Human organoids are considered physiological models that reflect human physiology; however, their applications in drug screening studies are limited. To develop a fundamental treatment for recurrent Crohn’s disease (CD), in which tumor necrosis factor (TNF) is a key pathogenic factor, we conducted phenotypic drug screening to prevent TNF-induced cell death in human intestinal epithelial organoids. Glycyrrhizin, a natural product of licorice root, dose-dependently blocked TNF-induced cell death in organoids but not in TNF-sensitive L929 cells; L929 cells exhibited necroptosis, whereas organoid-derived cells preferentially showed apoptosis upon TNF treatment, determining the specificity of glycyrrhizin. Glycyrrhizin inhibited downstream caspase-8 signaling, which is essential for TNF-dependent apoptosis, and ameliorated intestinal inflammation in vivo. These results demonstrate that glycyrrhizin may be a novel therapeutic compound for CD and highlight the importance of using organoids for phenotypic drug screening.

Microbiota-accessible carbohydrates modulate host immunity by shaping gut microbial composition and metabolism. However, their role in modulating the microbiota to influence allergic responses is unclear. Here we show that a widely used antidiabetic agent, the α-glucosidase inhibitor acarbose, redirects dietary carbohydrate utilization by gut bacteria to suppress mast-cell-dependent anaphylaxis in mice, independently of adaptive immune responses. Enhanced carbohydrate availability promoted the proliferation of Parabacteroides distasonis in the mouse gut, leading to increased succinate abundance and intracellular NAD+ levels, and reduced reliance on b-type cytochrome-dependent anaerobic respiration. Direct administration of succinate suppressed systemic anaphylaxis and mast cell degranulation in vitro, implicating succinate as a key effector. A human cohort analysis revealed that patients treated with α-glucosidase inhibitors showed a lower incidence of anaphylaxis than untreated individuals. These findings uncover a previously unrecognized gut-microbiota-mediated pathway linking dietary carbohydrate metabolism to systemic immune regulation.

BACKGROUND:Alterations in the intestinal microbiota contribute to the pathogenesis of various cardiovascular disorders, but how they affect the development of Kawasaki disease (KD) an acute pediatric vasculitis, remains unclear. METHODS:We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to assess the contribution of the intestinal microbiota to the development of vascular inflammation. We evaluated the severity of vasculitis in microbiota-depleted mice. 16S rRNA gene sequencing was used to characterize the fecal microbiome composition of LCWE-injected mice. Some groups of mice were orally treated with selected live or pasteurized bacteria, short-chain fatty acids, or Amuc_1100, the Toll-like receptor 2 signaling outer membrane protein from Akkermansia muciniphila, and their impact on vasculitis development was assessed. RESULTS:We report that depleting the gut microbiota reduces the development of cardiovascular inflammation in a murine model mimicking KD vasculitis. The development of cardiovascular lesions was associated with alterations in the intestinal microbiota composition and, notably, a decreased abundance of Akkermansia muciniphila and Faecalibacterium prausnitzii. Oral supplementation with either of these live or pasteurized individual bacteria or with short-chain fatty acids produced by them attenuated cardiovascular inflammation, as reflected by decreased local immune cell infiltrations. Treatment with Amuc_1100 also reduced the severity of vascular inflammation. CONCLUSIONS:This study reveals an underappreciated gut microbiota-cardiovascular inflammation axis in KD vasculitis pathogenesis and identifies specific intestinal commensals that regulate vasculitis in mice by producing metabolites or via extracellular proteins capable of enhancing and supporting gut barrier function.

CD4+ tissue-resident memory T (TRM) cells contribute to host defense and to the pathogenesis of chronic inflammatory diseases, but the molecules that direct their differentiation are unknown. We found that the transcription factor hepatic leukemia factor (HLF) could direct the tissue residency program and function of CD4+ TRM cells. HLF simultaneously up-regulated tissue retention receptors, down-regulated tissue egress receptors, and promoted proinflammatory CD4+ TRM cells by inducing Bhlhe40, and all of these processes were associated with changes in chromatin accessibility. Genetic deletion of Hlf inhibited CD4+ TRM cell generation and ameliorated airway tissue inflammation in vivo. HLF+ CD4+ TRM cells isolated from inflamed airway tissue in humans had a tissue residency signature and expressed inflammatory cytokines. We conclude that HLF may act as a central regulator of proinflammatory CD4+ TRM cell development and function.

While fermentable oligo- and di-, mono-saccharides and polyols (FODMAPs) have been implicated in exacerbating inflammatory bowel disease (IBD) symptoms, the exact influence of FODMAPs on gut microbiota and inflammation is unclear. Here, we show that sorbitol, a polyol, exacerbates colitis in mice induced by dextran sodium sulfate (DSS). Sorbitol increases the expression of inflammatory genes, including Il1b, in the colon, associated with M1 macrophage-related genes elevated in IBD patients. Indeed, sorbitol treatment leads to a higher proportion of M1 macrophages in the colon, worsening colitis, which is reversed in interleukin-1β (IL-1β)-deficient mice and mitigated with antibiotic treatment. Sorbitol alters the composition of gut microbiota and metabolites, with Prevotellaceae and tryptamine positively correlated with colonic M1 macrophages. Tryptamine stimulation enhances M1 macrophage polarization. Taken together, polyol consumption activates intestinal macrophages by altering the gut microbiome, which in turn promotes intestinal inflammation.

BACKGROUND:In 2022, the "New Capitalism Grand Design and Implementation Plan" was adopted in Japan, emphasizing the promotion and environmental development of startups. Given this context, an investigation into the startup and investment landscape in the allergy sector, both domestically and internationally, becomes imperative.METHODS:We analyzed 156 allergy-related startups from Japan, the US, and Europe from 2010 to 2021. Data on corporate information and investment trends were extracted from databases and VC websites.RESULTS:The total investment reached approximately 7.2 billion USD, with a ratio of 20:6:1 for the US, Europe, and Japan, respectively. The US showed a decline post its peak from 2016-2018, while Europe and Japan experienced growth. Notably, the US primarily invested in biopharmaceuticals for atopic dermatitis and food allergies, Europe in asthma-related apps, and Japan in healthcare apps and cross-border startups.DISCUSSION AND CONCLUSION:While Japan's investment environment in the allergy sector remains in its nascent stages and has room for development, the US and Europe are evidently ahead. Considering the rise of startups and funding limitations in Japan, external funding from regions like the US becomes a potential avenue. These findings are anticipated to contribute to the strategic activation of startups in allergy research and development.

BACKGROUND:In the enhancement of allergy care involving multidisciplinary and multiple medical departments, there is a perceived need for education that targets not only specialists but also non-specialists. However, research on the need for and methods of such education remains inadequate.OBJECTIVE:To design a remote allergy care education program for all medical practitioners and to validate its necessity and utility.METHODS:The Empowering Next Generation Allergist/immunologist toward Global Excellence Task Force (ENGAGE-TF), supported by the Japanese Society of Allergology, initiated a virtual educational program called 'Outreach Lectures' in collaboration with Keio University and Fukui University. This initiative was widely promoted through social media and various institutions, and a survey was conducted through its mailing list.RESULTS:1139 responses were obtained. More than half were physicians from non-allergy specialties, representing a diverse range of healthcare professions. Over 70% expressed being 'very satisfied,' and over 60% found the difficulty level 'appropriate.' Free-form feedback revealed differences in learning focus based on profession and learning approach based on years of experience.CONCLUSION:The high participation rate (90%) of non-specialist physicians underscores the demand for addressing allergic conditions in primary care. The effectiveness of virtual / recurrent education, particularly for healthcare professionals with over 11 years of experience, was implied. Further follow-up investigation focusing on quantitative and objective assessment of educational effectiveness is indispensable.

AbstractBackgroundHay fever (HF) presents with various symptoms, including allergic conjunctivitis and rhinitis, and requires cross‐organ treatment. This study assessed the impact of the coronavirus disease 2019 (COVID‐19) pandemic on HF treatment trends.MethodsThis retrospective cohort study utilized data from the JMDC database collected between January 2018 and May 2021. Patients with HF were identified based on the relevant International Classification of Diseases 10th Revision diagnosis codes and the prescription of HF‐related medications. The treatment approaches were compared during the cedar and cypress pollen allergy season (January to May in Japan) before and during the COVID‐19 pandemic (2018 and 2019, and 2020 and 2021, respectively).ResultsThis study included 2,598,178 patients with HF. The numbers of prescribed HF‐related claims in 2018, 2019, 2020, and 2021 were 3,332,854, 3,534,198, 2,774,380, and 2,786,681 times, respectively. Oral second‐generation antihistamine prescriptions decreased by >10% from 2019 to 2020, with a <10% change in the subsequent year. Anti‐allergic eye drop prescriptions also decreased by >10% from 2019 to 2020 but increased by >10% from 2020 to 2021. Compared with 2018, 2019, and 2020, the number of claims in the rhinitis symptoms dominant group was significantly decreased in 2021 (p < 0.001, all). In contrast, the number of claims in the eye symptoms dominant group and the rhinitis and eye symptoms dominant group increased in 2021 compared with that in 2018, 2019, and 2020 (p < 0.001, all).ConclusionChanges in HF treatment and related outcomes could be attributed to lifestyle modifications resulting from the COVID‐19 pandemic. Measures, such as limiting outdoor activities and adopting mask‐wearing practices may have influenced HF symptoms, preventive behaviors, and the overall approach to treating HF.

Glycoprotein 2 (GP2) is a widely distributed protein in the digestive tract, contributing to mucosal barrier maintenance, immune homeostasis, and antigen-specific immune response, while also being linked to inflammatory bowel disease (IBD) pathogenesis. This review sheds light on the extensive distribution of GP2 within the gastrointestinal tract and its intricate interplay with the immune system. Furthermore, the significance of GP2 autoantibodies in diagnosing and categorizing IBD is underscored, alongside the promising therapeutic avenues for modulating GP2 to regulate immunity and maintain mucosal balance.

Background This study examined the relationship between the disciplinary diversity of research teams and research output (RO) in allergy and immunology programs funded by the National Institutes of Health (NIH) in the United States, Medical Research Council (MRC) in the United Kingdom, and Japan Society for the Promotion of Science (JSPS). Methods Using a dataset containing 1243, 3645, and 1468 articles funded by the NIH, MRC, and JSPS, respectively, we analyzed the correlation between disciplinary diversity and RO in allergy and immunology programs that received grants from 2017 to 2021. Diversity was measured using All Science Journal Classification codes counts, Shannon-Wiener index, and newly developed Omnidisciplinary index (o-index). The impact of diversity on RO was evaluated Normalized Paper Count (reflecting research quantity), Normalized Top 1% Paper Count (reflecting research excellence), and Normalized Top 10% Paper Count (reflecting research substantiality). Results There were no significant differences in diversity between the funding agencies, indicating a marginal relationship between team composition and RO (p = 0.641 for Shannon-Winner index). RO was positively correlated with team diversity in NIH- and MRC-funded programs and positively correlated with the degree of specialization in JSPS-funded programs. Conclusions These results underscore the complexity of the relationship between research team diversity and RO and the influence of contextual factors such as country-specific characteristics and grant program objectives. Specifically, the analysis of JSPS-funded groups suggests that the degree of specialization has a greater impact on RO than disciplinary diversity. This study contributes to ongoing efforts to optimize team composition to improve RO in allergy and immunology programs.

Nasal vaccines induce pathogen-specific dual protective immunity at mucosal surfaces and systemically throughout the body. Consequently, nasal vaccines both prevent pathogen invasion and reduce disease severity. Because of these features, nasal vaccines are considered to be a next-generation tool for preventing respiratory infectious diseases, including COVID-19. However, nasal vaccines must overcome key safety concerns given the anatomic proximity of the central nervous system (CNS) via the olfactory bulbs which lie next to the nasal cavity. This review summarizes current efforts to develop safe and effective nasal vaccines and delivery systems, as well as their clinical applications for the prevention of respiratory infections. We also discuss various concerns regarding the safety of nasal vaccines and introduce a system for evaluating them.

The data that support the findings of this study are available from the corresponding author upon reasonable request. Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Respiratory syncytial virus (RSV) is a leading cause of upper and lower respiratory tract infection, especially in children and the elderly. Various vaccines containing the major transmembrane surface proteins of RSV (proteins F and G) have been tested; however, they have either afforded inadequate protection or are associated with the risk of vaccine-enhanced disease (VED). Recently, F protein-based maternal immunization and vaccines for elderly patients have shown promising results in phase III clinical trials, however, these vaccines have been administered by injection. Here, we examined the potential of using the ectodomain of small hydrophobic protein (SHe), also an RSV transmembrane surface protein, as a nasal vaccine antigen. A vaccine was formulated using our previously developed cationic cholesteryl-group-bearing pullulan nanogel as the delivery system, and SHe was linked in triplicate to pneumococcal surface protein A as a carrier protein. Nasal immunization of mice and cotton rats induced both SHe-specific serum IgG and mucosal IgA antibodies, preventing viral invasion in both the upper and lower respiratory tracts without inducing VED. Moreover, nasal immunization induced greater protective immunity against RSV in the upper respiratory tract than did systemic immunization, suggesting a critical role for mucosal RSV-specific IgA responses in viral elimination at the airway epithelium. Thus, our nasal vaccine induced effective protection against RSV infection in the airway mucosa and is therefore a promising vaccine candidate for further development.

Introduction Kawasaki disease (KD) is an acute systemic vasculitis that predominantly afflicts children. KD development is known to be associated with an aberrant immune response and abnormal platelet activation, however its etiology is still largely unknown. Myosin light chain 9 (Myl9) is known to regulate cellular contractility of both non-muscle and smooth muscle cells, and can be released from platelets, whereas any relations of Myl9 expression to KD vasculitis have not been examined. Methods Plasma Myl9 concentrations in KD patients and children with febrile illness were measured and associated with KD clinical course and prognosis. Myl9 release from platelets in KD patients was also evaluated in vitro. Myl9 expression was determined in coronary arteries from Lactobacillus casei cell wall extract (LCWE)-injected mice that develop experimental KD vasculitis, as well as in cardiac tissues obtained at autopsy from KD patients. Results and discussion Plasma Myl9 levels were significantly higher in KD patients during the acute phase compared with healthy controls or patients with other febrile illnesses, declined following IVIG therapy in IVIG-responders but not in non-responders. In vitro, platelets from KD patients released Myl9 independently of thrombin stimulation. In the LCWE-injected mice, Myl9 was detected in cardiac tissue at an early stage before inflammatory cell infiltration was observed. In tissues obtained at autopsy from KD patients, the highest Myl9 expression was observed in thrombi during the acute phase and in the intima and adventitia of coronary arteries during the chronic phase. Thus, our studies show that Myl9 expression is significantly increased during KD vasculitis and that Myl9 levels may be a useful biomarker to estimate inflammation and IVIG responsiveness to KD.

Paneth cells are intestinal epithelial cells that release antimicrobial peptides, such as α-defensin as part of host defense. Together with mesenchymal cells, Paneth cells provide niche factors for epithelial stem cell homeostasis. Here, we report two subtypes of murine Paneth cells, differentiated by their production and utilization of fucosyltransferase 2 (Fut2), which regulates α(1,2)fucosylation to create cohabitation niches for commensal bacteria and prevent invasion of the intestine by pathogenic bacteria. The majority of Fut2- Paneth cells were localized in the duodenum, whereas the majority of Fut2+ Paneth cells were in the ileum. Fut2+ Paneth cells showed higher granularity and structural complexity than did Fut2- Paneth cells, suggesting that Fut2+ Paneth cells are involved in host defense. Signaling by the commensal bacteria, together with interleukin 22 (IL-22), induced the development of Fut2+ Paneth cells. IL-22 was found to affect the α-defensin secretion system via modulation of Fut2 expression, and IL-17a was found to increase the production of α-defensin in the intestinal tract. Thus, these intestinal cytokines regulate the development and function of Fut2+ Paneth cells as part of gut defense.

Mast cells (MCs) are immune cells widely distributed in the body, accompanied by diverse phenotypes and functions. Committed mast cell precursors (MCPs) leave the bone marrow and enter the blood circulation, homing to peripheral sites under the control of various molecules from different microenvironments, where they eventually differentiate and mature. Partly attributable to the unique maturation mechanism, MCs display high functional heterogeneity and potentially plastic phenotypes. High plasticity also means that MCs can exhibit different subtypes to cope with different microenvironments, which we call "the peripheral immune education system". Under the peripheral immune education system, MCs showed a new character from previous cognition in some cases, namely regulation of allergy and inflammation. In this review, we focus on the mucosal tissues, such as the gastrointestinal tract, to gain insights into the mechanism underlying the migration of MCs to the gut or other organs and their heterogeneity, which is driven by different microenvironments. In particular, the immunosuppressive properties of MCs let us consider that positively utilizing MCs may be a new way to overcome inflammatory and allergic disorders.

The pancreas contains exocrine glands, which release enzymes (e.g., amylase, trypsin, and lipase) that are important for digestion and islets, which produce hormones. Digestive enzymes and hormones are secreted from the pancreas into the duodenum and bloodstream, respectively. Growing evidence suggests that the roles of the pancreas extend to not only the secretion of digestive enzymes and hormones but also to the regulation of intestinal homeostasis and inflammation (e.g., mucosal defense to pathogens and pathobionts). Organ crosstalk between the pancreas and intestine is linked to a range of physiological, immunological, and pathological activities, such as the regulation of the gut microbiota by the pancreatic proteins and lipids, the retroaction of the gut microbiota on the pancreas, the relationship between inflammatory bowel disease, and pancreatic diseases. We herein discuss the current understanding of the pancreas-intestinal barrier axis and the control of commensal bacteria in intestinal inflammation.