Materiały źródłowe

• #1 Molecular Mechanisms of Atopic Dermatitis Pathogenesis

  https://www.mdpi.com/1422-0067/22/8/4130

  Atopic dermatitis is a chronic, non-infectious inflammatory dermatosis. The pathophysiology of atopic dermatitis is complex and multifactorial. It includes genetic disorders, a defect in the epidermal barrier, an altered immune response, and disruption of the skin’s microbial balance. The numerous complex changes at the genetic level and innate and adaptive immunity provide the basis for characterizing the various phenotypes and endotypes of atopic dermatitis. The pathophysiology of atopic dermatitis is complex and multifactorial. Its understanding is complicated by the number of synergized factors that influence the disease. The most important are: genetic disorders, a defect in the epidermal barrier, an altered immune response and disturbed microbiological balance of the skin. Additionally, the environmental aspects, such as increased exposure to airborne or food allergens, pollution, infections, use of antibiotics, breastfeeding duration, diet, cosmetics or strong detergents, should be considered. The following paper presents some of the molecular mechanisms involved in the pathogenesis of atopic dermatitis. The initial suspicions of atopic dermatitis’s genetic background appeared along with the observations of a higher incidence of AD in families with atopy. It has been noted that children of parents with a history of allergic diseases have a greater risk of developing AD. There are many cooperating genes responsible for the disease’s pathogenesis. However, this is not a simple Mendelian inheritance. Genes are also subject to various heredity phenomena such as epigenetic changes, incomplete gene penetrance, and genomic imprinting. Gene mutations in the first group lead to impairment of the epidermal barrier function. The most popular of this group is the filaggrin gene mutation, considered one of AD’s major genes. The barrier defect causes degradation of intercellular connections, higher proteases activity, increased epidermal permeability, infiltration of antigens, and stimulation of proinflammatory cytokines. The chronic, relapsing course of the disease, economic burden, and the whole family’s involvement in the treatment process immensely reduce the quality of life in the case of patients and their families. The skin produces antimicrobial peptides (AMP) to destroy or inhibit microbes’ growth. Altered AMP expression and secretion may contribute to increased susceptibility to skin infections by viruses, bacteria and fungi in AD patients. The microbiome of healthy skin is characterized by species diversity and high stability over time. The disturbance and dysfunction of various microorganisms lead to diseases, including atopic dermatitis. It has been proven that the composition and diversity of microorganisms on the skin differ between people with eczema and those healthy ones. In atopic skin, there has been a reduction in commensal bacteria of the genera Streptococcus, Corynebacterium, Cutibacterium and the type Proteobacteria with the increase towards the genus Staphylococcus in general (S. aureus in particular).

• #2 Pathophysiology of atopic dermatitis: Clinical implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6399565/

  Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. Genetic predisposition, epidermal barrier disruption, and dysregulation of the immune system are some of the critical components of AD. An impaired skin barrier may be the initial step in the development of the atopic march as well as AD, which leads to further skin inflammation and allergic sensitization. Type 2 cytokines as well as interleukin 17 and interleukin 22 contribute to skin barrier dysfunction and the development of AD. […] Although the pathophysiology of AD is not completely understood, numerous studies demonstrated that skin barrier dysfunction and immune dysregulation contribute to the pathobiology of AD. […] Skin barrier dysfunction has been considered to be the first step in the development of atopic march as well as AD. However, it is also now evident that immune dysregulation, including the activation of type 2 immune responses, results in impairment of the epidermal barrier.

• #3 Molecular Mechanisms of Atopic Dermatitis Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8074061/

  Atopic dermatitis is a chronic, non-infectious inflammatory dermatosis. The pathophysiology of atopic dermatitis is complex and multifactorial. It includes genetic disorders, a defect in the epidermal barrier, an altered immune response, and disruption of the skin’s microbial balance. The numerous complex changes at the genetic level and innate and adaptive immunity provide the basis for characterizing the various phenotypes and endotypes of atopic dermatitis. The pathophysiology of atopic dermatitis is complex and multifactorial. Its understanding is complicated by the number of synergized factors that influence the disease. The most important are: genetic disorders, a defect in the epidermal barrier, an altered immune response and disturbed microbiological balance of the skin. The initial suspicions of atopic dermatitis’s genetic background appeared along with the observations of a higher incidence of AD in families with atopy. There are many cooperating genes responsible for the disease’s pathogenesis. However, this is not a simple Mendelian inheritance. Genes are also subject to various heredity phenomena such as epigenetic changes, incomplete gene penetrance, and genomic imprinting. The following paper presents some of the molecular mechanisms involved in the pathogenesis of atopic dermatitis. The likely mechanism of how the environment affects the organism’s cells are epigenetic changes. Epigenetic regulation is one of the determinants of AD development, next to the FLG gene polymorphisms and genes related to the immune system and the skin barrier. In AD, epigenetic changes concern genes known to affect the immune response regulation, genes of innate immunity, and genes encoding epidermis structural proteins. While describing atopic dermatitis causes, it is impossible to avoid disorders of immune regulation. Consequently, two different hypotheses have been proposed, from inside to outside and from outside to inside. The first one suggests that immunological aberrations are believed to be the primary initial event in development, and stimulation with allergens leads to weakening the epidermal barrier. The latter hypothesis assumes that an impaired skin barrier is the first step in atopic eczema’s pathogenesis and is required for immune dysregulation to occur. The skin produces antimicrobial peptides (AMP) to destroy or inhibit microbes growth. Altered AMP expression and secretion may contribute to increased susceptibility to skin infections by viruses, bacteria and fungi in AD patients. Atopic dermatitis is such a complex and diverse disease that different immune responses occur in various patient groups. Therefore, these specific molecular mechanisms underlying the disease have been defined as disease endotypes which set and variable constellations give rise to a particular phenotype.

• #4 The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-023-00992-4

  Atopic dermatitis (AD) is the most common inflammatory skin disease, and it is considered a complex and heterogeneous condition. […] Recent advancements in understanding AD pathogenesis resulted in a real translational revolution and led to the exponential expansion of the therapeutic pipeline. The study of biomarkers in clinical studies of emerging treatments is helping clarify the role of each cytokine and immune pathway in AD and will allow addressing the unique immune fingerprints of each AD subset. […] Two main contrasting hypotheses have been proposed in the past for the pathogenesis of AD. Based on the outside-in hypothesis, epidermal barrier dysfunction triggers immune activation; in contrast, based on the inside-out hypothesis, AD is primarily cytokine driven with secondary skin barrier dysfunction.

• #5 Atopic Dermatitis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/762045-overview

  Despite advances in the understanding of the genetics of AD, the pathophysiology remains poorly defined. Two main hypotheses have been proposed regarding the development of inflammation that leads to AD. The first suggests a primary immune dysfunction resulting in IgE sensitization, allergic inflammation, and a secondary epithelial barrier disturbance. The second proposes a primary defect in the epithelial barrier leading to secondary immunologic dysregulation and resulting in inflammation. […] In healthy individuals, balance exists between important subsets of T cells (eg, Th1, Th2, Th17, Th22). The primary immune dysfunction hypothesis invokes an imbalance in the T cell subsets, with Th2 cells predominating; this results in the production of type 2 cytokines such as interleukin (IL)-4, IL-5, and IL-13, causing an increase in IgE from plasma cells. Later, in persons with chronic AD, the Th1 cells have been shown to predominate. More recently, Th17 cells have been found to be elevated in patients with AD.

• #6 Overview of Atopic Dermatitis

  https://www.ajmc.com/view/overview-of-atopic-dermatitis-article

  Atopic dermatitis (AD) is a multifaceted, chronic relapsing inflammatory skin disease that is commonly associated with other atopic manifestations such as food allergy, allergic rhinitis, and asthma. It is the most common skin disease in children, affecting approximately 15% to 20% of children and 1% to 3% of adults. Onset of disease is most common by 5 years of age, and early diagnosis and treatment are essential to avoid complications of AD and improve quality of life. […] Two major theories have been proposed to explain the cause of AD, the inside-out and outside-in hypotheses. The inside-out hypothesis proposes that allergic triggering leads to a weakened skin barrier that furthers allergen introduction and presentation. This would suggest that inflammation is the culprit for an impaired skin barrier, leading to increased penetration of allergens and microbes causing a reaction. The outside-in hypothesis proposes that the impaired skin barrier precedes AD and is required for immune dysregulation to occur. For example, the down-regulation of filaggrin (FLG), required for proper skin barrier function, could make the skin more susceptible to immune dysregulation and lead to AD. It is unlikely that the 2 theories are exclusive and both most likely play a role in the pathogenesis of AD, discussed further below.

• #7 Pathophysiology of atopic dermatitis: Clinical implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6399565/

  Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. Genetic predisposition, epidermal barrier disruption, and dysregulation of the immune system are some of the critical components of AD. An impaired skin barrier may be the initial step in the development of the atopic march as well as AD, which leads to further skin inflammation and allergic sensitization. Type 2 cytokines as well as interleukin 17 and interleukin 22 contribute to skin barrier dysfunction and the development of AD. […] Although the pathophysiology of AD is not completely understood, numerous studies demonstrated that skin barrier dysfunction and immune dysregulation contribute to the pathobiology of AD. […] Skin barrier dysfunction has been considered to be the first step in the development of atopic march as well as AD. However, it is also now evident that immune dysregulation, including the activation of type 2 immune responses, results in impairment of the epidermal barrier.

• #8 The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-023-00992-4

  Environmental noxious stimuli, immune dysregulation, genetic factors, impaired epidermal barrier integrity, and skin microbiome abnormalities all play pathogenetic roles in initiating and sustaining a state of chronic inflammation in AD and contribute to orchestrating the disease phenotype. […] Epidermal barrier dysfunction in AD is characterized by a lower expression of terminal differentiation markers, such as filaggrin (FLG) and loricrin (LOR), and by a higher permeability defect caused by skin lipid film impairment and higher transepidermal water loss. […] Damaged keratinocytes produce epidermal alarmins such as IL-33, IL-25, and TSLP, which activate the dendritic cells (DCs) and type 2 innate lymphoid cells (ILC2s) that produce IL-5 and IL-13, which activate eosinophils and Th2 cells.

• #9 Atopic Dermatitis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/762045-overview

  The epidermal barrier dysfunction hypothesis suggests that patients develop AD as a result of skin barrier defects that allow antigens to enter, resulting in the production of inflammatory cytokines. Some authors question whether such antigens can also be absorbed from the gut (eg, from food), the lungs (eg, from house dust mites), or both. Xerosis and ichthyosis are known to be associated in many AD patients. Clinically, 37-50% of people with ichthyosis vulgaris have atopic disease, and as many as 37% of those with AD show evidence of ichthyosis. Mutations in the gene for filaggrin, a key epidermal barrier protein, cause ichthyosis vulgaris and are the strongest known genetic risk factors for AD. […] Furthermore, filaggrin mutations are associated with early-onset AD and with airway disease in the setting of AD. One mechanism by which filaggrin defects may influence inflammation is by the release of epithelial cell-derived cytokines, including TSLP, IL-25, and IL-33, all of which are known to be upregulated in the context of AD. TSLP has been shown to be a potent promoter of basophil and ILC2 responses in the skin, whereas IL-25 and IL-33 preferentially elicit ILC2s.

• #10 Atopic Dermatitis in Adults: Epidemiology, Risk Factors, Pathogenesis, Clinical Features, and Management | IntechOpen

  https://www.intechopen.com/chapters/76331

  The exact pathogenesis remains unclear and the underlying mechanism that is well known in the disease development and progression has been atopy. […] Although total Ig E elevation is mostly seen in many AD individuals, other factors also modulate the pathophysiology of AD giving rise to the non-atopic or non-T-2 inflammation form of the disease. […] A strong family history has been reported in 4060% of AD patients with filaggrin (FLG) null mutation in 2030%. […] Genetic mutations involving the epidermal differentiation complex (EDC) gene on chromosome 1q21 impairs epidermal differentiation resulting in stratum corneum barrier dysfunction. […] Recent studies have linked genetic FLG mutations to Th2 mediated AD and not non-Th2 inflammation AD giving rise to suggestions that skin barrier defect underlies the development of secondary allergic symptoms and respiratory atopy.

• #11 The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-023-00992-4

  Environmental noxious stimuli, immune dysregulation, genetic factors, impaired epidermal barrier integrity, and skin microbiome abnormalities all play pathogenetic roles in initiating and sustaining a state of chronic inflammation in AD and contribute to orchestrating the disease phenotype. […] Epidermal barrier dysfunction in AD is characterized by a lower expression of terminal differentiation markers, such as filaggrin (FLG) and loricrin (LOR), and by a higher permeability defect caused by skin lipid film impairment and higher transepidermal water loss. […] Damaged keratinocytes produce epidermal alarmins such as IL-33, IL-25, and TSLP, which activate the dendritic cells (DCs) and type 2 innate lymphoid cells (ILC2s) that produce IL-5 and IL-13, which activate eosinophils and Th2 cells.

• #12 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://clinics.elsevier.es/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  In AD, the unregulated and excessive production of cytokines, especially IL-4 and IL-13, causes the inhibition of the expression of epidermal proteins such as filaggrin, loricrin, and involucrin, which reinforces defects in the epidermal barrier, favoring the permeation of allergens and pathogens, feeding back the disease. […] The predominant Th2 imbalance in AD is implicated in reduced FLG expression, contributing to the barrier defect. […] The dysregulated type 2 inflammation cytokine response occurs in different anatomical sites of the body. At the level of the bronchi, IL-4 and IL-13 act by mediating inflammation and remodeling changes in the airways, predisposing the development of type 2-related asthma (50%-70% of asthmatics). […] The pathogenesis of AD comprises the interaction between alterations in barrier function, and environmental stimuli in the context of a dysregulated and spectral Th2 and Th17/22 immune response.

• #13 Pathophysiology of atopic dermatitis: Clinical implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6399565/

  Lipids, such as ceramides, long-chain FFAs, and cholesterol, constitute the lipid matrix that is organized in lamellar bodies and located between corneocytes. […] Altered lipid composition is observed in lesional and nonlesional AD skin. […] Recent studies demonstrated that appropriate probiotics are beneficial in the prevention and treatment of AD through the modulation of host immune responses. […] Multiple factors, including epidermal gene mutations, skin barrier dysfunction, immune dysregulation, neuroinflammation, altered lipid composition, and microbial imbalance, can contribute to the development of AD. Various strategies have been used to restore skin barrier function and control skin inflammation in patients with AD.

• #14 Pathogenesis and management of atopic dermatitis: insights into epidermal barrier dysfunction and immune mechanisms

  https://www.explorationpub.com/Journals/eaa/Article/100973

  The integrity of the skins epidermis depends significantly on the equilibrium between the skin proteases and their inhibitors. […] In AD patients, at least three factors contribute to barrier dysfunction: (1) abnormalities in FLG gene expression, (2) decreased skin ceramide levels, and (3) excessive activation of epidermal proteases. […] The FLG gene is crucial for preserving the function and integrity of the epidermal barrier, as it helps in forming bundles made up of KRT filaments and contributes to the hydration of the SC through its breakdown products, such as NMFs. […] Lack of FLG gene has demonstrated heightened penetration of antigens through the skin, resulting in amplified immune responses. […] The main lipids of the outermost skin layer, the SC, comprise ceramides, FFAs, etc. […] Abnormal skin lipids in AD are influenced by a heightened type 2 immune response, with inflammatory Th2 cytokines resulting in decreased total ceramide and long-chain fatty acid levels with altered chain lengths.

• #15 Pathogenesis and management of atopic dermatitis: insights into epidermal barrier dysfunction and immune mechanisms

  https://www.explorationpub.com/Journals/eaa/Article/100973

  The integrity of the skins epidermis depends significantly on the equilibrium between the skin proteases and their inhibitors. […] In AD patients, at least three factors contribute to barrier dysfunction: (1) abnormalities in FLG gene expression, (2) decreased skin ceramide levels, and (3) excessive activation of epidermal proteases. […] The FLG gene is crucial for preserving the function and integrity of the epidermal barrier, as it helps in forming bundles made up of KRT filaments and contributes to the hydration of the SC through its breakdown products, such as NMFs. […] Lack of FLG gene has demonstrated heightened penetration of antigens through the skin, resulting in amplified immune responses. […] The main lipids of the outermost skin layer, the SC, comprise ceramides, FFAs, etc. […] Abnormal skin lipids in AD are influenced by a heightened type 2 immune response, with inflammatory Th2 cytokines resulting in decreased total ceramide and long-chain fatty acid levels with altered chain lengths.

• #16 Atopic Dermatitis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/762045-overview

  Although filaggrin is strongly linked to AD, mutations are found in only 30% of European patients, raising the question of whether other genetic variants may also be responsible for some of the findings in the pathogenesis of AD. Indeed, genetic variants of TSLP have been shown to interact with mutations in filaggrin to influence AD disease persistence in patients. […] In AD, transepidermal water loss is increased. Whether primary immune dysregulation causes secondary epithelial barrier breakdown or whether primary epithelial barrier breakdown causes secondary immune dysregulation that results in disease remains unknown. However, given that filaggrin is critical for epithelial integrity, it is now thought that loss of filaggrin function leads to increased transepidermal penetration of environmental allergens, increasing inflammation and sensitivity and potentially leading to the atopic march.

• #17 Recent Advancements in the Atopic Dermatitis Mechanism

  https://www.imrpress.com/journal/FBL/29/2/10.31083/j.fbl2902084/htm

  Concerning the genetic component, the lower expression of terminal differentiation markers, such as filaggrin (FLG) and loricrin (LOR), and the respective barrier permeability defect associated with the epithelial lipid film impairment and increased transepidermal water loss (TEWL) are well-established determinants. […] Notably, the interleukin (IL)-31 network, comprising several cell types, such as macrophages, basophils, and the generated cytokines, is also involved in the pathogenesis of the itchiness in AD. […] The dysregulated T cell-mediated immune response, including different patterns of cytokine release, has a strong and robust role in the pathogenesis of AD. […] IL-4 and IL-13 represent the two main T2-cytokines associated with AD pathogenesis. […] The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is significant in the pathogenesis of AD and inflammation.

• #18 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://clinics.elsevier.es/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  In AD, the unregulated and excessive production of cytokines, especially IL-4 and IL-13, causes the inhibition of the expression of epidermal proteins such as filaggrin, loricrin, and involucrin, which reinforces defects in the epidermal barrier, favoring the permeation of allergens and pathogens, feeding back the disease. […] The predominant Th2 imbalance in AD is implicated in reduced FLG expression, contributing to the barrier defect. […] The dysregulated type 2 inflammation cytokine response occurs in different anatomical sites of the body. At the level of the bronchi, IL-4 and IL-13 act by mediating inflammation and remodeling changes in the airways, predisposing the development of type 2-related asthma (50%-70% of asthmatics). […] The pathogenesis of AD comprises the interaction between alterations in barrier function, and environmental stimuli in the context of a dysregulated and spectral Th2 and Th17/22 immune response.

• #19 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  This article constitutes a multidisciplinary narrative review of the current aspects of AD pathogenesis, which, although not fully elucidated, can be understood based on the interaction of unique aspects such as genetic predisposition; changes in the skin barrier; activation of keratinocytes by mechanical, physical or chemical stressors; imbalance of the innate and adaptive immunity responses/loss of immune tolerance; intrinsic and extrinsic factors as disease triggers or aggravating factors; associated organic comorbidities, and sensitization of the pruritus neural pathways, so that a bidirectional neural and immune interaction is established in AD. […] The skin barrier dysfunction that occurs in AD increases permeability to allergens and irritants, contributing to loss of hydration and persistence of subclinical skin inflammation.

• #20

  https://link.springer.com/article/10.1007/s12016-021-08880-3

  Atopic dermatitis (AD) is a common inflammatory skin disorder characterized by recurrent eczematous lesions and intense itch. […] The pathogenesis of AD is complex, and it is evident that a strong genetic predisposition, epidermal dysfunction, skin microbiome abnormalities, immune dysregulation, and the neuroimmune system are critical in AD development. […] Mutations in the genes associated with disrupted epidermal barrier, exaggerated pathological inflammation and inadequate antimicrobial peptides can promote enhanced Th2 inflammation and mediate pruritus. […] Current understanding of etiology highlights gut microbial diversity, NK cell deficiency, and different immunological phenotype with age and race. […] In-depth understanding of the pathogenesis of AD has led to the development of innovative and targeted therapies, such as biologic agents targeting interleukin (IL)-4, IL-13 and JAK/STAT inhibitors. […] Other potential therapeutic agents for AD include agents targeting the T helper (Th) 22 and Th17/IL23 pathway.

• #21 Atopic Dermatitis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/762045-overview

  In addition to T and B cells, other innate immune cells have also been implicated in the pathogenesis of AD, including eosinophils and mast cells. More recently, basophils and newly identified innate immune cells called group 2 innate lymphoid cells (ILC2s) have been shown to underlie the pathogenesis of AD. Together, basophils and ILC2s are critical sources of the type 2 cytokines IL-4, IL-5, and IL-13. Further, these cells appear to be potently regulated by a family of epithelial cell-derived cytokines directly released from damaged keratinocytes, including thymic stromal lymphopoietin (TSLP), IL-25, and IL-33. […] Taken together, these studies highlight a new paradigm in which, in addition to classical adaptive Th2 cells, innate type 2 immune cells play critical roles in the etiology of AD through interactions with epidermal-derived cytokines.

• #22 The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-023-00992-4

  Local Th2 polarization, in return, further diminishes barrier functions and sustains itching, causing skin barrier impairment and facilitating dysbiosis. […] AD emerged as a prototypical Th2 disease, and this was supported by multiple observations, including increased levels of Th2 products and lower levels of IFN- in the blood of patients with severe AD. […] Subsequent studies highlighted that AD lesions are primarily, but not exclusively, Th2-driven, with the overproduction of important Th2 cytokines and chemokines, including IL-4, IL-5, IL-13, CCL17, CCL18, and CCL22. […] The modern approach to defining AD pathogenesis is now centered on integrating these two mechanisms and is oriented toward characterizing their interplay in AD.

• #23 Disease Management: Atopic Dermatitis

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/dermatology/atopic-dermatitis/

  Atopic dermatitis is a type I IgE-mediated hypersensitivity reaction, but the exact etiology is unknown. The pathogenesis is multifactorial and involves a complex immunologic cascade, including disruption of the epidermal barrier, IgE dysregulation, defects in the cutaneous cell-mediated immune response, and genetic factors. […] The major elements in immune dysregulation are Langerhans’ cells, inflammatory dendritic epidermal cells, monocytes, macrophages, lymphocytes, mast cells, and keratinocytes, all of which interact through an intricate cascade of cytokines leading to a predominance of TH2 cells over TH1 cells. […] The TH2 cytokines, interleukin (IL)-4, IL-5, IL-10, and IL-13, are increased in the skin, and there is a corresponding decrease in TH1 cytokines, mainly interferon-gamma and IL-2.

• #24 Pathophysiology of atopic dermatitis: Clinical implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6399565/

  Recently, new insights into the pathophysiology of the development of AD focused on an important role of abnormalities in epidermal lipid layer as well as neuroimmune interactions and microbial dysbiosis. […] Polymorphisms of various immune pathway genes are associated with an increased risk of AD through alternations in the T-helper (Th) type 2 signaling pathway. Upregulation of interleukin (IL) 4 and IL-13 lowers FLG expression, which leads to skin barrier defects. […] Previous studies showed that type 2 immune cytokines, e.g., IL-4 and IL-13, play important roles in chemokine production, skin barrier dysfunction, suppression of antimicrobial peptides (AMP), and allergic inflammation. […] Although blockade of type 2-driven inflammation improves AD symptoms, the pathogenesis of AD is not exclusively explained by Th2 immunity. In this regard, IL-17 has been reported to reduce expression of FLG and involucrin.

• #25 DUPIXENT® (dupilumab) Mechanism of Action for Uncontrolled Moderate-to-Severe Atopic Dermatitis

  https://www.dupixenthcp.com/atopicdermatitis/about/mechanism-of-action

  The pathogenesis of atopic dermatitis involves a complex interplay between skin barrier dysfunction and type 2 inflammation, among other factors. […] Dysregulated IL-4 and IL-13 signaling may exacerbate epidermal barrier dysfunction, which contributes to the clinical manifestations of disease. […] The type 2 immune response involves the release of key cytokines from Th2, ILC2, Tc2, and a variety of other cell types. Several signaling cytokines, such as IL-4, IL-13, and IL-31, contribute to both the development and perpetuation of type 2 inflammation and clinical disease features of AD. Through both distinct and overlapping roles, IL-4 and IL-13 signaling through the IL-4 receptor alpha has shown to affect epidermal barrier dysfunction, increased susceptibility to skin infection, and chronic itch, factors that contribute to the development of eczematous skin lesions.

• #26 Pathophysiology of atopic dermatitis: Clinical implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6399565/

  Recently, new insights into the pathophysiology of the development of AD focused on an important role of abnormalities in epidermal lipid layer as well as neuroimmune interactions and microbial dysbiosis. […] Polymorphisms of various immune pathway genes are associated with an increased risk of AD through alternations in the T-helper (Th) type 2 signaling pathway. Upregulation of interleukin (IL) 4 and IL-13 lowers FLG expression, which leads to skin barrier defects. […] Previous studies showed that type 2 immune cytokines, e.g., IL-4 and IL-13, play important roles in chemokine production, skin barrier dysfunction, suppression of antimicrobial peptides (AMP), and allergic inflammation. […] Although blockade of type 2-driven inflammation improves AD symptoms, the pathogenesis of AD is not exclusively explained by Th2 immunity. In this regard, IL-17 has been reported to reduce expression of FLG and involucrin.

• #27 Overview of Atopic Dermatitis

  https://www.ajmc.com/view/overview-of-atopic-dermatitis-article

  The epidermis of the skin consists of several layers that act as barriers to prevent water loss and to protect the body from such foreign substances as microbes and allergens. The FLG gene, on chromosome 1q21.3, encodes a key protein in epidermal differentiation. This gene was originally identified as the gene involved in ichthyosis vulgaris, which will be discussed again later, and several loss-of-function mutations were identified in European and Japanese patients with AD. Since then, multiple studies have demonstrated that the FLG gene plays a pivotal role in skin barrier function and mutations of the FLG gene are a major risk factor for AD. […] Other immune system-related genes found to be associated with AD include those encoded on chromosome 5q31 to 5q33. These genes code for cytokines that regulate immunoglobulin E (IgE) synthesis: interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-12 (IL-12), interleukin-13 (IL-13), and granulocyte-macrophage colony-stimulating factor. Cytokines are mainly produced by type 1 and type 2 T helper lymphocytes (TH1 and TH2, respectively). TH1 cytokines (IL-12 and interferon-) suppress IgE production, and TH2 cytokines (IL-5 and IL-13) increase IgE production. Patients with AD have a genetically determined dominance of TH2 cells that may decrease expression of FLG and other molecules found in the skin barrier.

• #28 Dupilumab Treatment In AD Pediatric Patients Aged 6-11y | DDDT

  https://www.dovepress.com/dupilumab-treatment-in-pediatric-patients-aged-611-years-with-severe-a-peer-reviewed-fulltext-article-DDDT

  Atopic dermatitis (AD) is a common inflammatory skin disease of childhood affecting as many as 20% of children worldwide, with a prevalence of 13% in children aged 611 years. […] For decades, dermatologists considered skin barrier dysfunction to be an earlier factor in AD pathophysiology than inflammatory response. Recent data have shown that the skin barrier dysfunction that enables penetration of antigens is caused mainly by the type 2 inflammatory cytokines interleukin (IL)-4 and IL-13. These cytokines produced by keratinocytes, lymphocytes (eg, T helper type 2 cells), mast cells, basophils, and eosinophils disrupt the skin barrier through interference in several different components: downregulating filaggrin expression; reducing tight junction barrier function; reducing synthesis of long-chain ceramides; reducing production of antimicrobial peptides and natural moisturizing factors; and inducing microbiome dysbiosis. […] Additional clinical evidence has confirmed this finding by showing reversibility of skin barrier dysfunction with dupilumab treatment.

• #29 Dupilumab Treatment In AD Pediatric Patients Aged 6-11y | DDDT

  https://www.dovepress.com/dupilumab-treatment-in-pediatric-patients-aged-611-years-with-severe-a-peer-reviewed-fulltext-article-DDDT

  Atopic dermatitis (AD) is a common inflammatory skin disease of childhood affecting as many as 20% of children worldwide, with a prevalence of 13% in children aged 611 years. […] For decades, dermatologists considered skin barrier dysfunction to be an earlier factor in AD pathophysiology than inflammatory response. Recent data have shown that the skin barrier dysfunction that enables penetration of antigens is caused mainly by the type 2 inflammatory cytokines interleukin (IL)-4 and IL-13. These cytokines produced by keratinocytes, lymphocytes (eg, T helper type 2 cells), mast cells, basophils, and eosinophils disrupt the skin barrier through interference in several different components: downregulating filaggrin expression; reducing tight junction barrier function; reducing synthesis of long-chain ceramides; reducing production of antimicrobial peptides and natural moisturizing factors; and inducing microbiome dysbiosis. […] Additional clinical evidence has confirmed this finding by showing reversibility of skin barrier dysfunction with dupilumab treatment.

• #30 Unraveling Atopic Dermatitis: Insights into Pathophysiology, Therapeutic Advances, and Future Perspectives

  https://www.mdpi.com/2073-4409/13/5/425

  Atopic dermatitis (AD) is an inflammatory skin condition that frequently develops before the onset of allergic rhinitis or asthma. Recent research has connected the environment, genetics, the skin barrier, drugs, psychological factors, and the immune system to the onset and severity of AD. The pathogenesis of AD is multifaceted, involving genetic predispositions, abnormalities in skin function, immune system dysregulation, and environmental influences. The essential membrane protein filaggrin (FLG) has been discovered to have the greatest genetic association with AD. FLG null mutations weaken the skin barrier and heighten AD risk. In addition to FLG gene mutations, factors like DNA methylation, FLG copy number variations, environmental influences (skin irritation, damage, and low humidity), cytokines (Th2, interleukins (IL)-17, IL-22, IL-25, and IL-31) reducing FLG expression, skin microorganisms, and treatments (topical and systemic) can also alter FLG levels. The cells involved in host–environment interaction resulting in skin inflammation are eosinophils, basophils, dendritic cells (DCs), keratinocytes, mast cells, macrophages, and type 2 innate lymphoid cells (ILC2s). Additionally, reductions in the levels of epidermal barrier proteins, such as FLG, spinous layer proteins (SPINK), and claudins, alongside alterations of antimicrobial peptides, play a significant role. Both T and B cells, together with their respective cytokines, contribute to this disease’s immunological profile, highlighted by a dominant Th2 axis (including IL-4, IL-13, IL-5, thymic stromal lymphopoietin (TSLP), and IL-31), elevated Th17/IL-23 and Th22 pathways, and increased IgE levels. The main connection between skin bacteria and AD is S. aureus, often found on the skin of AD patients. Skin problems deriving from AD make it easier for S. aureus to grow. When there is a lack of FLG, there is usually more S. aureus in the skin’s microbiome. S. aureus prompts keratinocytes to produce proteases, worsening the skin’s barrier. It also releases harmful substances like δ-toxin and α-toxin; δ-toxin can trigger mast cells to release substances without killing them, particularly when IgE is present. The Th2 cytokines IL-4, IL-5, and IL-13 play a pivotal role in AD and have been linked to increased IgE response and eosinophils in AD patients. In AD patients, IL-4 and IL-4 receptors on peripheral blood lymphocytes were aberrant, with an increased production of IL-13. It was previously demonstrated that AD patients lost their capacity to release IFN-γ in response to different stimuli. Researchers have found a notable connection wherein the amount of IFN-γ produced is linked to lower levels of IgE found in the blood of individuals with AD. Studies on patients with acute AD revealed that they had higher amounts of IFN-γ and IL-4 in the skin and peripheral blood. These cytokines are secreted by T cells that are specific to the allergens. When an antigen is encountered by antigen-presenting cells such as DCs, they release TSLP and initiate signaling pathways that activate naïve T cells. This leads to the differentiation of T cells into Th1 and Th2 subtypes, which release interleukins and chemokines to combat the antigen. However, this immune response contributes to inflammation and may exacerbate skin barrier dysfunction in AD rather than directly cause barrier penetration. The exploration of interleukins and their influence on the immunological pathway in AD has been facilitated by using relevant biomarkers in clinical trials. This approach enables the identification of novel therapeutic modalities, fostering the potential for targeted translational research within the realm of personalized medicine.

• #31 Preclinical models of atopic dermatitis suitable for mechanistic and t | JIR

  https://www.dovepress.com/preclinical-models-of-atopic-dermatitis-suitable-for-mechanistic-and-t-peer-reviewed-fulltext-article-JIR

  Atopic dermatitis (AD) is a complex immune-mediated abnormality of the skin characterized by impaired barrier function, eczematous dermatitis, chronic pruritus and itch. The immunological response in AD is mediated by a Th2-dominated immune response in the early acute phase followed by a Th1/ Th2 mixed immune response in the chronic phase. […] The exact mechanism underlying the complex progression of AD is not yet well understood. However, considerable progress in understanding the disease mechanism has led to many findings related to genetic abnormalities, immunological dysfunction, and environmental factors as the prime drivers of AD exacerbation. […] Activated skin cells release thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33 from keratinocytes, leading to the activation of the Th2 immune axis through type 2 innate lymphoid cells (ILC2) and Th2 cells. In the acute phase of AD, Th2 cytokines (IL-4, IL-5, and IL-13) play major roles in barrier dysfunction.

• #32 Recent Advancements in the Atopic Dermatitis Mechanism

  https://www.imrpress.com/journal/FBL/29/2/10.31083/j.fbl2902084/htm

  Concerning the genetic component, the lower expression of terminal differentiation markers, such as filaggrin (FLG) and loricrin (LOR), and the respective barrier permeability defect associated with the epithelial lipid film impairment and increased transepidermal water loss (TEWL) are well-established determinants. […] Notably, the interleukin (IL)-31 network, comprising several cell types, such as macrophages, basophils, and the generated cytokines, is also involved in the pathogenesis of the itchiness in AD. […] The dysregulated T cell-mediated immune response, including different patterns of cytokine release, has a strong and robust role in the pathogenesis of AD. […] IL-4 and IL-13 represent the two main T2-cytokines associated with AD pathogenesis. […] The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is significant in the pathogenesis of AD and inflammation.

• #33 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://clinics.elsevier.es/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  This article constitutes a multidisciplinary narrative review of the current aspects of AD pathogenesis, which, although not fully elucidated, can be understood based on the interaction of unique aspects such as genetic predisposition; changes in the skin barrier; activation of keratinocytes by mechanical, physical or chemical stressors; imbalance of the innate and adaptive immunity responses/loss of immune tolerance; intrinsic and extrinsic factors as disease triggers or aggravating factors; associated organic comorbidities, and sensitization of the pruritus neural pathways, so that a bidirectional neural and immune interaction is established in AD. […] The TSLP alarmin produced by keratinocytes subjected to stress, allergens, or pathogens, causes the activation of dendritic cells and the secretion of chemokines, which attract type 2 helper T lymphocytes (Th2) to the skin, releasing pro-allergenic cytokines (type 2 inflammation cytokines, such as IL-4, IL-13, IL-5, IL-31).

• #34 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://clinics.elsevier.es/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  This article constitutes a multidisciplinary narrative review of the current aspects of AD pathogenesis, which, although not fully elucidated, can be understood based on the interaction of unique aspects such as genetic predisposition; changes in the skin barrier; activation of keratinocytes by mechanical, physical or chemical stressors; imbalance of the innate and adaptive immunity responses/loss of immune tolerance; intrinsic and extrinsic factors as disease triggers or aggravating factors; associated organic comorbidities, and sensitization of the pruritus neural pathways, so that a bidirectional neural and immune interaction is established in AD. […] The TSLP alarmin produced by keratinocytes subjected to stress, allergens, or pathogens, causes the activation of dendritic cells and the secretion of chemokines, which attract type 2 helper T lymphocytes (Th2) to the skin, releasing pro-allergenic cytokines (type 2 inflammation cytokines, such as IL-4, IL-13, IL-5, IL-31).

• #35 Atopic Dermatitis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/762045-overview

  The epidermal barrier dysfunction hypothesis suggests that patients develop AD as a result of skin barrier defects that allow antigens to enter, resulting in the production of inflammatory cytokines. Some authors question whether such antigens can also be absorbed from the gut (eg, from food), the lungs (eg, from house dust mites), or both. Xerosis and ichthyosis are known to be associated in many AD patients. Clinically, 37-50% of people with ichthyosis vulgaris have atopic disease, and as many as 37% of those with AD show evidence of ichthyosis. Mutations in the gene for filaggrin, a key epidermal barrier protein, cause ichthyosis vulgaris and are the strongest known genetic risk factors for AD. […] Furthermore, filaggrin mutations are associated with early-onset AD and with airway disease in the setting of AD. One mechanism by which filaggrin defects may influence inflammation is by the release of epithelial cell-derived cytokines, including TSLP, IL-25, and IL-33, all of which are known to be upregulated in the context of AD. TSLP has been shown to be a potent promoter of basophil and ILC2 responses in the skin, whereas IL-25 and IL-33 preferentially elicit ILC2s.

• #36 The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-023-00992-4

  Local Th2 polarization, in return, further diminishes barrier functions and sustains itching, causing skin barrier impairment and facilitating dysbiosis. […] AD emerged as a prototypical Th2 disease, and this was supported by multiple observations, including increased levels of Th2 products and lower levels of IFN- in the blood of patients with severe AD. […] Subsequent studies highlighted that AD lesions are primarily, but not exclusively, Th2-driven, with the overproduction of important Th2 cytokines and chemokines, including IL-4, IL-5, IL-13, CCL17, CCL18, and CCL22. […] The modern approach to defining AD pathogenesis is now centered on integrating these two mechanisms and is oriented toward characterizing their interplay in AD.

• #37 Preclinical models of atopic dermatitis suitable for mechanistic and t | JIR

  https://www.dovepress.com/preclinical-models-of-atopic-dermatitis-suitable-for-mechanistic-and-t-peer-reviewed-fulltext-article-JIR

  Chronic AD is characterized by Th1/ Th2 mixed immune responses with intensification of Th2, Th1, and Th17 responses. […] Increased levels of Th1 cytokine interferon-gamma (IFN-), IL-12, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are highly dominant in chronic AD. […] Furthermore, IL-17 stimulates B cells to differentiate into IgE-producing plasma cells and promotes the release of IL-8, TNF-, and TSLP, the combined actions of which trigger chronic AD. […] Skin barrier dysfunction is considered the first step in the development of atopic march. […] The classical atopic march is but only one possibility with regards to progression of AD to atopic multimorbidity and that early life AD phenotypes, genotypes and environmental factors influence overall atopic disease trajectory and the relationships between and timing of onset of atopic comorbidities are more complex and many different patterns exist.

• #38 Pathophysiology of atopic dermatitis: Clinical implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6399565/

  Recently, new insights into the pathophysiology of the development of AD focused on an important role of abnormalities in epidermal lipid layer as well as neuroimmune interactions and microbial dysbiosis. […] Polymorphisms of various immune pathway genes are associated with an increased risk of AD through alternations in the T-helper (Th) type 2 signaling pathway. Upregulation of interleukin (IL) 4 and IL-13 lowers FLG expression, which leads to skin barrier defects. […] Previous studies showed that type 2 immune cytokines, e.g., IL-4 and IL-13, play important roles in chemokine production, skin barrier dysfunction, suppression of antimicrobial peptides (AMP), and allergic inflammation. […] Although blockade of type 2-driven inflammation improves AD symptoms, the pathogenesis of AD is not exclusively explained by Th2 immunity. In this regard, IL-17 has been reported to reduce expression of FLG and involucrin.

• #39 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://clinics.elsevier.es/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  In AD, the unregulated and excessive production of cytokines, especially IL-4 and IL-13, causes the inhibition of the expression of epidermal proteins such as filaggrin, loricrin, and involucrin, which reinforces defects in the epidermal barrier, favoring the permeation of allergens and pathogens, feeding back the disease. […] The predominant Th2 imbalance in AD is implicated in reduced FLG expression, contributing to the barrier defect. […] The dysregulated type 2 inflammation cytokine response occurs in different anatomical sites of the body. At the level of the bronchi, IL-4 and IL-13 act by mediating inflammation and remodeling changes in the airways, predisposing the development of type 2-related asthma (50%-70% of asthmatics). […] The pathogenesis of AD comprises the interaction between alterations in barrier function, and environmental stimuli in the context of a dysregulated and spectral Th2 and Th17/22 immune response.

• #40 Pathophysiology of atopic dermatitis: Clinical implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6399565/

  IL-22 is also highly upregulated in the skin of patients with AD and is associated with skin barrier dysfunction and abnormal epidermal markers, such as keratin 6 and keratin 16. […] A damaged epidermal barrier not only leads to the development of AD but also heightens sensitization to allergens and contributes to the risk of Food allergy (FA) and airway hyperreactivity. […] Defects in epidermal barrier proteins, such as FLG, transglutaminases, keratins, and intercellular proteins, facilitate dysregulated immune responses to external antigens and drive skin and systemic inflammatory responses. […] AMPs, including cathelicidin (LL-37) and human -defensins, are produced by keratinocytes and play a pivotal role for host defense as well as control of host physiologic functions, such as inflammation and wound healing.

• #41 Pathogenesis of atopic dermatitis: Current concepts – Journal of Skin and Sexually Transmitted Diseases

  https://jsstd.org/pathogenesis-of-atopic-dermatitis-current-concepts/

  Once the permeability barrier is perturbed in a sustained manner, a number of defense mechanisms are activated to protect the underlying dermis. […] However, a sustained defect in the epidermal permeability barrier impairs the homeostatic response, allows the inflammation to spread and, recruits inflammatory cells consisting of lymphocytes, eosinophils, and mast cells. […] The defective barrier allows the entry of many noxious agents including environmental antigens, aeroallergens, and haptens as well as antigens derived from microorganisms, especially Staphylococcus aureus. […] The persistence of this process switches the specific protective adaptive immune responses to a more allergy dominant Th2 and Th22 dominant immune profile. […] This inflammation results in further deterioration of the permeability barrier.

• #42 Atopic Dermatitis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/762045-overview

  Despite advances in the understanding of the genetics of AD, the pathophysiology remains poorly defined. Two main hypotheses have been proposed regarding the development of inflammation that leads to AD. The first suggests a primary immune dysfunction resulting in IgE sensitization, allergic inflammation, and a secondary epithelial barrier disturbance. The second proposes a primary defect in the epithelial barrier leading to secondary immunologic dysregulation and resulting in inflammation. […] In healthy individuals, balance exists between important subsets of T cells (eg, Th1, Th2, Th17, Th22). The primary immune dysfunction hypothesis invokes an imbalance in the T cell subsets, with Th2 cells predominating; this results in the production of type 2 cytokines such as interleukin (IL)-4, IL-5, and IL-13, causing an increase in IgE from plasma cells. Later, in persons with chronic AD, the Th1 cells have been shown to predominate. More recently, Th17 cells have been found to be elevated in patients with AD.

• #43 Preclinical models of atopic dermatitis suitable for mechanistic and t | JIR

  https://www.dovepress.com/preclinical-models-of-atopic-dermatitis-suitable-for-mechanistic-and-t-peer-reviewed-fulltext-article-JIR

  Chronic AD is characterized by Th1/ Th2 mixed immune responses with intensification of Th2, Th1, and Th17 responses. […] Increased levels of Th1 cytokine interferon-gamma (IFN-), IL-12, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are highly dominant in chronic AD. […] Furthermore, IL-17 stimulates B cells to differentiate into IgE-producing plasma cells and promotes the release of IL-8, TNF-, and TSLP, the combined actions of which trigger chronic AD. […] Skin barrier dysfunction is considered the first step in the development of atopic march. […] The classical atopic march is but only one possibility with regards to progression of AD to atopic multimorbidity and that early life AD phenotypes, genotypes and environmental factors influence overall atopic disease trajectory and the relationships between and timing of onset of atopic comorbidities are more complex and many different patterns exist.

• #44 Atopic Dermatitis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/762045-overview

  In addition to T and B cells, other innate immune cells have also been implicated in the pathogenesis of AD, including eosinophils and mast cells. More recently, basophils and newly identified innate immune cells called group 2 innate lymphoid cells (ILC2s) have been shown to underlie the pathogenesis of AD. Together, basophils and ILC2s are critical sources of the type 2 cytokines IL-4, IL-5, and IL-13. Further, these cells appear to be potently regulated by a family of epithelial cell-derived cytokines directly released from damaged keratinocytes, including thymic stromal lymphopoietin (TSLP), IL-25, and IL-33. […] Taken together, these studies highlight a new paradigm in which, in addition to classical adaptive Th2 cells, innate type 2 immune cells play critical roles in the etiology of AD through interactions with epidermal-derived cytokines.

• #45 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://clinics.elsevier.es/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  After surpassing the skin barrier, the antigens are phagocytosed by different antigen-presenting cells, especially LCs. […] This contribution of LCs also occurs in the context of AD and food allergy through transcutaneous sensitization to food allergens. […] The immunopathogenesis of AD is based on a deregulated immune response, in a multidimensional and interconnected way, affecting the response to antigens, the induction of inflammation, immune homeostasis disruption, disarray of the architectural integrity of the epidermis and dermis, producing a cardinal symptom, which is pruritus.

• #46 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  A dysfunctional skin barrier is more prevalent in patients with AD, and this deficit has several clinical consequences, as these patients are characterized by high reactivity to environmental stimuli and pathogens, reinforcing the role of restoring the skin barrier and protection against triggers for disease control. […] The predominant Th2 imbalance in AD is implicated in reduced FLG expression, contributing to the barrier defect. […] The pathogenesis of AD comprises the interaction between alterations in barrier function, and environmental stimuli in the context of a dysregulated and spectral Th2 and Th17/22 immune response. […] After surpassing the skin barrier, the antigens are phagocytosed by different antigen-presenting cells, especially LCs. […] The immunopathogenesis of AD is based on a deregulated immune response, in a multidimensional and interconnected way, affecting the response to antigens, the induction of inflammation, immune homeostasis disruption, disarray of the architectural integrity of the epidermis and dermis, producing a cardinal symptom, which is pruritus.

• #47 Atopic Dermatitis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/762045-overview

  In addition to T and B cells, other innate immune cells have also been implicated in the pathogenesis of AD, including eosinophils and mast cells. More recently, basophils and newly identified innate immune cells called group 2 innate lymphoid cells (ILC2s) have been shown to underlie the pathogenesis of AD. Together, basophils and ILC2s are critical sources of the type 2 cytokines IL-4, IL-5, and IL-13. Further, these cells appear to be potently regulated by a family of epithelial cell-derived cytokines directly released from damaged keratinocytes, including thymic stromal lymphopoietin (TSLP), IL-25, and IL-33. […] Taken together, these studies highlight a new paradigm in which, in addition to classical adaptive Th2 cells, innate type 2 immune cells play critical roles in the etiology of AD through interactions with epidermal-derived cytokines.

• #48 Unraveling Atopic Dermatitis: Insights into Pathophysiology, Therapeutic Advances, and Future Perspectives

  https://www.mdpi.com/2073-4409/13/5/425

  Atopic dermatitis (AD) is an inflammatory skin condition that frequently develops before the onset of allergic rhinitis or asthma. Recent research has connected the environment, genetics, the skin barrier, drugs, psychological factors, and the immune system to the onset and severity of AD. The pathogenesis of AD is multifaceted, involving genetic predispositions, abnormalities in skin function, immune system dysregulation, and environmental influences. The essential membrane protein filaggrin (FLG) has been discovered to have the greatest genetic association with AD. FLG null mutations weaken the skin barrier and heighten AD risk. In addition to FLG gene mutations, factors like DNA methylation, FLG copy number variations, environmental influences (skin irritation, damage, and low humidity), cytokines (Th2, interleukins (IL)-17, IL-22, IL-25, and IL-31) reducing FLG expression, skin microorganisms, and treatments (topical and systemic) can also alter FLG levels. The cells involved in host–environment interaction resulting in skin inflammation are eosinophils, basophils, dendritic cells (DCs), keratinocytes, mast cells, macrophages, and type 2 innate lymphoid cells (ILC2s). Additionally, reductions in the levels of epidermal barrier proteins, such as FLG, spinous layer proteins (SPINK), and claudins, alongside alterations of antimicrobial peptides, play a significant role. Both T and B cells, together with their respective cytokines, contribute to this disease’s immunological profile, highlighted by a dominant Th2 axis (including IL-4, IL-13, IL-5, thymic stromal lymphopoietin (TSLP), and IL-31), elevated Th17/IL-23 and Th22 pathways, and increased IgE levels. The main connection between skin bacteria and AD is S. aureus, often found on the skin of AD patients. Skin problems deriving from AD make it easier for S. aureus to grow. When there is a lack of FLG, there is usually more S. aureus in the skin’s microbiome. S. aureus prompts keratinocytes to produce proteases, worsening the skin’s barrier. It also releases harmful substances like δ-toxin and α-toxin; δ-toxin can trigger mast cells to release substances without killing them, particularly when IgE is present. The Th2 cytokines IL-4, IL-5, and IL-13 play a pivotal role in AD and have been linked to increased IgE response and eosinophils in AD patients. In AD patients, IL-4 and IL-4 receptors on peripheral blood lymphocytes were aberrant, with an increased production of IL-13. It was previously demonstrated that AD patients lost their capacity to release IFN-γ in response to different stimuli. Researchers have found a notable connection wherein the amount of IFN-γ produced is linked to lower levels of IgE found in the blood of individuals with AD. Studies on patients with acute AD revealed that they had higher amounts of IFN-γ and IL-4 in the skin and peripheral blood. These cytokines are secreted by T cells that are specific to the allergens. When an antigen is encountered by antigen-presenting cells such as DCs, they release TSLP and initiate signaling pathways that activate naïve T cells. This leads to the differentiation of T cells into Th1 and Th2 subtypes, which release interleukins and chemokines to combat the antigen. However, this immune response contributes to inflammation and may exacerbate skin barrier dysfunction in AD rather than directly cause barrier penetration. The exploration of interleukins and their influence on the immunological pathway in AD has been facilitated by using relevant biomarkers in clinical trials. This approach enables the identification of novel therapeutic modalities, fostering the potential for targeted translational research within the realm of personalized medicine.

• #49 Atopic Dermatitis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/762045-overview

  In addition to T and B cells, other innate immune cells have also been implicated in the pathogenesis of AD, including eosinophils and mast cells. More recently, basophils and newly identified innate immune cells called group 2 innate lymphoid cells (ILC2s) have been shown to underlie the pathogenesis of AD. Together, basophils and ILC2s are critical sources of the type 2 cytokines IL-4, IL-5, and IL-13. Further, these cells appear to be potently regulated by a family of epithelial cell-derived cytokines directly released from damaged keratinocytes, including thymic stromal lymphopoietin (TSLP), IL-25, and IL-33. […] Taken together, these studies highlight a new paradigm in which, in addition to classical adaptive Th2 cells, innate type 2 immune cells play critical roles in the etiology of AD through interactions with epidermal-derived cytokines.

• #50 Unraveling Atopic Dermatitis: Insights into Pathophysiology, Therapeutic Advances, and Future Perspectives

  https://www.mdpi.com/2073-4409/13/5/425

  Atopic dermatitis (AD) is an inflammatory skin condition that frequently develops before the onset of allergic rhinitis or asthma. Recent research has connected the environment, genetics, the skin barrier, drugs, psychological factors, and the immune system to the onset and severity of AD. The pathogenesis of AD is multifaceted, involving genetic predispositions, abnormalities in skin function, immune system dysregulation, and environmental influences. The essential membrane protein filaggrin (FLG) has been discovered to have the greatest genetic association with AD. FLG null mutations weaken the skin barrier and heighten AD risk. In addition to FLG gene mutations, factors like DNA methylation, FLG copy number variations, environmental influences (skin irritation, damage, and low humidity), cytokines (Th2, interleukins (IL)-17, IL-22, IL-25, and IL-31) reducing FLG expression, skin microorganisms, and treatments (topical and systemic) can also alter FLG levels. The cells involved in host–environment interaction resulting in skin inflammation are eosinophils, basophils, dendritic cells (DCs), keratinocytes, mast cells, macrophages, and type 2 innate lymphoid cells (ILC2s). Additionally, reductions in the levels of epidermal barrier proteins, such as FLG, spinous layer proteins (SPINK), and claudins, alongside alterations of antimicrobial peptides, play a significant role. Both T and B cells, together with their respective cytokines, contribute to this disease’s immunological profile, highlighted by a dominant Th2 axis (including IL-4, IL-13, IL-5, thymic stromal lymphopoietin (TSLP), and IL-31), elevated Th17/IL-23 and Th22 pathways, and increased IgE levels. The main connection between skin bacteria and AD is S. aureus, often found on the skin of AD patients. Skin problems deriving from AD make it easier for S. aureus to grow. When there is a lack of FLG, there is usually more S. aureus in the skin’s microbiome. S. aureus prompts keratinocytes to produce proteases, worsening the skin’s barrier. It also releases harmful substances like δ-toxin and α-toxin; δ-toxin can trigger mast cells to release substances without killing them, particularly when IgE is present. The Th2 cytokines IL-4, IL-5, and IL-13 play a pivotal role in AD and have been linked to increased IgE response and eosinophils in AD patients. In AD patients, IL-4 and IL-4 receptors on peripheral blood lymphocytes were aberrant, with an increased production of IL-13. It was previously demonstrated that AD patients lost their capacity to release IFN-γ in response to different stimuli. Researchers have found a notable connection wherein the amount of IFN-γ produced is linked to lower levels of IgE found in the blood of individuals with AD. Studies on patients with acute AD revealed that they had higher amounts of IFN-γ and IL-4 in the skin and peripheral blood. These cytokines are secreted by T cells that are specific to the allergens. When an antigen is encountered by antigen-presenting cells such as DCs, they release TSLP and initiate signaling pathways that activate naïve T cells. This leads to the differentiation of T cells into Th1 and Th2 subtypes, which release interleukins and chemokines to combat the antigen. However, this immune response contributes to inflammation and may exacerbate skin barrier dysfunction in AD rather than directly cause barrier penetration. The exploration of interleukins and their influence on the immunological pathway in AD has been facilitated by using relevant biomarkers in clinical trials. This approach enables the identification of novel therapeutic modalities, fostering the potential for targeted translational research within the realm of personalized medicine.

• #51 Atopic Dermatitis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/762045-overview

  In addition to T and B cells, other innate immune cells have also been implicated in the pathogenesis of AD, including eosinophils and mast cells. More recently, basophils and newly identified innate immune cells called group 2 innate lymphoid cells (ILC2s) have been shown to underlie the pathogenesis of AD. Together, basophils and ILC2s are critical sources of the type 2 cytokines IL-4, IL-5, and IL-13. Further, these cells appear to be potently regulated by a family of epithelial cell-derived cytokines directly released from damaged keratinocytes, including thymic stromal lymphopoietin (TSLP), IL-25, and IL-33. […] Taken together, these studies highlight a new paradigm in which, in addition to classical adaptive Th2 cells, innate type 2 immune cells play critical roles in the etiology of AD through interactions with epidermal-derived cytokines.

• #52 Recent Advancements in the Atopic Dermatitis Mechanism

  https://www.imrpress.com/journal/FBL/29/2/10.31083/j.fbl2902084/htm

  Concerning the genetic component, the lower expression of terminal differentiation markers, such as filaggrin (FLG) and loricrin (LOR), and the respective barrier permeability defect associated with the epithelial lipid film impairment and increased transepidermal water loss (TEWL) are well-established determinants. […] Notably, the interleukin (IL)-31 network, comprising several cell types, such as macrophages, basophils, and the generated cytokines, is also involved in the pathogenesis of the itchiness in AD. […] The dysregulated T cell-mediated immune response, including different patterns of cytokine release, has a strong and robust role in the pathogenesis of AD. […] IL-4 and IL-13 represent the two main T2-cytokines associated with AD pathogenesis. […] The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is significant in the pathogenesis of AD and inflammation.

• #53 Atopic Dermatitis in Adults: Epidemiology, Risk Factors, Pathogenesis, Clinical Features, and Management | IntechOpen

  https://www.intechopen.com/chapters/76331

  The degree of membrane disruption directly correlates with the severity of AD. […] Polymorphisms of genes in the Th2 signaling pathway particularly cytokine receptors (IL-4R and IL-13R) are associated with immune dysfunction in AD. […] The TH2 cytokines (IL-4, IL-13, IL-31) and TH22 cytokine (IL-22) are believed to play roles in the overall pathogenesis of atopic dermatitis but mostly acute AD. […] Damage to the skin barrier allows penetration of the skin by allergens, environmental factors and infective organisms activating the skin antigen-presenting cells (APCs). […] The APCs migrate to lymph nodes and stimulate naive T cells differentiation into TH2 cells and B lymphocytes. […] The Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway acts downstream of more than 50 cytokines. […] It is central to inflammatory processes involving B-cells, T-cells, neutrophils, macrophages and natural killer cells.

• #54 Recent Advancements in the Atopic Dermatitis Mechanism

  https://www.imrpress.com/journal/FBL/29/2/10.31083/j.fbl2902084/htm

  The increased phosphodiesterase 4 (PDE4) activity observed in AD results in the reduction of intracellular cyclic adenosine monophosphate (cAMP), a negative regulator of cytokine production, leading to the augmented production of proinflammatory mediators and cytokines transcription involved in acute and chronic inflammation. […] The cardinal role of epidermal barrier dysfunction in the induction and perpetuation of AD is well established. […] The epithelial barrier consists of four cell layers: The stratum basal, the stratum spinosum, the stratum granulosum (SG), and the stratum corneum (SC) within the epidermis. […] Filaggrin (FLG) is an important structural protein responsible for the keratinocyte shaping and positioning of the cytoskeletal components. […] The dysregulated immune response in AD is intricate and multidimensional, affecting the antigenic response, the induction of inflammation, the disruption of the cutaneous architectural integrity, and pruritus.

• #55 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia (Portuguese)

  https://www.anaisdedermatologia.org.br/pt-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  The immunopathogenesis of AD comprises the interaction between alterations in barrier function, and environmental stimuli in the context of a dysregulated and spectral Th2 and Th17/22 immune response. […] After surpassing the skin barrier, the antigens are phagocytosed by different antigen-presenting cells, especially LCs. […] The pathogenesis of AD comprises the interaction between alterations in barrier function, and environmental stimuli in the context of a dysregulated and spectral Th2 and Th17/22 immune response. […] The increase in the enzymatic activity of phosphodiesterase 4 observed in AD determines a reduction in intracellular cyclic adenosine monophosphate, which is a negative regulator of cytokine production, and is another element that contributes to the increased secretion of pro-inflammatory mediators involved in acute and chronic inflammation in AD. […] The chronic inflammatory state can lead to major cardiovascular events (angina, acute myocardial infarction, cardiac arrhythmias, etc.), heart failure, venous thromboembolism, and lymphoproliferative malignancies in patients with AD.

• #56 Molecular Mechanisms of Atopic Dermatitis Pathogenesis

  https://www.mdpi.com/1422-0067/22/8/4130

  Atopic dermatitis is a chronic, non-infectious inflammatory dermatosis. The pathophysiology of atopic dermatitis is complex and multifactorial. It includes genetic disorders, a defect in the epidermal barrier, an altered immune response, and disruption of the skin’s microbial balance. The numerous complex changes at the genetic level and innate and adaptive immunity provide the basis for characterizing the various phenotypes and endotypes of atopic dermatitis. The pathophysiology of atopic dermatitis is complex and multifactorial. Its understanding is complicated by the number of synergized factors that influence the disease. The most important are: genetic disorders, a defect in the epidermal barrier, an altered immune response and disturbed microbiological balance of the skin. Additionally, the environmental aspects, such as increased exposure to airborne or food allergens, pollution, infections, use of antibiotics, breastfeeding duration, diet, cosmetics or strong detergents, should be considered. The following paper presents some of the molecular mechanisms involved in the pathogenesis of atopic dermatitis. The initial suspicions of atopic dermatitis’s genetic background appeared along with the observations of a higher incidence of AD in families with atopy. It has been noted that children of parents with a history of allergic diseases have a greater risk of developing AD. There are many cooperating genes responsible for the disease’s pathogenesis. However, this is not a simple Mendelian inheritance. Genes are also subject to various heredity phenomena such as epigenetic changes, incomplete gene penetrance, and genomic imprinting. Gene mutations in the first group lead to impairment of the epidermal barrier function. The most popular of this group is the filaggrin gene mutation, considered one of AD’s major genes. The barrier defect causes degradation of intercellular connections, higher proteases activity, increased epidermal permeability, infiltration of antigens, and stimulation of proinflammatory cytokines. The chronic, relapsing course of the disease, economic burden, and the whole family’s involvement in the treatment process immensely reduce the quality of life in the case of patients and their families. The skin produces antimicrobial peptides (AMP) to destroy or inhibit microbes’ growth. Altered AMP expression and secretion may contribute to increased susceptibility to skin infections by viruses, bacteria and fungi in AD patients. The microbiome of healthy skin is characterized by species diversity and high stability over time. The disturbance and dysfunction of various microorganisms lead to diseases, including atopic dermatitis. It has been proven that the composition and diversity of microorganisms on the skin differ between people with eczema and those healthy ones. In atopic skin, there has been a reduction in commensal bacteria of the genera Streptococcus, Corynebacterium, Cutibacterium and the type Proteobacteria with the increase towards the genus Staphylococcus in general (S. aureus in particular).

• #57 Recent Advancements in the Atopic Dermatitis Mechanism

  https://www.imrpress.com/journal/FBL/29/2/10.31083/j.fbl2902084/htm

  The key role of skin microbiome dysbiosis in the integrity of the skin barrier and the interplay between microbiome, exposome, skin-barrier leakage, and host immune response highlights the necessity for targeted interventions aiming at rebalancing the skin microbiome. […] The role of the exposome in the multidimensional model of AD pathogenesis has recently been explored. […] The exposome is the “master regulator” in the interplay between a disrupted and “leaky” epithelium barrier, microbiome, genome, and immune dysregulation in AD. […] The intricate and multifactorial interplay of well-established and novel pathogenetic mechanisms associated with AD, including dysregulated immune responses, disruption of the epithelial barrier, pruritus, microbiome dysbiosis, and the influence of the exposome is illustrated.

• #58 Molecular Mechanisms of Atopic Dermatitis Pathogenesis

  https://www.mdpi.com/1422-0067/22/8/4130

  Atopic dermatitis is a chronic, non-infectious inflammatory dermatosis. The pathophysiology of atopic dermatitis is complex and multifactorial. It includes genetic disorders, a defect in the epidermal barrier, an altered immune response, and disruption of the skin’s microbial balance. The numerous complex changes at the genetic level and innate and adaptive immunity provide the basis for characterizing the various phenotypes and endotypes of atopic dermatitis. The pathophysiology of atopic dermatitis is complex and multifactorial. Its understanding is complicated by the number of synergized factors that influence the disease. The most important are: genetic disorders, a defect in the epidermal barrier, an altered immune response and disturbed microbiological balance of the skin. Additionally, the environmental aspects, such as increased exposure to airborne or food allergens, pollution, infections, use of antibiotics, breastfeeding duration, diet, cosmetics or strong detergents, should be considered. The following paper presents some of the molecular mechanisms involved in the pathogenesis of atopic dermatitis. The initial suspicions of atopic dermatitis’s genetic background appeared along with the observations of a higher incidence of AD in families with atopy. It has been noted that children of parents with a history of allergic diseases have a greater risk of developing AD. There are many cooperating genes responsible for the disease’s pathogenesis. However, this is not a simple Mendelian inheritance. Genes are also subject to various heredity phenomena such as epigenetic changes, incomplete gene penetrance, and genomic imprinting. Gene mutations in the first group lead to impairment of the epidermal barrier function. The most popular of this group is the filaggrin gene mutation, considered one of AD’s major genes. The barrier defect causes degradation of intercellular connections, higher proteases activity, increased epidermal permeability, infiltration of antigens, and stimulation of proinflammatory cytokines. The chronic, relapsing course of the disease, economic burden, and the whole family’s involvement in the treatment process immensely reduce the quality of life in the case of patients and their families. The skin produces antimicrobial peptides (AMP) to destroy or inhibit microbes’ growth. Altered AMP expression and secretion may contribute to increased susceptibility to skin infections by viruses, bacteria and fungi in AD patients. The microbiome of healthy skin is characterized by species diversity and high stability over time. The disturbance and dysfunction of various microorganisms lead to diseases, including atopic dermatitis. It has been proven that the composition and diversity of microorganisms on the skin differ between people with eczema and those healthy ones. In atopic skin, there has been a reduction in commensal bacteria of the genera Streptococcus, Corynebacterium, Cutibacterium and the type Proteobacteria with the increase towards the genus Staphylococcus in general (S. aureus in particular).

• #59 Preclinical models of atopic dermatitis suitable for mechanistic and t | JIR

  https://www.dovepress.com/preclinical-models-of-atopic-dermatitis-suitable-for-mechanistic-and-t-peer-reviewed-fulltext-article-JIR

  Eczema has a strong heritability, as is evident from twin studies. […] The most important risk gene identified in eczema is filaggrin (FLG), a major component of the stratum corneum (SC). […] Another important factor contributing to eczema pathogenesis is a dysregulated Th2 immune response. Excessive production of cytokines IL-4, IL-5, and IL-13 stimulates IgE antibodies and eosinophils in the tissue, leading to inflammation. […] In eczema, a previous report indicated a reduction in commensal bacteria of the genera Streptococcus, Corynebacterium, Cutibacterium and Proteobacteria and an increase in the genus Staphylococcus (S. aureus in particular). […] Changes in qualitative and quantitative colonization by Staphylococcus aureus (S. aureus) precede the clinical manifestation of eczema and further exacerbate the disease.

• #60 Disease Management: Atopic Dermatitis

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/dermatology/atopic-dermatitis/

  Many factors exacerbate or trigger atopic dermatitis, including colonization with S aureus, stress, anxiety, systemic illness, and xerosis. […] The most common trigger is S aureus colonization. More than 90% of patients with atopic dermatitis have S aureus colonization of lesional skin, and more than 75% have colonization of uninvolved skin. […] Staphylococci exacerbate atopic dermatitis by 2 mechanisms: acting as superantigens by stimulating an augmented T cell response thereby exacerbating the skin disease and promoting increased production of IgE. […] Family studies support a genetic basis for atopic dermatitis. When both parents are atopic, their offspring have a 70% risk for atopic dermatitis; the risk of inheritance is higher if the mother is atopic. […] The mode of inheritance appears to be complex and likely involves several genes.

• #61 Atopic dermatitis – Wikipedia

  https://en.wikipedia.org/wiki/Atopic_dermatitis

  Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin. The cause is unknown but is believed to involve genetics, immune system dysfunction, environmental exposures, and difficulties with the permeability of the skin. Disruption of the epidermal barrier is thought to play an integral role in the pathogenesis of AD. Disruptions of the epidermal barrier allow allergens to penetrate the epidermis to deeper layers of the skin. This leads to activation of epidermal inflammatory dendritic and innate lymphoid cells which subsequently attracts Th2 CD4+ helper T cells to the skin. This dysregulated Th2 inflammatory response is thought to lead to the eczematous lesions. The Th2 helper T cells become activated, leading to the release of inflammatory cytokines including IL-4, IL-13 and IL-31 which activate downstream Janus kinase (Jak) pathways. The active Jak pathways lead to inflammation and downstream activation of plasma cells and B lymphocytes which release antigen specific IgE contributing to further inflammation. Mutations in the filaggrin gene, FLG, also cause impairment in the skin barrier that contributes to the pathogenesis of AD. Filaggrin mutations are also associated with a decrease in natural antimicrobial peptides found on the skin; subsequently leading to disruption of skin flora and bacterial overgrowth (commonly Staphylococcus aureus overgrowth or colonization). Excessive type 2 inflammation underlies the pathophysiology of atopic dermatitis. The role of Staphylococcus aureus in skin irritation occurs via inflammation factors that induce itching, which may damage the skin, further driving inflammation, and facilitating the growth of Staphylococcus aureus, thus promoting a chronic cycle.

• #62 Atopic dermatitis causes

  https://dermnetnz.org/topics/causes-of-atopic-dermatitis

  The main inherited abnormality causing disordered barrier function is filaggrin expression. […] It is postulated that the loss of filaggrin results in: Corneocyte deformation (flattening of surface skin cells), which disrupts the organisation of the extracellular lipid (fat) — the lamellar bilayers. […] The Th2 associated cytokines contribute to the loss of skin barrier function: Water is lost, Irritants may penetrate (soap, detergent, solvents, dirt etc.), Allergens may penetrate it (pollens, dust-mite antigens, microbes). […] The specialised immune cells of the epidermis (Langerhans cells) have an increased response to these antigens in atopic dermatitis and interact with dermal T cells to produce an even greater Th2 response further exacerbating the barrier defect. […] Infective organisms play an important role in triggering and aggravating atopic dermatitis. Bacteria (particularly staphylococci) and in some patients yeasts (malassezia and candida) contribute to chronic inflammation. […] People who have atopic dermatitis are particularly prone to skin infections with Staphylococcus aureus. […] The infection causes eczema to worsen and become more resistant to the usual treatment with emollients and topical steroids.

• #63 Atopic Dermatitis Treatment Strategies Using Ruxolitinib, Considering Crucial Role of Skin Microbiome

  https://www.ajmc.com/view/atopic-dermatitis-treatment-strategies-using-ruxolitinib-considering-crucial-role-of-skin-microbiome

  Lawrence F. Eichenfield, MD, FAAD, emphasized the role the skin microbiome plays in eczema pathogenesis, particularly the correlation between Staphylococcus (Staph) aureus counts and disease severity in an interview with The American Journal of Managed Care at the American Academy of Dermatology 2025 annual conference. […] The skin microbiome is very involved in part of the pathogenesis and clinical manifestations of eczema. We’ve known for decades that when eczema gets worse, the Staph aureus counts go up. If Staph aureus is more present, the eczema can be more severe as well. […] Once you have established atopic dermatitis, often, very commonly, we can have severe flares of the disease associated with clinical cutaneous infection. […] If you get the disease under control, you’ll decrease cutaneous infections, and that has an impact on the microbiome. The microbiome is responsive, it’s not static; but we have ways of influencing it. If you have effective anti-inflammatory care, you’ll often have [an] impact [on] changing or decreasing the amount of secondary cutaneous infections.

• #64 Atopic eczema treatment now and in the future: Targeting the skin barrier and key immune mechanisms in human skin

  https://www.wjgnet.com/2218-6190/full/v6/i3/42.htm

  The difficulty in describing the causes of atopic eczema are that the mutations or genetic variants being proposed as the culprits of the skin barrier dysfunction only occur in a proportion of affected individuals. […] The majority of candidate gene association studies point to null mutations in the filaggrin gene, FLG, and genes involved with the type 2 T helper lymphocytes (Th2 cell) function. […] The main mechanism by which S. aureus damages the skin barrier is through secretion of SspA/V8 protease. […] Immune dysfunction plays a key role in eczema pathogenesis. […] The balance of immune mechanisms in the skin is a closely regulated process, which involves a number of different immune and non-immune cells interacting to protect the body from pathogens. […] The adaptive and innate immune responses have both been highlighted as possibly playing a role in atopic eczema.

• #65 Unraveling Atopic Dermatitis: Insights into Pathophysiology, Therapeutic Advances, and Future Perspectives

  https://www.mdpi.com/2073-4409/13/5/425

  Atopic dermatitis (AD) is an inflammatory skin condition that frequently develops before the onset of allergic rhinitis or asthma. Recent research has connected the environment, genetics, the skin barrier, drugs, psychological factors, and the immune system to the onset and severity of AD. The pathogenesis of AD is multifaceted, involving genetic predispositions, abnormalities in skin function, immune system dysregulation, and environmental influences. The essential membrane protein filaggrin (FLG) has been discovered to have the greatest genetic association with AD. FLG null mutations weaken the skin barrier and heighten AD risk. In addition to FLG gene mutations, factors like DNA methylation, FLG copy number variations, environmental influences (skin irritation, damage, and low humidity), cytokines (Th2, interleukins (IL)-17, IL-22, IL-25, and IL-31) reducing FLG expression, skin microorganisms, and treatments (topical and systemic) can also alter FLG levels. The cells involved in host–environment interaction resulting in skin inflammation are eosinophils, basophils, dendritic cells (DCs), keratinocytes, mast cells, macrophages, and type 2 innate lymphoid cells (ILC2s). Additionally, reductions in the levels of epidermal barrier proteins, such as FLG, spinous layer proteins (SPINK), and claudins, alongside alterations of antimicrobial peptides, play a significant role. Both T and B cells, together with their respective cytokines, contribute to this disease’s immunological profile, highlighted by a dominant Th2 axis (including IL-4, IL-13, IL-5, thymic stromal lymphopoietin (TSLP), and IL-31), elevated Th17/IL-23 and Th22 pathways, and increased IgE levels. The main connection between skin bacteria and AD is S. aureus, often found on the skin of AD patients. Skin problems deriving from AD make it easier for S. aureus to grow. When there is a lack of FLG, there is usually more S. aureus in the skin’s microbiome. S. aureus prompts keratinocytes to produce proteases, worsening the skin’s barrier. It also releases harmful substances like δ-toxin and α-toxin; δ-toxin can trigger mast cells to release substances without killing them, particularly when IgE is present. The Th2 cytokines IL-4, IL-5, and IL-13 play a pivotal role in AD and have been linked to increased IgE response and eosinophils in AD patients. In AD patients, IL-4 and IL-4 receptors on peripheral blood lymphocytes were aberrant, with an increased production of IL-13. It was previously demonstrated that AD patients lost their capacity to release IFN-γ in response to different stimuli. Researchers have found a notable connection wherein the amount of IFN-γ produced is linked to lower levels of IgE found in the blood of individuals with AD. Studies on patients with acute AD revealed that they had higher amounts of IFN-γ and IL-4 in the skin and peripheral blood. These cytokines are secreted by T cells that are specific to the allergens. When an antigen is encountered by antigen-presenting cells such as DCs, they release TSLP and initiate signaling pathways that activate naïve T cells. This leads to the differentiation of T cells into Th1 and Th2 subtypes, which release interleukins and chemokines to combat the antigen. However, this immune response contributes to inflammation and may exacerbate skin barrier dysfunction in AD rather than directly cause barrier penetration. The exploration of interleukins and their influence on the immunological pathway in AD has been facilitated by using relevant biomarkers in clinical trials. This approach enables the identification of novel therapeutic modalities, fostering the potential for targeted translational research within the realm of personalized medicine.

• #66 Preclinical models of atopic dermatitis suitable for mechanistic and t | JIR

  https://www.dovepress.com/preclinical-models-of-atopic-dermatitis-suitable-for-mechanistic-and-t-peer-reviewed-fulltext-article-JIR

  Staphylococcal -toxin induces mast cell degranulation via PI3K and calcium influx, without IgE cross-linking. […] The use of genetically engineered mice to study AD-related pathogenesis has been well-documented in the literature. […] Genetically engineered mice provide detailed information on the gene-specific mechanisms of AD progression and can be valuable if these strains are crossed with other strains. […] The primary advantage of using these models is that they provide a natural course of human AD under normal conditions, without additional sensitization or manipulation. […] However, no single model can fully recapitulate the pathogenesis of AD.

• #67 Disease Management: Atopic Dermatitis

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/dermatology/atopic-dermatitis/

  Many factors exacerbate or trigger atopic dermatitis, including colonization with S aureus, stress, anxiety, systemic illness, and xerosis. […] The most common trigger is S aureus colonization. More than 90% of patients with atopic dermatitis have S aureus colonization of lesional skin, and more than 75% have colonization of uninvolved skin. […] Staphylococci exacerbate atopic dermatitis by 2 mechanisms: acting as superantigens by stimulating an augmented T cell response thereby exacerbating the skin disease and promoting increased production of IgE. […] Family studies support a genetic basis for atopic dermatitis. When both parents are atopic, their offspring have a 70% risk for atopic dermatitis; the risk of inheritance is higher if the mother is atopic. […] The mode of inheritance appears to be complex and likely involves several genes.

• #68 Atopic dermatitis – Wikipedia

  https://en.wikipedia.org/wiki/Atopic_dermatitis

  Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin. The cause is unknown but is believed to involve genetics, immune system dysfunction, environmental exposures, and difficulties with the permeability of the skin. Disruption of the epidermal barrier is thought to play an integral role in the pathogenesis of AD. Disruptions of the epidermal barrier allow allergens to penetrate the epidermis to deeper layers of the skin. This leads to activation of epidermal inflammatory dendritic and innate lymphoid cells which subsequently attracts Th2 CD4+ helper T cells to the skin. This dysregulated Th2 inflammatory response is thought to lead to the eczematous lesions. The Th2 helper T cells become activated, leading to the release of inflammatory cytokines including IL-4, IL-13 and IL-31 which activate downstream Janus kinase (Jak) pathways. The active Jak pathways lead to inflammation and downstream activation of plasma cells and B lymphocytes which release antigen specific IgE contributing to further inflammation. Mutations in the filaggrin gene, FLG, also cause impairment in the skin barrier that contributes to the pathogenesis of AD. Filaggrin mutations are also associated with a decrease in natural antimicrobial peptides found on the skin; subsequently leading to disruption of skin flora and bacterial overgrowth (commonly Staphylococcus aureus overgrowth or colonization). Excessive type 2 inflammation underlies the pathophysiology of atopic dermatitis. The role of Staphylococcus aureus in skin irritation occurs via inflammation factors that induce itching, which may damage the skin, further driving inflammation, and facilitating the growth of Staphylococcus aureus, thus promoting a chronic cycle.

• #69 Atopic Dermatitis Treatment Strategies Using Ruxolitinib, Considering Crucial Role of Skin Microbiome

  https://www.ajmc.com/view/atopic-dermatitis-treatment-strategies-using-ruxolitinib-considering-crucial-role-of-skin-microbiome

  Lawrence F. Eichenfield, MD, FAAD, emphasized the role the skin microbiome plays in eczema pathogenesis, particularly the correlation between Staphylococcus (Staph) aureus counts and disease severity in an interview with The American Journal of Managed Care at the American Academy of Dermatology 2025 annual conference. […] The skin microbiome is very involved in part of the pathogenesis and clinical manifestations of eczema. We’ve known for decades that when eczema gets worse, the Staph aureus counts go up. If Staph aureus is more present, the eczema can be more severe as well. […] Once you have established atopic dermatitis, often, very commonly, we can have severe flares of the disease associated with clinical cutaneous infection. […] If you get the disease under control, you’ll decrease cutaneous infections, and that has an impact on the microbiome. The microbiome is responsive, it’s not static; but we have ways of influencing it. If you have effective anti-inflammatory care, you’ll often have [an] impact [on] changing or decreasing the amount of secondary cutaneous infections.

• #70 Molecular Mechanisms of Atopic Dermatitis Pathogenesis

  https://www.mdpi.com/1422-0067/22/8/4130

  Atopic dermatitis is a chronic, non-infectious inflammatory dermatosis. The pathophysiology of atopic dermatitis is complex and multifactorial. It includes genetic disorders, a defect in the epidermal barrier, an altered immune response, and disruption of the skin’s microbial balance. The numerous complex changes at the genetic level and innate and adaptive immunity provide the basis for characterizing the various phenotypes and endotypes of atopic dermatitis. The pathophysiology of atopic dermatitis is complex and multifactorial. Its understanding is complicated by the number of synergized factors that influence the disease. The most important are: genetic disorders, a defect in the epidermal barrier, an altered immune response and disturbed microbiological balance of the skin. Additionally, the environmental aspects, such as increased exposure to airborne or food allergens, pollution, infections, use of antibiotics, breastfeeding duration, diet, cosmetics or strong detergents, should be considered. The following paper presents some of the molecular mechanisms involved in the pathogenesis of atopic dermatitis. The initial suspicions of atopic dermatitis’s genetic background appeared along with the observations of a higher incidence of AD in families with atopy. It has been noted that children of parents with a history of allergic diseases have a greater risk of developing AD. There are many cooperating genes responsible for the disease’s pathogenesis. However, this is not a simple Mendelian inheritance. Genes are also subject to various heredity phenomena such as epigenetic changes, incomplete gene penetrance, and genomic imprinting. Gene mutations in the first group lead to impairment of the epidermal barrier function. The most popular of this group is the filaggrin gene mutation, considered one of AD’s major genes. The barrier defect causes degradation of intercellular connections, higher proteases activity, increased epidermal permeability, infiltration of antigens, and stimulation of proinflammatory cytokines. The chronic, relapsing course of the disease, economic burden, and the whole family’s involvement in the treatment process immensely reduce the quality of life in the case of patients and their families. The skin produces antimicrobial peptides (AMP) to destroy or inhibit microbes’ growth. Altered AMP expression and secretion may contribute to increased susceptibility to skin infections by viruses, bacteria and fungi in AD patients. The microbiome of healthy skin is characterized by species diversity and high stability over time. The disturbance and dysfunction of various microorganisms lead to diseases, including atopic dermatitis. It has been proven that the composition and diversity of microorganisms on the skin differ between people with eczema and those healthy ones. In atopic skin, there has been a reduction in commensal bacteria of the genera Streptococcus, Corynebacterium, Cutibacterium and the type Proteobacteria with the increase towards the genus Staphylococcus in general (S. aureus in particular).

• #71 Overview of Atopic Dermatitis

  https://www.ajmc.com/view/overview-of-atopic-dermatitis-article

  There are 2 major risk factors for the development of AD: 1) genetic defect in the FLG gene and 2) family history of atopic disease. A family history of atopic disease is strongly correlated with AD, as approximately 70% of patients with AD are positive for this risk factor. Risk of AD increases with the number of parents positive for atopic disease by 2- to 3-fold and 3- to 5-fold (1 and 2 parents, respectively). […] The FLG gene is responsible for the development of the profilaggrin protein, found in the granular layer of the epidermis, and brings structural proteins together to create a strong barrier matrix. FLG mutations are common particularly among Caucasians. Approximately 10% of individuals of European descent are heterozygous carriers of a loss-of-function mutation in FLG, resulting in a 50% reduction in the expression of the protein. When FLG mutations are present, disease is more severe and persistent, occurs mainly in early-onset AD, and indicates a propensity toward asthma.

• #72 Molecular Mechanisms of Atopic Dermatitis Pathogenesis

  https://www.mdpi.com/1422-0067/22/8/4130

  Atopic dermatitis is a chronic, non-infectious inflammatory dermatosis. The pathophysiology of atopic dermatitis is complex and multifactorial. It includes genetic disorders, a defect in the epidermal barrier, an altered immune response, and disruption of the skin’s microbial balance. The numerous complex changes at the genetic level and innate and adaptive immunity provide the basis for characterizing the various phenotypes and endotypes of atopic dermatitis. The pathophysiology of atopic dermatitis is complex and multifactorial. Its understanding is complicated by the number of synergized factors that influence the disease. The most important are: genetic disorders, a defect in the epidermal barrier, an altered immune response and disturbed microbiological balance of the skin. Additionally, the environmental aspects, such as increased exposure to airborne or food allergens, pollution, infections, use of antibiotics, breastfeeding duration, diet, cosmetics or strong detergents, should be considered. The following paper presents some of the molecular mechanisms involved in the pathogenesis of atopic dermatitis. The initial suspicions of atopic dermatitis’s genetic background appeared along with the observations of a higher incidence of AD in families with atopy. It has been noted that children of parents with a history of allergic diseases have a greater risk of developing AD. There are many cooperating genes responsible for the disease’s pathogenesis. However, this is not a simple Mendelian inheritance. Genes are also subject to various heredity phenomena such as epigenetic changes, incomplete gene penetrance, and genomic imprinting. Gene mutations in the first group lead to impairment of the epidermal barrier function. The most popular of this group is the filaggrin gene mutation, considered one of AD’s major genes. The barrier defect causes degradation of intercellular connections, higher proteases activity, increased epidermal permeability, infiltration of antigens, and stimulation of proinflammatory cytokines. The chronic, relapsing course of the disease, economic burden, and the whole family’s involvement in the treatment process immensely reduce the quality of life in the case of patients and their families. The skin produces antimicrobial peptides (AMP) to destroy or inhibit microbes’ growth. Altered AMP expression and secretion may contribute to increased susceptibility to skin infections by viruses, bacteria and fungi in AD patients. The microbiome of healthy skin is characterized by species diversity and high stability over time. The disturbance and dysfunction of various microorganisms lead to diseases, including atopic dermatitis. It has been proven that the composition and diversity of microorganisms on the skin differ between people with eczema and those healthy ones. In atopic skin, there has been a reduction in commensal bacteria of the genera Streptococcus, Corynebacterium, Cutibacterium and the type Proteobacteria with the increase towards the genus Staphylococcus in general (S. aureus in particular).

• #73 Overview of Atopic Dermatitis

  https://www.ajmc.com/view/overview-of-atopic-dermatitis-article

  The epidermis of the skin consists of several layers that act as barriers to prevent water loss and to protect the body from such foreign substances as microbes and allergens. The FLG gene, on chromosome 1q21.3, encodes a key protein in epidermal differentiation. This gene was originally identified as the gene involved in ichthyosis vulgaris, which will be discussed again later, and several loss-of-function mutations were identified in European and Japanese patients with AD. Since then, multiple studies have demonstrated that the FLG gene plays a pivotal role in skin barrier function and mutations of the FLG gene are a major risk factor for AD. […] Other immune system-related genes found to be associated with AD include those encoded on chromosome 5q31 to 5q33. These genes code for cytokines that regulate immunoglobulin E (IgE) synthesis: interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-12 (IL-12), interleukin-13 (IL-13), and granulocyte-macrophage colony-stimulating factor. Cytokines are mainly produced by type 1 and type 2 T helper lymphocytes (TH1 and TH2, respectively). TH1 cytokines (IL-12 and interferon-) suppress IgE production, and TH2 cytokines (IL-5 and IL-13) increase IgE production. Patients with AD have a genetically determined dominance of TH2 cells that may decrease expression of FLG and other molecules found in the skin barrier.

• #74 Atopic Dermatitis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/762045-overview

  The epidermal barrier dysfunction hypothesis suggests that patients develop AD as a result of skin barrier defects that allow antigens to enter, resulting in the production of inflammatory cytokines. Some authors question whether such antigens can also be absorbed from the gut (eg, from food), the lungs (eg, from house dust mites), or both. Xerosis and ichthyosis are known to be associated in many AD patients. Clinically, 37-50% of people with ichthyosis vulgaris have atopic disease, and as many as 37% of those with AD show evidence of ichthyosis. Mutations in the gene for filaggrin, a key epidermal barrier protein, cause ichthyosis vulgaris and are the strongest known genetic risk factors for AD. […] Furthermore, filaggrin mutations are associated with early-onset AD and with airway disease in the setting of AD. One mechanism by which filaggrin defects may influence inflammation is by the release of epithelial cell-derived cytokines, including TSLP, IL-25, and IL-33, all of which are known to be upregulated in the context of AD. TSLP has been shown to be a potent promoter of basophil and ILC2 responses in the skin, whereas IL-25 and IL-33 preferentially elicit ILC2s.

• #75 Pathogenesis and management of atopic dermatitis: insights into epidermal barrier dysfunction and immune mechanisms

  https://www.explorationpub.com/Journals/eaa/Article/100973

  The integrity of the skins epidermis depends significantly on the equilibrium between the skin proteases and their inhibitors. […] In AD patients, at least three factors contribute to barrier dysfunction: (1) abnormalities in FLG gene expression, (2) decreased skin ceramide levels, and (3) excessive activation of epidermal proteases. […] The FLG gene is crucial for preserving the function and integrity of the epidermal barrier, as it helps in forming bundles made up of KRT filaments and contributes to the hydration of the SC through its breakdown products, such as NMFs. […] Lack of FLG gene has demonstrated heightened penetration of antigens through the skin, resulting in amplified immune responses. […] The main lipids of the outermost skin layer, the SC, comprise ceramides, FFAs, etc. […] Abnormal skin lipids in AD are influenced by a heightened type 2 immune response, with inflammatory Th2 cytokines resulting in decreased total ceramide and long-chain fatty acid levels with altered chain lengths.

• #76 The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-023-00992-4

  Environmental noxious stimuli, immune dysregulation, genetic factors, impaired epidermal barrier integrity, and skin microbiome abnormalities all play pathogenetic roles in initiating and sustaining a state of chronic inflammation in AD and contribute to orchestrating the disease phenotype. […] Epidermal barrier dysfunction in AD is characterized by a lower expression of terminal differentiation markers, such as filaggrin (FLG) and loricrin (LOR), and by a higher permeability defect caused by skin lipid film impairment and higher transepidermal water loss. […] Damaged keratinocytes produce epidermal alarmins such as IL-33, IL-25, and TSLP, which activate the dendritic cells (DCs) and type 2 innate lymphoid cells (ILC2s) that produce IL-5 and IL-13, which activate eosinophils and Th2 cells.

• #77 Atopic Dermatitis in Adults: Epidemiology, Risk Factors, Pathogenesis, Clinical Features, and Management | IntechOpen

  https://www.intechopen.com/chapters/76331

  The exact pathogenesis remains unclear and the underlying mechanism that is well known in the disease development and progression has been atopy. […] Although total Ig E elevation is mostly seen in many AD individuals, other factors also modulate the pathophysiology of AD giving rise to the non-atopic or non-T-2 inflammation form of the disease. […] A strong family history has been reported in 4060% of AD patients with filaggrin (FLG) null mutation in 2030%. […] Genetic mutations involving the epidermal differentiation complex (EDC) gene on chromosome 1q21 impairs epidermal differentiation resulting in stratum corneum barrier dysfunction. […] Recent studies have linked genetic FLG mutations to Th2 mediated AD and not non-Th2 inflammation AD giving rise to suggestions that skin barrier defect underlies the development of secondary allergic symptoms and respiratory atopy.

• #78 Overview of Atopic Dermatitis

  https://www.ajmc.com/view/overview-of-atopic-dermatitis-article

  The epidermis of the skin consists of several layers that act as barriers to prevent water loss and to protect the body from such foreign substances as microbes and allergens. The FLG gene, on chromosome 1q21.3, encodes a key protein in epidermal differentiation. This gene was originally identified as the gene involved in ichthyosis vulgaris, which will be discussed again later, and several loss-of-function mutations were identified in European and Japanese patients with AD. Since then, multiple studies have demonstrated that the FLG gene plays a pivotal role in skin barrier function and mutations of the FLG gene are a major risk factor for AD. […] Other immune system-related genes found to be associated with AD include those encoded on chromosome 5q31 to 5q33. These genes code for cytokines that regulate immunoglobulin E (IgE) synthesis: interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-12 (IL-12), interleukin-13 (IL-13), and granulocyte-macrophage colony-stimulating factor. Cytokines are mainly produced by type 1 and type 2 T helper lymphocytes (TH1 and TH2, respectively). TH1 cytokines (IL-12 and interferon-) suppress IgE production, and TH2 cytokines (IL-5 and IL-13) increase IgE production. Patients with AD have a genetically determined dominance of TH2 cells that may decrease expression of FLG and other molecules found in the skin barrier.

• #79 Atopic Dermatitis in Adults: Epidemiology, Risk Factors, Pathogenesis, Clinical Features, and Management | IntechOpen

  https://www.intechopen.com/chapters/76331

  The degree of membrane disruption directly correlates with the severity of AD. […] Polymorphisms of genes in the Th2 signaling pathway particularly cytokine receptors (IL-4R and IL-13R) are associated with immune dysfunction in AD. […] The TH2 cytokines (IL-4, IL-13, IL-31) and TH22 cytokine (IL-22) are believed to play roles in the overall pathogenesis of atopic dermatitis but mostly acute AD. […] Damage to the skin barrier allows penetration of the skin by allergens, environmental factors and infective organisms activating the skin antigen-presenting cells (APCs). […] The APCs migrate to lymph nodes and stimulate naive T cells differentiation into TH2 cells and B lymphocytes. […] The Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway acts downstream of more than 50 cytokines. […] It is central to inflammatory processes involving B-cells, T-cells, neutrophils, macrophages and natural killer cells.

• #80

  https://link.springer.com/article/10.1007/s13671-012-0021-y

  It is well accepted that certain infectious exposures may decrease the risk of developing AD. This is referred to as the hygiene hypothesis, which states that certain infections and exposures can help guide the immature immune system away from a pro-atopic or inflammatory state. […] Recent attention has been paid to the pathogenic role of defects of toll-like receptor 2 (TLR2) and other pathways of the innate immune system in AD and associated infections. […] Thus, some patients with AD have impaired aberrancies of innate immunity that may predispose them to increased microbial colonization and infection, aside from skin barrier defects. […] The mechanism(s) behind the association of metabolic factors and AD is unknown. Although the association of AD and FLG mutations is now well established, it is not clear how obesity interacts with such genetic predisposition. One possibility is that FLG and other genetic mutations involved in AD result in both an AD phenotype and increased risk for obesity and its sequel. Alternatively, obesity may be independent of FLG mutations and acts as a trigger in an already genetically predisposed person.

• #81 Atopic Dermatitis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/762045-overview

  Although filaggrin is strongly linked to AD, mutations are found in only 30% of European patients, raising the question of whether other genetic variants may also be responsible for some of the findings in the pathogenesis of AD. Indeed, genetic variants of TSLP have been shown to interact with mutations in filaggrin to influence AD disease persistence in patients. […] In AD, transepidermal water loss is increased. Whether primary immune dysregulation causes secondary epithelial barrier breakdown or whether primary epithelial barrier breakdown causes secondary immune dysregulation that results in disease remains unknown. However, given that filaggrin is critical for epithelial integrity, it is now thought that loss of filaggrin function leads to increased transepidermal penetration of environmental allergens, increasing inflammation and sensitivity and potentially leading to the atopic march.

• #82 Molecular Mechanisms of Atopic Dermatitis Pathogenesis

  https://www.mdpi.com/1422-0067/22/8/4130

  Atopic dermatitis is a chronic, non-infectious inflammatory dermatosis. The pathophysiology of atopic dermatitis is complex and multifactorial. It includes genetic disorders, a defect in the epidermal barrier, an altered immune response, and disruption of the skin’s microbial balance. The numerous complex changes at the genetic level and innate and adaptive immunity provide the basis for characterizing the various phenotypes and endotypes of atopic dermatitis. The pathophysiology of atopic dermatitis is complex and multifactorial. Its understanding is complicated by the number of synergized factors that influence the disease. The most important are: genetic disorders, a defect in the epidermal barrier, an altered immune response and disturbed microbiological balance of the skin. Additionally, the environmental aspects, such as increased exposure to airborne or food allergens, pollution, infections, use of antibiotics, breastfeeding duration, diet, cosmetics or strong detergents, should be considered. The following paper presents some of the molecular mechanisms involved in the pathogenesis of atopic dermatitis. The initial suspicions of atopic dermatitis’s genetic background appeared along with the observations of a higher incidence of AD in families with atopy. It has been noted that children of parents with a history of allergic diseases have a greater risk of developing AD. There are many cooperating genes responsible for the disease’s pathogenesis. However, this is not a simple Mendelian inheritance. Genes are also subject to various heredity phenomena such as epigenetic changes, incomplete gene penetrance, and genomic imprinting. Gene mutations in the first group lead to impairment of the epidermal barrier function. The most popular of this group is the filaggrin gene mutation, considered one of AD’s major genes. The barrier defect causes degradation of intercellular connections, higher proteases activity, increased epidermal permeability, infiltration of antigens, and stimulation of proinflammatory cytokines. The chronic, relapsing course of the disease, economic burden, and the whole family’s involvement in the treatment process immensely reduce the quality of life in the case of patients and their families. The skin produces antimicrobial peptides (AMP) to destroy or inhibit microbes’ growth. Altered AMP expression and secretion may contribute to increased susceptibility to skin infections by viruses, bacteria and fungi in AD patients. The microbiome of healthy skin is characterized by species diversity and high stability over time. The disturbance and dysfunction of various microorganisms lead to diseases, including atopic dermatitis. It has been proven that the composition and diversity of microorganisms on the skin differ between people with eczema and those healthy ones. In atopic skin, there has been a reduction in commensal bacteria of the genera Streptococcus, Corynebacterium, Cutibacterium and the type Proteobacteria with the increase towards the genus Staphylococcus in general (S. aureus in particular).

• #83 Molecular Mechanisms of Atopic Dermatitis Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8074061/

  Atopic dermatitis is a chronic, non-infectious inflammatory dermatosis. The pathophysiology of atopic dermatitis is complex and multifactorial. It includes genetic disorders, a defect in the epidermal barrier, an altered immune response, and disruption of the skin’s microbial balance. The numerous complex changes at the genetic level and innate and adaptive immunity provide the basis for characterizing the various phenotypes and endotypes of atopic dermatitis. The pathophysiology of atopic dermatitis is complex and multifactorial. Its understanding is complicated by the number of synergized factors that influence the disease. The most important are: genetic disorders, a defect in the epidermal barrier, an altered immune response and disturbed microbiological balance of the skin. The initial suspicions of atopic dermatitis’s genetic background appeared along with the observations of a higher incidence of AD in families with atopy. There are many cooperating genes responsible for the disease’s pathogenesis. However, this is not a simple Mendelian inheritance. Genes are also subject to various heredity phenomena such as epigenetic changes, incomplete gene penetrance, and genomic imprinting. The following paper presents some of the molecular mechanisms involved in the pathogenesis of atopic dermatitis. The likely mechanism of how the environment affects the organism’s cells are epigenetic changes. Epigenetic regulation is one of the determinants of AD development, next to the FLG gene polymorphisms and genes related to the immune system and the skin barrier. In AD, epigenetic changes concern genes known to affect the immune response regulation, genes of innate immunity, and genes encoding epidermis structural proteins. While describing atopic dermatitis causes, it is impossible to avoid disorders of immune regulation. Consequently, two different hypotheses have been proposed, from inside to outside and from outside to inside. The first one suggests that immunological aberrations are believed to be the primary initial event in development, and stimulation with allergens leads to weakening the epidermal barrier. The latter hypothesis assumes that an impaired skin barrier is the first step in atopic eczema’s pathogenesis and is required for immune dysregulation to occur. The skin produces antimicrobial peptides (AMP) to destroy or inhibit microbes growth. Altered AMP expression and secretion may contribute to increased susceptibility to skin infections by viruses, bacteria and fungi in AD patients. Atopic dermatitis is such a complex and diverse disease that different immune responses occur in various patient groups. Therefore, these specific molecular mechanisms underlying the disease have been defined as disease endotypes which set and variable constellations give rise to a particular phenotype.

• #84 Atopic Dermatitis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/762045-overview

  Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin condition that typically affects the face (cheeks), neck, arms, and legs but usually spares the groin and axillary regions. AD has enormous morbidity, and the incidence and prevalence appear to be increasing. AD usually starts in early infancy, but also affects a substantial number of adults. AD is commonly associated with elevated levels of immunoglobulin E (IgE) and may be associated with other atopic ([IgE-associated) diseases (eg, acute allergic reaction to foods, asthma, urticaria, and allergic rhinitis). […] The finding that AD is the first disease to present in a series of allergic diseases including food allergy, asthma, and allergic rhinitis, in order has given rise to the atopic march theory, which suggests that early or severe AD and cutaneous sensitization to environmental allergens may lead to subsequent allergic disease at other epithelial barrier surfaces (eg, gastrointestinal or respiratory tract). This hypothesis has been supported by cross-sectional and longitudinal studies.

• #85 Galderma RX Atopic Dermatitis Skin Condition

  https://www.galdermahcp.com/conditions/atopic-dermatitis

  Atopic march also called allergic march is a term that refers to the classical progression of atopic diseases from eczema (Atopic Dermatitis) to food allergies, asthma and allergic rhinitis. These conditions have common genetic and environmental predisposing traits and may appear very early in life, persist over decades or years and often remit spontaneously with age. […] The progression of atopic diseases follows an established path from Atopic Dermatitis (AD) and food allergies in early childhood to allergic rhinitis (AR) and asthma in later childhood. By some estimates, half of all patients with AD go on to develop AR and asthma. However, not all individuals with Atopic Dermatitis will progress through the atopic march, and not all individuals with one allergic disease will develop others.

• #86 Overview of Atopic Dermatitis

  https://www.ajmc.com/view/overview-of-atopic-dermatitis-article

  The atopic march describes the tendency for AD to precede the development of other atopic diseases such as food allergies, asthma, and allergic rhinitis in a temporal sequence. A 2008 study showed that the march does not necessarily always happen in order, as some patients with asthma develop AD. It has also been reported that while common in childhood, the atopic march can occur at any age. Still, multiple longitudinal studies have provided evidence supporting the atopic march between AD and subsequent allergies, and the interrelationships among subsequent allergic manifestations. Patients with atopic dermatitis, allergic rhinitis, and allergic asthma are considered to have the atopic triad. Approximately one-third of patients with AD develop asthma, and two-thirds develop allergic rhinitis.

• #87 Galderma RX Atopic Dermatitis Skin Condition

  https://www.galdermahcp.com/conditions/atopic-dermatitis

  That said, the presence of one atopic or allergic condition does increase the risk for developing others. Indeed, the presence of certain common characteristics among atopic diseases have led some researchers to suggest that they are all different manifestations of the same atopic disease. […] As the first manifestation of the atopic march, some recent studies support the possibility of a causal link between AD and later onset atopic disorders. It follows then that more effective management of AD may slow or stop the progression of atopic march. […] Ultimately, the etiology of AD is multifactorial with interaction between genetics, immune system and environmental factors. Thus, more effective management of AD is generally focused on improving or preserving skin barrier function, modulating the immune response and limiting or eliminating exposure to environmental allergens.

• #88 Galderma RX Atopic Dermatitis Skin Condition

  https://www.galdermahcp.com/conditions/atopic-dermatitis

  Skin barrier damage and/or dysfunction is the initial step in AD development. Multiple factors, including immune dysregulation, filaggrin mutations, deficiency of antimicrobial peptides, and skin dysbiosis can contribute to skin barrier defects. […] Once compromised, barrier integrity enables penetration of allergens, pollutants, and microbes that can trigger the initiation of an inflammatory immune cascade that leads to transcutaneous sensitization. The immune dysfunction is thought to further exacerbate the impaired skin barrier to create a vicious cycle. […] Genetically, understanding the variations that contribute to an individuals risk of Atopic Dermatitis has improved our understanding of mechanisms in the skin and our surrounding environment that can lead to a leaky barrier and inflammation.

• #89 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://clinics.elsevier.es/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  In AD, the unregulated and excessive production of cytokines, especially IL-4 and IL-13, causes the inhibition of the expression of epidermal proteins such as filaggrin, loricrin, and involucrin, which reinforces defects in the epidermal barrier, favoring the permeation of allergens and pathogens, feeding back the disease. […] The predominant Th2 imbalance in AD is implicated in reduced FLG expression, contributing to the barrier defect. […] The dysregulated type 2 inflammation cytokine response occurs in different anatomical sites of the body. At the level of the bronchi, IL-4 and IL-13 act by mediating inflammation and remodeling changes in the airways, predisposing the development of type 2-related asthma (50%-70% of asthmatics). […] The pathogenesis of AD comprises the interaction between alterations in barrier function, and environmental stimuli in the context of a dysregulated and spectral Th2 and Th17/22 immune response.

• #90 Pathophysiology of atopic dermatitis: Clinical implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6399565/

  IL-22 is also highly upregulated in the skin of patients with AD and is associated with skin barrier dysfunction and abnormal epidermal markers, such as keratin 6 and keratin 16. […] A damaged epidermal barrier not only leads to the development of AD but also heightens sensitization to allergens and contributes to the risk of Food allergy (FA) and airway hyperreactivity. […] Defects in epidermal barrier proteins, such as FLG, transglutaminases, keratins, and intercellular proteins, facilitate dysregulated immune responses to external antigens and drive skin and systemic inflammatory responses. […] AMPs, including cathelicidin (LL-37) and human -defensins, are produced by keratinocytes and play a pivotal role for host defense as well as control of host physiologic functions, such as inflammation and wound healing.

• #91 Galderma RX Atopic Dermatitis Skin Condition

  https://www.galdermahcp.com/conditions/atopic-dermatitis

  Skin barrier damage and/or dysfunction is the initial step in AD development. Multiple factors, including immune dysregulation, filaggrin mutations, deficiency of antimicrobial peptides, and skin dysbiosis can contribute to skin barrier defects. […] Once compromised, barrier integrity enables penetration of allergens, pollutants, and microbes that can trigger the initiation of an inflammatory immune cascade that leads to transcutaneous sensitization. The immune dysfunction is thought to further exacerbate the impaired skin barrier to create a vicious cycle. […] Genetically, understanding the variations that contribute to an individuals risk of Atopic Dermatitis has improved our understanding of mechanisms in the skin and our surrounding environment that can lead to a leaky barrier and inflammation.

• #92 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://clinics.elsevier.es/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  After surpassing the skin barrier, the antigens are phagocytosed by different antigen-presenting cells, especially LCs. […] This contribution of LCs also occurs in the context of AD and food allergy through transcutaneous sensitization to food allergens. […] The immunopathogenesis of AD is based on a deregulated immune response, in a multidimensional and interconnected way, affecting the response to antigens, the induction of inflammation, immune homeostasis disruption, disarray of the architectural integrity of the epidermis and dermis, producing a cardinal symptom, which is pruritus.

• #93 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://clinics.elsevier.es/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  In AD, the unregulated and excessive production of cytokines, especially IL-4 and IL-13, causes the inhibition of the expression of epidermal proteins such as filaggrin, loricrin, and involucrin, which reinforces defects in the epidermal barrier, favoring the permeation of allergens and pathogens, feeding back the disease. […] The predominant Th2 imbalance in AD is implicated in reduced FLG expression, contributing to the barrier defect. […] The dysregulated type 2 inflammation cytokine response occurs in different anatomical sites of the body. At the level of the bronchi, IL-4 and IL-13 act by mediating inflammation and remodeling changes in the airways, predisposing the development of type 2-related asthma (50%-70% of asthmatics). […] The pathogenesis of AD comprises the interaction between alterations in barrier function, and environmental stimuli in the context of a dysregulated and spectral Th2 and Th17/22 immune response.

• #94 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://clinics.elsevier.es/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  In AD, the unregulated and excessive production of cytokines, especially IL-4 and IL-13, causes the inhibition of the expression of epidermal proteins such as filaggrin, loricrin, and involucrin, which reinforces defects in the epidermal barrier, favoring the permeation of allergens and pathogens, feeding back the disease. […] The predominant Th2 imbalance in AD is implicated in reduced FLG expression, contributing to the barrier defect. […] The dysregulated type 2 inflammation cytokine response occurs in different anatomical sites of the body. At the level of the bronchi, IL-4 and IL-13 act by mediating inflammation and remodeling changes in the airways, predisposing the development of type 2-related asthma (50%-70% of asthmatics). […] The pathogenesis of AD comprises the interaction between alterations in barrier function, and environmental stimuli in the context of a dysregulated and spectral Th2 and Th17/22 immune response.

• #95 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia (Portuguese)

  https://www.anaisdedermatologia.org.br/pt-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  A dysfunctional skin barrier is more prevalent in patients with AD, and this deficit has several clinical consequences, as these patients are characterized by high reactivity to environmental stimuli and pathogens, reinforcing the role of restoring the skin barrier and protection against triggers for disease control. […] The predominant Th2 imbalance in AD is implicated in reduced FLG expression, contributing to the barrier defect. […] The dysregulated type 2 inflammation cytokine response occurs in different anatomical sites of the body. At the level of the bronchi, IL-4 and IL-13 act by mediating inflammation and remodeling changes in the airways, predisposing the development of type 2-related asthma. […] The TSLP alarmin produced by keratinocytes subjected to stress, allergens, or pathogens, causes the activation of dendritic cells and the secretion of chemokines, which attract type 2 helper T lymphocytes (Th2) to the skin, releasing pro-allergenic cytokines (type 2 inflammation cytokines, such as IL-4, IL-13, IL-5, IL-31).

• #96 Galderma RX Atopic Dermatitis Skin Condition

  https://www.galdermahcp.com/conditions/atopic-dermatitis

  Potential strategies for preventing the atopic march from AD to asthma include primary and secondary prevention of AD by systemic moisturizer use and management with a proactive regimen, which involves long-term, low-dose intermittent topical anti-inflammatory therapy for previously affected areas with subclinical inflammation. The goal is not only to prevent ongoing epidermal barrier dysfunction, residual inflammatory skin infiltrate and the immunological abnormalities which are all present but clinically invisible, but also to delay or prevent progression of the atopic march. […] The potential benefits of halting atopic march at AD are exciting to consider: reduced burden of AD, fewer food allergies, less allergic rhinitis, lower asthma incidence; asthma alone is responsible for more than one-third of childhood emergency room visits. These benefits go a long way towards explaining why there is so much interest in preventing or protecting the skin barrier from developing a proinflammatory atopic state. Evidence for the role of barrier defects and skin barrier dysfunction in atopic diseases is accumulating.

• #97 Pathogenesis of atopic dermatitis: Current concepts – Journal of Skin and Sexually Transmitted Diseases

  https://jsstd.org/pathogenesis-of-atopic-dermatitis-current-concepts/

  Once the permeability barrier is perturbed in a sustained manner, a number of defense mechanisms are activated to protect the underlying dermis. […] However, a sustained defect in the epidermal permeability barrier impairs the homeostatic response, allows the inflammation to spread and, recruits inflammatory cells consisting of lymphocytes, eosinophils, and mast cells. […] The defective barrier allows the entry of many noxious agents including environmental antigens, aeroallergens, and haptens as well as antigens derived from microorganisms, especially Staphylococcus aureus. […] The persistence of this process switches the specific protective adaptive immune responses to a more allergy dominant Th2 and Th22 dominant immune profile. […] This inflammation results in further deterioration of the permeability barrier.

• #98 Pathogenesis of atopic dermatitis: Current concepts – Journal of Skin and Sexually Transmitted Diseases

  https://jsstd.org/pathogenesis-of-atopic-dermatitis-current-concepts/

  As a result, barrier function is further compromised and barrier recovery is delayed. […] This further worsens the dermal inflammation resulting in a vicious cycle. […] Prolonged inflammation, especially when widespread, is very detrimental to the health of the individual. […] A better understanding of the intricate pathogenesis of atopic dermatitis may help to formulate effective treatment guidelines for this challenging disease.

• #99 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  This article constitutes a multidisciplinary narrative review of the current aspects of AD pathogenesis, which, although not fully elucidated, can be understood based on the interaction of unique aspects such as genetic predisposition; changes in the skin barrier; activation of keratinocytes by mechanical, physical or chemical stressors; imbalance of the innate and adaptive immunity responses/loss of immune tolerance; intrinsic and extrinsic factors as disease triggers or aggravating factors; associated organic comorbidities, and sensitization of the pruritus neural pathways, so that a bidirectional neural and immune interaction is established in AD. […] The skin barrier dysfunction that occurs in AD increases permeability to allergens and irritants, contributing to loss of hydration and persistence of subclinical skin inflammation.

• #100 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://clinics.elsevier.es/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  After surpassing the skin barrier, the antigens are phagocytosed by different antigen-presenting cells, especially LCs. […] This contribution of LCs also occurs in the context of AD and food allergy through transcutaneous sensitization to food allergens. […] The immunopathogenesis of AD is based on a deregulated immune response, in a multidimensional and interconnected way, affecting the response to antigens, the induction of inflammation, immune homeostasis disruption, disarray of the architectural integrity of the epidermis and dermis, producing a cardinal symptom, which is pruritus.

• #101 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia

  https://clinics.elsevier.es/en-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  In AD, the unregulated and excessive production of cytokines, especially IL-4 and IL-13, causes the inhibition of the expression of epidermal proteins such as filaggrin, loricrin, and involucrin, which reinforces defects in the epidermal barrier, favoring the permeation of allergens and pathogens, feeding back the disease. […] The predominant Th2 imbalance in AD is implicated in reduced FLG expression, contributing to the barrier defect. […] The dysregulated type 2 inflammation cytokine response occurs in different anatomical sites of the body. At the level of the bronchi, IL-4 and IL-13 act by mediating inflammation and remodeling changes in the airways, predisposing the development of type 2-related asthma (50%-70% of asthmatics). […] The pathogenesis of AD comprises the interaction between alterations in barrier function, and environmental stimuli in the context of a dysregulated and spectral Th2 and Th17/22 immune response.

• #102 Atopic dermatitis – Wikipedia

  https://en.wikipedia.org/wiki/Atopic_dermatitis

  Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin. The cause is unknown but is believed to involve genetics, immune system dysfunction, environmental exposures, and difficulties with the permeability of the skin. Disruption of the epidermal barrier is thought to play an integral role in the pathogenesis of AD. Disruptions of the epidermal barrier allow allergens to penetrate the epidermis to deeper layers of the skin. This leads to activation of epidermal inflammatory dendritic and innate lymphoid cells which subsequently attracts Th2 CD4+ helper T cells to the skin. This dysregulated Th2 inflammatory response is thought to lead to the eczematous lesions. The Th2 helper T cells become activated, leading to the release of inflammatory cytokines including IL-4, IL-13 and IL-31 which activate downstream Janus kinase (Jak) pathways. The active Jak pathways lead to inflammation and downstream activation of plasma cells and B lymphocytes which release antigen specific IgE contributing to further inflammation. Mutations in the filaggrin gene, FLG, also cause impairment in the skin barrier that contributes to the pathogenesis of AD. Filaggrin mutations are also associated with a decrease in natural antimicrobial peptides found on the skin; subsequently leading to disruption of skin flora and bacterial overgrowth (commonly Staphylococcus aureus overgrowth or colonization). Excessive type 2 inflammation underlies the pathophysiology of atopic dermatitis. The role of Staphylococcus aureus in skin irritation occurs via inflammation factors that induce itching, which may damage the skin, further driving inflammation, and facilitating the growth of Staphylococcus aureus, thus promoting a chronic cycle.

• #103 Atopic Dermatitis Treatment Strategies Using Ruxolitinib, Considering Crucial Role of Skin Microbiome

  https://www.ajmc.com/view/atopic-dermatitis-treatment-strategies-using-ruxolitinib-considering-crucial-role-of-skin-microbiome

  Lawrence F. Eichenfield, MD, FAAD, emphasized the role the skin microbiome plays in eczema pathogenesis, particularly the correlation between Staphylococcus (Staph) aureus counts and disease severity in an interview with The American Journal of Managed Care at the American Academy of Dermatology 2025 annual conference. […] The skin microbiome is very involved in part of the pathogenesis and clinical manifestations of eczema. We’ve known for decades that when eczema gets worse, the Staph aureus counts go up. If Staph aureus is more present, the eczema can be more severe as well. […] Once you have established atopic dermatitis, often, very commonly, we can have severe flares of the disease associated with clinical cutaneous infection. […] If you get the disease under control, you’ll decrease cutaneous infections, and that has an impact on the microbiome. The microbiome is responsive, it’s not static; but we have ways of influencing it. If you have effective anti-inflammatory care, you’ll often have [an] impact [on] changing or decreasing the amount of secondary cutaneous infections.

• #104 Recent Advancements in the Atopic Dermatitis Mechanism

  https://www.imrpress.com/journal/FBL/29/2/10.31083/j.fbl2902084/htm

  Concerning the genetic component, the lower expression of terminal differentiation markers, such as filaggrin (FLG) and loricrin (LOR), and the respective barrier permeability defect associated with the epithelial lipid film impairment and increased transepidermal water loss (TEWL) are well-established determinants. […] Notably, the interleukin (IL)-31 network, comprising several cell types, such as macrophages, basophils, and the generated cytokines, is also involved in the pathogenesis of the itchiness in AD. […] The dysregulated T cell-mediated immune response, including different patterns of cytokine release, has a strong and robust role in the pathogenesis of AD. […] IL-4 and IL-13 represent the two main T2-cytokines associated with AD pathogenesis. […] The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is significant in the pathogenesis of AD and inflammation.

• #105 Atopic dermatitis – Wikipedia

  https://en.wikipedia.org/wiki/Atopic_dermatitis

  Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin. The cause is unknown but is believed to involve genetics, immune system dysfunction, environmental exposures, and difficulties with the permeability of the skin. Disruption of the epidermal barrier is thought to play an integral role in the pathogenesis of AD. Disruptions of the epidermal barrier allow allergens to penetrate the epidermis to deeper layers of the skin. This leads to activation of epidermal inflammatory dendritic and innate lymphoid cells which subsequently attracts Th2 CD4+ helper T cells to the skin. This dysregulated Th2 inflammatory response is thought to lead to the eczematous lesions. The Th2 helper T cells become activated, leading to the release of inflammatory cytokines including IL-4, IL-13 and IL-31 which activate downstream Janus kinase (Jak) pathways. The active Jak pathways lead to inflammation and downstream activation of plasma cells and B lymphocytes which release antigen specific IgE contributing to further inflammation. Mutations in the filaggrin gene, FLG, also cause impairment in the skin barrier that contributes to the pathogenesis of AD. Filaggrin mutations are also associated with a decrease in natural antimicrobial peptides found on the skin; subsequently leading to disruption of skin flora and bacterial overgrowth (commonly Staphylococcus aureus overgrowth or colonization). Excessive type 2 inflammation underlies the pathophysiology of atopic dermatitis. The role of Staphylococcus aureus in skin irritation occurs via inflammation factors that induce itching, which may damage the skin, further driving inflammation, and facilitating the growth of Staphylococcus aureus, thus promoting a chronic cycle.

• #106 Atopic Dermatitis Treatment Strategies Using Ruxolitinib, Considering Crucial Role of Skin Microbiome

  https://www.ajmc.com/view/atopic-dermatitis-treatment-strategies-using-ruxolitinib-considering-crucial-role-of-skin-microbiome

  Lawrence F. Eichenfield, MD, FAAD, emphasized the role the skin microbiome plays in eczema pathogenesis, particularly the correlation between Staphylococcus (Staph) aureus counts and disease severity in an interview with The American Journal of Managed Care at the American Academy of Dermatology 2025 annual conference. […] The skin microbiome is very involved in part of the pathogenesis and clinical manifestations of eczema. We’ve known for decades that when eczema gets worse, the Staph aureus counts go up. If Staph aureus is more present, the eczema can be more severe as well. […] Once you have established atopic dermatitis, often, very commonly, we can have severe flares of the disease associated with clinical cutaneous infection. […] If you get the disease under control, you’ll decrease cutaneous infections, and that has an impact on the microbiome. The microbiome is responsive, it’s not static; but we have ways of influencing it. If you have effective anti-inflammatory care, you’ll often have [an] impact [on] changing or decreasing the amount of secondary cutaneous infections.

• #107 Pathogenesis of atopic dermatitis: Current concepts – Journal of Skin and Sexually Transmitted Diseases

  https://jsstd.org/pathogenesis-of-atopic-dermatitis-current-concepts/

  As a result, barrier function is further compromised and barrier recovery is delayed. […] This further worsens the dermal inflammation resulting in a vicious cycle. […] Prolonged inflammation, especially when widespread, is very detrimental to the health of the individual. […] A better understanding of the intricate pathogenesis of atopic dermatitis may help to formulate effective treatment guidelines for this challenging disease.

• #108 Recent Advancements in the Atopic Dermatitis Mechanism

  https://www.imrpress.com/journal/FBL/29/2/10.31083/j.fbl2902084/htm

  Atopic dermatitis (AD) is a recurrent, chronic, inflammatory, itchy skin disorder that affects up to 20% of the pediatric population and 10% of the adult population worldwide. […] The pathophysiology of AD includes a complex and multifaceted interplay between the impaired dysfunctional epidermal barrier, genetic predisposition, and environmental contributors, such as chemical and/or biological pollutants and allergens, in the context of dysregulated T2 and T17 skewed immune response. […] The two previously main pathogenetic hypotheses, the ‘outside–in’ and the contrasting ‘inside–out’, which prioritize either the epidermal barrier dysfunction or the dysregulated immune activation as the primary trigger in the pathophysiology of AD, are now integrated into a complex and multifaceted model, including the genetic component and, the effect of environmental pollutants, in the context of a dysregulated T2 and T17 skewed immune response.

• #109 Update on the pathogenesis of atopic dermatitis | Anais Brasileiros de Dermatologia (Portuguese)

  https://www.anaisdedermatologia.org.br/pt-update-on-pathogenesis-atopic-dermatitis-articulo-S0365059624001764

  Atopic dermatitis is a chronic, recurrent, and multifactorial skin-mucosal manifestation resulting from the interaction between elements mainly associated with the skin barrier deficit, the homeostasis of the immune response, neurological aspects, and patterns of reactivity to environmental antigens, which are established in genetically predisposed individuals. […] The scientific knowledge about the different aspects of AD and atopic diathesis has advanced considerably in recent years. Its pathogenesis is complex, involving immune-mediated mechanisms, and its understanding is advancing in relation to genetic predisposition, structural and functional changes in the epidermal barrier, innate and adaptive immune responses, colonization of the skin by microorganisms, bacteria and fungi, reactivity to house dust mites, neurobehavioral elements, and triggers for exacerbation of the subclinical disease.

• #110 Molecular Mechanisms of Atopic Dermatitis Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8074061/

  Atopic dermatitis is a chronic, non-infectious inflammatory dermatosis. The pathophysiology of atopic dermatitis is complex and multifactorial. It includes genetic disorders, a defect in the epidermal barrier, an altered immune response, and disruption of the skin’s microbial balance. The numerous complex changes at the genetic level and innate and adaptive immunity provide the basis for characterizing the various phenotypes and endotypes of atopic dermatitis. The pathophysiology of atopic dermatitis is complex and multifactorial. Its understanding is complicated by the number of synergized factors that influence the disease. The most important are: genetic disorders, a defect in the epidermal barrier, an altered immune response and disturbed microbiological balance of the skin. The initial suspicions of atopic dermatitis’s genetic background appeared along with the observations of a higher incidence of AD in families with atopy. There are many cooperating genes responsible for the disease’s pathogenesis. However, this is not a simple Mendelian inheritance. Genes are also subject to various heredity phenomena such as epigenetic changes, incomplete gene penetrance, and genomic imprinting. The following paper presents some of the molecular mechanisms involved in the pathogenesis of atopic dermatitis. The likely mechanism of how the environment affects the organism’s cells are epigenetic changes. Epigenetic regulation is one of the determinants of AD development, next to the FLG gene polymorphisms and genes related to the immune system and the skin barrier. In AD, epigenetic changes concern genes known to affect the immune response regulation, genes of innate immunity, and genes encoding epidermis structural proteins. While describing atopic dermatitis causes, it is impossible to avoid disorders of immune regulation. Consequently, two different hypotheses have been proposed, from inside to outside and from outside to inside. The first one suggests that immunological aberrations are believed to be the primary initial event in development, and stimulation with allergens leads to weakening the epidermal barrier. The latter hypothesis assumes that an impaired skin barrier is the first step in atopic eczema’s pathogenesis and is required for immune dysregulation to occur. The skin produces antimicrobial peptides (AMP) to destroy or inhibit microbes growth. Altered AMP expression and secretion may contribute to increased susceptibility to skin infections by viruses, bacteria and fungi in AD patients. Atopic dermatitis is such a complex and diverse disease that different immune responses occur in various patient groups. Therefore, these specific molecular mechanisms underlying the disease have been defined as disease endotypes which set and variable constellations give rise to a particular phenotype.

• #111 Recent Advancements in the Atopic Dermatitis Mechanism

  https://www.imrpress.com/journal/FBL/29/2/10.31083/j.fbl2902084

  Notably, the interleukin (IL)-31 network, comprising several cell types, including macrophages, basophils, and the generated cytokines involved in the pathogenesis of itch in AD, has recently been explored. […] Unraveling the specific AD endotypes, highlighting the implicated molecular pathogenetic mechanisms of clinically relevant AD phenotypes, has emerged as a crucial step toward targeted therapies for personalized treatment in AD patients.

• #112

  https://link.springer.com/article/10.1007/s12016-021-08880-3

  Atopic dermatitis (AD) is a common inflammatory skin disorder characterized by recurrent eczematous lesions and intense itch. […] The pathogenesis of AD is complex, and it is evident that a strong genetic predisposition, epidermal dysfunction, skin microbiome abnormalities, immune dysregulation, and the neuroimmune system are critical in AD development. […] Mutations in the genes associated with disrupted epidermal barrier, exaggerated pathological inflammation and inadequate antimicrobial peptides can promote enhanced Th2 inflammation and mediate pruritus. […] Current understanding of etiology highlights gut microbial diversity, NK cell deficiency, and different immunological phenotype with age and race. […] In-depth understanding of the pathogenesis of AD has led to the development of innovative and targeted therapies, such as biologic agents targeting interleukin (IL)-4, IL-13 and JAK/STAT inhibitors. […] Other potential therapeutic agents for AD include agents targeting the T helper (Th) 22 and Th17/IL23 pathway.

• #113 An Overview of Atopic Dermatitis Disease Burden, Pathogenesis, and the Current Treatment Landscape: Recommendations for Appropriate Utilization of Systemic Therapies | JCAD – The Journal of Clinical and Aesthetic Dermatology

  https://jcadonline.com/current-treatments-for-atopic-dermatitis/

  IL-13 has also been shown to have a significant role in driving skin barrier impairment and dysbiosis of the skin microbiome. […] Newer systemic treatments that interfere with the Type 2 inflammatory pathway include dupilumab (blocks both IL-4 and IL-13 signaling), tralokinumab (specifically blocks the IL-13 cytokine), lebrikizumab (blocks a different epitope of IL-13 than tralokinumab), nemolizumab (blocks IL-31), and the JAK inhibitors upadacitinib and abrocitinib (block numerous cytokine pathways in addition to IL-4 and IL-13).

• #114 Unraveling Atopic Dermatitis: Insights into Pathophysiology, Therapeutic Advances, and Future Perspectives

  https://www.mdpi.com/2073-4409/13/5/425

  Atopic dermatitis (AD) is an inflammatory skin condition that frequently develops before the onset of allergic rhinitis or asthma. Recent research has connected the environment, genetics, the skin barrier, drugs, psychological factors, and the immune system to the onset and severity of AD. The pathogenesis of AD is multifaceted, involving genetic predispositions, abnormalities in skin function, immune system dysregulation, and environmental influences. The essential membrane protein filaggrin (FLG) has been discovered to have the greatest genetic association with AD. FLG null mutations weaken the skin barrier and heighten AD risk. In addition to FLG gene mutations, factors like DNA methylation, FLG copy number variations, environmental influences (skin irritation, damage, and low humidity), cytokines (Th2, interleukins (IL)-17, IL-22, IL-25, and IL-31) reducing FLG expression, skin microorganisms, and treatments (topical and systemic) can also alter FLG levels. The cells involved in host–environment interaction resulting in skin inflammation are eosinophils, basophils, dendritic cells (DCs), keratinocytes, mast cells, macrophages, and type 2 innate lymphoid cells (ILC2s). Additionally, reductions in the levels of epidermal barrier proteins, such as FLG, spinous layer proteins (SPINK), and claudins, alongside alterations of antimicrobial peptides, play a significant role. Both T and B cells, together with their respective cytokines, contribute to this disease’s immunological profile, highlighted by a dominant Th2 axis (including IL-4, IL-13, IL-5, thymic stromal lymphopoietin (TSLP), and IL-31), elevated Th17/IL-23 and Th22 pathways, and increased IgE levels. The main connection between skin bacteria and AD is S. aureus, often found on the skin of AD patients. Skin problems deriving from AD make it easier for S. aureus to grow. When there is a lack of FLG, there is usually more S. aureus in the skin’s microbiome. S. aureus prompts keratinocytes to produce proteases, worsening the skin’s barrier. It also releases harmful substances like δ-toxin and α-toxin; δ-toxin can trigger mast cells to release substances without killing them, particularly when IgE is present. The Th2 cytokines IL-4, IL-5, and IL-13 play a pivotal role in AD and have been linked to increased IgE response and eosinophils in AD patients. In AD patients, IL-4 and IL-4 receptors on peripheral blood lymphocytes were aberrant, with an increased production of IL-13. It was previously demonstrated that AD patients lost their capacity to release IFN-γ in response to different stimuli. Researchers have found a notable connection wherein the amount of IFN-γ produced is linked to lower levels of IgE found in the blood of individuals with AD. Studies on patients with acute AD revealed that they had higher amounts of IFN-γ and IL-4 in the skin and peripheral blood. These cytokines are secreted by T cells that are specific to the allergens. When an antigen is encountered by antigen-presenting cells such as DCs, they release TSLP and initiate signaling pathways that activate naïve T cells. This leads to the differentiation of T cells into Th1 and Th2 subtypes, which release interleukins and chemokines to combat the antigen. However, this immune response contributes to inflammation and may exacerbate skin barrier dysfunction in AD rather than directly cause barrier penetration. The exploration of interleukins and their influence on the immunological pathway in AD has been facilitated by using relevant biomarkers in clinical trials. This approach enables the identification of novel therapeutic modalities, fostering the potential for targeted translational research within the realm of personalized medicine.

• #115 Recent Advancements in the Atopic Dermatitis Mechanism

  https://www.imrpress.com/journal/FBL/29/2/10.31083/j.fbl2902084/htm

  The key role of skin microbiome dysbiosis in the integrity of the skin barrier and the interplay between microbiome, exposome, skin-barrier leakage, and host immune response highlights the necessity for targeted interventions aiming at rebalancing the skin microbiome. […] The role of the exposome in the multidimensional model of AD pathogenesis has recently been explored. […] The exposome is the “master regulator” in the interplay between a disrupted and “leaky” epithelium barrier, microbiome, genome, and immune dysregulation in AD. […] The intricate and multifactorial interplay of well-established and novel pathogenetic mechanisms associated with AD, including dysregulated immune responses, disruption of the epithelial barrier, pruritus, microbiome dysbiosis, and the influence of the exposome is illustrated.

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