Publications by authors named "Yoshimichi Okayama"

89 Publications

Serum level of hemokinin-1 is significantly lower in patients with chronic spontaneous urticaria than in healthy subjects.

Allergol Int 2021 Jun 2. Epub 2021 Jun 2.

Allergy and Immunology Research Project Team, Nihon University School of Medicine, Tokyo, Japan; Center for Medical Education, Nihon University School of Medicine, Tokyo, Japan; Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan. Electronic address:

Background: We previously reported upregulation of expression of Mas-related G protein-coupled receptor X2 (MRGPRX2) on mast cells (MCs) in the skin of patients with severe chronic spontaneous urticaria (CSU). Serum levels of substance P (SP) were reportedly significantly elevated, in correlation with the severity of CSU. Hemokinin-1 (HK-1) reportedly induced histamine release from LAD2 cells via MRGPRX2. We aimed to investigate HK-1's role in CSU.

Methods: The concentrations of HK-1 and SP were measured using ELISAs. Skin- and synovium-derived cultured MCs were generated by culturing dispersed skin and synovial cells, respectively, with stem cell factor. MRGPRX2 expression in the MCs was reduced using a lentiviral shRNA silencing technique.

Results: Anti-SP Ab used in the SP ELISA showed 100% cross-reactivity to HK-1, but anti-HK-1 Ab showed 0% cross-reactivity to SP. The serum level of HK-1 was significantly lower in patients with CSU (n = 151) than in non-atopic healthy control (NC) subjects (n = 114). The EC of histamine release from MCs induced by HK-1 (5056 nM) was 12-fold higher than by SP (426 nM). Brief pretreatment of MCs with HK-1 at concentrations of 3.0-10 μM significantly reduced histamine release by 0.1 μM SP. However, brief incubation of MCs with HK-1 did not elicit rapid MRGPRX2 internalization.

Conclusions: In NC subjects, high HK-1 concentrations may desensitize MGRPRX2-mediated MC activation, thereby preventing MC degranulation by SP.
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http://dx.doi.org/10.1016/j.alit.2021.05.002DOI Listing
June 2021

Higher PGD production by synovial mast cells from rheumatoid arthritis patients compared with osteoarthritis patients via miR-199a-3p/prostaglandin synthetase 2 axis.

Sci Rep 2021 Mar 11;11(1):5738. Epub 2021 Mar 11.

Allergy and Immunology Research Project Team, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan.

We previously reported that synovial mast cells (MCs) from patients with rheumatoid arthritis (RA) produced TNF-α in response to immune complexes via FcγRI and FcγRIIA. However, the specific functions of synovial MCs in RA remain unclear. This study aimed to elucidate those functions. Synovial tissues and fluid were obtained from RA and osteoarthritis (OA) patients undergoing joint replacement surgery. Synovium-derived, cultured MCs were generated by culturing dispersed synovial cells with stem cell factor. We performed microarray-based screening of mRNA and microRNA (miRNA), followed by quantitative RT-PCR-based verification. Synovial MCs from RA patients showed significantly higher prostaglandin systhetase (PTGS)1 and PTGS2 expression compared with OA patients' MCs, and they produced significantly more prostaglandin D (PGD) following aggregation of FcγRI. PGD induced IL-8 production by human group 2 innate lymphoid cells, suggesting that PGD-producing MCs induce neutrophil recruitment into the synovium of RA patients. PTGS2 mRNA expression in RA patients' MCs correlated inversely with miRNA-199a-3p expression, which down-regulated PTGS2. RA patients' synovial fluid contained significantly more PGD compared with OA patients' fluid. Synovial MCs might regulate inflammation in RA through hyper-production of PGD following FcRγ aggregation. Our findings indicate functional heterogeneity of human MCs among diseases.
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http://dx.doi.org/10.1038/s41598-021-84963-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952410PMC
March 2021

Enzymatic activity of ACE2 regulates type 2 airway inflammation in mice.

Allergy 2021 06 2;76(6):1913-1917. Epub 2021 Mar 2.

Department of Internal Medicine, Division of Respiratory Medicine, Nihon University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/all.14754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013183PMC
June 2021

miR103a-3p in extracellular vesicles from FcεRI-aggregated human mast cells enhances IL-5 production by group 2 innate lymphoid cells.

J Allergy Clin Immunol 2021 May 17;147(5):1878-1891. Epub 2021 Jan 17.

Allergy and Immunology Research Project Team, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Center for Medical Education, Nihon University School of Medicine, Tokyo, Japan. Electronic address:

Background: Mast cells (MCs) are key regulators of IgE-mediated allergic inflammation. Cell-derived extracellular vesicles (EVs) contain bioactive compounds such as microRNAs. EVs can transfer signals to recipient cells, thus using a novel mechanism of cell-to-cell communication. However, whether MC-derived EVs are involved in FcεRI-mediated allergic inflammation is unclear.

Objective: We sought to investigate the effect of EVs derived from FcεRI-aggregated human MCs on the function of human group 2 innate lymphoid cells (ILC2s).

Methods: Human cultured MCs were sensitized with and without IgE for 1 hour and then incubated with anti-IgE antibody, IL-33, or medium alone for 24 hours. EVs in the MC supernatant were isolated by using ExoQuick-TC.

Results: Coculture of ILC2s with EVs derived from the FcεRI-aggregated MCs significantly enhanced IL-5 production and sustained upregulation of IL-5 mRNA expression in IL-33-stimulated ILC2s, but IL-13 production and IL-13 mRNA expression were unchanged. miR103a-3p expression was upregulated in IL-33-stimulated ILC2s that had been cocultured with EVs derived from anti-IgE antibody-stimulated MCs. Transduction of an miR103a-3p mimic to ILC2s significantly enhanced IL-5 production by IL-33-stimulated ILC2s. miR103a-3p promoted demethylation of an arginine residue of GATA3 by downregulating protein arginine methyltransferase 5 (PRMT5) mRNA. Reduction of protein arginine methyltransferase 5 expression in ILC2s by using a small interfering RNA technique resulted in upregulation of IL-5 production by IL-33-stimulated ILC2s. Furthermore, the level of miR103a-3p expression was significantly higher in EVs from sera of patients with atopic dermatitis than in EVs from nonatopic healthy control subjects.

Conclusion: Eosinophilic allergic inflammation may be exacerbated owing to ILC2 activation by MC-derived miR103a-3p.
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http://dx.doi.org/10.1016/j.jaci.2021.01.002DOI Listing
May 2021

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

Mucosal Immunol 2021 05 10;14(3):640-651. Epub 2020 Dec 10.

Department of Mucosal Immunology, The University of Tokyo Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.

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.
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http://dx.doi.org/10.1038/s41385-020-00358-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075951PMC
May 2021

Activation of inflammation and resolution pathways of lipid mediators in synovial fluid from patients with severe rheumatoid arthritis compared with severe osteoarthritis.

Asia Pac Allergy 2020 Apr 27;10(2):e21. Epub 2020 Apr 27.

Allergy and Immunology Research Project Team, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan.

Background: The upregulation of the cyclooxygenase and lipoxygenase pathways of arachidonic acid is thought to be involved in the development of rheumatoid arthritis. Recently, the presence of specialized pro-resolving lipid mediators in synovial tissues from patients with osteoarthritis has been reported.

Objective: To clarify the quantitative and qualitative changes in lipid mediators in the synovium of severe rheumatoid arthritis patients, we compared the profiles of lipid mediators in synovial fluid obtained from patients with severe rheumatoid arthritis and from those with severe osteoarthritis.

Methods: We enrolled 18 patients with rheumatoid arthritis and 26 patients with osteoarthritis. All the patients had undergone total knee replacement surgery. Synovial fluid samples had been obtained during the surgery. Lipid profiling in the synovial fluid from these patients was performed using liquid chromatography-tandem mass spectrometry/mass spectrometry.

Results: Among the 150 oxidized fatty acids examined so far, 119 were substantially detected in synovial fluid from the patients. Not only the concentrations of pro-inflammatory lipid mediators such as prostaglandins and leukotrienes, but also those of specialized pro-resolving lipid mediators such as lipoxins, resolvins, and protectin D1 were significantly higher in synovial fluid obtained from rheumatoid arthritis patients than from synovial fluid obtained from osteoarthritis patients.

Conclusion: The activation of both inflammation and resolution pathways of lipid mediators might be a fatty acid signature in the synovial fluid of patients with severe rheumatoid arthritis. Inflammatory, anti-inflammatory and pro-resolving mediators in synovial fluid could be good biomarkers for differentiating between severe rheumatoid arthritis and severe osteoarthritis.
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http://dx.doi.org/10.5415/apallergy.2020.10.e21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203435PMC
April 2020

Relationship between changes in the 7-day urticaria activity score after treatment with omalizumab and the responsiveness of basophils to FcεRI stimulation in patients with chronic spontaneous urticaria.

Asia Pac Allergy 2020 Apr 10;10(2):e12. Epub 2020 Apr 10.

Allergy and Immunology Research Project Team, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan.

Background: About one-half of all patients with chronic spontaneous urticaria have low or less reactivity of the basophils to FcεRI stimulation. However, the differences in the clinical characteristics between patients who show normal and attenuated basophil reactivities to FcεRI stimulation are still unclear. Furthermore, it also remains unknown as to what factors induce the poor reactivity of basophils to FcεRI stimulation.

Objective: The aim of the study is to investigate the differences in the clinical characteristics between patients who show normal and attenuated basophil reactivities to FcεRI stimulation.

Methods: We compared the clinical characteristics, including the autologous serum skin test-positive rates, serum concentrations of anti-IgE and anti-FcεRIα autoantibodies, and the FcεRI-crosslinking ability of these autoantibodies between patients with a negative basophil activation test (BAT) (≤10% CD203c basophils, n = 9) and positive BAT (>10% CD203c basophils, n = 13). We also monitored the changes in the 7-day urticaria activity scores after treatment with omalizumab, as compared to the score at the baseline, between the BAT-positive and BAT-negative patients.

Results: The BAT-negative patients showed a significantly higher urticaria control test score than the BAT-positive patients ( = 0.01). There were no significant differences in the autologous serum skin test-positive rates, concentrations of anti-IgE and anti-FcεRIα autoantibodies, and the FcεRI-crosslinking ability of these autoantibodies between the 2 groups. After treatment with omalizumab for 35 days, the score decreased to under 15 (corresponding to controlled or mild chronic spontaneous urticaria) in all of the BAT-negative patients, whereas in 6 out of the 13 BAT-positive patients, the scores remained over 16 (corresponding to moderate or severe chronic spontaneous urticaria).

Conclusions: The weak reactivity of basophils to FcεRI stimulation may not be due to the desensitization of basophils by anti-IgE or anti-FcεRIα autoantibodies. The time to response to omalizumab might differ between BAT-negative and BAT-positive patients with chronic spontaneous urticaria.
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http://dx.doi.org/10.5415/apallergy.2020.10.e12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203440PMC
April 2020

Roles of omalizumab in various allergic diseases.

Allergol Int 2020 Apr 14;69(2):167-177. Epub 2020 Feb 14.

Department of Otorhinolaryngology, Nippon Medical School, Tokyo, Japan. Electronic address:

IgE and mast cells play a pivotal role in various allergic diseases, including asthma, allergic rhinitis, and urticaria. Treatment with omalizumab, a monoclonal anti-IgE antibody, has significantly improved control of these allergic diseases and introduced a new era for the management of severe allergic conditions. About 10 years of experience with omalizumab treatment for severe allergic asthma confirmed its effectiveness and safety, reducing symptoms, frequency of reliever use, and severe exacerbations in patients with intractable conditions. Omalizumab is particularly useful in childhood asthma, where atopic conditions often determine clinical courses of asthma. Recently, omalizumab is approved for the treatment of chronic spontaneous urticaria (CSU) with the fixed dose of 300 mg. Although the mechanisms underlying the actions of omalizumab in CSU are not fully clarified, nearly 90% of patients with CSU showed a complete or a partial response to omalizumab treatment. Furthermore, omalizumab is just approved for the treatment of severe Japanese cedar pollinosis (JC) based on the successful results of an add-on study of omalizumab for inadequately controlled severe pollinosis despite antihistamines and nasal corticosteroids. For proper use of omalizumab to treat severe JC, co-administration of antihistamines is necessary, while patients should meet the criteria including strong sensitization to Japanese cedar pollen (≥class 3) and poor control under standard treatment. In the management of severe allergic diseases using omalizumab, issues including cost and concerns about relapse after its discontinuation should be overcome. At the same time, possibilities for application to other intractable allergic diseases should be considered.
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http://dx.doi.org/10.1016/j.alit.2020.01.004DOI Listing
April 2020

Patients who have anti-FcεRI nonreactive basophils do not represent patients with severe chronic spontaneous urticaria.

J Allergy Clin Immunol Pract 2020 02;8(2):824-825.e2

Allergy and Immunology Research Project Team, Research Institute of Medical Science, Tokyo, Japan; Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Center for Medical Education, Nihon University School of Medicine, Tokyo, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2019.11.032DOI Listing
February 2020

Preface to the proceedings of the 32nd Workshop on Eosinophils in Allergy and Related Diseases 2018.

Allergol Int 2019 Sep;68S:S1-S2

Allergy and Immunology Research Project Team, Research Institute of Medical Science, Center for Allergy, Center for Medical Education, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.alit.2019.07.003DOI Listing
September 2019

Mast cells play role in wound healing through the ZnT2/GPR39/IL-6 axis.

Sci Rep 2019 07 25;9(1):10842. Epub 2019 Jul 25.

Headquarters, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan.

Zinc (Zn) is an essential nutrient and its deficiency causes immunodeficiency and skin disorders. Various cells including mast cells release Zn-containing granules when activated; however, the biological role of the released Zn is currently unclear. Here we report our findings that Zn transporter ZnT2 is required for the release of Zn from mast cells. In addition, we found that Zn and mast cells induce IL-6 production from inflammatory cells such as skin fibroblasts and promote wound healing, a process that involves inflammation. Zn induces the production of a variety of pro-inflammatory cytokines including IL-6 through signaling pathways mediated by the Zn receptor GPR39. Consistent with these findings, wound healing was impaired in mice lacking IL-6 or GPR39. Thus, our results show that Zn and mast cells play a critical role in wound healing through activation of the GPR39/IL-6 signaling axis.
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http://dx.doi.org/10.1038/s41598-019-47132-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658492PMC
July 2019

Autonomous regulation of IgE-mediated mast cell degranulation and immediate hypersensitivity reaction by an inhibitory receptor CD300a.

J Allergy Clin Immunol 2019 07 30;144(1):323-327.e7. Epub 2019 May 30.

Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Life Science Center of Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.03.005DOI Listing
July 2019

Differentiation between control subjects and patients with chronic spontaneous urticaria based on the ability of anti-IgE autoantibodies (AAbs) to induce FcεRI crosslinking, as compared to anti-FcεRIα AAbs.

Allergol Int 2019 Jul 22;68(3):342-351. Epub 2019 Feb 22.

Allergy and Immunology Research Project Team, Nihon University School of Medicine, Tokyo, Japan; Center for Institutional Research and Medical Education, Nihon University School of Medicine, Tokyo, Japan. Electronic address:

Background: The reported prevalences of IgG autoantibodies (AAbs) to FcεRIα and IgE in sera from patients with chronic spontaneous urticaria (CSU) have varied, and these AAbs are also often observed in healthy control subjects. Regarding the histamine release activity of purified IgG from patients with CSU, the number of examined patients has been small. Thus, we sought to determine the prevalence and FcεRI crosslinking ability of these AAbs in a large number of patients with CSU and non-atopic control (NC) subjects.

Methods: We compared the concentrations of anti-IgE and anti-FcεRIα AAbs and the abilities of these AAbs to cause FcεRI aggregation in patients with CSU (n = 134) and NC subjects (n = 55) using ELISA and an in vitro elicitation test, respectively.

Results: The concentration of anti-IgE AAbs was significantly different between the NC subjects and the CSU patients (P < 0.0001, cutoff value: 0.558 μg/mL), whereas the concentration of anti-FcεRIα AAbs was not. A significant difference in the duration of illness was noted between patients with lower and those with higher concentrations of anti-IgE AAbs relative to the cutoff value. The abilities of anti-IgE AAbs, but not anti-FcεRIα AAbs, to induce FcεRI crosslinking were significantly higher in CSU patients than in NC subjects (P = 0.0106).

Conclusions: In the Japanese population of CSU patients studied, the ability of the anti-IgE AAbs to induce FcεRI crosslinking differed significantly between NC subjects and CSU patients, suggesting the involvement of anti-IgE AAbs in the pathogenesis of CSU in the Japanese population.
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http://dx.doi.org/10.1016/j.alit.2019.01.003DOI Listing
July 2019

A humanized mouse model to study asthmatic airway inflammation via the human IL-33/IL-13 axis.

JCI Insight 2018 11 2;3(21). Epub 2018 Nov 2.

Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga, Japan.

Asthma is one of the most common immunological diseases and is characterized by airway hyperresponsiveness (AHR), mucus overproduction, and airway eosinophilia. Although mouse models have provided insight into the mechanisms by which type-2 cytokines induce asthmatic airway inflammation, differences between the rodent and human immune systems hamper efforts to improve understanding of human allergic diseases. In this study, we aim to establish a preclinical animal model of asthmatic airway inflammation using humanized IL-3/GM-CSF or IL-3/GM-CSF/IL-5 Tg NOD/Shi-scid-IL2rγnull (NOG) mice and investigate the roles of human type-2 immune responses in the asthmatic mice. Several important characteristics of asthma - such as AHR, goblet cell hyperplasia, T cell infiltration, IL-13 production, and periostin secretion - were induced in IL-3/GM-CSF Tg mice by intratracheally administered human IL-33. In addition to these characteristics, human eosinophilic inflammation was observed in IL-3/GM-CSF/IL-5 Tg mice. The asthmatic mechanisms of the humanized mice were driven by activation of human Th2 and mast cells by IL-33 stimulation. Furthermore, treatment of the humanized mice with an anti-human IL-13 antibody significantly suppressed these characteristics. Therefore, the humanized mice may enhance our understanding of the pathophysiology of allergic disorders and facilitate the preclinical development of new therapeutics for IL-33-mediated type-2 inflammation in asthma.
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http://dx.doi.org/10.1172/jci.insight.121580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238753PMC
November 2018

Identification of biomarkers for predicting the response to cyclosporine A therapy in patients with chronic spontaneous urticaria.

Allergol Int 2019 Apr 22;68(2):270-273. Epub 2018 Oct 22.

Allergy and Immunology Research Project Team, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Center for Institutional Research and Medical Education, Nihon University School of Medicine, Tokyo, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.alit.2018.09.006DOI Listing
April 2019

Characterization of human decidual mast cells and establishment of a culture system.

Allergol Int 2018 Sep 18;67S:S18-S24. Epub 2018 May 18.

Allergy and Immunology Project Team, Nihon University School of Medicine, Tokyo, Japan; Center for Institutional Research and Medical Education, Nihon University School of Medicine, Tokyo, Japan. Electronic address:

Background: Although rodent decidual mast cells (MCs) reportedly play an important role in implantation and placenta formation, the characterization of human decidual MCs has been not well clarified. The aims of this study were to investigate the distribution and characteristics of MCs in human decidua and to establish a culture system for decidua-derived MCs.

Methods: Decidual tissues were obtained from patients who underwent a legal elective abortion (6th week to 9th week of pregnancy), and decidual MCs were enzymatically dispersed. Cultured decidua-derived MCs were generated by culturing decidual cells with stem cell factor. An ultrastructural analysis of primary decidual MCs and cultured decidua-derived MCs was performed using a transmission electron microscope. Receptor and protease expression was analyzed using FACS. Histamine released from MCs was measured using enzyme immune assays.

Results: A larger proportion of tryptase positive MCs in decidua was present on the maternal side. Both enzymatically dispersed decidual MCs and cultured decidua-derived MCs showed an FcεRIαKittryptasechymase phenotype. Their granules contenting particles exhibited variable amounts of electron-lucent space separating electron-dense particles. Both enzymatically dispersed decidual MCs and cultured decidua-derived MCs released comparable amounts of histamine following FcεRI aggregation.

Conclusions: The isolation method for MCs from decidua during early pregnancy and the culture system for decidua-derived MCs may enable the roles of decidual MC during pregnancy to be explored.
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http://dx.doi.org/10.1016/j.alit.2018.05.001DOI Listing
September 2018

[ACTIVATION MECHANISMS OF MAST CELLS IN CHRONIC SPONTANEOUS URTICARIA].

Arerugi 2018;67(3):192-196

Allergy and Immunology Research Project Team, Center for Institutional Research and Medical Education, Nihon University School of Medicine.

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http://dx.doi.org/10.15036/arerugi.67.192DOI Listing
May 2019

Omega-3 fatty acid epoxides are autocrine mediators that control the magnitude of IgE-mediated mast cell activation.

Nat Med 2017 Nov 9;23(11):1287-1297. Epub 2017 Oct 9.

Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.

Critical to the function of mast cells in immune responses including allergy is their production of lipid mediators, among which only omega-6 (ω-6) arachidonate-derived eicosanoids have been well characterized. Here, by employing comprehensive lipidomics, we identify omega-3 (ω-3) fatty acid epoxides as new mast cell-derived lipid mediators and show that they are produced by PAF-AH2, an oxidized-phospholipid-selective phospholipase A2. Genetic or pharmacological deletion of PAF-AH2 reduced the steady-state production of ω-3 epoxides, leading to attenuated mast cell activation and anaphylaxis following FcɛRI cross-linking. Mechanistically, the ω-3 epoxides promote IgE-mediated activation of mast cells by downregulating Srcin1, a Src-inhibitory protein that counteracts FcɛRI signaling, through a pathway involving PPARg. Thus, the PAF-AH2-ω-3 epoxide-Srcin1 axis presents new potential drug targets for allergic diseases.
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http://dx.doi.org/10.1038/nm.4417DOI Listing
November 2017

Disulfide-linked dimerization of the FcRγ chain is required for positive and negative regulation of mast cell activation via FcεRI.

Allergol Int 2017 Sep 17;66S:S41-S43. Epub 2017 Jun 17.

Allergy and Immunology Project Team, Nihon University School of Medicine, Tokyo, Japan; Division of Medical Education Planning and Development, Nihon University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1016/j.alit.2017.04.010DOI Listing
September 2017

The dual regulation of substance P-mediated inflammation via human synovial mast cells in rheumatoid arthritis.

Allergol Int 2017 Sep 31;66S:S9-S20. Epub 2017 Mar 31.

Allergy and Immunology Project Team, Nihon University School of Medicine, Tokyo, Japan; Division of Medical Education Planning and Development, Nihon University School of Medicine, Tokyo, Japan. Electronic address:

Background: Neural pathways are thought to be directly involved in the pathogenesis of rheumatoid arthritis (RA). Although synovial mast cells (MCs) are activated by substance P (SP), the role of MCs in neural pathways in RA remains unknown. The aims of this study were to investigate 1) whether tachykinins are produced by synovial MCs and whether production differs in RA and osteoarthritis (OA) patients, and 2) what is the responsible receptor for SP in synovial MCs.

Methods: Synovial tissues were obtained from patients with RA or OA undergoing joint replacement surgery. Cultured synovium-derived MCs were generated by culturing dispersed synovial cells with stem cell factor. SP expression was investigated using immunofluorescence and enzyme immunoassays. Mas-related gene X2 (MrgX2) expression was reduced in human MCs using a lentiviral shRNA silencing technique.

Results: SP expression was localized around the cell membrane in 41% (median) of the MCs in synovium from RA but in only 7% of that from OA, suggesting the activation of MCs. Synovial MCs expressed tachykinin (TAC) 1 mRNA, the expression of which was upregulated by the aggregation of FcɛRI or the addition of aggregated IgG. However, the released SP appeared to be rapidly degraded by MC chymase. Synovial MCs were activated with SP through MrgX2 to release histamine without producing proinflammatory cytokines.

Conclusions: Activated synovial MCs may rapidly degrade SP, which may downregulate the SP-mediated activation of synoviocytes in RA. On the other hand, SP activates MCs to induce inflammatory mediators, suggesting the dual regulation of SP-mediated inflammation by MCs in RA.
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http://dx.doi.org/10.1016/j.alit.2017.03.002DOI Listing
September 2017

CEACAM1 long isoform has opposite effects on the growth of human mastocytosis and medullary thyroid carcinoma cells.

Cancer Med 2017 Apr 23;6(4):845-856. Epub 2017 Mar 23.

Department of Diagnostic Pathology, Kyoto University, Kyoto, Japan.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed in a number of tumor cell types. The immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing isoforms of this molecule which possess a long cytoplasmic tail (CEACAM1-L) generally play inhibitory roles in cell function by interacting with Src homology 2 domain-containing tyrosine phosphatase (SHP)-1 and/or SHP-2. Src family kinases (SFKs) are also known to bind to and phosphorylate CEACAM1-L isoforms. Here, we report that CEACAM1 was uniquely expressed at high levels in both human neoplastic mast cells (mastocytosis) and medullary thyroid carcinoma cell (MTC) lines, when compared with their expression in nonneoplastic mast cells or nonneoplastic C cells. This expression was mainly derived from CEACAM1-L isoforms based upon assessment of CEACAM1 mRNA expression. CEACAM1 knockdown upregulated cell growth of HMC1.2 cells harboring KIT mutations detected in clinical mastocytosis, whereas downregulated the growth of TT cells harboring RET mutations detected in clinical MTCs. Immunoblotting, ELISA and immunoprecipitaion analysis showed that activated SHP-1 is preferentially associated with CEACAM1 in HMC1.2 cells harboring KIT mutations, whereas Src family kinases (SFKs) are preferentially associated with CEACAM1 in TT cells harboring RET mutations. These studies suggest that the dominantly interacting proteins SHP1 or SFK determine whether CEACAM1-L displays a positive or negative role in tumor cells.
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http://dx.doi.org/10.1002/cam4.1050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387134PMC
April 2017

Interleukin-17A expression in human synovial mast cells in rheumatoid arthritis and osteoarthritis.

Allergol Int 2016 Sep 18;65 Suppl:S11-6. Epub 2016 May 18.

Allergy and Immunology Project Team, Nihon University School of Medicine, Tokyo, Japan; Division of Medical Education Planning and Development, Nihon University School of Medicine, Tokyo, Japan. Electronic address:

Background: Interleukin (IL)-17A plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). The expression of IL-17A in synovial mast cells (MCs) in RA and osteoarthritis (OA) has been reported, but the frequencies of IL-17A expression in synovial MCs have varied. The aim of this study was to investigate whether IL-17A expression is upregulated in human synovial MCs in RA and to elucidate the mechanism of IL-17A expression in synovial MCs.

Methods: Synovial tissues were obtained from patients with RA or OA undergoing joint replacement surgery, and synovial MCs were enzymatically dispersed. Synovium-derived cultured MCs were generated by culturing synovial cells with stem cell factor. IL-17A expression was investigated using immunofluorescence in synovial tissues. IL-17A mRNA expression and its production from MCs were examined using RT-PCR and ELISA, respectively.

Results: The number of IL-17A-positive ((+)) synovial MCs and the percentage of IL-17A(+) MCs among all the IL-17A(+) cells from RA patients were not significantly increased compared with those from OA subjects. The synovium-derived cultured MCs spontaneously released small amounts of IL-17A. Neither IgE- nor IgG-dependent stimulation increased IL-17A production from the MCs. IL-33, tumor necrosis factor-α, C5a, lipopolysaccharide or IL-23 plus IL-1β did not affect IL-17A production in MCs.

Conclusions: The synovial MCs are not a main source of IL-17A in RA.
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http://dx.doi.org/10.1016/j.alit.2016.04.007DOI Listing
September 2016

Biomarkers of the involvement of mast cells, basophils and eosinophils in asthma and allergic diseases.

World Allergy Organ J 2016 11;9. Epub 2016 Feb 11.

Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy.

Biomarkers of disease activity have come into wide use in the study of mechanisms of human disease and in clinical medicine to both diagnose and predict disease course; as well as to monitor response to therapeutic intervention. Here we review biomarkers of the involvement of mast cells, basophils, and eosinophils in human allergic inflammation. Included are surface markers of cell activation as well as specific products of these inflammatory cells that implicate specific cell types in the inflammatory process and are of possible value in clinical research as well as within decisions made in the practice of allergy-immunology.
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http://dx.doi.org/10.1186/s40413-016-0094-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751725PMC
February 2016

MIP-1α level in nasopharyngeal aspirates at the first wheezing episode predicts recurrent wheezing.

J Allergy Clin Immunol 2016 Mar 19;137(3):774-81. Epub 2015 Oct 19.

Allergy and Immunology Group, Research Institute of Medical Science, Division of Medical Education Planning and Development, Nihon University School of Medicine, Tokyo, Japan. Electronic address:

Background: Respiratory virus-induced wheezing, such as that induced by respiratory syncytial virus (RSV) and human rhinovirus, is an important risk factor for recurrent wheezing and childhood asthma. However, no biomarkers for predicting recurrent wheezing have been identified.

Objective: We searched for predictors of recurrent wheezing using nasopharyngeal aspirates obtained from patients during the first wheezing episode who were hospitalized with an acute lower respiratory tract illness.

Methods: We enrolled 82 infants during the first wheezing episode (median age, 5.0 months) who were hospitalized for acute lower respiratory tract illness between August 2009 and June 2012 and followed these patients for 2.5 years. Nasopharyngeal aspirates and blood samples were obtained on the first day of hospitalization. Viral genomes were identified by using RT-PCR and sequencing. Levels of 33 cytokines, tryptase, IgE, anti-RSV IgE, and anti-RSV IgG were measured by using ELISAs or the Bio-Plex multiplex assay. Predictors of recurrent wheezing were examined by using a stepwise logistic regression model with backward elimination.

Results: Sixty percent of the patients experienced recurrent wheezing episodes. One or more viruses were detected in the nasopharynxes of 93% of the patients during the first wheezing episode. IFN-γ, IL-2, IL-9, MIP-1α, and MIP-1β levels were significantly higher among patients with recurrent wheezing than among those without recurrent wheezing (P < .05 or .01). The stepwise model demonstrated that the MIP-1α level (odds ratio, 7.72; 95% CI, 1.50-39.77; P = .015) was the strongest independent predictor of the occurrence of recurrent wheezing.

Conclusion: An increased MIP-1α level in nasopharyngeal aspirates from patients with acute respiratory symptoms during the first wheezing episode caused by viral infections might predict recurrent wheezing.
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http://dx.doi.org/10.1016/j.jaci.2015.08.032DOI Listing
March 2016

Activation of LXRs using the synthetic agonist GW3965 represses the production of pro-inflammatory cytokines by murine mast cells.

Allergol Int 2015 Sep 31;64 Suppl:S11-7. Epub 2015 Mar 31.

Allergy and Immunology Group, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Department of Microbiology, Nihon University School of Medicine, Tokyo, Japan; Asahi Hospital, Chiba, Japan.

Background: The activation of liver X receptor (LXR) α or LXRβ negatively regulates the expression of pro-inflammatory genes in mammalian cells. We recently reported that 25-hydroxycholesterol, a representative LXR-activating oxysterol, suppresses IL-6 production in mouse mast cells (MCs) following its engagement of the high-affinity IgE receptor (FcεRI). This finding suggests that murine MCs express functional LXRs; however, the mechanisms underlying the LXR-dependent repression of the MC-mediated production of pro-inflammatory cytokines, including IL-6, are poorly understood. Therefore, we employed the synthetic LXR ligand GW3965 to examine the functions of LXRα and LXRβ in the production of pro-inflammatory cytokines by murine bone marrow-derived MCs (BMMCs).

Methods: We prepared BMMCs from wild-type (WT), LXRα(-/-), and LXRα/β(-/-) mice. Each group of BMMCs was pretreated with GW3965 and then stimulated with IgE+antigen (Ag) or lipopolysaccharide (LPS). Cytokine production was then analyzed using specific ELISA kits.

Results: The activation of LXRs by GW3965 significantly attenuated the production of IL-1α and IL-1β, but not of IL-6, in the WT and LXRα(-/-) BMMCs stimulated with IgE+Ag. However, GW3965 treatment decreased the production of IL-1α, IL-1β, and IL-6 in WT and LXRα(-/-) BMMCs upon stimulation with LPS, while the GW3965-mediated suppression of cytokine production was nearly absent from the LXRα/β(-/-) BMMCs.

Conclusions: These findings demonstrate, for the first time, that the activation of LXRs by GW3965 attenuates the antigen- or LPS-induced production of pro-inflammatory cytokines, such as IL-1α and IL-1β, in murine MCs and that LXRβ plays an important role in the LXR-mediated repression of cytokine production.
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http://dx.doi.org/10.1016/j.alit.2015.03.001DOI Listing
September 2015

NKp46 regulates the production of serine proteases and IL-22 in human mast cells in urticaria pigmentosa.

Exp Dermatol 2015 Sep 26;24(9):675-9. Epub 2015 May 26.

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

NKp46 (natural cytotoxic receptor 1/CD335) is expressed on natural killer cells and Th2-type innate lymphocytes. However, NKp46 expression in human mast cells has not yet been reported. Here, we explored the expression of, and possible role played by, NKp46 in such cells. NKp46 protein was expressed in human mast cells in urticaria pigmentosa principally of the tryptase-positive/chymase-negative type (MCT), but not in human non-neoplastic skin mast cells of the tryptase-positive/chymase-positive (MCTC) type. NKp46 expression was also evident in the human neoplastic mast cell line HMC1.2. NKp46 knockdown changed the phenotype of this cell line from MCT to MCTC and downregulated GrB production, but did not influence IL-22 production. An agonistic anti-NKp46 antibody upregulated production of GrB and IL-22, but did not change the MCT-like phenotype of HMC1.2 cells. NKp46 was thus involved in the production of serine proteases and IL-22 in human mast cells.
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http://dx.doi.org/10.1111/exd.12741DOI Listing
September 2015

[Target molecules for the treatment of allergic diseases].

Arerugi 2015 Feb;64(1):9-13

Allergy and Immunology Group, Research Institute of Medical Science, Nihon University School of Medicine.

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February 2015

The Killer Cell Ig-like Receptor 2DL4 Expression in Human Mast Cells and Its Potential Role in Breast Cancer Invasion.

Cancer Immunol Res 2015 Aug 3;3(8):871-80. Epub 2015 Mar 3.

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

The killer-cell Ig-like receptor (KIR) 2DL4 (CD158d) acts as a receptor for human leukocyte antigen (HLA)-G and is expressed on almost all human natural killer (NK) cells. The expression and function of KIR2DL4 in other hematopoietic cells is poorly understood. Here, we focused on human mast cells, which exhibit cytotoxic activity similar to that of NK cells. KIR2DL4 was detected in all examined human cultured mast cells established from peripheral blood derived from healthy volunteers (PB-mast), the human mast cell line LAD2, and human nonneoplastic mast cells, including those on pathologic specimens. An agonistic antibody against KIR2DL4 decreased KIT-mediated and IgE-triggered responses, and enhanced the granzyme B production by PB-mast and LAD2 cells, by activating Src homology 2-containing protein tyrosine phosphatase (SHP-2). Next, we performed a coculture assay between LAD2 cells and the HLA-G(+) cancer cells, MCF-7 and JEG-3, and showed that KIR2DL4 on LAD2 cells enhanced MMP-9 production and the invasive activity of both cell lines via HLA-G. Immunohistochemical analysis revealed that the direct interaction between HLA-G(+) breast cancer cells and KIR2DL4(+) tissue mast cells (observed in 12 of 36 cases; 33.3%) was statistically correlated with the presence of lymph node metastasis or lymph-vascular invasion (observed in 11 of 12 cases; 91.7%; χ(2) = 7.439; P < 0.01; degrees of freedom, 1) in the clinical samples. These findings suggest that the KIR2DL4 on human mast cells facilitates HLA-G-expressing cancer invasion and the subsequent metastasis.
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http://dx.doi.org/10.1158/2326-6066.CIR-14-0199DOI Listing
August 2015

Differentiation ability of multipotent hematopoietic stem/progenitor cells detected by a porcine specific anti-CD117 monoclonal antibody.

Biosci Trends 2014 Dec;8(6):308-15

Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine.

CD117 is a cytokine receptor expressed on the surface of hematopoietic stem cells with a likely role in cell survival, proliferation and differentiation. In order to study the differentiation activity of porcine CD117 hematopoietic cells in vitro and in vivo we prepared an anti-swine CD117 Mab (2A1) with high specificity for flow-cytometrical analysis. The 2A1 Mab did not recognize mouse or human mast cells suggesting that 2A1 is species-specific. Swine bone marrow (BM) CD117+ cells differentiated in vitro mainly into erythroid and monocyte lineages in the methylcellulose-based colony assay. When the swine BM CD117+ cells were transplanted in vivo into immunodeficient NOG (NOD/SCID/IL-2gc-null) mice, a significant amount of swine CD45+ leukocytes, including CD3 positive T cells, were developed in the mice. These results revealed that the swine BM CD117+ cells possess hematopoietic stem/progenitor activity and when monitored in immunodeficient mice or in vitro they can develop into lymphoid, erythroid, and myeloid cells efficiently with the new monoclonal antibody.
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http://dx.doi.org/10.5582/bst.2014.01084DOI Listing
December 2014

Treatment of murine mast cells with IgEκ and protein L enhances apoptotic cell death induced by IL-3 withdrawal.

Biochem Biophys Res Commun 2015 Jan 15;456(2):700-5. Epub 2014 Dec 15.

Allergy and Immunology Group, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Department of Microbiology, Nihon University School of Medicine, Tokyo, Japan; Asahi Hospital, Chiba, Japan.

Engagement of the high-affinity IgE receptor (FcεRI) can be either protective or non-protective against apoptotic cell death (ACD) in bone marrow-derived murine mast cells (BMMCs) after IL-3 withdrawal, depending on the avidity between IgE and its antigen. We recently reported that protein L (PpL), a bacterial Igκ-binding soluble protein, is able to stimulate intracellular signaling to induce activation of BMMCs by interacting with the IgEκ-FcεRI complex. However, it is unclear if cross-linking of FcεRI with IgEκ and PpL prevents or enhances IL-3-dependent ACD in BMMCs. In the present study, we found that IL-3-dependent ACD of BMMCs is accelerated by loading soluble PpL in the presence of IgEκ-occupied FcεRIα. For this purpose, soluble PpL was incorporated into the BMMCs. Unlike soluble PpL, immobilized PpL failed to enhance ACD, although both forms of PpL induced IL-6 production equally in BMMCs. In addition, we observed that DNS5-BSA protected anti-DNS IgE-sensitized BMMCs from IL-3 depletion-mediated ACD by inducing the production of autocrine IL-3. In contrast, DNS5-PpL enhanced IL-3 withdrawal-induced ACD of anti-DNS IgE-sensitized BMMCs and reduced the production of autocrine IL-3. These findings suggest that PpL increases IL-3 withdrawal-induced ACD of IgEκ-sensitized BMMCs by incorporating PpL into the BMMCs and that this internalized PpL may interfere with survival signals via FcεRI.
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http://dx.doi.org/10.1016/j.bbrc.2014.12.045DOI Listing
January 2015
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