Allergic Skin Diseases Research Articles

Evaluation of the Frequency of Restless Legs Syndrome in Children Diagnosed with Allergic Diseases

Objective We aimed to determine the frequency of restless legs syndrome (RLS) in children with allergic diseases. Methods The age, gender, height, weight, BMI z-scores, and laboratory values of children diagnosed with asthma, allergic rhinitis, atopic dermatitis, and chronic urticaria, as well as a healthy control group, were examined. RLS was assessed using a questionnaire based on the diagnostic criteria of the International Restless Legs Syndrome Study Group. Neurological examination findings, questionnaire results, and RLS severity scores were evaluated by a pediatric neurology specialist. Results The study evaluated data from 270 children diagnosed with allergic diseases and 150 healthy controlsBoth groups were statistically similar in terms of age, gender, weight, height, and BMI z-scores (p > 0.05). The frequency of RLS was reported as 13.3% in children with allergic airway disease, 15.5% in those with allergic skin disease, and 6.7% in the control group. The frequency of RLS in children with allergic airway disease and allergic skin disease was significantly higher compared to the control group (p = 0.041 and p = 0.022, respectively). The frequency of mild RLS in children with allergic diseases and the control group was 43.6% (n = 17) and 50% (n = 5), respectively (p = 0.737). The rate of females with RLS was significantly higher than those without RLS (69.2% vs. 30.8%) (p = 0.045). According to logistic regression analysis, individuals with allergic diseases were 2.307 (95.0% C.I. of OR: 1.087 to 4.897) times more likely to develop RLS compared to those without allergic diseases (p = 0.029). Conclusion The frequency of RLS is higher in children with allergic diseases. Early diagnosis of RLS may allow for a holistic management of quality-of-life-reducing problems, such as sleep disorders, that may be associated with both conditions.

Association Of Eosinophil And Total Ige Values With Allergy Test Results In Patients With Atopic Dermatitis

AOBJECTIVES: Atopic dermatitis (AD) is a chronic, recurrent, allergic inflammatory skin disease that may have a genetic predisposition. Eosinophilia is a common finding in patients with atopy. In our study, we aimed to investigate the relationship between eosinophil and IgE levels and allergy test results in patients with atopic dermatitis. METHODS: In this descriptive study, the files of patients diagnosed with atopic dermatitis and followed up in our Pediatric Allergy and Immunology Clinic between January 2021 and December 2022 were retrospectively reviewed. Age, gender, eosinophil, total IgE and specific IgE (for food and inhaled allergens) values were analyzed in the study. Skin prick test (SPT) was also performed in patients who had negative results for allergen-specific IgE. RESULTS: The absolute eosinophil count, eosinophil (%) and total IgE values of patients sensitized to at least one of the food and aeroallergens were significantly higher than those without allergen sensitization. The cut-off point of total IgE in predicting allergen sensitization was found to be 91.5 by ROC analysis. The sensitivity and specificity values for the cut-off point of total IgE were 73.3% and 72.9%. CONCLUSION: In this study, allergen sensitization was detected in 3 out of every 4 AD patients with total IgE and eosinophil values above the cut-off point we analyzed. Accordingly, we think that total IgE and eosinophil values are successful in predicting allergen sensitization. In clinics where specific IgE or SPT cannot be performed, eosinophil and total IgE values in whole blood will be useful for preliminary diagnosis.

Pharmacological blockade of the mast cell MRGPRX2 receptor supports investigation of its relevance in skin disorders.

Because MRGPRX2 is now recognized as the mast cell receptor for basic secretagogues, there is currently a tremendous interest in whether MRGRPX2 could play an important role in various pruritic dermatoses such as chronic spontaneous urticaria. Therefore, we sought to identify new potent and selective antagonists to pharmacologically characterize the biological role of MRGPRX2. Various relevant in vitro, ex vivo, and in vivo model systems were used to investigate the role of MRGPRX2. This included the study of freshly isolated human skin mast cells and human basophils as well as an ex vivo human skin microdialysis preparation. The additivity of MRGPRX2 and FcεR1-mediated degranulation was also investigated. Human MRGPRX2 knock-in mice were generated to interrogate pharmacokinetic/pharmacodynamic relationships because both antagonists studied were shown to be human specific. Two novel and structurally distinct MRGPRX2 antagonists were identified with one, Compound B, being orally active and demonstrating high potency in blocking Substance P-mediated degranulation using freshly isolated human skin mast cells with half maximal inhibitory concentration (IC50) at 0.42 nM. Compound B also potently blocked Substance P-stimulated histamine release from resident mast cells in a human skin explant setup as well as blocking itch in an established behavioral scratching model using MRGPRX2 knock-in mice. Unlike human mast cells, Substance P failed to elicit a functional response in human basophils. These data fully support the investigation of MRGPRX2 receptor antagonists in mast cell-driven allergic skin disorders such as chronic spontaneous urticaria.

Interleukin 31 mediates pruritus in horses.

This study investigated the effects of recombinant equine IL-31 (eIL-31) in vivo and in vitro. Equine IL-31 mRNA sequences were verified by sequencing. Recombinant eIL-31 was produced using mammalian and bacterial expression systems. From November 2019 through February 2021, 12 normal horses, 6 to 10 years old with no history or clinical signs consistent with allergic skin disease, were injected ID with eIL-31 and saline in 2 challenge studies. Pruritus-associated behaviors were recorded for a minimum of 15 minutes preinjection and 4 hours postinjection. Adherent monocytes from 3 pruritic horses, exhibiting insect bite hypersensitivity and/or atopic dermatitis, were stimulated with bacterial eIL-31, and subsequent phosphorylation of signal transducer and activator of transcription 3 (STAT3) was measured by western blot and AlphaLISA. The bacterial eIL-31 was produced with greater purity than the mammalian eIL-31 (> 95% vs 70%). Pruritus was elicited by both recombinant proteins. The mammalian eIL-31 induced mild pruritus (cumulative seconds spent itching postinjection ranged from 6 to 313). The bacterial eIL-31 induced marked pruritus in some horses (a cumulative maximum of 5,529 seconds spent itching in 1 horse) and a milder response in others (range of cumulative seconds spent itching, 17 to 2,313). Most pruritus occurred after 2 hours and subsided by 4 hours postinjection. Bacterial eIL-31 induced STAT3 phosphorylation in adherent monocytes from allergic horses. In this proof-of-concept study, IL-31 was found to mediate pruritus and was associated with STAT3 phosphorylation in horses as in other species. Interleukin 31 is a promising therapeutic target for equine allergic pruritus.

Single-Atom Catalysts with Isolated Cu1-N4 Sites for Atopic Dermatitis Cascade Catalytic Therapy via Activating PPAR Signaling.

Atopic dermatitis (AD) is one of the most common allergic skin disorders affecting over 230 million people worldwide, while safe and efficient therapeutic options for AD are currently rarely available. Reactive oxygen species (ROS) accumulation plays a key role in AD's disease progression. Therefore, a novel single-atom catalyst is designed with isolated Cu1-N4 sites anchored on carbon support (Cu1-N4 ISAC), featuring triple antioxidant enzyme-mimicking activities, for efficient AD cascade catalytic therapy (CCT). The excellent superoxide dismutase (SOD)-, glutathione peroxidase (GPx)-, and ascorbate peroxidase (APx)-like activities of Cu1-N4 ISACs enable the sequential conversion of O2•- to H2O2 and then to harmless H2O, thereby protecting keratinocytes from oxidative stress damage. Notably, two novel experimental methods are developed to directly prove the SOD-GPx and SOD-APx cascade catalytic activities for the first time. In vivo experiments show that Cu1-N4 ISACs are more potent than a recommended typical medicine (halcinonide solution). Additionally, RNA sequencing and bioinformatic analysis reveal that Cu1-N4 ISACs reduce inflammation and inhibit ROS production by activating PPAR signaling, which is aberrantly reduced in AD. Therefore, the synthesized catalytic medicine offers an alternative to alleviate AD and has the potential to serve as PPAR agonists for treating similar diseases.

Schizonepeta tenuifolia Briq-Saposhnikovia divaricata decoction alleviates atopic dermatitis via downregulating macrophage TRPV1.

Schizonepeta tenuifolia -Saposhnikovia divaricata (Jingjie-Fangfeng, JF) has been used for years to treat allergic inflammatory skin diseases like atopic dermatitis, but the specific effects and mechanisms of JF are still unclear. We aim to investigate the therapeutic effect and mechanism of JF in MC903-induced atopic dermatitis-like model. JF decoction was subjected to rigorous HPLC and GC analysis. The JF decoction was then freshly prepared and administered to MC903-induced atopic dermatitis -like mice models to investigate its therapeutic effects. Our evaluation focused on several markers of inflammation including the TEWL index, ear thickness, swelling, and specific inflammation indicators such as TSLP, IL33, IgE, and immune cell presence at the lesion sites. We measured Transient Receptor Potential Vanilloid 1 (TRPV1) expression levels through immunofluorescent staining in skin tissue from both atopic dermatitis patients and the MC903-treated mice. Furthermore, TRPV1 expression and macrophage activation markers were measured in LPS/IFN-γ-stimulated Raw264.7 and THP-1 cell models in vitro. Additionally, we developed cell lines that overexpress TRPV1 and investigated how JF treatment affects NF-κB p65 phosphorylation in these cells to understand better the role of TRPV1 in atopic dermatitis. The JF decoction met the standards outlined in the Chinese pharmacopeia. The JF decoction significantly alleviated inflammatory skin symptoms and helped restore skin barrier function. Additionally, it reduced the levels of IgE and pro-inflammatory cytokines TSLP, IL-33, and IL-4. There was also a noticeable decrease in mast cell infiltration and degranulation. Notably, JF decoction reduced infiltrated macrophages with limited affection on T cell infiltration. It also decreased F4/80+/TRPV1+ cells in atopic dermatitis mice and TRPV1 expression in LPS/IFNγ-stimulated microphages. Additionally, we observed that CD68+/TRPV1+ cells increased in human atopic dermatitis tissue. Further studies showed that JF water extract (JF-WE) suppressed TRPV1 expression in macrophages, potentially by affecting NF-κB p65 phosphorylation rather than the JAK-STAT6 pathway. This study offers initial evidence of the effectiveness of JF-WE in suppressing inflammation in atopic dermatitis. The therapeutic effect might stems from its ability to downregulate TRPV1 expression and subsequent NF-κB p65 phosphorylation in macrophages.

A practical guide to recognize allergic and immunologic skin diseases: diagnosis at first sight

Allergic and immunologic skin diseases are becoming increasingly common and this requires clinicians to be able to recognize and diagnose them. A joint meeting (GET TOGETHER 2022) of the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC) and the Italian Society of Allergological, Occupational and Environmental Dermatology (SIDAPA) aimed to review the current knowledge on the differential diagnosis of contact dermatitis, atopic dermatitis, hereditary angioedema, urticaria, and cutaneous mastocytosis. The most important aspects to take into consideration when faced with a new cutaneous manifestation are the clinical features of the lesions, their distribution, age of onset, and comorbidities/aggravating factors. The document does not aim to provide an exhaustive and comprehensive description of all allergic and immunologic skin diseases. Instead, it should be a reference tool for the clinician who is faced with the onset of a new skin manifestation and its differential diagnosis.

Unveiling the immune-modulating power of THz-FEL irradiation

As terahertz (THz) technology advances, the interaction between THz radiation and the living body, particularly its effects on the immune system, has attracted extensive attention but remains poorly understood. This study firstly elucidated that exposure to 3 THz-FEL radiation markedly suppressed contact hypersensitivity reactions in mice induced by DNFB, as evidenced by a reduction in ear thickness and a discernible recovery in the Th1/Th2 cell balance. 3 THz irradiation led to cellular stress in the irradiated skin locale, increasing the levels of IL-4 and IL-10 and modulating the activity and migration of dendritic cells and mast cells. Furthermore, THz irradiation precipitated a rapid alteration in the skin lipidome, altering several categories of bioactive lipids. These findings offer new insights into the immunomodulatory effects of THz radiation on living organisms and the potential underlying mechanisms, with implications for the development of therapeutic approaches in managing skin allergic diseases.

Oral and topical administration of a geranyl acetophenone attenuates DNCB-induced atopic dermatitis-like skin lesions in BALB/c mice

Atopic dermatitis (AD) is a chronic, allergic inflammatory skin disorder that lacks a definite cure. Using a mouse DNCB-induced AD-like skin lesions model, this study evaluated the potential therapeutic utility of tHGA as an oral and topical treatment for AD. Male BALB/c mice were sensitised and challenged with 1% and 0.5% DNCB on their shaved dorsal skin. Mice in the treatment group were administered tHGA (20, 40, and 80 mg/kg) orally three times per week for 2 weeks, or tHGA (0.2%, 1%, and 5%) topically once daily for 12 days. On day 34, the mice were euthanized, and blood and dorsal skin samples were obtained for analysis. All doses of orally and topically administered tHGA significantly improved scratching, epidermal thickness, blood eosinophilia and mast cell infiltration. There was a minor discrepancy between the two routes of administration, with orally treated tHGA showing significant reductions in Scoring of Atopic Dermatitis (SCORAD), tissue eosinophil infiltration, serum IgE and skin IL-4 levels with treatment of 40 and 80 mg/kg tHGA, whereas topically applied tHGA showed significant reductions in all dosages. These findings suggest that tHGA exhibited therapeutic potential for AD as both oral and topical treatment ameliorates AD-like symptoms in the murine model.

Zinc Deficiency and Zinc Supplementation in Allergic Diseases.

In recent decades, it has become clear that allergic diseases are on the rise in both Western and developing countries. The exact reason for the increase in prevalence has not been conclusively clarified yet. Multidimensional approaches are suspected in which diet and nutrition seem to play a particularly important role. Allergic diseases are characterized by a hyper-reactive immune system to usually harmless allergens, leading to chronic inflammatory diseases comprising respiratory diseases like asthma and allergic rhinitis (AR), allergic skin diseases like atopic dermatitis (AD), and food allergies. There is evidence that diet can have a positive or negative influence on both the development and severity of allergic diseases. In particular, the intake of the essential trace element zinc plays a very important role in modulating the immune response, which was first demonstrated around 60 years ago. The most prevalent type I allergies are mainly based on altered immunoglobulin (Ig)E and T helper (Th)2 cytokine production, leading to type 2 inflammation. This immune status can also be observed during zinc deficiency and can be positively influenced by zinc supplementation. The underlying immunological mechanisms are very complex and multidimensional. Since zinc supplements vary in dose and bioavailability, and clinical trials often differ in design and structure, different results can be observed. Therefore, different results are not surprising. However, the current literature suggests a link between zinc deficiency and the development of allergies, and shows positive effects of zinc supplementation on modulating the immune system and reducing allergic symptoms, which are discussed in more detail in this review.

Exploring the Potentiality of a Plant Platform for Monoclonal Antibody Production in Veterinary Medicine.

Canine atopic dermatitis (CAD) is an allergic, inflammatory, and pruritic skin disease associated with the production of IgE antibodies against environmental allergens and mainly house dust mite allergens. This complex dermatological pathology involves Interleukin 31 (IL-31) as a central itch mediator. One of the most effective CAD treatments is a caninized monoclonal antibody (mAb) called Lokivetmab. It is produced in CHO cells and targets specifically canine IL-31 (cIL-31) and blocks its cellular messaging. This treatment has undoubtedly contributed to a breakthrough in dermatitis-related pruritus. However, its production in mammalian cells requires time-consuming procedures, high production costs, and investment. Plants are considered an emerging protein production platform for recombinant biopharmaceuticals due to their cost-effectiveness and rapidity for production. Here, we use transient expression in Nicotiana benthamiana plants to produce recombinant canine Interleukin 31 (cIL-31) and an anti-IL-31 monoclonal antibody (M1). First, we describe the production and characterization of M1 and then its activity on an IL-31-induced pruritic model in dogs compared to its commercial homolog. Dogs treated with the plant-made M1 mAb have shown similar improvements to Lokivetmab-treated ones after different challenges using canine IL-31. Furthermore, M1 injections were not associated with any side effects. These results demonstrate the safety and efficacy of this plant-made Lokivetmab biosimilar to control dogs' pruritus in a well-established model. Finally, this study shows that the plant-production platform can be utilized to produce rapidly functional mAbs and bring hope to the immunotherapy field of veterinary medicine.

Comparison of the chemical constituents of Saposhnikoviae Radix associated with three different growth patterns and its therapeutic effect against atopic dermatitis

Ethnopharmacological relevanceSaposhnikoviae Radix (SR) was initially documented in Shennong Bencao Jing classics for its properties in dispelling wind, dissolving surface, relieving pain, and alleviating spasms. This herb is commonly used in traditional Chinese medicine to address conditions that affect the body's surface, by aiding in the expulsion of pathogens from the surface and alleviating pain associated with the immune response. Atopic dermatitis (AD) is a prevalent allergic skin disorder, and the therapeutic effects of SR in dispelling wind and relieving the body's surface are consistent with the clinical symptoms commonly observed in AD. Aim of the studyThe anti-AD effects of SR were examined under three different growth patterns to identify active pharmacodynamic compounds. The results provide insight into the clinical efficacy of wild and cultivated SR. Materials and methodsThe efficacy of wild, wild-simulated, and cultivated SR was assessed in a mouse model of AD. In addition, the effects of wild and varying doses of cultivated SR were evaluated in mice with short-term AD symptoms. GC-MS and UPLC-MS/MS were used to analyze the chemical components of the three SR treatments and molecular docking was used to identify active components. ResultsA mouse model of AD was used to assess the pharmacodynamic effects of SR prepared by three different cultivation methods. The study found that all three SR preparations improved phenotypic markers and histopathological features in the AD mouse model. The efficacy of wild SR and wild-simulated SR was similar, although there was a significant difference between wild and cultivated SR. Both wild SR and various doses of cultivated SR ameliorated skin injuries and reduced inflammation in serum and skin tissues. Furthermore, skin thickness, inflammatory cells, mast cell infiltration, and IL-33 expression improved following treatment. Notably, wild SR, double-cultivated SR, and triple-cultivated SR demonstrated significant therapeutic effects. An analysis using GC-MS revealed the presence of 55, 52, and 43 volatile oils in the three SR preparations, with more common components observed between wild and wild-simulated SR. Fewer common components were evident between cultivated and wild SR. UPLC-MS/MS analysis identified a total of 37 compounds, with larger relative peak areas observed for the chromogenic ketones. Molecular docking studies revealed that certain compounds, such as n-propyl 9,12-octadecadienoate, (E)-9-octadecenoic acid ethyl ester, and various chromogenic ketones, such as cimifugin, 5-O-methyIvisamminol, hamaudol, 3′-O-acetylhamaudol, 3′-O-angeloyhamandol, adenosine and farnesylaceton, may be the major substances that distinguish the activities of SR with three different growth patterns. ConclusionVariations in the anti-AD efficacy of SR with three growth patterns were identified, and their chemical composition differences were determined. These findings suggest that increasing the dosage of cultivated SR could potentially be a viable clinical alternative for atopic dermatitis treatment.

Ampelopsis Brevipedunculata (Maxim.) Trautv Extract Alleviates Symptoms of Atopic Dermatitis in NC/Nga Mice

Atopic dermatitis is a common allergic skin disease characterized by eczema, dryness, and severe itching, which has a significant impact on patients’ quality of life. Its pathogenesis involves immune dysregulation and impaired skin barrier function. In this study, the therapeutic potential of Ampelopsis brevipedunculata (Maxim.) Trautv for alleviating atopic dermatitis symptoms was investigated using the NC/Nga mouse model. A. brevipedunculata (Maxim.) Trautv was effective in attenuating the atopic dermatitis-like epidermal thickening and the immune cell infiltration in the skin lesions induced by the atopic dermatitis ointment. Additionally, A. brevipedunculata (Maxim.) Trautv suppressed the production of inflammatory mediators and chemokines associated with atopic dermatitis progression. In addition, A. brevipedunculata (Maxim.) Trautv exhibited restorative effects on skin barrier dysfunction by increasing the expression of key barrier proteins. Mechanistically, A. brevipedunculata (Maxim.) Trautv modulated the mitogen-activated protein kinase pathway and inhibited nuclear factor-kappa B activation. These findings highlight the potential of A. brevipedunculata (Maxim.) Trautv as a promising therapeutic agent for treating atopic dermatitis and provide insight into its mechanisms of action.

The role of the environment in allergic skin disease.

This paper explores how environmental factors influence allergic skin diseases, including atopic dermatitis (AD), contact dermatitis (CD), urticaria, angioedema, and reactions to drugs and insect bites. Research indicates a significant impact of environmental elements on allergic skin diseases. High air pollution levels exacerbate symptoms, while climate change contributes to increased skin barrier dysfunction, particularly affecting AD. Allergen prevalence is influenced by climate and pollution. Irritants, like those in detergents and cosmetics, play a major role in CD. Plants also contribute, causing various skin reactions. Understanding the interplay between environmental factors and allergic skin diseases is crucial for effective management. Physicians must address these factors to support patient well-being and promote skin health amidst environmental changes.

Diagnosis and treatment of atopic skin syndrome in cats

Background: Feline allergic skin disease presents a diagnostic challenge due to the potentially subtle and widely variable clinical presentations known as feline reaction patterns. Cats are often secretive in their pruritic behaviours and so, unlike with canine disease, the clinical history for a cat may not give insight into the presence of pruritus. Once a diagnosis of feline allergic disease is achieved, there are several treatment options available; however, the majority have not been studied extensively in cats and many represent off‐license use.Aim of the article: This article outlines the relevant steps in making a diagnosis of feline atopic skin syndrome and reviews the treatment options available.

Risk of Trace Element Imbalance in Cases of Occupational Allergic Diseases

Introduction: The relevance of the study is attributed to the lack of knowledge of the mechanisms of development and specifics of the clinical picture of occupational allergic diseases. Objective: To establish the levels of essential trace elements in biological substrates of patients with occupational allergies. Materials and methods: In 2014–2018, we analyzed zinc and copper levels in urine, blood serum, and lymphocytes of patients with occupational allergic skin and respiratory diseases by the atomic absorption method. Relative risk was calculated using a four-field contingency table. Results: In patients with work-related allergic contact dermatitis and bronchial asthma, zinc and copper concentrations in blood serum increased while urinary excretion of these elements decreased. Quantitative patterns of the concentrations of trace elements in body fluids of the patients with skin and respiratory allergies were unidirectional compared to the reference group. Relative risk values showed that lower levels of copper in urine and zinc in blood serum and lymphocytes, as well as higher serum copper indicated the risk of trace element imbalance in the body. Conclusion: The risk of trace element imbalance due to occupational allergic diseases is associated with impaired copper and zinc balance. Our findings prove that the levels of microelements are additional factors that aggravate the course of occupational allergic disorders.

Lymphatic-Dependent Modulation of the Sensitization and Elicitation Phases of Contact Hypersensitivity

Allergic contact dermatitis is a common inflammatory skin disease comprising 2 phases. During sensitization, immune cells are activated by exposure to various allergens, whereas repeated antigen exposure induces local inflammation during elicitation. In this study, we utilized mouse models lacking lymphatics in different skin regions to characterize the role of lymphatics separately in the 2 phases, using contact hypersensitivity as a model of human allergic inflammatory skin diseases. Lymphatic-deficient mice exhibited no major difference to single antigen exposure compared to controls. However, mice lacking lymphatics in both phases displayed reduced inflammation after repeated antigen exposure. Similarly, diminished immune response was observed in mice lacking lymphatics only in sensitization, whereas the absence of lymphatics only in the elicitation phase resulted in a more pronounced inflammatory immune response. This exaggerated inflammation is driven by neutrophils impacting regulatory T cell number. Collectively, our results demonstrate that skin lymphatics play an important but distinct role in the 2 phases of contact hypersensitivity. During sensitization, lymphatics contribute to the development of the antigen-specific immunization, whereas in elicitation, they moderate the inflammatory response and leukocyte infiltration in a neutrophil-dependent manner. These findings underscore the need for novel therapeutic strategies targeting the lymphatics in the context of allergic skin diseases.

A Novel CARMIL2 Immunodeficiency Identified in a Subset of Cavalier King Charles Spaniels with Pneumocystis and Bordetella Pneumonia.

Pet dogs are a valuable natural animal model for studying relationships between primary immunodeficiencies and susceptibility to Pneumocystis and other opportunistic respiratory pathogens. Certain breeds, such as the Cavalier King Charles Spaniel, are over-represented for Pneumocystis pneumonia (PCP), suggesting the presence of a primary immunodeficiency in the breed. Here, we report the discovery of a CARMIL2 nonsense variant in three Cavalier King Charles Spaniel dogs with either PCP (n = 2) or refractory Bordetella pneumonia (n = 1). CARMIL2 encodes a protein that plays critical roles in T-cell activation and other aspects of immune function. Deleterious CARMIL2 variants have recently been reported in human patients with PCP and other recurrent pneumonias. In addition to opportunistic respiratory infection, the affected dogs also exhibited other clinical manifestations of CARMIL2 deficiencies that have been reported in humans, including early-onset gastrointestinal disease, allergic skin disease, mucocutaneous lesions, abscesses, autoimmune disorders, and gastrointestinal parasitism. This discovery highlights the potential utility of a natural canine model in identifying and studying primary immunodeficiencies in patients affected by PCP.

PJ‑001, a small‑molecule proteolysis‑targeting chimera, ameliorates atopic dermatitis‑like inflammation in mice by inhibiting the JAK2/STAT3 pathway and repairing the skin barrier.

Atopic dermatitis (AD) is a common allergic skin disease, and its pathogenesis involves genetic and environmental factors, as well as the immune response and skin barrier. PJ-001 is a small-molecule proteolysis-targeting chimera, which can degrade proteins related to the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. In the present study, 0.5% 2,4-dinitrofluorobenzene was used to induce a mouse model of AD. Following treatment with PJ-001, the number of scratches and the severity of skin damage in the AD mice were recorded. Pathological changes in skin lesions were observed with hematoxylin and eosin staining. The expression levels of JAK2/STAT3, Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB), Beclin 1 and microtubule-associated protein 1 light chain 3 (LC3) were detected using western blotting. Furthermore, reverse transcription-PCR was used to detect the mRNA expression levels of filaggrin (FLG) and keratin 17, and the change in interleukin-10 levels in the splenic tissue of the mice. Compared with in the control group, the model group exhibited severe skin lesions. Following treatment with PJ-001, the AD-like inflammation in mice decreased. The expression levels of LC3 II/LC3 I and Beclin 1 were significantly reduced (P<0.01), and the expression levels of JAK2, STAT3, TLR4 and NF-κB were significantly downregulated (P<0.001). Additionally, the mRNA expression levels of FLG were significantly upregulated (P<0.001). These results indicated that PJ-001 may alleviate the skin condition in a mouse model of AD. The underlying mechanism may involve inhibition of the JAK/STAT signaling pathway, thereby suppressing the release of inflammatory factors, reducing excessive autophagy at the site of skin lesions, and enhancing the skin barrier function. In conclusion, PJ-001 could be considered a potential therapeutic option for AD.

Dendritic cells under allergic condition enhance the activation of pruritogen-responsive neurons via inducing itch receptors in a co-culture study

BackgroundItch sensitization has been reported in patients with chronic allergic skin diseases and observed in a mouse model of allergic contact dermatitis (ACD). There is evidence suggesting that neuroimmune interactions may contribute to itch sensitization, as an increase in dendritic cells (DCs) within ganglia has been observed during allergic conditions. However, how DCs interact with sensory neurons in ganglia during allergic conditions is still not known. This study aims to investigate the role of DCs in dorsal root ganglion (DRG) under ACD conditions, specifically focusing on itch sensitization within the DRG. The tolylene-2,4-diisocyanate (TDI) mouse model for ACD and the co-culture model of DCs and DRG neurons was employed in this study.ResultsWe successfully induced ACD by TDI, as evidenced by the development of edema, elevated total serum IgE levels, and an observed itch reaction in TDI-sensitized mice. Calcium imaging and RT-qPCR analysis revealed that TDI-sensitized mice exhibited signs of peripheral sensitization, including a higher percentage of neurons responding to pruritogens and increased activation and expression of itch receptors in excised DRG of TDI-sensitized mice. Immunofluorescence and flow cytometric analysis displayed an increase of MHCII+ cells, which serves as a marker for DCs, within DRG during ACD. The co-culture study revealed that when DRG neurons were cultured with DCs, there was an increase in the number of neurons responsive to pruritogens and activation of itch receptors such as TRPA1, TRPV1, H1R, and TRPV4. In addition, the immunofluorescence and RT-qPCR study confirmed an upregulation of TRPV4.ConclusionsOur findings indicate that there is an increase of MHCII+ cells and itch peripheral sensitization in DRG under TDI-induced ACD condition. It has been found that MHCII+ cells in DRG might contribute to the itch peripheral sensitization by activating itch receptors, as shown through co-culture studies between DRG neurons and DCs. Further studies are required to identify the specific mediator(s) responsible for peripheral sensitization induced by activated DCs.