The enzyme Cyp26b1 mediates inhibition of mast cell activation by fibroblasts to maintain skin-barrier homeostasis.

Mast cells (MCs) mature locally, thus possessing tissue-dependent phenotypes for their critical roles in both protective immunity against pathogens and the development of allergy or inflammation. We previously reported that MCs highly express P2X7, a receptor for extracellular ATP, in the colon but not in the skin. The ATP-P2X7 pathway induces MC activation and consequently exacerbates the inflammation. Here, we identified the mechanisms by which P2X7 expression on MCs is reduced by fibroblasts in the skin, but not in the other tissues. The retinoic-acid-degrading enzyme Cyp26b1 is highly expressed in skin fibroblasts, and its inhibition resulted in the upregulation of P2X7 on MCs. We also noted the increased expression of P2X7 on skin MCs and consequent P2X7- and MC-dependent dermatitis (so-called retinoid dermatitis) in the presence of excessive amounts of retinoic acid. These results demonstrate a unique skin-barrier homeostatic network operating through Cyp26b1-mediated inhibition of ATP-dependent MC activation by fibroblasts.

Using the AllerSearch Smartphone App to Assess the Association Between Dry Eye and Hay Fever: mHealth-Based Cross-Sectional Study.

BACKGROUND: Dry eye (DE) and hay fever (HF) show synergistic exacerbation of each other's pathology through inflammatory pathways. OBJECTIVE: This study aimed to investigate the association between DE and HF comorbidity and the related risk factors. METHODS: A cross-sectional observational study was conducted using crowdsourced multidimensional data from individuals who downloaded the AllerSearch smartphone app in Japan between February 2018 and May 2020. AllerSearch collected the demographics, medical history, lifestyle and residential information, HF status, DE symptoms, and HF-related quality of life. HF symptoms were evaluated using the nasal symptom score (0-15 points) and nonnasal symptom score (0-12 points). HF was defined by the participants' responses to the questionnaire as HF, non-HF, or unknown. Symptomatic DE was defined as an Ocular Surface Disease Index total score (0-100 points), with a threshold score of 13 points. HF-related quality of life was assessed using the Japanese Allergic Conjunctival Disease Standard Quality of Life Questionnaire (0-68 points). We conducted a multivariable linear regression analysis to examine the association between the severity of DE and HF symptoms. We subsequently conducted a multivariable logistic regression analysis to identify the factors associated with symptomatic DE (vs nonsymptomatic DE) among individuals with HF. Dimension reduction via Uniform Manifold Approximation and Projection stratified the comorbid DE and HF symptoms. The symptom profiles in each cluster were identified using hierarchical heat maps. RESULTS: This study included 11,284 participants, classified into experiencing HF (9041 participants), non-HF (720 participants), and unknown (1523 participants) groups. The prevalence of symptomatic DE among individuals with HF was 49.99% (4429/9041). Severe DE symptoms were significantly associated with severe HF symptoms: coefficient 1.33 (95% CI 1.10-1.57; P<.001) for mild DE, coefficient 2.16 (95% CI 1.84-2.48; P<.001) for moderate DE, and coefficient 3.80 (95% CI 3.50-4.11; P<.001) for severe DE. The risk factors for comorbid symptomatic DE among individuals with HF were identified as female sex; lower BMI; medicated hypertension; history of hematologic, collagen, heart, liver, respiratory, or atopic disease; tomato allergy; current and previous mental illness; pet ownership; living room and bedrooms furnished with materials other than hardwood, carpet, tatami, and vinyl; discontinuation of contact lens use during the HF season; current contact lens use; smoking habits; and sleep duration of <6 hours per day. Uniform Manifold Approximation and Projection stratified the heterogeneous comorbid DE and HF symptoms into 14 clusters. In the hierarchical heat map, cluster 9 was comorbid with the most severe HF and DE symptoms, and cluster 1 showed severe HF symptoms with minimal DE-related symptoms. CONCLUSIONS: This crowdsourced study suggested a significant association between severe DE and HF symptoms. Detecting DE among individuals with HF could allow effective prevention and interventions through concurrent treatment for ocular surface management along with HF treatment.

Individual characteristics and associated factors of hay fever: A large-scale mHealth study using AllerSearch.

BACKGROUND: The prevalence of hay fever, a multifactorial allergic disease, is increasing. Identifying individual characteristics and associated factors of hay fever is essential for predictive, preventive, personalized, and participatory (P4) medicine. This study aimed to identify individual characteristics and associated factors of hay fever using an iPhone application AllerSearch. METHODS: This large-scale mobile health-based cross-sectional study was conducted between February 2018 and May 2020. Individuals who downloaded AllerSearch in Japan and provided a comprehensive self-assessment (general characteristics, medical history, lifestyle habits, and hay fever symptoms [score range 0-36]) were included. Associated factors of hay fever (vs. non-hay fever) and severe hay fever symptoms were identified using multivariate logistic and linear regression analyses, respectively. RESULTS: Of the included 11,284 individuals, 9041 had hay fever. Factors associated with hay fever (odds ratio) included age (0.98), female sex (1.33), atopic dermatitis (1.40), history of dry eye diagnosis (1.36), discontinuation of contact lens use during hay fever season (3.34), frequent bowel movements (1.03), and less sleep duration (0.91). The factors associated with severe hay fever symptoms among individuals with hay fever (coefficient) included age (-0.104), female sex (1.329), history of respiratory disease (1.539), history of dry eye diagnosis (0.824), tomato allergy (1.346), discontinuation of contact lens use during hay fever season (1.479), smoking habit (0.614), and having a pet (0.303). CONCLUSIONS: Our large-scale mobile health-based study using AllerSearch elucidated distinct hay fever presentation patterns, characteristics, and factors associated with hay fever. Our study establishes the groundwork for effective individualized interventions for P4 medicine.

New medical big data for P4 medicine on allergic conjunctivitis.

Allergic conjunctivitis affects approximately 15-20% of the global population and can permanently deteriorate one's quality of life (QoL) and work productivity, leading to societal work force costs. Although not fully understood, allergic conjunctivitis is a multifactorial disease with a complex network of environmental, lifestyle, and host contributory risk factors. To effectively enhance the quality of treatment for patients with allergic conjunctivitis, as well as other allergic diseases, the field must first comprehend the pathology underlying various individualized subjective symptoms and stratify the disease according to risk factors and presentations. Such competent stratification and societal reconstruction that targets the alleviation of the damage due to allergic diseases would greatly help ramify personalized treatments and prevent the projected increase in societal costs imposed by allergic diseases. Owing to the rapid advancements in the information and technology sector, medical big data are greatly accessible and useful to decipher the pathophysiology of many diseases. Such data collected through multi-omics and mobile health have been effective for research on chronic diseases including allergic and immune-mediated diseases. Novel big data containing vast and continuous information on individuals with allergic conjunctivitis and other allergic symptoms are being used to search for causative genes of diseases, gain insights into new biomarkers, prevent disease progression, and, ultimately, improve QoL. The individualized and holistic data accrued from new angles using technological innovations are helping the field realize the principles of P4 medicine: predictive, preventive, personalized, and participatory medicine.

Attitudes towards human fetal tissue research: Survey of researchers and the public in Japan.

Introduction: The rules for human fetal tissue (HFT) research in Japan are unclear. Methods: In this paper, we conducted a web survey to examine the attitudes of Japanese researchers (n=535) and the public (n=3,000) toward HFT research. Results: The results demonstrated that 5.8% of researchers and 18.8% of the public explicitly opposed HFT research, and 71.8% of the researchers thought that the rules for HFT research need to be clarified. Even among researchers who intended to consider conducting HFT research, 74.2% responded that the rules should be clarified. Although different from attitudes to make decisions regarding HFT donation, being non-religious and in their reproductive age among women in the public group were factors for accepting attitudes toward HFT research. Conclusion: To establish the rules, it is necessary to develop a system that can adequately protect vulnerable women who are asked to provide HFT.

Survey of Japanese researchers and the public regarding the culture of human embryos in vitro beyond 14 days.

The International Society for Stem Cell Research (ISSCR) has eliminated its prohibition on research involving the culturing of human embryos beyond 14 days within the updated 2021 guidelines. We conducted a survey of Japanese researchers working in stem cell- or embryo-related research (n = 535) and the public (n = 3,000) about their attitudes toward the 14-day rule. Among the researchers, 46.2% agreed that embryos could be cultured beyond 14 days, a result that was slightly lower among the public (37.9%). Among those that disagreed with embryo culturing beyond 14 days, 9.5% of researchers and 5.1% of the public agreed with culturing embryos within 14 days. Among the public, higher comprehension levels correlated with both agreement and disagreement with the culture of embryos beyond 14 days compared with "cannot judge." Further research and pubic discourse are necessary in order to better understand the factors informing participant decisions regarding the 14-day rule.

Patient and public involvement in mobile health-based research for hay fever: a qualitative study of patient and public involvement implementation process.

BACKGROUND: Smartphones are being increasingly used for research owing to their multifunctionality and flexibility, and crowdsourced research using smartphone applications (apps) is effective in the early detection and management of chronic diseases. We developed the AllerSearch app to gather real-world data on individual subjective symptoms and lifestyle factors related to hay fever. This study established a foundation for interactive research by adopting novel, diverse perspectives accrued through implementing the principles of patient and public involvement (PPI) in the development of our app. METHODS: Patients and members of the public with a history or family history of hay fever were recruited from November 2019 to December 2021 through a dedicated website, social networking services, and web briefing according to the PPI Guidebook 2019 by the Japan Agency for Medical Research and Development. Nine opinion exchange meetings were held from February 2020 to December 2021 to collect opinions and suggestions for updating the app. After each meeting, interactive evaluations from PPI contributors and researchers were collected. The compiled suggestions were then incorporated into the app, establishing an active feedback loop fed by the consistently interactive infrastructure. RESULTS: Four PPI contributors (one man and three women) were recruited, and 93 items were added/changed in the in-app survey questionnaire in accordance with discussions from the exchange meetings. The exchange meetings emphasized an atmosphere and opportunity for participants to speak up, ensuring frequent opportunities for them to contribute to the research. In March 2020, a public website was created to display real-time outcomes of the number of participants and users' hay-fever-preventative behaviors. In August 2020, a new PPI-implemented AllerSearch app was released. CONCLUSIONS: This study marks the first research on clinical smartphone apps for hay fever in Japan that implements PPI throughout its timeline from research and development to the publication of research results. Taking advantage of the distinct perspectives offered by PPI contributors, a step was taken toward actualizing a foundation for an interactive research environment. These results should promote future PPI research and foster the establishment of a social construct that enables PPI efforts in various fields.

Patient and public involvement (PPI) plays an important role in promoting effective execution of health science research, as well as in the establishment of a social agreement and infrastructure for the care of various diseases, including cancer, chronic diseases, and allergic illnesses. Hay fever is one of the most common allergic diseases, affecting more than 30 million people in Japan. It is known for its myriad factors and diverse presentations. Previously, we developed a mobile health (mHealth) smartphone application (app) for hay fever­AllerSearch­released in February 2018. This app is capable of collecting relevant digital phenotypes and user-provided information, which are used in providing tailored, evidence-based suggestions. To our knowledge, no other studies have been conducted on the implementation of PPI in mHealth. Since hay fever presents with a wide variety of symptoms and risk factors, PPI principles appear well-suited for eliciting insights from the patient/public population and for incorporating new, expert perspectives into the research process. In this study, we included PPI contributors in the research plan, app development, and evaluation. Most notably, the survey questionnaire and user interface of the app was tailored based on PPI feedback. The updated AllerSearch app was released during this study period. Since hay fever is a widespread and variable illness, the multifaceted input from patients and public experts enabled by PPI implementation holds promise for improving society-wide healthcare and in empowering a culture toward medical involvement.

Orally desensitized mast cells form a regulatory network with Treg cells for the control of food allergy.

Oral immunotherapy (OIT) is an effective approach to controlling food allergy. Although the detailed molecular and cellular mechanisms of OIT are unknown currently, they must be understood to advance the treatment of allergic diseases in general. To elucidate the mechanisms of OIT, especially during the immunological transition from desensitization to allergy regulation, we generated a clinical OIT murine model and used it to examine immunological events of OIT. We found that in mice that completed OIT successfully, desensitized mast cells (MCs) showed functionally beneficial alterations, such as increased induction of regulatory cytokines and enhanced expansion of regulatory T cells. Importantly, these regulatory-T-cell-mediated inhibitions of allergic responses were dramatically decreased in mice lacking OIT-induced desensitized MC. Collectively, these findings show that the desensitization process modulates the activation of MCs, leading directly to enhanced induction of regulatory-T-cell expansion and promotion of clinical allergic unresponsiveness. Our results suggest that efficiently inducing regulatory MCs is a novel strategy for the treatment of allergic disease.

MafB deficiency accelerates the development of obesity in mice.

MafB, a transcription factor expressed selectively in macrophages, has important roles in some macrophage-related diseases, especially in atherosclerosis. In this study, we investigated the mechanism by which hematopoietic-specific MafB deficiency induces the development of obesity. Wild-type and hematopoietic cell-specific Mafb-deficient mice were fed a high-fat diet for 10 weeks. The Mafb-deficient mice exhibited higher body weights and faster rates of body weight increase than control mice. The Mafb-deficient mice also had a higher percentage of body fat than the wild-type mice, due to increased adipocyte size and serum cholesterol levels. Reverse transcription-PCR analysis showed a reduction in apoptosis inhibitor of macrophage (AIM) in Mafb-deficient adipose tissue. AIM is known as an inhibitor of lipogenesis in adipocytes and is expressed in adipose tissue macrophages. Collectively, our data suggest that Mafb deficiency in hematopoietic cells accelerates the development of obesity.

Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors.

Mast cells are known effector cells in allergic and inflammatory diseases, but their precise roles in intestinal inflammation remain unknown. Here we show that activation of mast cells in intestinal inflammation is mediated by ATP-reactive P2X7 purinoceptors. We find an increase in the numbers of mast cells expressing P2X7 purinoceptors in the colons of mice with colitis and of patients with Crohn's disease. Treatment of mice with a P2X7 purinoceptor-specific antibody inhibits mast cell activation and subsequent intestinal inflammation. Similarly, intestinal inflammation is ameliorated in mast cell-deficient Kit(W-sh/W-sh) mice, and reconstitution with wild-type, but not P2x7(-/-) mast cells results in susceptibility to inflammation. ATP-P2X7 purinoceptor-mediated activation of mast cells not only induces inflammatory cytokines, but also chemokines and leukotrienes, to recruit neutrophils and subsequently exacerbate intestinal inflammation. These findings reveal the role of P2X7 purinoceptor-mediated mast cell activation in both the initiation and exacerbation of intestinal inflammation.