Primary Atopic Disorders.

Primary atopic disorders describes a series of monogenic diseases that have allergy- or atopic effector-related symptoms as a substantial feature. The underlying pathogenic genetic lesions help illustrate fundamental pathways in atopy, opening up diagnostic and therapeutic options for further study in those patients, but ultimately for common allergic diseases as well. Key pathways affected in these disorders include T cell receptor and B cell receptor signaling, cytokine signaling, skin barrier function, and mast cell function, as well as pathways that have not yet been elucidated. While comorbidities such as classically syndromic presentation or immune deficiency are often present, in some cases allergy alone is the presenting symptom, suggesting that commonly encountered allergic diseases exist on a spectrum of monogenic and complex genetic etiologies that are impacted by environmental risk factors.

Sensory neurons promote immune homeostasis in the lung.

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPß was dependent on JAK1 in the vagus nerve, and CGRPß suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.

A basophil-neuronal axis promotes itch.

Itch is an evolutionarily conserved sensation that facilitates expulsion of pathogens and noxious stimuli from the skin. However, in organ failure, cancer, and chronic inflammatory disorders such as atopic dermatitis (AD), itch becomes chronic, intractable, and debilitating. In addition to chronic itch, patients often experience intense acute itch exacerbations. Recent discoveries have unearthed the neuroimmune circuitry of itch, leading to the development of anti-itch treatments. However, mechanisms underlying acute itch exacerbations remain overlooked. Herein, we identify that a large proportion of patients with AD harbor allergen-specific immunoglobulin E (IgE) and exhibit a propensity for acute itch flares. In mice, while allergen-provoked acute itch is mediated by the mast cell-histamine axis in steady state, AD-associated inflammation renders this pathway dispensable. Instead, a previously unrecognized basophil-leukotriene (LT) axis emerges as critical for acute itch flares. By probing fundamental itch mechanisms, our study highlights a basophil-neuronal circuit that may underlie a variety of neuroimmune processes.

Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch.

Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.

Mechanisms for initiation of food allergy by skin pre-disposed to atopic dermatitis.

Food allergy can be life-threatening and often develops early in life. In infants and children, loss-of-function mutations in skin barrier genes associate with food allergy. In a mouse model with skin barrier mutations (Flakey Tail, FT+/- mice), topical epicutaneous sensitization to a food allergen peanut extract (PNE), an environmental allergen Alternaria alternata (Alt) and a detergent induce food allergy and then an oral PNE-challenge induces anaphylaxis. Exposures to these allergens and detergents can occur for infants and children in a household setting. From the clinical and preclinical studies of neonates and children with skin barrier mutations, early oral exposure to allergenic foods before skin sensitization may induce tolerance to food allergens and thus protect against development of food allergy. In the FT+/- mice, oral food allergen prior to skin sensitization induce tolerance to food allergens. However, when the skin of FT+/- pups are exposed to a ubiquitous environmental allergen at the time of oral consumption of food allergens, this blocks the induction of tolerance to the food allergen and the mice can then be skin sensitized with the food allergen. The development of food allergy in neonatal FT+/- mice is mediated by altered skin responses to allergens with increases in skin expression of interleukin 33, oncostatin M and amphiregulin. The development of neonate food allergy is enhanced when born to an allergic mother, but it is inhibited by maternal supplementation with α-tocopherol. Moreover, preclinical studies suggest that food allergen skin sensitization can occur before manifestation of clinical features of atopic dermatitis. Thus, these parameters may impact design of clinical studies for food allergy, when stratifying individuals by loss of skin barrier function or maternal atopy before offspring development of atopic dermatitis.

Physiology and Pathophysiology of Itch.

Itch is a topic to which everyone can relate. The physiological roles of itch are increasingly understood and appreciated. The pathophysiological consequences of itch impact quality of life as much as pain. These dynamics have led to increasingly deep dives into the mechanisms that underlie and contribute to the sensation of itch. When the prior review on the physiology of itching was published in this journal in 1941, itch was a black box of interest to a small number of neuroscientists and dermatologists. Itch is now appreciated as a complex and colorful Rubik's cube. Acute and chronic itch are being carefully scratched apart and reassembled by puzzle solvers across the biomedical spectrum. New mediators are being identified. Mechanisms blur boundaries of the circuitry that blend neuroscience and immunology. Measures involve psychophysics and behavioral psychology. The efforts associated with these approaches are positively impacting the care of itchy patients. There is now the potential to markedly alleviate chronic itch, a condition that does not end life, but often ruins it. We review the itch field and provide a current understanding of the pathophysiology of itch. Itch is a disease, not only a symptom of disease.

Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond.

Signal transducer and activator of transcription (STAT)-6 is a transcription factor central to pro-allergic immune responses, although the function of human STAT6 at the whole-organism level has long remained unknown. Germline heterozygous gain-of-function (GOF) rare variants in STAT6 have been recently recognized to cause a broad and severe clinical phenotype of early-onset, multi-system allergic disease. Here, we provide an overview of the clinical presentation of STAT6-GOF disease, discussing how dysregulation of the STAT6 pathway causes severe allergic disease, and identifying possible targeted treatment approaches. Finally, we explore the mechanistic overlap between STAT6-GOF disease and other monogenic atopic disorders, and how this group of inborn errors of immunity (IEIs) powerfully inform our fundamental understanding of common human allergic disease.

Exploring the roles of prostanoids, leukotriens, and dietary fatty acids in cutaneous inflammatory diseases: Insights from pharmacological and genetic approaches.

Prostanoids and leukotrienes (LTs) are representative of ω6 fatty acid-derived metabolites that exert their actions through specific receptors on the cell surface. These lipid mediators, being unstable in vivo, act locally at their production sites; thus, their physiological functions remain unclear. However, recent pharmacological and genetic approaches using experimental murine models have provided significant insights into the roles of these lipid mediators in various pathophysiological conditions, including cutaneous inflammatory diseases. These lipid mediators act not only through signaling by themselves but also by potentiating the signaling of other chemical mediators, such as cytokines and chemokines. For instance, prostaglandin E2 -EP4 and LTB4 -BLT1 signaling on cutaneous dendritic cells substantially facilitate their chemokine-induced migration ability into the skin and play critical roles in the priming and/or activation of antigen-specific effector T cells in the skin. In addition to these ω6 fatty acid-derived metabolites, various ω3 fatty acid-derived metabolites regulate skin immune cell functions, and some exert potent anti-inflammatory functions. Lipid mediators act as modulators of cutaneous immune responses, and manipulating the signaling from lipid mediators has the potential as a novel therapeutic approach for human skin diseases.

Human milk oligosaccharides: potential therapeutic aids for allergic diseases.

Childhood allergy, including asthma, eczema, and food allergies, is a major global health burden, with prevalence increasing dramatically and novel interventions needed. Emerging research suggests that human milk oligosaccharides (HMOs), complex glycans found in breastmilk, have allergy-protective properties, indicating exciting therapeutic potential. This review evaluates current literature on the role of HMOs in allergy, assesses underlying immunological mechanisms, and discusses future research needed to translate findings into clinical implications. HMOs may mediate allergy risk through multiple structure-specific mechanisms, including microbiome modification, intestinal barrier maturation, immunomodulation, and gene regulation. Findings emphasize the importance of breastfeeding encouragement and HMO-supplemented formula milk for high allergy-risk infants. Although further investigation is necessary to determine the most efficacious structures against varying allergy phenotypes and their long-term efficacy, HMOs may represent a promising complementary tool for childhood allergy prevention.

Epithelial-immune cell interactions in allergic diseases.

Epithelial/immune interactions are characterized by the different properties of the various epithelial tissues, the mediators involved, and the varying immune cells that initiate, sustain, or abrogate allergic diseases on the surface. The intestinal mucosa, respiratory mucosa, and regular skin feature structural differences according to their primary function and surroundings. In the context of these specialized functions, the active role of the epithelium in shaping immune responses is increasingly recognizable. Crosstalk between epithelial and immune cells plays an important role in maintaining homeostatic conditions. While cells of the myeloid cell lineage, mainly macrophages, are the dominating immune cell population in the skin and the respiratory tract, lymphocytes comprise most intraepithelial immune cells in the intestine under healthy conditions. Common to all surface epithelia is the fact that innate immune cells represent the first line of immunosurveillance that either directly defeats invading pathogens or initiates and coordinates more effective successive immune responses involving adaptive immune cells and effector cells. Pharmacological approaches for the treatment of allergic and chronic inflammatory diseases involving epithelial barriers target immunological mediators downstream of the epithelium (such as IL-4, IL-5, IL-13, and IgE). The next generation of therapeutics involves upstream events of the inflammatory cascade, such as epithelial-derived alarmins and related mediators.

Langerhans cells and skin immune diseases.

Langerhans cells (LCs) are the key antigen-presenting cells in the epidermis in normal conditions and respond differentially to environmental and/or endogenous stimuli, exerting either proinflammatory or anti-inflammatory effects. Current knowledge about LCs mainly originates from studies utilizing mouse models, whereas with the development of single-cell techniques, there has been significant progress for human LCs, which has updated our understanding of the phenotype, ontogeny, differentiation regulation, and function of LCs. In this review, we delineated the progress of human LCs and summarized LCs' function in inflammatory skin diseases, providing new ideas for precise regulation of LC function in the prevention and treatment of skin diseases.

The role of dendritic cells in the instruction of helper T cells in the allergic march.

Allergy is a complex array of diseases influenced by innate and adaptive immunity, genetic polymorphisms, and environmental triggers. Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by barrier defects and immune dysregulation, sometimes leading to asthma and food allergies because of the atopic march. During atopic skin inflammation, Langerhans cells and dendritic cells (DCs) in the skin capture and deliver allergen information to local lymph nodes. DCs are essential immune sensors coordinating immune reactions by capturing and presenting antigens to T cells. In the context of allergic responses, DCs play a crucial role in instructing two types of helper T cells - type 2 helper T (Th2) cells and follicular helper T (TFH) cells - in allergic responses and IgE antibody responses. In skin sensitization, the differentiation and function of Th2 cells and TFH cells are influenced by skin-derived factors, including epithelial cytokines, chemokines, and signaling pathways to modify the function of migratory DCs and conventional DCs. In this review, we aim to understand the specific mechanisms involving DCs in allergic responses to provide insights into the pathogenesis of allergic diseases and potential therapeutic strategies.

Blockade of OSMRß signaling ameliorates skin lesions in a mouse model of human atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by severe pruritus and eczematous skin lesions. Although IL-31, a type 2 helper T (Th2)-derived cytokine, is important to the development of pruritus and skin lesions in AD, the blockade of IL-31 signaling does not improve the skin lesions in AD. Oncostatin M (OSM), a member of IL-6 family of cytokines, plays important roles in the regulation of various inflammatory responses through OSM receptor ß subunit (OSMRß), a common receptor subunit for OSM and IL-31. However, the effects of OSM on the pathogenesis of AD remain to be elucidated. When AD model mice were treated with OSM, skin lesions were exacerbated and IL-4 production was increased in the lymph nodes. Next, we investigated the effects of the monoclonal antibody (mAb) against OSMRß on the pathogenesis of AD. Treatment with the anti-OSMRß mAb (7D2) reduced skin severity score in AD model mice. In addition to skin lesions, scratching behavior was decreased by 7D2 mAb with the reduction in the number of OSMRß-positive neurons in the dorsal root ganglia of AD model mice. 7D2 mAb also reduced the serum concentration of IL-4, IL-13, and IgE as well as the gene expressions of IL-4 and IL-13 in the lymph nodes of AD model mice. Blockade of both IL-31 and OSM signaling is suggested to suppress both pruritus and Th2 responses, resulting in the improvement of skin lesions in AD. The anti-OSMRß mAb may be a new therapeutic candidate for the treatment of AD.

Unexpected connections of the IL-23/IL-17 and IL-4/IL-13 cytokine axes in inflammatory arthritis and enthesitis.

The IL-23/IL-17 cytokine axis is related to spondyloarthropathy (SpA) pattern diseases that target the skin, eye, gut and joints. These share overlapping target tissues with Th2 type or allergic diseases, including the skin, eye and gut but SpA diseases exhibit distinct microanatomical topography, molecular characteristics, and clinical features including uveitis, psoriasis, apical pulmonary involvement, lower gastrointestinal involvement with colitis, and related arthritides including psoriatic arthritis and ankylosing spondylitis. Inflammatory arthritis is conspicuously absent from the Th2 diseases which are characterised IL-4/IL-13 dependent pathway activation including allergic rhino-conjunctivitis, atopic eczema, allergic asthma and food allergies. This traditional understanding of non-overlap of musculoskeletal territory between that atopic diseases and the IL-17 -mediated SpA diseases is undergoing a critical reappraisal with the recent demonstration of IL-4/IL-13 blockade, may be associated with the development of SpA pattern arthritis, psoriasiform skin disease and occasional anterior uveitis. Given the known plasticity within Th paradigm pathways, these findings suggest dynamic Th2 cytokine and Th17 cytokine counter regulation in vivo in humans. Unexpected, this is the case in peripheral enthesis and when the IL-4/13 immunological brake on IL-23/17 cytokines is removed, a SpA phenotype may emerge. We discuss hitherto unexpected observations in SpA, showing counter regulation between the Th17 and Th2 pathways at sites including the entheses that collectively indicate that the emergent reverse translational therapeutic data is more than coincidental and offers new insights into the "Th paradigms" in atopy and SpA.

Single-cell analysis of CD4+ tissue residency memory cells (TRMs) in adult atopic dermatitis: A new potential mechanism.

The pathophysiology of atopic dermatitis (AD) is complex. CD4+ T cells play an essential role in the development of lesions in AD. However, the underlying mechanism remains unclear. In the present study, we investigated the differentially expressed genes (DEGs) between adult AD lesioned and non-lesioned skin using two datasets from the Gene Expression Omnibus (GEO) database. 62 DEGs were shown to be related to cytokine response. Compared to non-lesioned skin, lesioned skin showed immune infiltration with increased numbers of activated natural killer (NK) cells and CD4+ T memory cells (p < 0.01). We then identified 13 hub genes with a strong association with CD4+ T cells using weighted correlation network analysis. Single-cell analysis of AD detected a novel CD4+ T subcluster, CD4+ tissue residency memory cells (TRMs), which were verified through immunohistochemistry (IHC) to be increased in the dermal area of AD. The significant relationship between CD4+ TRM and AD was assessed through further analyses. FOXO1 and SBNO2, two of the 13 hub genes, were characteristically expressed in the CD4+ TRM, but down-regulated in IFN-γ/TNF-α-induced HaCaT cells, as shown using quantitative polymerase chain reaction (qPCR). Moreover, SBNO2 expression was associated with increased Th1 infiltration in AD (p < 0.05). In addition, genes filtered using Mendelian randomization were positively correlated with CD4+ TRM and were highly expressed in IFN-γ/TNF-α-induced HaCaT cells, as determined using qPCR and western blotting. Collectively, our results revealed that the newly identified CD4+ TRM may be involved in the pathogenesis of adult AD.

Atopic dermatitis phenotype affects expression of atopic diseases despite similar mononuclear cell cytokine response.

BACKGROUND: The atopic march refers to the coexpression and progression of atopic diseases in childhood, often beginning with atopic dermatitis (AD), although children may not progress through each atopic disease. OBJECTIVE: We hypothesized that future atopic disease expression is modified by AD phenotype and that these differences result from underlying dysregulation of cytokine signaling. METHODS: Children (n = 285) were enrolled into the Childhood Origins of Asthma (COAST) birth cohort and followed prospectively. Rates of AD, food allergy, allergic rhinitis, and asthma were assessed longitudinally from birth to 18 years of age. Associations between AD phenotype and food allergy, allergic rhinitis, asthma, allergic sensitization, exhaled nitric oxide, and lung function were determined. Peripheral blood mononuclear cell responses (IL-5, IL-10, IL-13, IFN-γ) to dust mite, phytohemagglutinin, Staphylococcus aureus Cowan I, and tetanus toxoid were compared among AD phenotypes. RESULTS: AD at year 1 was associated with an increased risk of food allergy (P = .004). Both persistent and late-onset AD were associated with an increased risk of asthma (P < .001), rhinitis (P < .001), elevated total IgE (P < .001), percentage of aeroallergens with detectable IgE (P < .001), and elevated exhaled nitric oxide (P = .002). Longitudinal analyses did not reveal consistent differences in peripheral blood mononuclear cell responses among dermatitis phenotypes. CONCLUSION: AD phenotype is associated with differential expression of other atopic diseases. Our findings suggest that peripheral blood cytokine dysregulation is not a mechanism underlying this process, and immune dysregulation may be mediated at mucosal surfaces or in secondary lymphoid organs.

The circadian metabolome of atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by dry, pruritic skin. Several studies have described nocturnal increases in itching behavior, suggesting a role for the circadian rhythm in modulating symptom severity. However, the circadian rhythm of metabolites in the skin and serum of patients with AD is yet to be described. OBJECTIVE: We sought to assess circadian patterns of skin and serum metabolism in patients with AD. METHODS: Twelve patients with moderate to severe AD and 5 healthy volunteers were monitored for 28 hours in a controlled environment. Serum was collected every 2 hours and tape strips every 4 hours from both lesional and nonlesional skin in participants with AD and location-, sex-, and age-matched healthy skin of controls. We then performed an untargeted metabolomics analysis, examining the circadian peaks of metabolism in patients with AD. RESULTS: Distinct metabolic profiles were observed in AD versus control samples. When accounting for time of collection, the greatest differences in serum metabolic pathways were observed in arachidonic acid, steroid biosynthesis, and terpenoid backbone biosynthesis. We identified 42 circadian peaks in AD or control serum and 17 in the skin. Pathway enrichment and serum-skin metabolite correlation varied throughout the day. Differences were most evident in the late morning and immediately after sleep onset. CONCLUSIONS: Although limited by a small sample size and observational design, our findings suggest that accounting for sample collection time could improve biomarker detection studies in AD and highlight that metabolic changes may be associated with nocturnal differences in symptom severity.

Basophils are important for development of allergic skin inflammation.

BACKGROUND: Atopic dermatitis skin lesions exhibit increased infiltration by basophils. Basophils produce IL-4, which plays an important role in the pathogenesis of atopic dermatitis. OBJECTIVE: We sought to determine the role of basophils in a mouse model of antigen-driven allergic skin inflammation. METHODS: Wild-type mice, mice with selective and inducible depletion of basophils, and mice expressing Il4-driven enhanced green fluorescent protein were subjected to epicutaneous sensitization with ovalbumin or saline. Sensitized skin was examined by histology for epidermal thickening. Cells were analyzed for surface markers and intracellular expression of enhanced green fluorescent protein by flow cytometry. Gene expression was evaluated by real-time reverse transcription-quantitative PCR. RESULTS: Basophils were important for epidermal hyperplasia, dermal infiltration by CD4+ T cells, mast cells, and eosinophils in ovalbumin-sensitized mouse skin and for the local and systemic TH2 response to epicutaneous sensitization. Moreover, basophils were the major source of IL-4 in epicutaneous-sensitized mouse skin and promote the ability of dendritic cells to drive TH2 polarization of naive T cells. CONCLUSION: Basophils play an important role in the development of allergic skin inflammation induced by cutaneous exposure to antigen in mice.

Skin microdialysis detects distinct immunological patterns in chronic inflammatory skin diseases.

BACKGROUND: Insight into the pathophysiology of inflammatory skin diseases, especially at the proteomic level, is severely hampered by the lack of adequate in situ data. OBJECTIVE: Characterize lesional and nonlesional skin of inflammatory skin diseases using skin microdialysis. METHODS: Skin microdialysis samples from patients with atopic dermatitis (AD, n=6), psoriasis vulgaris (PSO, n=7) or prurigo nodularis (PN, n=6), as well as healthy controls (n=7) were subjected to proteomics and multiplex cytokine analysis. Single-cell RNA sequencing of skin biopsy specimens was used to identify the cellular origin of cytokines. RESULTS: Among the top 20 enriched GO annotations, NAD metabolic process, regulation of secretion by cell, and pyruvate metabolic process were elevated in microdialysates from lesional AD skin compared with both nonlesional skin and controls. The top 20 enriched KEGG pathways in these three groups overlapped almost completely. In contrast, nonlesional skin from patients with PSO or PN and control skin showed no overlap with lesional skin in this KEGG pathway analysis. Lesional skin from patients with PSO, but not AD or PN, showed significantly elevated protein levels of MCP-1 compared to nonlesional skin. IL-8 was elevated in lesional vs nonlesional AD and PSO skin, whereas IL-12p40 and IL-22 were higher only in lesional PSO skin. Integrated single-cell RNA-seq data revealed identical cellular sources of these cytokines in AD, PSO and PN. CONCLUSION: Based on microdialysate, proteomic data of lesional PSO and PN skin, but not lesional AD skin, differed significantly from those of nonlesional skin. IL-8, IL-22, MCP-1 and IL-12p40 might be suitable markers for minimally invasive molecular profiling.

Exploring the skin microbiome in atopic dermatitis pathogenesis and disease modification.

Inflammatory skin diseases such as atopic eczema (atopic dermatitis [AD]) affect children and adults globally. In AD, the skin barrier is impaired on multiple levels. Underlying factors include genetic, chemical, immunologic, and microbial components. Increased skin pH in AD is part of the altered microbial microenvironment that promotes overgrowth of the skin microbiome with Staphylococcus aureus. The secretion of virulence factors, such as toxins and proteases, by S aureus further aggravates the skin barrier deficiency and additionally disrupts the balance of an already skewed immune response. Skin commensal bacteria, however, can inhibit the growth and pathogenicity of S aureus through quorum sensing. Therefore, restoring a healthy skin microbiome could contribute to remission induction in AD. This review discusses direct and indirect approaches to targeting the skin microbiome through modulation of the skin pH; UV treatment; and use of prebiotics, probiotics, and postbiotics. Furthermore, exploratory techniques such as skin microbiome transplantation, ozone therapy, and phage therapy are discussed. Finally, we summarize the latest findings on disease and microbiome modification through targeted immunomodulatory systemic treatments and biologics. We believe that targeting the skin microbiome should be considered a crucial component of successful AD treatment in the future.