Atopic dermatitis: immune deviation,barrier dysfunction,IgE autoreactivity and new therapies

Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder mostly associated with IgE elevation and skin barrier dysfunction due to decreased filaggrin expression. The lesional skin of AD exhibits Th2- and Th22-deviated immune reactions that are progressive during disease chronicity. Th2 and Th22 cytokines further deteriorate the skin barrier by inhibiting filaggrin expression. Some IgEs are reactive to self-antigens. The IgE autoreactivity may precipitate the chronicity of AD. Upon activation of the ORAI1 calcium channel, atopic epidermis releases large amounts of thymic stromal lymphopoietin (TSLP), which initiates the Th2 and Th22 immune response. Th2-derived interleukin-31 and TSLP induce an itch sensation. Taken together, TSLP/Th2/Th22 pathway is a promising target for developing new therapeutics for AD. Enhancing filaggrin expression using ligands for the aryl hydrocarbon receptor may also be an adjunctive measure to restore the disrupted barrier function specifically for AD.     

Skin barrier defects in atopic dermatitis: From old idea to new opportunity

Atopic dermatitis (AD) is the most common chronic skin inflammatory disease, with a profound impact on patients’ quality of life. AD varies considerably in clinical course, age of onset and degree to which it is accompanied by allergic and non-allergic comorbidities. Skin barrier impairment in both lesional and nonlesional skin is now recognized as a critical and often early feature of AD. This may be explained by a number of abnormalities identified within both the stratum corneum and stratum granulosum layers of the epidermis. The goal of this review is to provide an overview of key barrier defects in AD, starting with a historical perspective. We will also highlight some of the commonly used methods to characterize and quantify skin barrier function. There is ample opportunity for further investigative work which we call out throughout this review. These include: quantifying the relative impact of individual epidermal abnormalities and putting this in a more holistic view with physiological measures of barrier function, as well as determining whether these barrier-specific endotypes predict clinical phenotypes (e.g. age of onset, natural history, comorbidities, response to therapies, etc). Mechanistic studies with new (and in development) AD therapies that specifically target immune pathways, Staphylococcus aureus abundance and/or skin barrier will help us understand the dynamic crosstalk between these compartments and their relative importance in AD.     

Skin microbiome of atopic dermatitis

The skin microbiome is a key component of pathogenesis in atopic dermatitis (AD). The skin of AD patients is characterized by microbial dysbiosis, with a reduction of microbial diversity and overrepresentation of pathogenic Staphylococcus aureus (S. aureus). Recent exciting studies have elucidated an importance of establishing an appropriate immune response to microbes in early life and uncovered the new mechanisms of microbial community dynamics in modulating our skin microbiome. Several microbes are associated with AD pathogenesis, with proposed pathogenic effects from S. aureus and Malassezia. The complex relationships between microbes within the skin microbiome consortia includes various species, such as Staphylococcal, Roseomonas and Cutibacterium strains, that can inhibit S. aureus and are potential probiotics for AD skin. Numerous microbes are now also reported to modulate host response via communication with keratinocytes, specialized immune cells and adipocytes to improve skin health and barrier function. This increased understanding of skin microbiota bioactives has led to new biotherapeutic approaches that target the skin surface microenvironment for AD treatment.     

The role of food allergy in atopic dermatitis

Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease affecting more than 10% of all children. Sensitization to foods triggers isolated skin symptoms in about 30% of children. These symptoms include immediate reactions within minutes after ingesting food without exacerbation of AD and early and late exacerbations of AD. It is important to identify clinically relevant sensitizations to foods using skin prick tests, a specific IgE blood test (ImmunoCAP; Phadia, Portage, MI, USA), and double-blind, placebo-controlled food challenges to initiate appropriate dietary interventions and avoid unnecessary dietary restrictions. Children with AD triggered by food allergens demonstrate a distinct immune response upon stimulation of their peripheral blood mononuclear cells with food allergen. A defective skin barrier and increased intestinal permeability appear to facilitate allergen sensitization. Appropriate skin care to maintain skin barrier function and dietary avoidance of highly allergenic foods during infancy may help to prevent allergen sensitization, thereby reducing the severity of AD and food allergies.     

Staphylococcus aureus in atopic dermatitis: Strain-specific cell wall proteins and skin immunity

Atopic dermatitis (AD) is a common chronic skin disease. The presence of the bacterium Staphylococcus aureus (S. aureus) is frequently detected on skin affected with AD. In this review, we focused on the characteristics of S. aureus strains isolated from AD skin, particularly the proteins on the cell surface that modulates the interactions between Langerhans cell, keratinocyte, and S. aureus. The skin microbiome plays an important role in maintaining homeostasis of the skin, and colonization of S. aureus in AD is considered to be deeply involved in the clinical manifestation and pathogenesis of skin flares. Colonizing S. aureus strains in AD harbor different surface proteins at the strain level, which are indicated as clonal complexes. Moreover, the cell wall proteins of S. aureus affect skin adhesion and induce altered immune responses. S. aureus from AD skin (AD strain) exhibits internalization into keratinocytes and induces imbalanced Th1/Th2 adaptive immune responses via Langerhans cells. AD strain-derived cell wall proteins and secreted virulence factors are expected to represent therapeutic targets. In addition, the microbiome on the AD skin surface is associated with skin immunity; thus, microbiome-based immunotherapy, whose mechanism of action completely differs from that of typical steroid ointments, are expected to be developed in the future.     

Subtypes of atopic dermatitis: From phenotype to endotype

Atopic dermatitis (AD) is a heterogenous disorder and can be classified into different types. Stratification of subtypes may enable personalized medicine approaches. AD can be categorized into the IgE-high, extrinsic subtype and the IgE-normal, intrinsic subtype. While extrinsic AD is the major subtype possessing skin barrier impairment (high incidence of filaggrin mutations), intrinsic AD occupies about 20% of AD with female dominance and preserved barrier. Extrinsic AD exhibits protein allergy and food allergy, but intrinsic AD shows metal allergy possibly in association with suprabasin deficiency. In particular, accumulated knowledge of food allergy has more clearly characterized extrinsic AD. European American (EA) and Asian AD subtypes have been also proposed. Asian patients with AD are characterized by a unique blended immune dysregulation and barrier feature phenotype between EA patients with AD and those with psoriasis. In another ethnic study, filaggrin loss-of-function mutations are not prevalent in African American patients with AD, and Th1/Th17 attenuation and Th2/Th22 skewing were seen in these patients. Recent endotype classification provides new insights for AD and other allergic disorders. Endotype is defined as the molecular mechanisms underlying the visible features/phenotype. Endotype repertoire harbors activation of type 2 cytokines, type 1 cytokines, and IL-17/IL-22, impairment of epidermal barrier, and abnormalities of intercellular lipids. Classification of endotype has been attempted with serum markers. These lines of evidence indicate a need for personalized or precision medicine appropriate for each subtype of AD.     

Skin Barrier Defects in Atopic Dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin condition with complex etiology that is dependent upon interactions between the host and the environment. Acute skin lesions exhibit the features of a Th2-driven inflammatory disorder, and many patients are highly atopic. The skin barrier plays key roles in immune surveillance and homeostasis, and in preventing penetration of microbial products and allergens. Defects that compromise the structural integrity or else the immune function of the skin barrier play a pivotal role in the pathogenesis of AD. This article provides an overview of the array of molecular building blocks that are essential to maintaining healthy skin. The basis for structural defects in the skin is discussed in relation to AD, with an emphasis on filaggrin and its genetic underpinnings. Aspects of innate immunity, including the role of antimicrobial peptides and proteases, are also discussed.     

Sweat allergy

Sweat allergy is defined as a type I hypersensitivity against the contents of sweat, and is specifically observed in patients with atopic dermatitis (AD) and cholinergic urticaria (CholU). The allergic reaction is clinically revealed by positive reactions in the intradermal skin test and the basophil histamine release assay by sweat. A major histamine-releasing antigen in sweat, MGL_1304, has been identified. MGL_1304 is produced at a size of 29 kDa by Malassezia (M.) globosa and secreted into sweat after being processed and converted into the mature form of 17 kDa. It induces significant histamine release from basophils of patients with AD and/or CholU with MGL_1304-specific IgE, which is detected in their sera. Patients with AD also show cross-reactivity to MGL_1304-homologs in Malassezia restricta and Malassezia sympodialis, but MGL_1304 does not share cross antigenicity with human intrinsic proteins. Malassezia or its components may penetrate the damaged epidermis of AD lesions and interact with the skin immune system, resulting in the sensitization and reaction to the fungal antigen. As well as the improvement of impaired barrier functions by topical interventions, approaches such as anti-microbial treatment, the induction of tolerance and antibody/substance neutralizing the sweat antigen may be beneficial for the patients with intractable AD or CholU due to sweat allergy. The identification of antigens other than MGL_1304 in sweat should be the scope for future studies, which may lead to better understanding of sweat allergy and therapeutic innovations.     

Microbial translocation,residual viremia and immune senescence in the pathogenesis of HIV-1 infection

The pathophysiological mechanisms that underlie the progression of human immunodeficiency virus-1 (HIV-1) disease to full-blown AIDS are not well understood. Findings suggest that, during HIV-1 infection, plasma lipopolysaccharide (LPS) levels, which are used as an indicator of microbial translocation (MT), are elevated throughout the acute and chronic phases of HIV-1 disease. The translocation of bacterial products through the damaged gastrointestinal barrier into the systemic circulation has been described as a driver of immune activation. In contrast, comorbidities that are associated with HIV-1 infection have been attributed to chronic inflammation and immune system dysfunction secondary to MT or low-level HIV-1 replication in plasma and cell reservoirs. Moreover, accelerated aging is significantly associated with chronic inflammation, immune activation, and immune senescence. In this review, we aimed to investigate the role of inflammation as a pivotal marker in the pathogenesis of HIV-1 disease. We will discuss the key features of chronic inflammation and immune activation that are observed during the natural course of the disease and those features that are detected in cART-modified infection. The review will focus on the following aspects of HIV-1 infection: (1) MT; (2) the role of residual viremia; and (3) “immune senescence” or “inflammaging.” Many questions remain unanswered about the potential mechanisms that are involved in HIV-1 pathogenesis. Further studies are needed to better investigate the mechanisms that underlie immune activation and their correlation with HIV-1 disease progression.     

Melatonin inhibits neuronal dysfunction‐associated with neuroinflammation by atopic psychological stress in NC/Nga atopic‐like mouse models

Atopic dermatitis (AD), also known as atopic eczema, is chronic pruritic skin disease. AD can increase psychological stress as well, increasing glucocorticoid release and exacerbating the associated symptoms. Chronic glucocorticoid elevation disturbs neuroendocrine signaling and can induce neuroinflammation, neurotoxicity, and cognitive impairment; however, it is unclear whether AD‐related psychological stress elevates glucocorticoids enough to cause neuronal damage. Therefore, we assessed the effects of AD‐induced stress in a mouse AD model. AD‐related psychological stress increased astroglial and microglial activation, neuroinflammatory cytokine expression, and markers of neuronal loss. Notably, melatonin administration inhibited the development of skin lesions, scratching behavior, and serum IgE levels in the model mice, and additionally caused a significant reduction in corticotropin‐releasing hormone responsiveness, and a significant reduction in neuronal damage. Finally, we produced similar results in a corticosterone‐induced AD‐like skin model. This is the first study to demonstrate that AD‐related psychological stress increases neuroendocrine dysfunction, exacerbates neuroinflammation, and potentially accelerates other neurodegenerative disease states.     

Filaggrin Gene Defects and the Risk of Developing Allergic Disorders

Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris (IV) and have been shown to be major predisposing factors for atopic dermatitis (AD). Approximately 40 loss-of-function FLG mutations have been identified in patients with ichthyosis vulgaris (IV) and/or atopic dermatitis (AD) in Europe and Asia. Major differences exist in the spectra of FLG mutations observed between different ancestral groups. Notably, prevalent FLG mutations are distinct between European and Asian populations. Many cohort studies on FLG mutations in AD have revealed that approximately 25-50% of AD patients harbour filaggrin mutations as a predisposing factor. In addition, FLG mutations are significantly associated with AD-associated asthma. The risk for developing allergic rhinitis is also significantly higher with a FLG mutation, both with and without accompanying AD. Recent studies have hypothesized that skin barrier defects caused by FLG mutations allows allergens to penetrate the epidermis and to interact with antigen-presenting cells, leading to the development of atopic disorders including asthma. The restoration of skin barrier function seems a feasible and promising strategy for prophylactic treatment of AD patients with FLG mutations.     

Interleukins 4 and 13 drive lipid abnormalities in skin cells through regulation of sex steroid hormone synthesis

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by skin dryness, inflammation, and itch. A major hallmark of AD is an elevation of the immune cytokines IL-4 and IL-13. These cytokines lead to skin barrier disruption and lipid abnormalities in AD, yet the underlying mechanisms are unclear. Sebaceous glands are specialized sebum-producing epithelial cells that promote skin barrier function by releasing lipids and antimicrobial proteins to the skin surface. Here, we show that in AD, IL-4 and IL-13 stimulate the expression of 3β-hydroxysteroid dehydrogenase 1 (HSD3B1), a key rate-limiting enzyme in sex steroid hormone synthesis, predominantly expressed by sebaceous glands in human skin. HSD3B1 enhances androgen production in sebocytes, and IL-4 and IL-13 drive lipid abnormalities in human sebocytes and keratinocytes through HSD3B1. Consistent with our findings in cells, HSD3B1 expression is elevated in the skin of AD patients and can be restored by treatment with the IL-4Rα monoclonal antibody, Dupilumab. Androgens are also elevated in a mouse model of AD, though the mechanism in mice remains unclear. Our findings illuminate a connection between type 2 immunity and sex steroid hormone synthesis in the skin and suggest that abnormalities in sex steroid hormone synthesis may underlie the disrupted skin barrier in AD. Furthermore, targeting sex steroid hormone synthesis pathways may be a therapeutic avenue to restoring normal skin barrier function in AD patients.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by stratum corneum lipid abnormalities (1, 2) and a dysfunctional skin barrier (3). The skin is a vital organ separating the host from its environment, and thus, the barrier breakdown seen in AD has systemic consequences for the host. AD patients experience more frequent episodes of skin infection from the increased exposure to commensal microbes. Additionally, the deeper penetration of environmental allergens in AD skin promotes the sequential progression of AD to other atopic diseases, including allergic rhinitis, food allergy, and asthma (4). AD is also an increasingly common condition with up to 13% of children and 10% of adults suffering from AD, with an annual treatment cost of $5.3 billion in the United States alone (5, 6).A major hallmark of AD is the elevated production of interleukins 4 and 13 (IL-4 and IL-13), both type 2 cytokines. These cytokines are pathogenic and drive the inflammation and barrier disruption seen in AD (7). Dupilumab is a human monoclonal antibody directed against the shared alpha subunit of the IL-4 and IL-13 receptors (IL-4Rα) and has revolutionized therapy for patients with moderate to severe AD and asthma (8). It is clear that blockade of IL-4Rα signaling restores skin barrier function and skin lipid metabolism in AD patients (9–11); however; how these classical immune pathways impact the skin epithelium is less clearly defined.Sebaceous glands are composed of specialized epithelial cells called sebocytes that generate sebum—a unique oily mixture of wax esters, squalene, triglycerides, proteins, and fatty acids required for normal skin ecology (12–15). Sebum is essential for barrier function, yet few current studies have examined the impact of sebaceous glands in the pathogenesis of AD (3, 11, 16, 17). Here, we explore how human sebocytes respond to the cytokines IL-4 and IL-13 to begin to establish how these cells impact barrier dysfunction in AD. We show that IL-4 and IL-13 up-regulate the expression of 3β-hydroxysteroid dehydrogenase 1 (HSD3B1) in sebaceous glands through the activation of STAT6. HSD3B1 is the rate-limiting enzyme in the synthesis of all classes of steroid hormones in primates (18, 19). Thus, IL-4 and IL-13 stimulate the production of the sex steroids androstenedione and dihydrotestosterone in sebocytes. Consistent with our findings in culture, the expression of HSD3B1 is also highly elevated in the lesional skin of human AD patients, which can be restored by Dupilumab treatment. Furthermore, we utilized small interfering RNA (siRNA) targeting HSD3B1 and show that depletion of HSD3B1-derived sex steroids in sebocytes increases lipid synthesis machinery in sebocytes and keratinocytes. Current treatments for AD primarily focus on immunosuppression to combat type 2 inflammation (20). Our findings provide insight into the impact of type 2 cytokines on skin ecology and uncover the sex steroid hormone synthesis pathway as a potential therapeutic target for the treatment of AD in humans.     

Pathogenesis of atopic dermatitis: New developments

Atopic dermatitis (AD) is a paradigmatic skin disease in which multiple gene-gene and gene-environment interactions play a pivotal role. Although the complex pathophysiologic network of AD explains the large spectrum of risk and trigger factors, it is far from being comprehensively understood. Hence, genetic modifications underlying the dysfunction of the epidermal skin barrier as well as the close interaction of innate and adaptive immune mechanisms were the focus of intensive research studies. This review aims to summarize the most recent findings in this field.     

Lessons from murine models of atopic dermatitis

Atopic dermatitis (AD) is a complex disease that manifests immunologic abnormalities in the skin. The immunologic changes of AD are characterized by a T helper cell type 2 (Th2)-dominated immune response in its acute phase and a Th1/Th2 mixed immune response in its chronic phase. Although the clinical presentation and pathologic changes are initially in the skin, AD may be, in part, a systemic disorder. In fact, AD is often considered to be the initial manifestation of the “atopic march” that progresses from AD to allergic rhinitis and asthma. In the past several years, a number of murine models of AD have been developed or discovered, and studies on these models have contributed greatly to our understanding of the immunopathogenesis of this disease. This review is focused on these recent, illuminating advances in animal models of AD.     

Immune dysregulation in atopic dermatitis.

Atopic dermatitis (AD) is a chronic, relapsing, highly pruritic, inflammatory skin disease characterized by cutaneous hyperreactivity to environmentals triggers. Recent data suggest the presence of two different forms of AD: an extrinsic AD with elevated IgE involving 70-80% of the patients and an intrinsic AD with serum IgE not elevated and no specific IgE. Patients with extrinsic AD have elevated Th2- and decreased Thl-expressing cells in the peripheral blood, with elevated IL-4 and IL-13 expression, as well as IL-5. On the contrary, the intrinsic AD is linked with much lower levels of IL-4 and IL-13. Genetic factors are involved in the control of the disease and in the intrinsic AD the same chromosomal regions seem to be associated with psoriasis susceptibility. The AD is characterized by a complex of immunological alterations involving interactions between IgE-bearing antigen-presenting cells, T-cell activation, mast-cell degranulation, keratinocytes, eosinophils, and a combination of immediate and cellular immune responses. Inflammatory dendritic epidermal cells constitute a distinct dendritic cells population that is mainly found in AD and could induce the Th2/Thl isotopic switch contributing to AD chronic phase. Therapy is based on interventation in the pathophysiology of atopic eczema and elimination of exogenous provocation factors.     

Pathogenesis of Atopic Dermatitis: Current Paradigm

Atopic dermatitis (AD) is characterized by skin inflammation, barrier dysfunction and chronic pruritus. In this review, recent advances in the pathogenesis of AD are summarized. Clinical efficacy of the anti-IL-4 receptor antibody dupilumab implies that type 2 cytokines IL-4 and IL-13 have pivotal roles in atopic inflammation. The expression of IL-4 and IL-13 as well as type 2 chemokines such as CCL17, CCL22 and CCL26 is increased in the lesional skin of AD. In addition, IL-4 and IL-13 down-regulate the expression of filaggrin in keratinocytes and exacerbate epidermal barrier dysfunction. Keratinocytes in barrier-disrupted epidermis produce large amounts of thymic stromal lymphopoietin, IL-25 and IL-33, conducing to type 2 immune deviation via OX40L/OX40 signaling. IL-31, produced by type 2 T cells, is a cardinal pruritogenic cytokine. IL-4 and IL-13 also amplify the IL-31-mediated sensory nerve signal. These molecules are particularly important targets for future drug development for AD.     

Reduced plasma levels of P-selectin and L-selectin in a pilot study from Alzheimer disease: relationship with neuro-degeneration

Neurodegenerative processes associated with Alzheimer’s disease (AD) are accompanied by reactive astrogliosis and microglia activation and a role for chronic inflammation in the brain degeneration of these patients has been suggested. Moreover impaired immune functions in AD brains might also influence the disease’s progression. Therefore, it is of interest to further characterized inflammatory molecules in the peripheral blood of patients with AD and its relationship with cognitive decline. A complex picture emerged in this pilot study and IL-8, IFN-gamma, MCP-1 and VEGF levels were increased in AD. Levels of P-selectin and L-selectin were decreased in AD and lowest in AD patients with highest cognitive decline. Our findings suggest that these molecules may induce alterations of endothelial regulation and influence neurodegenerative processes of AD.     

Genetic susceptibility to atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disorder with an increasing prevalence in industrialized countries. AD belongs to the group of allergic disorders that includes food allergy, allergic rhinitis, and asthma. A multifactorial background for AD has been suggested, with genetic as well as environmental factors influencing disease development. Recent breakthroughs in genetic methodology have greatly augmented our understanding of the contribution of genetics to susceptibility to AD. A candidate gene association study is a general approach to identify susceptibility genes. Fifty three candidate gene studies (50 genes) have identified 19 genes associated with AD risk in at least one study. Significant associations between single nucleotide polymorphisms (SNPs) in chemokines (chymase 1-1903A > G), cytokines (interleukin13 Arg144Gln), cytokine receptors (interleukin 4 receptor 1727G > A) and SPINK 1258G > A have been replicated in more than one studies. These SNPs may be promising for identifying at-risk individuals. SNPs, even those not strongly associated with AD, should be considered potentially important because AD is a common disease. Even a small increase in risk can translate to a large number of AD cases. Consortia and international collaborative studies, which may maximize study efficacy and overcome the limitations of individual studies, are needed to help further illuminate the complex landscape of AD risk and genetic variations.     

Keratinocytes in Atopic dermatitis: Inflammatory signals

Atopic dermatitis (AD) is a chronic inflammatory skin disorder that usually predates the development of allergic airway disease. In most cases, this is thought to be an allergen-driven disease with prominent roles played by antigen presenting cells and effector Th2 cells. But keratinocytes, by virtue of their location, provide an important window to the environment and are also thought to contribute to the development of AD. In this review, we discuss several biologic attributes of keratinocytes that are relevant for AD: 1) intrinsic defects in barrier function, 2) production of inflammatory mediators that promote or maintain allergic inflammation, 3) keratinocyte apoptosis, 4) effects of staphylococcal toxins on keratinocytes, and 5) potential consequences of the expression of cosignaling molecules (eg, B7 family members) and receptors important for innate immune responses (eg, Toll receptors). Clearly, these findings have highlighted a more active role played by the epithelium than was previously recognized.