論文 - 加畑　宏樹

Lysophosphatidylcholine Acyltransferase 1 Deficiency Promotes Pulmonary Emphysema via Apoptosis of Alveolar Epithelial Cells.

Tanosaki T, Mikami Y, Shindou H, Suzuki T, Hashidate-Yoshida T, Hosoki K, Kagawa S, Miyata J, Kabata H, Masaki K, Hamamoto R, Kage H, Miyashita N, Makita K, Matsuzaki H, Suzuki Y, Mitani A, Nagase T, Shimizu T, Fukunaga K

Inflammation （Inflammation）  45 （ 4 ） 1765 - 1779 2022年08月

ISSN  0360-3997

　概要を見る

Chronic obstructive pulmonary disease (COPD) is primarily caused by inhalation of cigarette smoke and is the third leading cause of death worldwide. Pulmonary surfactant, a complex of phospholipids and proteins, plays an essential role in respiration by reducing the surface tension in the alveoli. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is an enzyme that catalyzes the biosynthesis of surfactant lipids and is expressed in type 2 alveolar epithelial cells. Its dysfunction is suggested to be involved in various lung diseases; however, the relationship between LPCAT1 and COPD remains unclear. To investigate the role of LPCAT1 in the pathology of COPD, we analyzed an elastase-induced emphysema model using Lpcat1 knockout (KO) mice. In Lpcat1 KO mice, elastase-induced emphysema was significantly exacerbated with increased apoptotic cells, which was not ameliorated by supplementation with dipalmitoylphosphatidylcholine, which is a major component of the surfactant synthesized by LPCAT1. We subsequently evaluated the effects of cigarette smoking on primary human type 2 alveolar epithelial cells (hAEC2s) and found that cigarette smoke extract (CSE) downregulated the expression of Lpcat1. Furthermore, RNA sequencing analysis revealed that the apoptosis pathway was significantly enriched in CSE-treated primary hAEC2s. Finally, we downregulated the expression of Lpcat1 using small interfering RNA, which resulted in enhanced CSE-induced apoptosis in A549 cells. Taken together, cigarette smoke–induced downregulation of LPCAT1 can promote the exacerbation of pulmonary emphysema by increasing the susceptibility of alveolar epithelial cells to apoptosis, thereby suggesting that Lpcat1 is a novel therapeutic target for irreversible emphysema.

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Young woman with multiple lung nodules: a pulmonary oxymoron.

Tanaka H, Kabata H, Emoto K, Hayashi S, Masai K, Fukunaga K

Thorax 2022年07月

ISSN  0040-6376

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One-year follow-up CT findings in COVID-19 patients: A systematic review and meta-analysis.

Watanabe A, So M, Iwagami M, Fukunaga K, Takagi H, Kabata H, Kuno T

Respirology (Carlton, Vic.) （Respirology）  27 （ 8 ） 605 - 616 2022年06月

ISSN  1323-7799

　概要を見る

Coronavirus disease 2019 (COVID-19) often causes radiological and functional pulmonary sequelae. However, evidence on 1-year follow-up of pulmonary sequelae is limited. We aimed to investigate the characteristics and time-course of pulmonary sequelae after recovery from COVID-19 through 1-year follow-up. We searched PubMed and EMBASE databases on 25 February 2022, and included studies with computed tomography (CT) findings at the 1-year follow-up. The extracted data on CT findings were analysed using a one-group meta-analysis. We further analysed the data in relation to COVID-19 severity, improvement rate and lung function. Fifteen eligible studies (N = 3134) were included. One year after COVID-19, 32.6% (95% CI 24.0–42.6, I2 = 92.9%) presented with residual CT abnormalities. Ground-glass opacity and fibrotic-like changes were frequently observed in 21.2% (95% CI 15.4–28.4, I2 = 86.7%) and 20.6% (95% CI 11.0–35.2, I2 = 91.9%), respectively. While the gradual recovery was seen on CT (52.9% [mid-term] vs. 32.6% [1 year]), the frequency of CT abnormalities was higher in the severe/critical cases than in the mild/moderate cases (37.7% vs. 20.7%). In particular, fibrotic changes showed little improvement between 4–7 months and 1 year after COVID-19. Pulmonary function tests at 1 year also showed the decline in diffusing capacity of the lung for carbon monoxide, especially in severe/critical cases. Our meta-analysis indicated that residual CT abnormalities were common in hospitalized COVID-19 patients 1 year after recovery, especially fibrotic changes in severe/critical cases. As these sequelae may last long, vigilant observations and longer follow-up periods are warranted.

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An Inhalation Device With Inertial Measurement Unit for Monitoring Inhaler Technique

Takano Shunya, Shimono Tomoyuki, Masaki Katsunori, Fukunaga Koichi, Kabata Hiroki, Nishie Miyuki, Ezaki Taiko, Nakada Hideo, Hakamata Jun, Hasegawa Atsushi

IEEE-ASME TRANSACTIONS ON MECHATRONICS （IEEE/ASME Transactions on Mechatronics）  2022年06月

ISSN  1083-4435

　概要を見る

Inhalers are commonly used to treat asthma and chronic obstructive pulmonary disease. Regular and correct usage of inhalers is necessary for effective use. However, approximately 70% of patients do not use their inhalers as directed. This is due to a lack of understanding about the medication and misunderstanding of directions. Assessment of patients’ inhaler techniques are usually conducted in person. However, doctors or pharmacists have no objective information regarding how patients use their inhalers at home. Therefore, monitoring daily inhaler use is necessary for precise medical treatment. This article proposes an inhalation monitoring device using an inertial measurement unit (IMU). The IMU is used to measure a patient’s inhalation motion. Incorrect inhalation usage can be determined by comparing the measurement data against data that indicate correct usage. The experimental results show the utility of the proposed device.

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Early intubation and decreased in-hospital mortality in patients with coronavirus disease 2019.

Yamamoto R, Kaito D, Homma K, Endo A, Tagami T, Suzuki M, Umetani N, Yagi M, Nashiki E, Suhara T, Nagata H, Kabata H, Fukunaga K, Yamakawa K, Hayakawa M, Ogura T, Hirayama A, Yasunaga H, Sasaki J, J-RECOVER study group.

Critical care (London, England) （Critical Care）  26 （ 1 ） 124 2022年05月

ISSN  1364-8535

　概要を見る

Background: Some academic organizations recommended that physicians intubate patients with COVID-19 with a relatively lower threshold of oxygen usage particularly in the early phase of pandemic. We aimed to elucidate whether early intubation is associated with decreased in-hospital mortality among patients with novel coronavirus disease 2019 (COVID-19) who required intubation. Methods: A multicenter, retrospective, observational study was conducted at 66 hospitals in Japan where patients with moderate-to-severe COVID-19 were treated between January and September 2020. Patients who were diagnosed as COVID-19 with a positive reverse-transcription polymerase chain reaction test and intubated during admission were included. Early intubation was defined as intubation conducted in the setting of ≤ 6 L/min of oxygen usage. In-hospital mortality was compared between patients with early and non-early intubation. Inverse probability weighting analyses with propensity scores were performed to adjust patient demographics, comorbidities, hemodynamic status on admission and time at intubation, medications before intubation, severity of COVID-19, and institution characteristics. Subgroup analyses were conducted on the basis of age, severity of hypoxemia at intubation, and days from admission to intubation. Results: Among 412 patients eligible for the study, 110 underwent early intubation. In-hospital mortality was lower in patients with early intubation than those with non-early intubation (18 [16.4%] vs. 88 [29.1%]; odds ratio, 0.48 [95% confidence interval 0.27–0.84]; p = 0.009, and adjusted odds ratio, 0.28 [95% confidence interval 0.19–0.42]; p < 0.001). The beneficial effects of early intubation were observed regardless of age and severity of hypoxemia at time of intubation; however, early intubation was associated with lower in-hospital mortality only among patients who were intubated later than 2 days after admission. Conclusions: Early intubation in the setting of ≤ 6 L/min of oxygen usage was associated with decreased in-hospital mortality among patients with COVID-19 who required intubation. Trial Registration None.

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A 70-Year-Old Woman With Long-Term Nonresolving Pneumonia.

Tomiyasu S, Kabata H, Emoto K, Azekawa S, Maeda C, Masai K, Yasuda H, Fukunaga K

Chest （Chest）  161 （ 4 ） e219 - e223 2022年04月

ISSN  0012-3692

　概要を見る

Case Presentation: A 70-year-old woman who had received a diagnosis of pneumonia in the right lower lobe was treated with antibiotics at a general practitioner's clinic 9 months earlier. Her pneumonia had improved, but the cough and lung infiltrates persisted for > 6 months, so the patient was referred to our hospital. She had undergone surgery for breast cancer 30 years earlier but had no other medical history. She was not taking any medications and had no history of smoking, including passive smoking.

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Current overview of the role of neuropeptides in ILC2s and future directions.

Irie M, Sasahara K, Artis D, Kabata H

Allergology international : official journal of the Japanese Society of Allergology （Allergology International）  71 （ 3 ） 294 - 300 2022年03月

ISSN  1323-8930

　概要を見る

The neural and immune systems are closely connected, and recently, their molecular mechanisms and relationships with diseases have attracted substantial attention. Particularly, it has been increasingly reported that ILC2s, which produce type 2 cytokines independent of acquired immunity, are regulated by neuropeptides such as catecholamines, acetylcholine, vasoactive intestinal peptide, neuromedins, and calcitonin gene-related peptide. However, the regulatory mechanisms in this regard are only partially understood, implying that further studies are still needed to clarify the complete mechanisms and processes. In this review, we summarize current reports on the regulatory effect of neuropeptides on ILC2s, some of which have conflicting results, possibly owing to the complexity of G-protein coupled receptors. By summarizing the current evidence, we hope to be able to identify what is currently unknown as well as what needs to be clarified in the future.

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ILCs and Allergy.

Kabata H, Motomura Y, Kiniwa T, Kobayashi T, Moro K

Advances in experimental medicine and biology （Advances in Experimental Medicine and Biology）  1365   75 - 95 2022年

ISSN  0065-2598

　概要を見る

The recent discovery of new innate lymphoid cells (ILCs) has revolutionized the field of allergies. Since most allergic diseases induce a type 2 immune response, Th2 cells, which produce IL-4, IL-5, and IL-13 in an antigen-dependent manner, in addition to basophils and mast cells which are activated by antigen-specific IgE, are thought to play a major role in the pathogenesis. However, since group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines (i.e., IL-2, IL-4, IL-5, IL-6, IL-9, IL-13, GM-CSF, and amphiregulin) in response to various cytokines, including IL-33 in the surrounding environment, the possibility has emerged that there are two types of allergies: allergies induced in an antigen-dependent manner by Th2 cells and allergies induced in an antigen-independent manner by ILC2s. In order to make an impact on the increasing incidence of allergic diseases in the world, it is essential to research and develop new treatments that focus not only on Th2 cells but also on ILC2s. In this chapter, the role of ILCs in allergic diseases, which has rapidly changed with the discovery of ILCs, is discussed, focusing mainly on ILC2s.

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Heterogeneity of ILC2s in the Lungs.

Asaoka M, Kabata H, Fukunaga K

Frontiers in immunology （Frontiers in Immunology）  13   918458 2022年

ISSN  1664-3224

　概要を見る

Group 2 innate lymphoid cells (ILC2s) are GATA3-expressing type 2 cytokine-producing innate lymphocytes that are present in various organs throughout the body. Basically, ILC2s are tissue-resident cells associated with a variety of pathological conditions in each tissue. Differences in the tissue-specific properties of ILC2s are formed by the post-natal tissue environment; however, diversity exists among ILC2s within each localized tissue due to developmental timing and activation. Diversity between steady-state and activated ILC2s in mice and humans has been gradually clarified with the advancement of single-cell RNA-seq technology. Another layer of complexity is that ILC2s can acquire other ILC-like functions, depending on their tissue environment. Further, ILC2s with immunological memory and exhausted ILC2s are both present in tissues, and the nature of ILC2s varies with senescence. To clarify how ILC2s affect human diseases, research should be conducted with a comprehensive understanding of ILC2s, taking into consideration the diversity of ILC2s rather than a snapshot of a single section. In this review, we summarize the current understanding of the heterogeneity of ILC2s in the lungs and highlight a novel field of immunology.

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Mapping the human genetic architecture of COVID-19

Niemi M.E.K., Karjalainen J., Liao R.G., Neale B.M., Daly M., Ganna A., Pathak G.A., Andrews S.J., Kanai M., Veerapen K., Fernandez-Cadenas I., Schulte E.C., Striano P., Marttila M., Minica C., Marouli E., Karim M.A., Wendt F.R., Savage J., Sloofman L., Butler-Laporte G., Kim H.N., Kanoni S., Okada Y., Byun J., Han Y., Uddin M.J., Smith G.D., Willer C.J., Buxbaum J.D., Mehtonen J., Finucane H., Cordioli M., Martin A.R., Zhou W., Pasaniuc B., Julienne H., Aschard H., Shi H., Yengo L., Polimanti R., Ghoussaini M., Schwartzentruber J., Dunham I., Chwialkowska K., Francescatto M., Trankiem A., Balaconis M.K., Davis L., Lee S., Priest J., Renieri A., Sankaran V.G., van Heel D., Deelen P., Brent Richards J., Nakanishi T., Biesecker L., Eric Kerchberger V., Kenneth Baillie J., Mari F., Bernasconi A., Ceri S., Canakoglu A., Wolford B., Faucon A., Dutta A.K., Schurmann C., Harry E., Birney E., Nguyen H., Nasir J., Kaunisto M., Solomonson M., Dueker N., Vadgama N., Limou S., Rahmouni S., Mbarek H., Darwish D., Uddin M.M., Albertos R., Pérez-Tur J., Li R., Folkersen L., Moltke I., Koelling N., Teumer A., Kousathanas A., Utrilla A., Verdugo R.A., Zárate R., Medina-Gómez C., Gómez-Cabrero D., Carnero-Montoro E., Cadilla C.L., Moreno-Estrada A., Garmendia A., Moya L., Sedaghati-Khayat B.

Nature （Nature）  600 （ 7889 ） 472 - 477 2021年12月

ISSN  00280836

　概要を見る

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

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Clinical Characteristics of Patients with Coronavirus Disease (COVID-19): Preliminary Baseline Report of Japan COVID-19 Task Force, a Nationwide Consortium to Investigate Host Genetics of COVID-19.

Tanaka H, Lee H, Morita A, Namkoong H, Chubachi S, Kabata H, Kamata H, Ishii M, Hasegawa N, Harada N, Ueda T, Ueda S, Ishiguro T, Arimura K, Saito F, Yoshiyama T, Nakano Y, Mutoh Y, Suzuki Y, Murakami K, Okada Y, Koike R, Kitagawa Y, Tokunaga K, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K, Japan COVID-19 Task Force.

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases （International Journal of Infectious Diseases）  113   74 - 81 2021年12月

ISSN  1201-9712

　概要を見る

Background and design:: The coronavirus disease (COVID-19) pandemic is having a devastating effect worldwide. Host genome differences between populations may influence the severity of COVID-19. The Japan COVID-19 Task Force is conducting host genome analysis of hospitalized patients with COVID-19 from more than 70 institutions nationwide in Japan. This report describes the clinical characteristics of patients enrolled to date. Results:: The median (interquartile range) age of the 1674 patients included in the analysis was 59 (45–71) years, and more than half of the patients (66.2%) were male. Less than half of the patients (41.2%) had severe disease. The case fatality rate was 3.2%. Conclusions:: Since this is a hospital-based study, the number of severe cases was relatively high, but the case fatality rate was relatively low, when compared to that of other countries. In the future, we will continue to enroll patients and conduct genome analyses of patients with COVID-19.

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Comprehensive and long-term surveys of COVID-19 sequelae in Japan, an ambidirectional multicentre cohort study: study protocol.

Nakagawara K, Namkoong H, Terai H, Masaki K, Tanosaki T, Shimamoto K, Lee H, Tanaka H, Okamori S, Kabata H, Chubachi S, Ikemura S, Kamata H, Yasuda H, Kawada I, Ishii M, Ishibashi Y, Harada S, Fujita T, Ito D, Bun S, Tabuchi H, Kanzaki S, Shimizu E, Fukuda K, Yamagami J, Kobayashi K, Hirano T, Inoue T, Kagyo J, Shiomi T, Ohgino K, Sayama K, Otsuka K, Miyao N, Odani T, Oyamada Y, Masuzawa K, Nakayama S, Suzuki Y, Baba R, Nakachi I, Kuwahara N, Ishiguro T, Mashimo S, Minematsu N, Ueda S, Manabe T, Funatsu Y, Koh H, Yoshiyama T, Saito F, Ishioka K, Takahashi S, Nakamura M, Goto A, Harada N, Kusaka Y, Nakano Y, Nishio K, Tateno H, Edahiro R, Takeda Y, Kumanogoh A, Kodama N, Okamoto M, Umeda A, Hagimura K, Sato T, Miyazaki N, Takemura R, Sato Y, Takebayashi T, Nakahara J, Mimura M, Ogawa K, Shimmura S, Negishi K, Tsubota K, Amagai M, Goto R, Ibuka Y, Hasegawa N, Kitagawa Y, Kanai T, Fukunaga K

BMJ open respiratory research （BMJ Open Respiratory Research）  8 （ 1 ）  2021年11月

　概要を見る

Introduction The rapid spread of COVID-19 posed a global burden. Substantial number of people died of the disease in the acute phase of infection. In addition, a significant proportion of patients have been reported to suffer from post-acute phase symptoms, sequelae of COVID-19, which may negatively influence the quality of daily living and/or socioeconomic circumstances of the patients. However, no previous study has comprehensively and objectively assessed the quality of life of patients by using existing international scales. Further, evidence of socioeconomic consequences among patients with COVID-19 is scarce. To address the multidimensional issues from sequelae of COVID-19, evidence from comprehensive surveys beyond clinical perspectives is critical that investigates health, and social determinants of disease progression as well as socioeconomic consequences at a large scale. Methods and analysis In this study, we plan to conduct a nationwide and comprehensive survey for the sequelae of COVID-19 in a total of 1000 patients diagnosed at 27 hospitals throughout Japan. This study will evaluate not only the health-related status of patients from clinical perspectives but also the Health-related Quality of Life (HRQoL) scores, socioeconomic status and consequences to discuss the sequelae of the disease and the related risk factors. The primary endpoint is the frequency of long-term complications of COVID-19 infection. The secondary endpoints are risk factors for progression to sequelae of COVID-19 infection. The study will provide robust and important evidence as a resource to tackle the issues from the sequelae of COVID-19 from the multi-dimensional perspectives. Ethics and dissemination This trial was approved by the Keio University School of Medicine Ethics Committee (20200243, UMIN000042299). The results of this study will be reported at a society meeting or published in a peer-reviewed journal.

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The Association of Inhaled Corticosteroid Before Admission and Survival of Patients with COVID-19.

So M, Kabata H, Takahashi M, Egorova NN, Kuno T

Journal of aerosol medicine and pulmonary drug delivery （Journal of Aerosol Medicine and Pulmonary Drug Delivery）  34 （ 4 ） 265 - 267 2021年08月

ISSN  1941-2711

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Successful treatment of a patient with adult food allergy and severe asthma using omalizumab.

Nishie M, Masaki K, Okuzumi S, Mochimaru T, Kabata H, Miyata J, Takahashi H, Fukunaga K

Asia Pacific allergy （Asia Pacific Allergy）  11 （ 3 ） e27 2021年07月

ISSN  2233-8276

　概要を見る

Food allergy is a typical immediate-onset allergic disease in which symptoms are provoked by exposure to the sensitized antigens. Although previous reports have shown that omalizumab has helped children with egg or milk allergy achieve oral immunotherapy safely, there is still no established method for induction of remission in adult food allergy. A 51-year-old woman with oral steroid-dependent severe asthma was treated with omalizumab for 6 years. She had shellfish and wheat food allergy and oral allergy syndrome induced by kiwi and other foods associated with latex-fruit syndrome. Since omalizumab treatment, her food allergy symptoms had disappeared. After 7 years of this treatment, disseminated erythema suddenly appeared; omalizumab was discontinued because of suspected drug-induced eruption. After omalizumab interruption, she felt an itching sensation in her throat with worsened asthma control immediately after wheat ingestion. Readministration of omalizumab improved these symptoms. Thus, we raised the possibility that omalizumab not only improved asthma control but also induced pharmacological remission of the patient's food allergy. Omalizumab may be considered as a treatment option for adult patients with food allergies and severe asthma.

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Eosinophilic annular erythema showing eosinophil cytolytic ETosis successfully treated with benralizumab.

Masaki K, Ueki S, Tanese K, Nagao G, Kanzaki S, Matsuki E, Irie H, Kabata H, Miyata J, Kawada I, Fukunaga K

Asia Pacific allergy （Asia Pacific Allergy）  11 （ 3 ） e28 2021年07月

ISSN  2233-8276

　概要を見る

A 56-year-old woman presented with repeated swelling of the lips and face. She had a history of childhood asthma; she had a recurrence of asthma when she was 54 years old and was taking inhaled corticosteroids, and other antiasthma drugs. The swelling of her lips and face improved temporarily with oral corticosteroids (OCS), but recurred soon after discontinuing OCS. Her peripheral blood eosinophil count was 632/μL (9.3%), and her serum was negative for myeloperoxidase-anti-neutrophil cytoplasmic antibody and serine proteinase3-anti-neutrophil cytoplasmic antibody. Hematoxylin and eosin staining of her back skin revealed abundant eosinophilic infiltrate around the vascular area of the shallow dermis layer, but no evidence of vasculitis and we diagnosed her as eosinophilic annular erythema (EAE). Punctate staining of galectin-10, chromatolytic eosinophils, and net-like DNA was also evident in close proximity to the free granules, indicating extracellular vesicles and eosinophil extracellular traps (ETosis). We started daily OCS to control her asthma and skin eruption/oedema. Three months after administering daily OCS, benralizumab was initiated for withdrawal from OCS dependence and treatment of severe asthma. After initiation of benralizumab, her skin and subcutaneous tissue symptoms promptly improved. OCS was discontinued, and no edematous erythema has been observed since then. Bronchial asthma has also been well-controlled. This is the first report on the evidence of eosinophil ETosis in the dermis of EAE patients and the efficacy of benralizumab in a patient with EAE. Benralizumab may be a useful drug for treating refractory EAE with severe eosinophilic asthma.

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TLR7 Agonist Suppresses ILC2-mediated Inflammation via IL-27-producing Interstitial Macrophages.

Okuzumi S, Miyata J, Kabata H, Mochimaru T, Kagawa S, Masaki K, Irie M, Morita H, Fukunaga K

American journal of respiratory cell and molecular biology （American Journal of Respiratory Cell and Molecular Biology）  65 （ 3 ） 309 - 318 2021年05月

ISSN  1044-1549

　概要を見る

Group 2 innate lymphoid cells (ILC2s) play an important role in the pathophysiology of asthma via the robust production of type 2 cytokines. Recent studies have demonstrated that TLR7 (Toll-like receptor 7) signaling skews toward a type 1 inflammatory response in asthma, which may lead to the development of novel treatment strategies. However, the effect of TLR7 signaling on ILC2-dependent nonallergic eosinophilic inflammation remains unclear. In this study, we investigated the effects of R848, a TLR7 agonist, in a mouse model of IL-33–induced eosinophilic airway inflammation. Intranasal administration of R848 decreased infiltration of airway eosinophils and ILC2s, mucus production in epithelial cells, and type 2 cytokine production. Flow cytometric analysis identified an increased number of interstitial macrophages (IMs) expressing a high level of TLR7 in the lung upon IL-33 stimulation. IL-33–induced IMs also expressed high levels of alternatively activated (M2)-type genes and chemokines (CCL17 and CCL24). However, R848 stimulation modified these gene expressions and elicited the production of IL-27. Coculture experiments revealed that IL-33–induced IMs directly suppressed ILC2 activation in response to R848. In addition, the inhibitory effects of R848 on ILC2-induced type 2 inflammation were defective in WSX-1–deficient mice lacking the IL-27 receptor. Taken together, these findings indicate that R848 stimulates IL-33–induced IMs to suppress ILC2-mediated type 2 airway inflammation via IL-27. These findings highlight the therapeutic potential of TLR7 agonists and/or IL-27 cascades in nonallergic asthma.

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Accelerometer-Equipped External Attachments to Detect Critical Errors While Using Inhalation Devices

Ezaki T., Masaki K., Nishie M., Nakada H., Hakamata J., Takano S., Sunata K., Akiyama Y., Irie M., Okuzumi S., Kabata H., Shimono T., Tsuda S., Aomori T., Fukunaga K.

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 203 （ 9 ）  2021年05月

ISSN  1073-449X

Radiological and Functional Lung Sequelae of COVID-19: Systematic Review and Meta-Analysis

So M., Kabata H., Fukunaga K., Takagi H., Kuno T.

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 203 （ 9 ）  2021年05月

ISSN  1073-449X

COVID-19 shares clinical features with anti-melanoma differentiation-associated protein 5 positive dermatomyositis and adult Still's disease.

Kondo Y, Kaneko Y, Takei H, Tamai H, Kabata H, Suhara T, Yamamoto R, Nagata H, Ishii M, Sasaki J, Hasegawa N, Fukunaga K, Takeuchi T, Keio Donner Project.

Clinical and experimental rheumatology （Clinical and Experimental Rheumatology）  39 （ 3 ） 631 - 638 2021年05月

ISSN  0392-856X

　概要を見る

Objective To investigate the similarities and differences between Coronavirus disease 2019 (COVID-19) and autoimmune and autoinflammatory rheumatic diseases characterised by hyperferritinaemia, such as antimelanoma differentiation-associated protein 5 (MDA5) autoantibody-positive dermatomyositis and adult Still’s disease. Methods We reviewed consecutive, newly diagnosed, untreated patients with COVID-19, anti-MDA5 dermatomyositis, or adult Still’s disease. We compared their clinical, laboratory, and radiological characteristics, including the prevalence of macrophage activation syndrome and lung involvement in each disease. Results The numbers of patients with COVID-19, anti-MDA5 dermatomyositis, and adult-onset Still’s disease with hyperferritinaemia (serum ferritin ≥500ng/dL) who were included for main analysis were 22, 14, and 59, respectively. COVID-19 and adult Still’s disease both featured hyperinflammatory status, such as high fever and elevated serum C-reactive protein, whereas COVID-19 and anti-MDA5 dermatomyositis both presented with severe interstitial lung disease and hypoxaemia. While two-thirds of the patients in each group met the criteria for macrophage-activated syndrome that is used in systemic juvenile idiopathic arthritis, the HScore, an indicator of haemophagocytic lymphohistiocytosis, was low in anti-MDA5 dermatomyositis and COVID-19 even in severe or critical cases. The findings of chest computed tomography were similar between COVID-19 and anti-MDA5 dermatomyositis. Conclusion COVID-19 shared clinical features with rheumatic diseases characterised by hyperferritinaemia, including anti-MDA5 dermatomyositis and adult Still’s disease. These findings should be investigated further in order to shed light on the pathogenesis of not only COVID-19 but also the aforementioned rheumatic diseases.

Radiological and functional lung sequelae of COVID-19: a systematic review and meta-analysis.

So M, Kabata H, Fukunaga K, Takagi H, Kuno T

BMC pulmonary medicine （BMC Pulmonary Medicine）  21 （ 1 ） 97 2021年03月

ISSN  1471-2466

　概要を見る

Background: The coronavirus disease 2019 (COVID-19) causes a wide spectrum of lung manifestations ranging from mild asymptomatic disease to severe respiratory failure. We aimed to clarify the characteristics of radiological and functional lung sequelae of COVID-19 patients described in follow-up period. Method: PubMed and EMBASE were searched on January 20th, 2021 to investigate characteristics of lung sequelae in COVID-19 patients. Chest computed tomography (CT) and pulmonary function test (PFT) data were collected and analyzed using one-group meta-analysis. Results: Our search identified 15 eligible studies with follow-up period in a range of 1–6 months. A total of 3066 discharged patients were included in these studies. Among them, 1232 and 1359 patients were evaluated by chest CT and PFT, respectively. The approximate follow-up timing on average was 90 days after either symptom onset or hospital discharge. The frequency of residual CT abnormalities after hospital discharge was 55.7% (95% confidential interval (CI) 41.2–70.1, I2 = 96.2%). The most frequent chest CT abnormality was ground glass opacity in 44.1% (95% CI 30.5–57.8, I2 = 96.2%), followed by parenchymal band or fibrous stripe in 33.9% (95% CI 18.4–49.4, I2 = 95.0%). The frequency of abnormal pulmonary function test was 44.3% (95% CI 32.2–56.4, I2 = 82.1%), and impaired diffusion capacity was the most frequently observed finding in 34.8% (95% CI 25.8–43.8, I2 = 91.5%). Restrictive and obstructive patterns were observed in 16.4% (95% CI 8.9–23.9, I2 = 89.8%) and 7.7% (95% CI 4.2–11.2, I2 = 62.0%), respectively. Conclusions: This systematic review suggested that about half of the patients with COVID-19 still had residual abnormalities on chest CT and PFT at about 3 months. Further studies with longer follow-up term are warranted.

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The effect of statins for asthma. A systematic review and meta-analysis.

Sunata K, Kabata H, Kuno T, Takagi H, So M, Masaki K, Fukunaga K

The Journal of asthma : official journal of the Association for the Care of Asthma （Journal of Asthma）  59 （ 4 ） 1 - 10 2021年02月

ISSN  0277-0903

　概要を見る

Objective: To assess the effects of statins on asthma by systematically reviewing and conducting a meta-analysis on all clinical studies, including randomized controlled trials (RCTs) and observational studies, that examined the effects of statins on asthma. Methods: PubMed, EMBASE databases, and Cochrane reviews were searched to identify RCTs and observational studies, conducted through June 16, 2020, that assessed the effect of statins as a treatment for asthma. A meta-analysis was conducted using the following main outcomes: asthma control test (ACT), asthma control questionnaire (ACQ), pre- and post-bronchodilator forced expiratory volume in one second (FEV1), peak flow (PEF), and asthma exacerbation (asthma-related emergency department (ED) visits and hospitalization). Results: Our search revealed 11 RCTs and 8 observational studies that met the inclusion criteria. A meta-analysis demonstrated that statin treatment significantly improved ACT scores (mean difference: 1.61, P < 0.001) and ACQ scores (mean difference: −0.38, P < 0.001) compared to a placebo. Furthermore, statin treatment significantly reduced asthma-related ED visits (hazard ratio [HR], 95% confidence interval [CI], 0.83 [0.75–0.92], P < 0.001, number needed to treat [NNT], 5.9). However, statin treatment did not improve pulmonary function (FEV1 and PEF). Conclusion: Our results suggest that statins have the potential to improve asthma control and reduce asthma exacerbation without any improvement in pulmonary function. Supplemental data for this article can be accessed at publisher’s website.

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The real-time reverse transcription-polymerase chain reaction threshold cycle values for severe acute respiratory syndrome coronavirus 2 predict the prognosis of coronavirus disease 2019 pneumonia.

Fukushima T, Kabata H, Yamamoto R, Suhara T, Uwamino Y, Kondo Y, Masaki K, Kamata H, Nagata H, Homma K, Kaneko Y, Ishii M, Sasaki J, Morisaki H, Hasegawa N, Fukunaga K, Keio Donner Project Team.

Respiratory investigation （Respiratory Investigation）  59 （ 3 ） 360 - 363 2021年01月

ISSN  2212-5345

　概要を見る

The clinical course of coronavirus disease 2019 (COVID-19) varies from mild to critical. We retrospectively examined whether clinical and laboratory findings on admission could predict COVID-19 prognosis. Among various factors associated with COVID-19 severity, our results indicated that the real-time reverse transcription-polymerase chain reaction (RT-PCR) threshold cycle (Ct) values for severe acute respiratory syndrome coronavirus 2 were the most useful predictor of COVID-19 prognosis.

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Left Ventricular Thrombus With COVID-19 Complication in a Patient With Dilated Cardiomyopathy.

Imaeda S, Kabata H, Shiraishi Y, Kamata H, Tsuruta H, Yuasa S, Ishii M, Fukuda K, Fukunaga K

CJC open （CJC Open）  3 （ 1 ） 124 - 126 2021年01月

　概要を見る

© 2020 Canadian Cardiovascular Society Thrombosis, especially venous thromboembolism, is a complication often associated with coronavirus disease 2019 (COVID-19). However, there have been relatively few reports of arterial thrombosis. Here, we describe a case of non-severe COVID-19 in a patient with dilated cardiomyopathy. After admission, symptoms, laboratory data, and imaging findings improved, but D-dimer levels gradually increased. Contrast computed tomography and echocardiography revealed a left ventricular thrombus. Anticoagulant treatment diminished the thrombus, and the patient recovered and was discharged. Although a left ventricular thrombus is a rare COVID-19 complication, performing appropriate diagnostic tests could improve COVID-19 mortality in patients with dilated cardiomyopathy.

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Clinical characteristics of patients with not well-controlled severe asthma in Japan: Analysis of the Keio Severe Asthma Research Program in Japanese population (KEIO-SARP) registry.

Tanosaki T, Kabata H, Matsusaka M, Miyata J, Masaki K, Mochimaru T, Okuzumi S, Kuwae M, Watanabe R, Suzuki Y, Sayama K, Izuhara K, Asano K, Fukunaga K

Allergology international : official journal of the Japanese Society of Allergology （Allergology International）  70 （ 1 ） 61 - 67 2021年01月

ISSN  1323-8930

　概要を見る

© 2020 Japanese Society of Allergology Background: Multiple phenotypes exist within the classification of severe asthma. However, characteristics of patients with not well-controlled severe asthma have not been well identified. Methods: Japanese patients with asthma (age ≥ 20 years) were enrolled at the Keio University Hospital and its affiliated hospitals in this observational study (Keio Severe Asthma Research Program). Among them, patients with severe asthma (those undergoing Global Initiative for Asthma [GINA] 2018 step 4 or 5 treatment) were included in this analysis and investigated clinical characteristics based on asthma control status. Results: Of the 154 patients (men, 46.8%; age, 60.1 ± 14.9 years), 87 (56.5%) had not well-controlled (partly controlled and uncontrolled) asthma (GINA step 4, 42 patients; step 5, 45 patients). Overall, there were no significant differences in clinical characteristics between patients with well-controlled and not well-controlled asthma. However, cluster analysis revealed that distinct 5 clusters (cluster 1, well-controlled; cluster 2, eosinophilic; cluster 3, non–type 2 inflammation; cluster 4, high periostin; and cluster 5, late-onset type 2 inflammation), and clusters 2–5 were not well-controlled. Among them, cluster 3 was characterized by low eosinophil counts, low periostin levels, and less frequent olfactory disturbance, and this cluster had the worst asthma control. Conclusions: Japanese patients with severe asthma were divided into well-controlled and not-well controlled asthma, and we confirmed heterogeneity of not well-controlled severe asthma. These patients, especially non-type 2 phenotype, require a further therapeutic approach. (University Hospital Medical Information Network Clinical Trials Registry, UMIN000002980)

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Accuracy and stability of saliva as a sample for reverse transcription PCR detection of SARS-CoV-2.

Uwamino Y, Nagata M, Aoki W, Fujimori Y, Nakagawa T, Yokota H, Sakai-Tagawa Y, Iwatsuki-Horimoto K, Shiraki T, Uchida S, Uno S, Kabata H, Ikemura S, Kamata H, Ishii M, Fukunaga K, Kawaoka Y, Hasegawa N, Murata M

Journal of clinical pathology （Journal of Clinical Pathology）  74 （ 1 ） 67 - 68 2021年01月

ISSN  0021-9746

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Clinical characteristics of 345 patients with coronavirus disease 2019 in Japan: A multicenter retrospective study.

Ishii M, Terai H, Kabata H, Masaki K, Chubachi S, Tateno H, Nakamura M, Nishio K, Koh H, Watanabe R, Ueda S, Terashima T, Suzuki Y, Yagi K, Miyao N, Minematsu N, Inoue T, Nakachi I, Namkoong H, Okamori S, Ikemura S, Kamata H, Yasuda H, Kawada I, Hasegawa N, Fukunaga K, Keio COVID-19 Research Consortium (K-CORC) and the Keio Donner Project Team.

The Journal of infection （Journal of Infection）  81 （ 5 ） e3 - e5 2020年11月

ISSN  0163-4453

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Effectiveness of Face Masks in Preventing Airborne Transmission of SARS-CoV-2.

Ueki H, Furusawa Y, Iwatsuki-Horimoto K, Imai M, Kabata H, Nishimura H, Kawaoka Y

mSphere （mSphere）  5 （ 5 ）  2020年10月

ISSN  2379-5042

　概要を見る

Copyright © 2020 Ueki et al. Guidelines from the CDC and the WHO recommend the wearing of face masks to prevent the spread of coronavirus (CoV) disease 2019 (COVID-19); however, the protective efficiency of such masks against airborne transmission of infectious severe acute respiratory syndrome CoV-2 (SARS-CoV-2) droplets/aerosols is unknown. Here, we developed an airborne transmission simulator of infectious SARS-CoV-2-containing droplets/aerosols produced by human respiration and coughs and assessed the transmissibility of the infectious droplets/aerosols and the ability of various types of face masks to block the transmission. We found that cotton masks, surgical masks, and N95 masks all have a protective effect with respect to the transmission of infective droplets/aerosols of SARS-CoV-2 and that the protective efficiency was higher when masks were worn by a virus spreader. Importantly, medical masks (surgical masks and even N95 masks) were not able to completely block the transmission of virus droplets/aerosols even when completely sealed. Our data will help medical workers understand the proper use and performance of masks and determine whether they need additional equipment to protect themselves from infected patients.IMPORTANCE Airborne simulation experiments showed that cotton masks, surgical masks, and N95 masks provide some protection from the transmission of infective SARS-CoV-2 droplets/aerosols; however, medical masks (surgical masks and even N95 masks) could not completely block the transmission of virus droplets/aerosols even when sealed.

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Acute onset olfactory/taste disorders are associated with a high viral burden in mild or asymptomatic SARS-CoV-2 infections.

Nakagawara K, Masaki K, Uwamino Y, Kabata H, Uchida S, Uno S, Asakura T, Funakoshi T, Kanzaki S, Ishii M, Hasegawa N, Fukunaga K, Keio Donner Project.

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases （International Journal of Infectious Diseases）  99   19 - 22 2020年10月

ISSN  1201-9712

　概要を見る

© 2020 The Author(s) This study investigated, using cycle threshold (Ct) qPCR values, the association between symptoms and viral clearance in 57 patients with asymptomatic/mild SARS-CoV-2 infection. Patients with olfactory/taste disorders (OTDs) exhibited lower qPCR Ct values and longer time to negative qPCR than those without OTDs, suggesting an association between OTDs and high viral burden.

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A case of non-severe COVID-19 complicated by pulmonary embolism.

Akiyama Y, Horiuchi K, Kondo Y, Kabata H, Ishii M, Fukunaga K

Respirology case reports （Respirology Case Reports）  8 （ 7 ） e00622 2020年10月

ISSN  2051-3380

　概要を見る

© 2020 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology. Novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 is rapidly spreading worldwide. A typical clinical manifestation of COVID-19 is pneumonia, which can progress to acute respiratory distress syndrome and respiratory failure. Recent studies have reported that COVID-19 is often accompanied by coagulopathy, and a significant number of patients with severe or critical COVID-19 develop concomitant thrombosis, including pulmonary embolism (PE). However, there are limited reports of the incidence of PE in non-severe COVID-19 patients. Here, we report a case of non-severe COVID-19 complicated by PE, which indicates that the possibility of PE should consistently be considered, even in non-severe cases of COVID-19 without any risk of thrombosis.

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Coronavirus disease 2019-associated rapidly progressive organizing pneumonia with fibrotic feature: Two case reports.

Okamori S, Lee H, Kondo Y, Akiyama Y, Kabata H, Kaneko Y, Ishii M, Hasegawa N, Fukunaga K

Medicine （Medicine）  99 （ 35 ） e21804 2020年08月

ISSN  0025-7974

　概要を見る

INTRODUCTION: Pneumonia is one of the most important characteristics of coronavirus disease 2019 (COVID-19) and imaging findings of COVID-19 pneumonia are diverse and change over disease course. However, the detailed clinical course of organizing pneumonia (OP) caused by COVID-19 has not been clarified. PATIENT CONCERNS: A 60-year-old man and a 61-year-old woman diagnosed with mild COVID-19 were admitted to our hospital. Their respiratory symptoms were deteriorating even after initiating treatment with antiviral drugs. DIAGNOSIS: Chest X-rays and computed tomography scan showed a rapid progression of linear consolidation with reversed halo sign, distributed in subpleural and peri-bronchial regions. They also presented with pulmonary fibrosis findings, including traction bronchiectasis and marked lung volume reduction. They were diagnosed with rapidly progressing OP. INTERVENTIONS: They were treated with systemic corticosteroids. OUTCOMES: The patients' imaging findings and respiratory conditions improved rapidly without any adverse effects. CONCLUSION: Physicians should carefully monitor patients with COVID-19, as they can develop rapidly progressive and fibrotic OP, which respond to corticosteroids.

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Targeted deletion of the TSLP receptor reveals cellular mechanisms that promote type 2 airway inflammation.

Kabata H, Flamar AL, Mahlakõiv T, Moriyama S, Rodewald HR, Ziegler SF, Artis D

Mucosal immunology （Mucosal Immunology）  13 （ 4 ） 626 - 636 2020年07月

ISSN  1933-0219

　概要を見る

© 2020, The Author(s). Thymic stromal lymphopoietin (TSLP) is a critical upstream cytokine inducing type 2 inflammation in various diseases, including asthma and atopic dermatitis. Accumulating evidence suggests that TSLP can directly stimulate a variety of immune cells, such as dendritic cells (DCs), basophils, T cells, and group 2 innate lymphoid cells (ILC2s). However, which cell types directly respond to TSLP in vivo and how TSLP initiates type 2 inflammation has remained controversial. To define the precise role of TSLP in vivo, for the first time we generated multiple cell lineage-specific TSLP receptor-deficient mice to systematically dissect the cell-intrinsic requirements for TSLP responsiveness in type 2 inflammation in the lung. In papain-induced innate immune-mediated type 2 airway inflammation, TSLP directly stimulated ILC2s, but not basophils, leading to enhanced type 2 inflammation. On the other hand, in OVA-induced adaptive immune-mediated type 2 airway inflammation, TSLP principally acted on DCs and CD4 + T cells during the sensitization phase, but not basophils or ILC2s, and facilitated the development of Th2 cell-mediated airway inflammation. Together, these findings reveal that TSLP activates distinct immune cell cascades in the context of innate and adaptive immune-mediated type 2 inflammation.

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Risk factors for poor adherence to inhaled corticosteroid therapy in patients with moderate to severe asthma.

Masaki K, Miyata J, Kamatani T, Tanosaki T, Mochimaru T, Kabata H, Suzuki Y, Asano K, Betsuyaku T, Fukunaga K

Asian Pacific journal of allergy and immunology 2020年06月

ISSN  0125-877X

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Anti-TSLP antibodies: Targeting a master regulator of type 2 immune responses.

Nakajima S, Kabata H, Kabashima K, Asano K

Allergology international : official journal of the Japanese Society of Allergology （Allergology International）  69 （ 2 ） 197 - 203 2020年04月

ISSN  1323-8930

　概要を見る

© 2020 Japanese Society of Allergology TSLP is an epithelial cell-derived cytokine synthesized in response to various stimuli, including protease allergens and microorganisms like viruses and bacteria. Biological functions of TSLP require heterodimer formation between the TSLP receptor (TSLPR) and IL-7 receptor-α, which polarize dendritic cells to induce type 2 inflammation and directly expand and/or activate Th2 cells, group 2 innate lymphoid cells, basophils, and other immune cells. TSLP is thus considered a master regulator of type 2 immune responses at the barrier surfaces of skin and the respiratory/gastrointestinal tract. Indeed, genetic, experimental, and clinical evidence suggests that the TSLP-TSLPR pathway is associated with the pathogenesis of allergic diseases such as atopic dermatitis (AD) and asthma. Tezepelumab (AMG-157/MEDI9929) is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. A phase 2 trial for moderate to severe AD showed that a greater but not statistically significant percentage of tezepelumab-treated patients showed clinical improvements compared to the placebo group. A phase 2 trial for uncontrolled, severe asthma showed significant decreases in asthma exacerbation rate and improved pulmonary function and asthma control for tezepelumab-treated patients. Levels of biomarkers of type 2 inflammation, such as blood/sputum eosinophil counts and fraction of exhaled nitric oxide decreased, however, clinical efficacy was observed irrespective of the baseline levels of these biomarkers. A blockade of the TSLP-TSLPR pathway likely will exert significant clinical effects on AD, asthma, and other allergic diseases. The efficacy of anti-TSLP antibodies compared to other biologics needs to be further examined.

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Distinct TSLP-Immune Cell Cascades Provoke Acute Versus Chronic Type 2 Airway Inflammation

Kabata H., Artis D.

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 201 2020年

ISSN  1073-449X

Neuro-immune crosstalk and allergic inflammation

Kabata H., Artis D.

Journal of Clinical Investigation （Journal of Clinical Investigation）  129 （ 4 ） 1475 - 1482 2019年04月

査読有り,  ISSN  00219738

　概要を見る

© 2019 American Society for Clinical Investigation. The neuronal and immune systems exhibit bidirectional interactions that play a critical role in tissue homeostasis, infection, and inflammation. Neuron-derived neuropeptides and neurotransmitters regulate immune cell functions, whereas inflammatory mediators produced by immune cells enhance neuronal activation. In recent years, accumulating evidence suggests that peripheral neurons and immune cells are colocalized and affect each other in local tissues. A variety of cytokines, inflammatory mediators, neuropeptides, and neurotransmitters appear to facilitate this crosstalk and positive-feedback loops between multiple types of immune cells and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems. In this Review, we discuss these recent findings regarding neuro-immune crosstalk that are uncovering molecular mechanisms that regulate inflammation. Finally, neuro-immune crosstalk has a key role in the pathophysiology of allergic diseases, and we present evidence indicating that neuro-immune interactions regulate asthma pathophysiology through both direct and indirect mechanisms.

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Innate lymphoid cells support regulatory T cells in the intestine through interleukin-2.

Zhou L, Chu C, Teng F, Bessman NJ, Goc J, Santosa EK, Putzel GG, Kabata H, Kelsen JR, Baldassano RN, Shah MA, Sockolow RE, Vivier E, Eberl G, Smith KA, Sonnenberg GF

Nature （Nature）  568 （ 7752 ） 405 - 409 2019年04月

ISSN  0028-0836

　概要を見る

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. Interleukin (IL)-2 is a pleiotropic cytokine that is necessary to prevent chronic inflammation in the gastrointestinal tract 1–4 . The protective effects of IL-2 involve the generation, maintenance and function of regulatory T (T reg ) cells 4–8 , and the use of low doses of IL-2 has emerged as a potential therapeutic strategy for patients with inflammatory bowel disease 9 . However, the cellular and molecular pathways that control the production of IL-2 in the context of intestinal health are undefined. Here we show, in a mouse model, that IL-2 is acutely required to maintain T reg cells and immunological homeostasis throughout the gastrointestinal tract. Notably, lineage-specific deletion of IL-2 in T cells did not reduce T reg cells in the small intestine. Unbiased analyses revealed that, in the small intestine, group-3 innate lymphoid cells (ILC3s) are the dominant cellular source of IL-2, which is induced selectively by IL-1β. Macrophages in the small intestine produce IL-1β, and activation of this pathway involves MYD88- and NOD2-dependent sensing of the microbiota. Our loss-of-function studies show that ILC3-derived IL-2 is essential for maintaining T reg cells, immunological homeostasis and oral tolerance to dietary antigens in the small intestine. Furthermore, production of IL-2 by ILC3s was significantly reduced in the small intestine of patients with Crohn’s disease, and this correlated with lower frequencies of T reg cells. Our results reveal a previously unappreciated pathway in which a microbiota- and IL-1β-dependent axis promotes the production of IL-2 by ILC3s to orchestrate immune regulation in the intestine.

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Influence of the Number Multiple Disease-Modifying Factors in Japanese Patients with Severe Asthma

Watanabe R., Baba R., Kamatani T., Kuwae M., Okuzumi S., Tanosaki T., Matsusaka M., Mochimaru T., Kabata H., Ueda S., Suzuki Y., Asano K., Fukunaga K.

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 199 2019年

ISSN  1073-449X

Response to Fungal Dysbiosis by Gut-Resident CX3CR1 ⁺ Mononuclear Phagocytes Aggravates Allergic Airway Disease

Li X., Leonardi I., Semon A., Doron I., Gao I., Putzel G., Kim Y., Kabata H., Artis D., Fiers W., Ramer-Tait A., Iliev I.

Cell Host and Microbe （Cell Host and Microbe）  24 （ 6 ） 847 - 856.e4 2018年12月

ISSN  19313128

　概要を見る

© 2018 Elsevier Inc. How mycobiota influence immunity in gut distal sites is not well understood. Li et al. developed protocols for gut-targeted depletion of phagocytes and mycobiota-free mice to investigate the influence of fungi on gut-lung crosstalk. They reveal that intestinal phagocytes sense fungal dysbiosis and mediate gut-lung-directed immunity to aggravate allergic airway disease.

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The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms

Kabata H., Moro K., Koyasu S.

Immunological Reviews （Immunological Reviews）  286 （ 1 ） 37 - 52 2018年11月

ISSN  01052896

　概要を見る

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Group 2 innate lymphoid cells (ILC2s) play critical roles in the induction of type 2 inflammation, response to parasite infection, metabolic homeostasis, and tissue repair. These multifunctional roles of ILC2s are tightly controlled by complex regulatory systems in the local microenvironment, the disruption of which may cause various health problems. This review summarizes up-to-date knowledge regarding positive and negative regulators for ILC2s based on their function and signaling pathways, including activating cytokines (IL-33, IL-25; MAPK, NF-κB pathways), co-stimulatory cytokines (IL-2, IL-7, IL-9, TSLP; STAT5, IL-4; STAT6, TNF superfamily; MAPK, NF-κB pathways), suppressive cytokines (type1 IFNs, IFN-γ, IL-27; STAT1, IL-10, TGF-β), transdifferentiation cytokines (IL-12; STAT4, IL-1β, IL-18), lipid mediators (LTC4, LTD4, LTE4, PGD2; Ca2+-NFAT pathways, PGE2, PGI2; AC/cAMP/PKA pathways, LXA4, LTB4), neuropeptides (NMU; Ca2+-NFAT, MAPK pathways, VIP, CGRP, catecholamine, acetylcholine), sex hormones (androgen, estrogen), nutrients (butyrate; HDAC inhibitors, vitamins), and cell-to-cell interactions (ICOSL-ICOS; STAT5, B7-H6-NKp30, E-cadherin-KLRG1). This comprehensive review affords a better understanding of the regulatory network system for ILC2s, providing impetus to develop new treatment strategies for ILC2-related health problems.

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12-OH-17,18-Epoxyeicosatetraenoic acid alleviates eosinophilic airway inflammation in murine lungs

Mochimaru T., Fukunaga K., Miyata J., Matsusaka M., Masaki K., Kabata H., Ueda S., Suzuki Y., Goto T., Urabe D., Inoue M., Isobe Y., Arita M., Betsuyaku T.

Allergy: European Journal of Allergy and Clinical Immunology （Allergy: European Journal of Allergy and Clinical Immunology）  73 （ 2 ） 369 - 378 2018年02月

ISSN  01054538

　概要を見る

© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd. Background: Asthma is characterized by airway inflammation and obstruction with eosinophil infiltration into the airway. Arachidonic acid, an omega-6 fatty acid, is metabolized into cysteinyl leukotriene with pro-inflammatory properties for allergic inflammation, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) and its downstream metabolites are known to have anti-inflammatory effects. In this study, we investigated the mechanism underlying the counter-regulatory roles of EPA in inflamed lungs. Methods: Male C57BL6 mice were sensitized and challenged by ovalbumin (OVA). After EPA treatment, we evaluated the cell count of Bronchoalveolar lavage fluid (BALF), mRNA expressions in the lungs by q-PCR, and the amounts of lipid mediators by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics. We investigated the effect of the metabolite of EPA by in vivo and in vitro studies. Results: Eicosapentaenoic acid treatment reduced the accumulation of eosinophils in the airway and decreased mRNA expression of selected inflammatory mediators in the lung. Lipidomics clarified the metabolomic profile in the lungs. Among EPA-derived metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE) was identified as one of the major biosynthesized molecules; the production of this molecule was amplified by EPA administration and allergic inflammation. Intravenous administration of 12-OH-17,18-EpETE attenuated airway eosinophilic inflammation through downregulation of C-C chemokine motif 11 (CCL11) mRNA expression in the lungs. In vitro, this molecule also inhibited the release of CCL11 from human airway epithelial cells stimulated with interleukin-4. Conclusion: These results demonstrated that EPA alleviated airway eosinophilic inflammation through its conversion into bioactive metabolites. Additionally, our results suggest that 12-OH-17,18-EpETE is a potential therapeutic target for the management of asthma.

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Subphenotypes of type 2 severe asthma in adults

Matsusaka M., Fukunaga K., Kabata H., Izuhara K., Asano K., Betsuyaku T.

Journal of Allergy and Clinical Immunology: In Practice （Journal of Allergy and Clinical Immunology: In Practice）  6 （ 1 ） 274 - 276.e2 2018年01月

ISSN  22132198

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The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation.

Klose CSN, Mahlakõiv T, Moeller JB, Rankin LC, Flamar AL, Kabata H, Monticelli LA, Moriyama S, Putzel GG, Rakhilin N, Shen X, Kostenis E, König GM, Senda T, Carpenter D, Farber DL, Artis D

Nature 549 （ 7671 ） 282 - 286 2017年09月

ISSN  0028-0836

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Characteristics of severe asthma with fungal sensitization.

Masaki K, Fukunaga K, Matsusaka M, Kabata H, Tanosaki T, Mochimaru T, Kamatani T, Ohtsuka K, Baba R, Ueda S, Suzuki Y, Sakamaki F, Oyamada Y, Inoue T, Oguma T, Sayama K, Koh H, Nakamura M, Umeda A, Kamei K, Izuhara K, Asano K, Betsuyaku T

Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 119 （ 3 ） 253 - 257 2017年09月

ISSN  1081-1206

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A keratan sulfate disaccharide prevents inflammation and the progression of emphysema in murine models.

Gao C, Fujinawa R, Yoshida T, Ueno M, Ota F, Kizuka Y, Hirayama T, Korekane H, Kitazume S, Maeno T, Ohtsubo K, Yoshida K, Yamaguchi Y, Lepenies B, Aretz J, Rademacher C, Kabata H, Hegab AE, Seeberger PH, Betsuyaku T, Kida K, Taniguchi N

American journal of physiology. Lung cellular and molecular physiology 312 （ 2 ） L268 - L276 2017年02月

ISSN  1040-0605

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Mechanisms to Suppress ILC2-induced Airway Inflammation.

Kabata H, Moro K, Koyasu S, Fukunaga K, Asano K, Betsuyaku T

Annals of the American Thoracic Society 13 Suppl 1   S95 2016年03月

ISSN  2329-6933

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Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses.

Moro K, Kabata H, Tanabe M, Koga S, Takeno N, Mochizuki M, Fukunaga K, Asano K, Betsuyaku T, Koyasu S

Nature immunology 17 （ 1 ） 76 - 86 2016年01月

ISSN  1529-2908

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Group 2 innate lymphoid cells and asthma.

Kabata H, Moro K, Koyasu S, Asano K

Allergology international : official journal of the Japanese Society of Allergology 64 （ 3 ） 227 - 34 2015年07月

ISSN  1323-8930

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Determinants of Long-Term Persistence with Tiotropium Bromide for Chronic Obstructive Pulmonary Disease.

Tanaka K, Kamiishi N, Miyata J, Kabata H, Masaki K, Ogura-Tomomatsu H, Tomomatsu K, Suzuki Y, Fukunaga K, Sayama K, Betsuyaku T, Asano K

COPD 12 （ 3 ） 233 - 9 2015年06月

ISSN  1541-2555

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Isolation and analysis of group 2 innate lymphoid cells in mice.

Moro K, Ealey KN, Kabata H, Koyasu S

Nature protocols 10 （ 5 ） 792 - 806 2015年05月

ISSN  1754-2189

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A Phase II study of S-1 and irinotecan combination therapy in previously treated patients with advanced non-small cell lung cancer.

Ikemura S, Naoki K, Yasuda H, Kawada I, Yoda S, Terai H, Sato T, Ishioka K, Arai D, Ohgino K, Kamata H, Miyata J, Kabata H, Betsuyaku T, Soejima K

Japanese journal of clinical oncology 45 （ 4 ） 356 - 61 2015年04月

ISSN  0368-2811

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Phenotype of asthma related with high serum periostin levels.

Matsusaka M, Kabata H, Fukunaga K, Suzuki Y, Masaki K, Mochimaru T, Sakamaki F, Oyamada Y, Inoue T, Oguma T, Sayama K, Koh H, Nakamura M, Umeda A, Ono J, Ohta S, Izuhara K, Asano K, Betsuyaku T

Allergology international : official journal of the Japanese Society of Allergology 64 （ 2 ） 175 - 80 2015年04月

ISSN  1323-8930

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[Group 2 innate lymphoid cells (ILC2s)].

Kabata H, Moro K, Koyasu S, Asano K

Arerugi = [Allergy] 64 （ 1 ） 46 - 56 2015年02月

ISSN  0021-4884

Dual role of interleukin-23 in epicutaneously-sensitized asthma in mice.

Masaki K, Suzuki Y, Kagawa S, Kodama M, Kabata H, Miyata J, Tanaka K, Fukunaga K, Sayama K, Oguma T, Kimura T, Amagai M, Betsuyaku T, Asano K

Allergology international : official journal of the Japanese Society of Allergology 63 Suppl 1   13 - 22 2014年05月

ISSN  1323-8930

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Bone morphogenetic protein receptor type 2 mutations, clinical phenotypes and outcomes of Japanese patients with sporadic or familial pulmonary hypertension.

Kabata H, Satoh T, Kataoka M, Tamura Y, Ono T, Yamamoto M, Huqun, Hagiwara K, Fukuda K, Betsuyaku T, Asano K

Respirology (Carlton, Vic.) 18 （ 7 ） 1076 - 82 2013年10月

ISSN  1323-7799

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Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation.

Kabata H, Moro K, Fukunaga K, Suzuki Y, Miyata J, Masaki K, Betsuyaku T, Koyasu S, Asano K

Nature communications 4   2675 2013年

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