging its clinical and pathophysiological aspects. Advanced understanding of the clinical diversity and underlying mechanisms is crucial for an informed and optimal management of this constantly evolving chronic skin condition.

"Outside-to-inside," "inside-to-outside," and "intrinsic" endogenous pathogenic mechanisms in atopic dermatitis: keratinocytes as the key functional cells involved in both permeability barrier dysfunction and immunological alterations.

Permeability barrier disruption has been shown to induce immunological alterations (i.e., an "outside-to-inside" pathogenic mechanism). Conversely, several inflammatory and immunological mechanisms reportedly interrupt permeability barrier homeostasis (i.e., an "inside-to-outside" pathogenic mechanism). It is now widely recognized that alterations of even a single molecule in keratinocytes can lead to not only permeability barrier dysfunction but also to immunological alterations. Such a simultaneous, bidirectional functional change by keratinocytes is herein named an "intrinsic" pathogenic mechanism. Molecules and/or pathways involved in this mechanism could be important not only as factors in disease pathogenesis but also as potential therapeutic targets for inflammatory cutaneous diseases, such as atopic dermatitis, psoriasis, and prurigo nodularis. Elevation of skin surface pH following permeability barrier abrogation comprises one of the key pathogenic phenomena of the "outside-to-inside" mechanism. Not only type 2 cytokines (e.g., IL-4, IL-13, IL-31) but also type 1 (e.g. IFN-γ), and type 3 (e.g., IL-17, IL-22) as well as several other inflammatory factors (e.g. histamine) can disrupt permeability barrier homeostasis and are all considered part of the "inside-to-outside" mechanism. Finally, examples of molecules relevant to the "intrinsic" pathogenic mechanism include keratin 1, filaggrin, and peroxisome proliferator-activated receptor-α (PPARα).

CLA+ memory T cells in atopic dermatitis

Circulating skin-homing cutaneous lymphocyte-associated antigen (CLA)+ T cells constitute a small subset of human memory T cells involved in several aspects of atopic dermatitis: Staphylococcus aureus related mechanisms, the abnormal Th2 immune response, biomarkers, clinical aspects of the patients, pruritus, and the mechanism of action of targeted therapies. Superantigens, IL-13, IL-31, pruritus, CCL17 and early effects on dupilumab-treated patients have in common that they are associated with the CLA+ T cell mechanisms in atopic dermatitis patients. The function of CLA+ T cells corresponds with the role of T cells belonging to the skin-associated lymphoid tissue and could be a reason why they reflect different mechanisms of atopic dermatitis and many other T cell mediated skin diseases. The goal of this review is to gather all this translational information of atopic dermatitis pathology.

Fracture risks and their mechanisms in atopic dermatitis, focusing on receptor activator of nuclear factor kappa-Β ligand.

Recent multiple studies have shown that the long-term consequences of AD include an increased risk of osteoporosis and fracture, especially in hip, pelvic, spinal, and wrist fractures. AD is very common worldwide, and some kinds of fractures, such as hip fractures, are associated with increased mortality, which has a substantial socio-economic impact; however, the precise mechanisms for that remain unclear. Receptor activator of nuclear factor kappa-Β (RANK) ligand (RANKL) and osteoprotegerin (OPG) are members of the tumor necrosis factor ligand and receptor family, members of which also are known as bone biomarkers. Alterations in the RANKL/RANK/OPG system and the balance among these factors (represented by the RANKL/OPG ratio) are central to the pathogenesis of bone loss from osteoporosis, and it is postulated that the potential association between the serum levels of RANKL and OPG, and bone density or fracture. Recently, we demonstrated that serum RANKL/OPG ratio positively correlated with AD severity and suggests fracture risk in older women with AD. This review summarizes and discusses the risk and mechanisms of osteoporotic fracture in AD. RANKL may be involved in the pathogenesis of AD, regarding not only bone abnormality but also inflammation. Although further investigation will be needed to verify the hypotheses, recent findings may provide new insights into AD's pathogenesis and therapeutic targets.

Heterogeneous Regulation of StaphylococcusAureus by Different StaphylococcusEpidermidisagr Types in Atopic Dermatitis

The skin commensal Staphylococcus epidermidis exhibits a protective role in skin inflammation; however, the exact functions of S.epidermidis and their mechanisms in atopic dermatitis (AD) are not fully understood. Here, whole-genome sequencing was conducted on strains of S.epidermidis isolated from pediatric patients with AD and revealed significant strain-level heterogeneity in functional genes. Specific sequence analysis of S.epidermidis identified four types of accessory gene regulator (agr) according to locus variations in the agr operon, which was consistent with the metagenomic data of the contextual microbiota. The number of S.epidermidisagr type I was slightly decreased among AD isolates, whereas agr type IV was hardly detected in AD isolates. Functional experiments showed that strains of S.epidermidisagr types I and IV, but not types II and III, inhibited the expression of S.aureusagr-mediated virulence factors invitro, suppressed S.aureus epidermal colonization, and attenuated skin inflammation in a mouse model. The delineation of genome signatures of S.epidermidis at the strain level in AD and the quorum-sensing interference between S.epidermidisagr type IV and S.aureus provide a foundation for the modulation of the skin microbiota and the treatment of AD.

State of liver functional activity in children with atopic dermatitis

BACKGROUND: The problem of atopic dermatitis today remains one of the unsolved problems of pediatrics and pediatric allergology. Among the etiopathogenetic mechanisms of atopic dermatitis, the role of endo-allergens formed as a result of impaired digestion and absorption processes in the gastrointestinal tract of a child is separately noted. In such conditions, the load on the detoxification function of the liver increases. In connection with this circumstance, the study of the functional activity of the liver in children with atopic dermatitis is of particular interest. One of its criteria is the nature of intrahepatic hemodynamics.
 AIM: To find out the features of intrahepatic hemodynamics in the development of atopic dermatitis in children.
 MATERIALS AND METHODS: 83 children aged 6 months to 5 years with a diagnosis of atopic dermatitis, who made up the main research group, and 33 practically healthy children of the same age, who formed a control group, were examined. The nature of heredity for allergic pathology and morbidity of the gastrointestinal tract was found out in all patients. To obtain information about the functional activity of the liver in all children, hepatic blood flow in the hepatic artery and hepatic vein was studied.
 RESULTS: Violation of intrahepatic hemodynamics was revealed in children with atopic dermatitis. The blood flow in the hepatic artery in them was characterized by a decrease, and the blood flow in the hepatic vein was characterized by an increase in speed indicators. The detected violations of intrahepatic hemodynamics in children with atopic dermatitis are regarded by the authors of this study as a manifestation of a decrease in the functional activity of hepatocytes in conditions of increased allergenic load.
 CONCLUSIONS: The study clearly demonstrated a violation of the functional state of hepatocytes in children suffering from atopic dermatitis, expressed in the suppression of hepatic hemodynamics. The question of the primary or secondary nature of this violation is the subject of discussion and further scientific research.

Mentha arvensis Essential Oil Exerts Anti-Inflammatory in LPS-Stimulated Inflammatory Responses via Inhibition of ERK/NF-κB Signaling Pathway and Anti-Atopic Dermatitis-like Effects in 2,4-Dinitrochlorobezene-Induced BALB/c Mice.

The mechanism of atopic dermatitis (AD) is modulated by the release of cytokines and chemokines through the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB) signaling pathway. Topical steroids are used to treat AD, but some people need safer anti-inflammatory drugs to avoid side effects. Mentha arvensis has been used as a herbal plant with medicinal properties, but its anti-inflammatory effects have not been elucidated in an AD model. In this study, we investigated the anti-inflammatory effects of M. arvensis essential oil (MAEO) and its underlying molecular mechanism in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and HaCaT cells (human epidermal keratinocyte). Additionally, we examined the ameliorating effects of the MAEO in a dinitrochlorobenzene (DNCB)-induced murine model of AD. We found, in both RAW 264.7 cells and HaCaT cells, MAEO inhibited LPS-stimulated inflammatory mediators such as nitric oxide (NO) and prostaglandin E2 and proinflammatory cytokines, including IL-1β and IL-6, due to the suppression of COX-2 and iNOS expression. In LPS-stimulated macrophages, we also observed that MAEO inhibited the phosphorylation of ERK and P65. Furthermore, MAEO treatment attenuated AD symptoms, including the dermatitis score, ear thickness, epidermal thickness and infiltration of mast cells, in a DNCB-induced animal model of AD. Overall, our findings suggest that MAEO exerts anti-inflammatory and anti-atopic dermatitis effects via inhibition of the ERK/NF-κB signaling pathway.

Уровень цинка и особенности течения атопического дерматита у детей

Актуальность. В поисках основных патогенетических механизмов атопического дерматита (АД) и улучшения вариантов профилактики и лечения все больше внимания уделяется обеспечению организма ребенка микроэлементами. Особая роль принадлежит цинку, который является одним из самых многофункциональных микроэлементов. Цель: изучить особенности клинического течения АД у детей в зависимости от содержания цинка в сыворотке крови. Материалы и методы. В работе представлены материалы клинического наблюдения, клинико-лабораторного и инструментального обследования 168 детей в возрасте от 7 до 18 лет с АД. Контрольную группу составили 60 практически здоровых детей. Содержание цинка в сыворотке крови определяли методом атомно-абсорбционной спектроскопии на спектрофотометре С-115-М1, согласно инструкциям, прилагаемым к прибору. Результаты. Более половины детей (55,6 %) имели очень низкий уровень цинка — 0,35 ± 0,11 мг/л, еще 22,2 % — крайне низкий (0,12 ± 0,02 мг/л). Отмечен ряд особенностей клинического течения АД: более частые эпизоды острых респираторных вирусных инфекций, преобладание среднетяжелого и тяжелого течения с периорбитальным, периоральным, перианальным дерматитом, дистрофическими изменениями и гиперкератозом ногтей, повышенной ломкостью волос, выраженной сухостью кожи (2,31 ± 0,73 балла против 1,92 ± 0,69 балла; p < 0,01). Выявлены обратные корреляционные связи между концентрацией цинка в сыворотке крови и сухостью кожных покровов (р = 0,001; r = –0,67; t = –2,99), значением индекса SСORAD (р = 0,01; r = –0,49; t = –2,34) и длительностью течения АД (р = 0,001; r = –0,46; t = –2,13). Установлены достоверно более низкие показатели роста (p < 0,05), особенно у детей с очень низким содержанием цинка (0,12 ± 0,02 мг/л). Выводы. У детей с атопическим дерматитом содержание цинка в плазме крови достоверно ниже, чем у здоровых детей. У детей с пониженным содержанием цинка в организме отмечен ряд особенностей клинического течения атопического дерматита (более тяжелое и затяжное течение с периорбитальной и перианальной локализацией, частые респираторные инфекции, выраженные дистрофические изменения придатков кожи, задержка роста).

Dupilumab for the treatment of adolescents with atopic dermatitis

ABSTRACT Introduction Dupilumab is a treatment option newly licensed for adolescents with moderate to severe atopic dermatitis (AD). It reduces type 2 inflammation by blocking the shared receptor subunit for IL-4/-13. Dupilumab affects three disease mechanisms in atopic dermatitis: the skin barrier, the Th2-cell differentiation and the class switch to IgE. This report is based on a systematic literature search of the PubMed Database. Areas covered Dupilumab showed promising results in improving AD signs, symptoms and quality of life in adolescents with moderate to severe AD. The safety profile of dupilumab in adolescents with moderate to severe AD closely resembled the known safety profile of dupilumab in adults with moderate to severe AD. Injection-site reactions and conjunctivitis were the relevant side-effects. Skin infections were less frequently observed compared to placebo. Expert commentary Dupilumab was approved by the Food and Drug Administration in March 2019 and by the European Medicines Agency in August 2019 for the treatment of adolescents with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical therapies or when those therapies are not advisable. Since it is the first licensed drug it will likely become the reference drug for adolescents with moderate to severe AD.

Disease Mechanisms in Atopic Dermatitis: A Review of Aetiological Factors.

Atopic dermatitis is a prevalent inflammatory skin condition characterized by itch and dry skin, which affects 15–20% of children and 3–5% of adults. This article reviews epidemiological, clinical and experimental data to provide an overview of the most important disease mechanisms in atopic dermatitis. Genetic predisposition, environmental insults, atopic triggers, complex host immune response and skin barrier changes, and altered skin microbiota are discussed. Whilst our understanding of atopic dermatitis has improved dramatically in recent years, many basic aspects are still not understood. Further research is needed to fully understand this complex skin disease.

Systemic immune mechanisms in atopic dermatitis and psoriasis with implications for treatment.

Atopic dermatitis (AD) and psoriasis are inflammatory skin diseases that negatively affect patients' quality of life. Although distinctions exist between these diseases, both are characterized by erythematous, thickened epidermal lesions that vary in intensity and affected body surface area. Early models of aetiology attributed symptoms of both diseases to cutaneous inflammation at lesion sites, but recent studies have established that activated immune mediators in the circulation drive disease severity. Activation of T helper 2 (Th2) and Th22 cells in the circulation appears to be the principal initiator of acute AD pathology, with the emergence of Th1 and Th17/interleukin (IL)-23 pathway activation marking the transition to a chronic state. The Th17/IL-23 pathway also has an important role in psoriasis. The role of systemic inflammation in AD and psoriasis is supported by the occurrence of non-cutaneous comorbidities that affect patients, most of which intensify morbidity and disability associated with lesional skin. Atopic dermatitis is associated with allergic disorders consisting of the "atopic march," whereas psoriasis is frequently accompanied by psoriatic arthritis. Patients with both disorders are at significantly higher risk of obesity, metabolic disorders, and cardiovascular diseases, all of which feature inflammatory components in their pathology models. These insights have led to novel therapeutics aimed at addressing psoriasis by targeting tumor necrosis factor- and Th17-related cytokine pathways. The success of these agents in psoriasis management is driving new therapeutic approaches for moderate-to-severe AD, including agents targeting the Th2 and Th17/Th22 cytokine pathways.

7,3′,4′-Trihydroxyisoflavone Ameliorates the Development ofDermatophagoides farinae-Induced Atopic Dermatitis in NC/Nga Mice

Atopic dermatitis is an inflammatory and chronically relapsing skin disorder that commonly occurs in children; the number of atopic dermatitis patients is increasing. The cause and mechanism of atopic dermatitis have not been defined clearly, although many studies are ongoing. Epidemiological studies suggest that soybean and its isoflavones have immunoregulatory activities. Here, we report that 7,3′,4′-trihydroxyisoflavone (7,3′,4′-THIF), a major metabolite of daidzin, effectively inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 production in RAW 264.7 cells, and also reduced β-hexosaminidase secretion in RBL-2H3 cells. Moreover, 7,3′,4′-THIF significantly reduced scratching time, transepidermal water loss, and mast cell infiltration. It also decreased protease-activated receptor (PAR)-2 and IL-4 expression and increased filaggrin expression in skin lesions of NC/Nga mice. These results suggest that 7,3′,4′-THIF improves Dermatophagoides farina body extract-induced atopic dermatitis in NC/Nga mice.

New Trends in Allergy and Atopic EczemaEdited by JohannesRing, UlfDarsow and HeidrunBehrendt. Published by Karger, Basel, Switzerland, 2012. 146 pp, price $ 198 or £104, ISBN 978‐3‐8055‐9894‐1, Volume 96 in the ‘Chemical Immunology and Allergy’ series.

New Trends in Allergy and Atopic EczemaEdited by JohannesRing, UlfDarsow and HeidrunBehrendt. Published by Karger, Basel, Switzerland, 2012. 146 pp, price $ 198 or £104, ISBN 978‐3‐8055‐9894‐1, Volume 96 in the ‘Chemical Immunology and Allergy’ series.

Theory of traditional Chinese medicine on etiology and mechanism of atopic dermatitis

Atopic dermatitis ( AD ) is an inherited allergic skin disease commonly seen among children.While Western medicine can not explain the pathogenesis of the disorder clearly and has no specific treatment,traditional Chinese therapies have their own advantages. Through statistical analysis and summary of ancient and modern literatures on traditional Chinese medicine on the etiology and mechanism of AD, we provide support for treatment based on syndrome differentiation. Key words: Atopic dermatitis; Traditional Chinese medicine; Etiology and Mechanism

アトピー性皮膚炎の治療と免疫・アレルギー機序に関する問題 T細胞とアトピー性皮膚炎(環境汚染物質による免疫変調作用)

アトピー性皮膚炎の治療と免疫・アレルギー機序に関する問題 T細胞とアトピー性皮膚炎(環境汚染物質による免疫変調作用)

Pathological Mechanisms of Skin Homing T Cells in Atopic Dermatitis

Skin infiltration of circulating memory T cells with cutaneous tropism is considered one of the pathologic mechanisms in atopic dermatitis (AD). Skin-seeking circulating T lymphocytes can be identified by their expression of the cutaneous lymphocyte-associated antigen on the cell surface. Recent studies have contributed useful new information about the function and recirculation properties of those cells in AD patients. This review integrates the latest findings on peripheral cutaneous lymphocyte-associated antigen memory T cells in AD and highlights the relevance of this cell type and its importance to our understanding of the pathologic mechanisms of AD.

Participation of Neuropeptides and β-endorphin in Pathogenesis of Atopic Dermatitis. Evaluation of Levocetirizine Effectiveness upon Neuropeptides' Levels at Children with Atopic Dermatitis

Objective. Determination of the role of neuropeptides and p-endorphin in developmental mechanisms of atopic dermatitis, and assessment of the effectiveness of levocetirizine, a modern Hl-antihistamine, on atopic dermatitis symptoms and its influence on the SCORAD index in children with atopic dermatitis. Materials and methods. 84 children with atopic dermatitis of moderate-to-severe or severe clinical nature, aged 1 to 17 years, were enrolled in this (double-blind or open, randomised, etc.) study. Patients were treated with levocetirizine 5 mg once daily during 14 days. The levels of P substance, neurokinin A, neurokinin B, and p-endorphin in blood serum, as well as levocetirizine effectiveness on disease symptoms and the SCORAD index were evaluated. Results. Lower neuropeptide levels were associated with disease severity; children with severe atopic dermatitis had lower neuropeptide values. Before treatment, SCORAD index in children with severe atopic dermatitis was 76,5±11,3, and after 7 days of therapy SCORAD index was 14±6,2 points (p< 0,01). By the 7th day after treatment initiation, the acute atopic dermatitis became of subacute nature and was accompanied by a regression of the cutaneous eruption in the form of significant decreasing of skin manifestations and pruritus, absence of new eruption and normalized sleep. In children with moderate-to-severe atopic dermatitis the SCORAD index before levocetirizine treatment was 44,2±3,4 points; on the 3rd day, this index was 20,4±2,6 points; and on the 7th day there was a complete absence of clinical symptoms of the main disease. Levocetirizine administration led to the disappearance of the disease clinical symptoms and pruritus in children with moderate-to-severe atopic dermatitis. Conclusion. This trial demonstrated that neuropeptides are involved in the developmental mechanisms of atopic dermatitis and that levocetirizine can significantly improve the signs and symptoms of children with moderate-to-severe or severe atopic dermatitis.

“Outside-to-Inside” (and Now Back to “Outside”) Pathogenic Mechanisms in Atopic Dermatitis

The pathogenesis of atopic dermatitis (AD) has been attributed largely to abnormalities in the adaptive immune system, with key roles played by T-helper 1(Th1)/Th2 cell dysregulation, IgE production, dendritic cell signaling, and mast-cell hyperactivity, resulting in the pruritic, inflammatory dermatosis that characterizes AD (Leung et al., 2004). Accordingly, therapy has been focused on ameliorating Th2-mediated inflammation and pruritus (eg, Leung, 2000). Indeed, there is emerging evidence that inflammation in AD results first from inherited and acquired insults that converge to alter epidermal structure and function, followed by immune system activation, which in turn has negative consequences for skin-barrier homeostasis. This cycle comprises an "outside-inside-outside" model of AD pathogenesis (Elias et al., in press).

Development of new atopic dermatitis models characterized by not only itching but also inflammatory skin in mice

The present study was performed to develop a new atopic dermatitis model characterized by not only itching but also inflammatory skin using BALB/c mice. From 18 days after the first systemic immunization, daily epicutaneous application of ovalbumin was performed for 2 weeks. Antigen challenge (ovalbumin) resulted in a significant increase of scratching behavior from day 23 to day 32. Moreover, skin symptoms such as erythema/hemorrhage, edema, excoriation/erosion and dryness/desquamation were also observed from day 19 to day 32. The frequency of scratching in the first stage (from day 24 to day 26 after the systemic first immunization) was decreased by chlorpheniramine and epinastine; however, in the last stage (from day 27 to day 30 after the systemic first immunization), both drugs showed no inhibition of scratching behavior. Therefore, an endogenous mediator other than histamine may be responsible for provoking the itching sensation in the last stage. Naloxone dose-dependently reduced the frequency of scratching in the last stage. Moreover, repeated local application of dexametasone significantly inhibited both scratching behavior and skin symptoms from day 24 to day 30. From these findings, it may be concluded that this model is essentially similar to atopic dermatitis in humans and could be used to elucidate the pathogenic mechanisms of atopic dermatitis and to develop appropriate new drugs for therapy.