Materiały źródłowe

• #1 Disease Mechanisms in Atopic Dermatitis: A Review of Aetiological Factors | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3512

  Atopic dermatitis is a prevalent inflammatory skin condition characterized by itch and dry skin, which affects 15-20% of children and 3-5% of adults. This article reviews epidemiological, clinical and experimental data to provide an overview of the most important disease mechanisms in atopic dermatitis. Genetic predisposition, environmental insults, atopic triggers, complex host immune response and skin barrier changes, and altered skin microbiota are discussed. Whilst our understanding of atopic dermatitis has improved dramatically in recent years, many basic aspects are still not understood. Further research is needed to fully understand this complex skin disease. […] The pathogenesis of AD is complex and poorly understood. However, in recent years, there has been major advancements in our understanding of the disease mechanism of AD, e.g. through the discovery of common filaggrin gene (FLG) mutations as a strong risk factor for AD, as well as the significant clinical effects of antagonistic therapy against interleukins (IL) 4, 13, 22 and 31.

• #2 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 loss of function mutations encoding structural proteins such as filaggrin, a fundamental epidermal protein, and the more recently identified variations in the epidermal differentiation complex are well-established determinants resulting in an impaired skin barrier in AD. […] 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.

• #3 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.

• #4 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. […] 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.

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

  https://emedicine.medscape.com/article/1049085-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 Recent Advancements in the Atopic Dermatitis Mechanism

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

  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. […] 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. […] The dysregulated T cell-mediated immune response, including different patterns of cytokine release, has a strong and robust role in the pathogenesis of AD.

• #7 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. […] 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.

• #8 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). In addition, a maternal history may be more predictive for AD. […] 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. FLG gene defects have also been associated with peanut allergy, contact dermatitis, and infections such as the herpes virus.

• #9 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. It has been noted that children of parents with a history of allergic diseases have a greater risk of developing AD. 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 filaggrin gene is located in the epidermal differentiation gene complex (EDC) on the long arm of the 1q21 chromosome. The resulting FLG monomers aggregate keratin fibres through the catalytic activity of the transglutaminase-1 enzyme, which results in the flattening of cells. 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 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 following paper presents some of the molecular mechanisms involved in the pathogenesis of atopic dermatitis.

• #10 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. […] 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. […] 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. […] Mutations in the gene for filaggrin, a key epidermal barrier protein, cause ichthyosis vulgaris and are the strongest known genetic risk factors for AD.

• #11 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. It has been noted that children of parents with a history of allergic diseases have a greater risk of developing AD. 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 filaggrin gene is located in the epidermal differentiation gene complex (EDC) on the long arm of the 1q21 chromosome. The resulting FLG monomers aggregate keratin fibres through the catalytic activity of the transglutaminase-1 enzyme, which results in the flattening of cells. 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 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 following paper presents some of the molecular mechanisms involved in the pathogenesis of atopic dermatitis.

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

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

  Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by a compromised epidermal barrier and heightened immunoglobulin E (IgE) levels, often associated with filaggrin (FLG) gene mutations. […] The diseases pathogenesis involves complex interactions between genetic predispositions, immune responses, and environmental triggers. […] The barrier dysfunction in AD is often linked to mutations in the filaggrin (FLG) gene, which disrupts skin integrity and predisposes individuals to allergic sensitization, and elevated serum IgE levels. […] Lipid dysregulation is another critical aspect of AD pathogenesis. […] The immunological dysfunction in AD involves abnormal innate, adaptive, and humoral immunity, possibly influenced by epigenetic changes. […] The Global Burden of Disease (GBD) report highlights AD as a significant public health concern, with symptoms varying by region, climate, age, and other factors.

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

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

  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. […] Dephosphorylation and proteolytic cleavage transform Pro-FLG polymers into FLG monomers, crucial for stratum corneum (SC) formation and keratin buildup. FLG null mutations weaken the skin barrier and heighten AD risk. Having FLG null alleles may trigger early AD onset, potentially extending into adulthood. 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.

• #14 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. It has been noted that children of parents with a history of allergic diseases have a greater risk of developing AD. 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 filaggrin gene is located in the epidermal differentiation gene complex (EDC) on the long arm of the 1q21 chromosome. The resulting FLG monomers aggregate keratin fibres through the catalytic activity of the transglutaminase-1 enzyme, which results in the flattening of cells. 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 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 following paper presents some of the molecular mechanisms involved in the pathogenesis of atopic dermatitis.

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

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

  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. […] Dephosphorylation and proteolytic cleavage transform Pro-FLG polymers into FLG monomers, crucial for stratum corneum (SC) formation and keratin buildup. FLG null mutations weaken the skin barrier and heighten AD risk. Having FLG null alleles may trigger early AD onset, potentially extending into adulthood. 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.

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

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

  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. […] Dephosphorylation and proteolytic cleavage transform Pro-FLG polymers into FLG monomers, crucial for stratum corneum (SC) formation and keratin buildup. FLG null mutations weaken the skin barrier and heighten AD risk. Having FLG null alleles may trigger early AD onset, potentially extending into adulthood. 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.

• #17 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). In addition, a maternal history may be more predictive for AD. […] 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. FLG gene defects have also been associated with peanut allergy, contact dermatitis, and infections such as the herpes virus.

• #18 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). In addition, a maternal history may be more predictive for AD. […] 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. FLG gene defects have also been associated with peanut allergy, contact dermatitis, and infections such as the herpes virus.

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

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

  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. […] Dephosphorylation and proteolytic cleavage transform Pro-FLG polymers into FLG monomers, crucial for stratum corneum (SC) formation and keratin buildup. FLG null mutations weaken the skin barrier and heighten AD risk. Having FLG null alleles may trigger early AD onset, potentially extending into adulthood. 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.

• #20 Overview of Atopic Dermatitis

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

  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. Genetically modified mice engineered to overexpress TH2 cytokines developed skin barrier defects and AD spontaneously. Naturally, many of these cytokines are targets for novel therapies for the treatment of AD.

• #21 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.

• #22 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 skin barrier factors may include a deficiency of skin barrier proteins, increased peptidase activity, lack of certain protease inhibitors, and lipid abnormalities. High-molecular-weight allergens in pollens, house dust-mite particles, microbes, and foods can only penetrate the skin barrier when there is epidermal barrier dysfunction.

• #23 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

  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. […] 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.

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

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

  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. […] 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. […] The introduction of biologics, particularly dupilumab, which inhibits IL-4 and IL-13 signaling pathways, signifies a transformative advancement in managing mild-to-extreme AD conditions.

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

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

  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. […] 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. […] The introduction of biologics, particularly dupilumab, which inhibits IL-4 and IL-13 signaling pathways, signifies a transformative advancement in managing mild-to-extreme AD conditions.

• #26 Atopic dermatitis causes

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

  The main inherited abnormality causing disordered barrier function is filaggrin expression. Filaggrins are filament-associated proteins which bind to keratin fibres in the epidermal cells. The gene for filaggrin (FLG) resides on chromosome 1 (1q21.3). This gene was first identified as the gene involved in ichthyosis vulgaris. Abnormal filaggrin is associated with early-onset, severe and persistent atopic dermatitis. […] 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. A reduction in natural moisturising factors, which include metabolites of pro-filaggrin. An increase in skin pH which encourages serine protease activity — these are enzymes which digest lipid-processing enzymes and the proteins that hold epidermal cells together. Serine proteases also generate active cytokines like IL-1a and Il-1beta and promote skin inflammation.

• #27 Atopic dermatitis causes

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

  The main inherited abnormality causing disordered barrier function is filaggrin expression. Filaggrins are filament-associated proteins which bind to keratin fibres in the epidermal cells. The gene for filaggrin (FLG) resides on chromosome 1 (1q21.3). This gene was first identified as the gene involved in ichthyosis vulgaris. Abnormal filaggrin is associated with early-onset, severe and persistent atopic dermatitis. […] 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. A reduction in natural moisturising factors, which include metabolites of pro-filaggrin. An increase in skin pH which encourages serine protease activity — these are enzymes which digest lipid-processing enzymes and the proteins that hold epidermal cells together. Serine proteases also generate active cytokines like IL-1a and Il-1beta and promote skin inflammation.

• #28 Atopic dermatitis causes

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

  The main inherited abnormality causing disordered barrier function is filaggrin expression. Filaggrins are filament-associated proteins which bind to keratin fibres in the epidermal cells. The gene for filaggrin (FLG) resides on chromosome 1 (1q21.3). This gene was first identified as the gene involved in ichthyosis vulgaris. Abnormal filaggrin is associated with early-onset, severe and persistent atopic dermatitis. […] 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. A reduction in natural moisturising factors, which include metabolites of pro-filaggrin. An increase in skin pH which encourages serine protease activity — these are enzymes which digest lipid-processing enzymes and the proteins that hold epidermal cells together. Serine proteases also generate active cytokines like IL-1a and Il-1beta and promote skin inflammation.

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

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

  Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by a compromised epidermal barrier and heightened immunoglobulin E (IgE) levels, often associated with filaggrin (FLG) gene mutations. […] The diseases pathogenesis involves complex interactions between genetic predispositions, immune responses, and environmental triggers. […] The barrier dysfunction in AD is often linked to mutations in the filaggrin (FLG) gene, which disrupts skin integrity and predisposes individuals to allergic sensitization, and elevated serum IgE levels. […] Lipid dysregulation is another critical aspect of AD pathogenesis. […] The immunological dysfunction in AD involves abnormal innate, adaptive, and humoral immunity, possibly influenced by epigenetic changes. […] The Global Burden of Disease (GBD) report highlights AD as a significant public health concern, with symptoms varying by region, climate, age, and other factors.

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

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

  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. […] 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. […] The introduction of biologics, particularly dupilumab, which inhibits IL-4 and IL-13 signaling pathways, signifies a transformative advancement in managing mild-to-extreme AD conditions.

• #31 SciELO Brazil – Update on the pathogenesis of atopic dermatitis Update on the pathogenesis of atopic dermatitis

  https://www.scielo.br/j/abd/a/vFghvqwtgKCCPN5wZRNkdCf/

  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. […] Skin barrier dysfunction fundamentally favors the impact of environmental elements on the pathogenesis of AD. The bidirectional interaction of the external environment with human health and disease is called exposome, complementing the lifelong interactions between genes and environment in the pathogenesis of diseases. […] The elevated pH of the stratum corneum and the increased activity of serine proteinase promote the inactivation and degradation of acid sphingomyelinase and -glucocerebrosidase, which are the enzymes required for ceramide synthesis.

• #32 SciELO Brazil – Update on the pathogenesis of atopic dermatitis Update on the pathogenesis of atopic dermatitis

  https://www.scielo.br/j/abd/a/vFghvqwtgKCCPN5wZRNkdCf/

  In patients with chronic AD, increased kallikrein activity can also lead to these changes in lipid structure by inducing degradation of very long-chain fatty acid elongation protein. […] The predominant Th2 imbalance in AD is implicated in reduced FLG expression, contributing to the barrier defect. […] 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.

• #33 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.

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

  https://emedicine.medscape.com/article/1049085-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. […]

• #35 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

  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 Th2 response is triggered by environmental irritants and allergens that penetrate the skin barrier. […] IL-4 and IL-13 are considered the main drivers of the Th2 immune axis and key cytokines for the pathogenesis of AD. […] In AD skin, IL-4 and IL-13 contribute to skin barrier impairment, reducing the expression of terminal differentiation proteins such as FLG, LOR, and involucrin (INV) in both lesional and nonlesional skin. […] The activation of the Th22 pathway is believed to play a key role in linking the barrier and the immune defects in AD. Th22 cells produce IL-22, which contributes to skin barrier damage by acting on keratinocytes, inhibiting their differentiation and promoting epidermal hyperplasia. […] Overall, these results represent an example of the application of a personalized medicine approach and confirm IL-22 as a pathogenetic cytokine in AD.

• #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

  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 Th2 response is triggered by environmental irritants and allergens that penetrate the skin barrier. […] IL-4 and IL-13 are considered the main drivers of the Th2 immune axis and key cytokines for the pathogenesis of AD. […] In AD skin, IL-4 and IL-13 contribute to skin barrier impairment, reducing the expression of terminal differentiation proteins such as FLG, LOR, and involucrin (INV) in both lesional and nonlesional skin. […] The activation of the Th22 pathway is believed to play a key role in linking the barrier and the immune defects in AD. Th22 cells produce IL-22, which contributes to skin barrier damage by acting on keratinocytes, inhibiting their differentiation and promoting epidermal hyperplasia. […] Overall, these results represent an example of the application of a personalized medicine approach and confirm IL-22 as a pathogenetic cytokine in AD.

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

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

  When mast cells are activated, they release various substances linked to inflammation. These include cytokines associated with Th17 cells like IL-6, IL-17A, and IL-23, as well as proinflammatory cytokines such as IL-1β, IL-6, and IL-8, and chemokines like macrophage inflammatory protein (MIP)-1α, MIP-1β, and Monocyte chemoattractant protein (MCP)-1. […] 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. […] 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.

• #38 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

  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). 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.

• #39 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

  Thus, IL-4 and IL-13 constitute the main cytokines associated with the pathogenesis of early AD, as in addition to promoting type 2 inflammatory responses and recruiting eosinophils to the skin, they damage the epidermal barrier by suppressing the expression of structural proteins such as filaggrin, loricrin, and lipids, while concomitantly increasing collagen deposition in the dermis, which results in skin remodeling and lichenification.

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

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

  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. […] Thus, IL-4 and IL-13 constitute the main cytokines associated with the pathogenesis of early AD, as in addition to promoting type 2 inflammatory responses and recruiting eosinophils to the skin, they damage the epidermal barrier by suppressing the expression of structural proteins such as filaggrin, loricrin, and lipids, while concomitantly increasing collagen deposition in the dermis, which results in skin remodeling and lichenification. […] 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.

• #41 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

  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 Th2 response is triggered by environmental irritants and allergens that penetrate the skin barrier. […] IL-4 and IL-13 are considered the main drivers of the Th2 immune axis and key cytokines for the pathogenesis of AD. […] In AD skin, IL-4 and IL-13 contribute to skin barrier impairment, reducing the expression of terminal differentiation proteins such as FLG, LOR, and involucrin (INV) in both lesional and nonlesional skin. […] The activation of the Th22 pathway is believed to play a key role in linking the barrier and the immune defects in AD. Th22 cells produce IL-22, which contributes to skin barrier damage by acting on keratinocytes, inhibiting their differentiation and promoting epidermal hyperplasia. […] Overall, these results represent an example of the application of a personalized medicine approach and confirm IL-22 as a pathogenetic cytokine in AD.

• #42 Disease Mechanisms in Atopic Dermatitis: A Review of Aetiological Factors | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3512

  It is important to understand that non-lesional AD skin is also different from the skin of normal controls. It shows decreased or altered synthesis of important epidermal proteins, e.g. filaggrin, filaggrin 2, involucrin, loricrin, hornerin, and tight junctions, but also decreased synthesis of antimicrobial peptides and lipids, as well as increased expression of high-affinity IgE receptor on dendritic CD1a, along with increased numbers of T cells and their cytokines. […] Type 2 immunity-associated cytokines, such as IL-4 and IL-13, as well as other cytokines, including, but not limited to, IL-1, IL-17, IL-22, IL-31 IL-33, and thymic stromal lymphopoietin (TSLP) have important roles in AD. […] Predominantly Th2 (IL-4, IL-5, IL-13, IL-31) and Th22 (IL-22) deviation is observed in acute and chronic AD lesions, which, in turn, down-regulate expression of important skin barrier proteins, such as filaggrin.

• #43 Disease Mechanisms in Atopic Dermatitis: A Review of Aetiological Factors | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3512

  It is important to understand that non-lesional AD skin is also different from the skin of normal controls. It shows decreased or altered synthesis of important epidermal proteins, e.g. filaggrin, filaggrin 2, involucrin, loricrin, hornerin, and tight junctions, but also decreased synthesis of antimicrobial peptides and lipids, as well as increased expression of high-affinity IgE receptor on dendritic CD1a, along with increased numbers of T cells and their cytokines. […] Type 2 immunity-associated cytokines, such as IL-4 and IL-13, as well as other cytokines, including, but not limited to, IL-1, IL-17, IL-22, IL-31 IL-33, and thymic stromal lymphopoietin (TSLP) have important roles in AD. […] Predominantly Th2 (IL-4, IL-5, IL-13, IL-31) and Th22 (IL-22) deviation is observed in acute and chronic AD lesions, which, in turn, down-regulate expression of important skin barrier proteins, such as filaggrin.

• #44 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

  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). 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.

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

  https://clinics.elsevier.es/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 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).

• #46 Recent Advancements in the Atopic Dermatitis Mechanism

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

  The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is significant in the pathogenesis of AD and inflammation. […] The JAK family consists of four intracellular kinases, JAK1, JAK2, JAK3, and TYK2, which are activated in pairs when cytokines bind to their respective receptors. […] 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 “leaking epithelial barrier” results in chronic peri-epithelial inflammation in the epithelium-lined human organs, including the skin, the gastrointestinal and respiratory systems, and, consequently, in certain autoimmune, metabolic, and neuropsychiatric diseases. […] The epidermal barrier plays a pivotal role in AD by serving as the primary defense mechanism against external irritants and allergens.

• #47 Recent Advancements in the Atopic Dermatitis Mechanism

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

  The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is significant in the pathogenesis of AD and inflammation. […] The JAK family consists of four intracellular kinases, JAK1, JAK2, JAK3, and TYK2, which are activated in pairs when cytokines bind to their respective receptors. […] 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 “leaking epithelial barrier” results in chronic peri-epithelial inflammation in the epithelium-lined human organs, including the skin, the gastrointestinal and respiratory systems, and, consequently, in certain autoimmune, metabolic, and neuropsychiatric diseases. […] The epidermal barrier plays a pivotal role in AD by serving as the primary defense mechanism against external irritants and allergens.

• #48 Mechanism of Action | Atopic Dermatitis | OPZELURA® (ruxolitinib) HCP

  https://www.opzelurahcp.com/atopic-dermatitis/mechanism-of-action

  Atopic dermatitis (AD) is a chronic skin disease marked by itch, inflammation, and skin barrier dysfunction. Dysregulation of inflammatory cytokines (IL-4, IL-13, IL-31, and TSLP) is believed to be involved in AD pathogenesis. […] These cytokines signal through the JAK-STAT pathway and are thought to perpetuate the cycle of itch and inflammation in AD. […] JAKs are intracellular signaling enzymes that act downstream of key cytokines (IL-4, IL-13, IL-31, and TSLP) and therefore are believed to play a key role in AD itch and inflammation. […] OPZELURA is a topical JAK inhibitor designed to target the JAK-STAT pathway, thereby helping to regulate the signaling of key cytokines believed to be involved in AD itch and inflammation. […] OPZELURA is thought to interrupt IL-31 signaling by providing JAK inhibition in a topical.

• #49 Recent Advancements in the Atopic Dermatitis Mechanism

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

  The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is significant in the pathogenesis of AD and inflammation. […] The JAK family consists of four intracellular kinases, JAK1, JAK2, JAK3, and TYK2, which are activated in pairs when cytokines bind to their respective receptors. […] 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 “leaking epithelial barrier” results in chronic peri-epithelial inflammation in the epithelium-lined human organs, including the skin, the gastrointestinal and respiratory systems, and, consequently, in certain autoimmune, metabolic, and neuropsychiatric diseases. […] The epidermal barrier plays a pivotal role in AD by serving as the primary defense mechanism against external irritants and allergens.

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

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

  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. […] Furthermore, changes in microbial diversity on the skin, characterized by an excessive presence of S. aureus strains, highlight the complexity of AD’s etiology. 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.

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

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

  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. […] Furthermore, changes in microbial diversity on the skin, characterized by an excessive presence of S. aureus strains, highlight the complexity of AD’s etiology. 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.

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

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

  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. […] Furthermore, changes in microbial diversity on the skin, characterized by an excessive presence of S. aureus strains, highlight the complexity of AD’s etiology. 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.

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

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

  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. […] Furthermore, changes in microbial diversity on the skin, characterized by an excessive presence of S. aureus strains, highlight the complexity of AD’s etiology. 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.

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

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

  When mast cells are activated, they release various substances linked to inflammation. These include cytokines associated with Th17 cells like IL-6, IL-17A, and IL-23, as well as proinflammatory cytokines such as IL-1β, IL-6, and IL-8, and chemokines like macrophage inflammatory protein (MIP)-1α, MIP-1β, and Monocyte chemoattractant protein (MCP)-1. […] 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. […] 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.

• #55 Disease Mechanisms in Atopic Dermatitis: A Review of Aetiological Factors | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3512

  AD is a skin condition in which primary (or secondary) skin barrier impairment leads to (further) skin inflammation, and in which S. aureus colonization may increase, and in turn may drive both eczema severity and the relentless sensation of itch. This leads to scratching and additional barrier impairment, thus creating a vicious cycle. […] While the exact role of bacteria in the pathogenesis of AD is unclear, colonization with S. aureus is very common in lesional and non-lesional AD skin. Antimicrobial peptides, which work as broad-spectrum antibiotics to kill Gram-negative and Gram-positive bacteria, are reduced in patients with AD, which, in turn, allows bacteria to colonize the skin. S. aureus can induce serine protease activity, which will destroy corneodesmosomes, and allow invasion.

• #56 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.

• #57 Atopic Dermatitis (Eczema) – Dermatologic Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/dermatologic-disorders/dermatitis/atopic-dermatitis-eczema

  The cutaneous inflammation, in contrast, is a T-cell-mediated delayed-type hypersensitivity and includes a Th2-dominant component in the skin. […] However, because the major mechanism mediating atopic dermatitis is delayed cell-mediated immunity, avoidance of immediate-type allergens usually does not improve atopic dermatitis. […] In patients with atopic diathesis, atopic dermatitis typically precedes allergic rhinoconjunctivitis and asthma. Sometimes, this sequence is called the „atopic march” and occurs because the skin barrier defect is the primary deficiency in atopic conditions.

• #58 SciELO Brazil – Update on the pathogenesis of atopic dermatitis Update on the pathogenesis of atopic dermatitis

  https://www.scielo.br/j/abd/a/vFghvqwtgKCCPN5wZRNkdCf/

  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. […] 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 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).

• #59 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

  A novel treatment that presents the greatest opportunity to powerfully target atopic eczema inflammation involves using monoclonal antibodies which are currently being developed to treat several different atopic diseases. […] The multitude of causes is what has brought about the variety of treatments for atopic eczema. […] Novel treatments have become more specific in targeting molecular mechanisms in atopic eczema, which, it is hoped, will make them more effective and with fewer side effects.

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

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

  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. […] 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. […] The introduction of biologics, particularly dupilumab, which inhibits IL-4 and IL-13 signaling pathways, signifies a transformative advancement in managing mild-to-extreme AD conditions.

• #61 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

  Dupilumab is a fully human monoclonal antibody that blocks the shared receptor component for IL-4 and IL-13, inhibiting signaling of both IL-4 and IL-13, key and central drivers of type 2-mediated inflammation in multiple diseases. The efficacy and safety of dupilumab have also been established in adult and adolescent patients with moderate-to-severe AD. […] The lower incidence of infections with dupilumab treatment compared with placebo is likely due to its targeted action on IL-4 and IL-13, key type 2 inflammation cytokines that drive skin barrier dysfunction. It has been demonstrated that dupilumab treatment normalizes the skin barrier, including Staphylococcus aureus colonization, in both lesional and non-lesional skin.

• #62 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/

  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).

• #63 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 loss of function mutations encoding structural proteins such as filaggrin, a fundamental epidermal protein, and the more recently identified variations in the epidermal differentiation complex are well-established determinants resulting in an impaired skin barrier in AD. […] 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.

• #64 Recent Advancements in the Atopic Dermatitis Mechanism

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

  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. […] Regarding the genetic component, the loss of function mutations encoding structural proteins such as filaggrin, a fundamental epidermal protein, and the more recently identified variations in the epidermal differentiation complex are well-established determinants resulting in an impaired skin barrier in AD.

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

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

  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. […] Thus, IL-4 and IL-13 constitute the main cytokines associated with the pathogenesis of early AD, as in addition to promoting type 2 inflammatory responses and recruiting eosinophils to the skin, they damage the epidermal barrier by suppressing the expression of structural proteins such as filaggrin, loricrin, and lipids, while concomitantly increasing collagen deposition in the dermis, which results in skin remodeling and lichenification. […] 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.

• #66 Insights Into Atopic Dermatitis – From Pathogenesis to…

  https://sciendo.com/article/10.2478/amb-2023-0022

  Atopic dermatitis (AD), or eczema, is a common skin disease that is often associated with other atopic disorders, such as allergic rhinitis and asthma. […] The review analyzes the genetical, immunological, and environmental factors in the pathogenesis of AD. […] The role of the skin barrier function is also considered in regard of the main hypotheses for AD development. […] Further elucidation of the mechanisms involved in the pathogenesis of AD could give interesting and useful clues for therapeutic protocols and prophylactic approaches.

• #67 Recent Advancements in the Atopic Dermatitis Mechanism

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

  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. […] 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. […] The dysregulated T cell-mediated immune response, including different patterns of cytokine release, has a strong and robust role in the pathogenesis of AD.

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