Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Nobuyuki Ono Last modified date:2021.08.05

Assistant Professor / DEPARTMENT OF MEDICINE AND BIOSYSTEMIC SCIENCE / Department of Clinical Immunology and Rheumatology / Infectious Disease / Kyushu University Hospital


Papers
1. Aya Kawasaki, Natsumi Namba, Ken-Ei Sada, Fumio Hirano, Shigeto Kobayashi, Kenji Nagasaka, Takahiko Sugihara, Nobuyuki Ono, Takashi Fujimoto, Makio Kusaoi, Naoto Tamura, Kunihiro Yamagata, Takayuki Sumida, Hiroshi Hashimoto, Shoichi Ozaki, Hirofumi Makino, Yoshihiro Arimura, Masayoshi Harigai, Naoyuki Tsuchiya, Association of TERT and DSP variants with microscopic polyangiitis and myeloperoxidase-ANCA positive vasculitis in a Japanese population: a genetic association study., Arthritis research & therapy, 10.1186/s13075-020-02347-0, 22, 1, 246-246, 2020.10, BACKGROUND: Interstitial lung disease (ILD) is a severe complication with poor prognosis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Prevalence of AAV-associated ILD (AAV-ILD) in Japan is considerably higher than that in Europe. Recently, we reported that a MUC5B variant rs35705950, the strongest susceptibility variant to idiopathic pulmonary fibrosis (IPF), was strikingly increased in AAV-ILD patients but not in AAV patients without ILD; however, due to the low allele frequency in the Japanese population, the MUC5B variant alone cannot account for the high prevalence of AAV-ILD in Japan. In this study, we examined whether other IPF susceptibility alleles in TERT and DSP genes are associated with susceptibility to AAV subsets and AAV-ILD. METHODS: Five hundred and forty-four Japanese patients with AAV and 5558 controls were analyzed. Among the AAV patients, 432 were positive for myeloperoxidase (MPO)-ANCA (MPO-AAV). A total of 176 MPO-AAV patients were positive and 216 were negative for ILD based on CT or high-resolution CT. Genotypes of TERT and DSP variants were determined by TaqMan SNP Genotyping Assay, and their association was tested by chi-square test. RESULTS: When the frequencies of the IPF risk alleles TERT rs2736100A and DSP rs2076295G were compared between AAV subsets and healthy controls, both alleles were significantly increased in microscopic polyangiitis (MPA) (TERT P = 2.3 × 10-4, Pc = 0.0023, odds ratio [OR] 1.38; DSP P = 6.9 × 10-4, Pc = 0.0069, OR 1.32) and MPO-AAV (TERT P = 1.5 × 10-4, Pc = 0.0015, OR 1.33; DSP P = 0.0011, Pc = 0.011, OR 1.26). On the other hand, no significant association was detected when the allele frequencies were compared between MPO-AAV patients with and without ILD. CONCLUSIONS: Unexpectedly, TERT and DSP IPF risk alleles were found to be associated with MPA and MPO-AAV, regardless of the presence of ILD. These findings suggest that TERT and DSP may be novel susceptibility genes to MPA/MPO-AAV and also that some susceptibility genes may be shared between IPF and MPA/MPO-AAV..
2. Yukiko Takeyama, Nobuyuki Ono, Yuri Shirahama, Yasushi Inoue, Atsushi Tanaka, Naoyasu Ueda, Naoya Nishimura, Shuji Nagano, Ayumi Uchino, Tomoya Miyamura, Kensuke Oryoji, Hisako Inoue, Akihito Maruyama, Shun-Ichiro Ota, Seiji Yoshizawa, Takuya Sawabe, Naoko Himuro, Katsuhisa Miyake, Yasutaka Kimoto, Takahiko Horiuchi, Hiroki Mitoma, Hiroaki Niiro, Ayako Takamori, Yoshifumi Tada, Rituximab maintenance therapy for patients with antineutrophil cytoplasmic antibody-associated vasculitis in Japan., Modern rheumatology, 10.1080/14397595.2020.1790778, 1-9, 2020.07, OBJECTIVES: We examined the efficacy and safety of rituximab (RTX) maintenance therapy for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan. METHODS: We conducted a retrospective study using a multi-center cohort database of vasculitis patients. All maintenance treatment courses were divided into three groups: a RTX group, a group treated with other immunosuppressant drugs (IS) and a group receiving glucocorticoid monotherapy (GC). The primary endpoint was the comparison of relapse-free survival after 1 year. We also analyzed the occurrence of severe adverse events (SAEs) to assess safety. RESULTS: We included 123 courses of 107 patients (RTX n = 14, IS n = 64, GC n = 45). Twelve of 14 in the RTX group patients were diagnosed with granulomatosis with polyangiitis (GPA). The relapse-free survival of RTX maintenance therapy was comparable to that in the other groups (p = .122). After 1 year of treatment, the RTX group was administered lower steroid doses and one-third of them could withdraw corticosteroid. The overall incidence of SAE was 0.54/patient-year in the RTX group, 0.39/patient-year in the IS group and 0.34/patient-year in the GC group. CONCLUSION: RTX maintenance therapy could be effective and safe in Japanese GPA patients..
3. Nobuyuki Ono, Keita Kai, Akihito Maruyama, Mariko Sakai, Yuri Sadanaga, Shuichi Koarada, Takuya Inoue, Yoshifumi Tada, The relationship between type 1 IFN and vasculopathy in anti-MDA5 antibody-positive dermatomyositis patients, Rheumatology (Oxford, England), 10.1093/rheumatology/keaa033, 59, 4, 2020.04.
4. Yukiko Takeyama, Nobuyuki Ono, Yuri Shirahama, Yasushi Inoue, Atsushi Tanaka, Naoyasu Ueda, Naoya Nishimura, Shuji Nagano, Ayumi Uchino, Tomoya Miyamura, Kensuke Oryoji, Hisako Inoue, Akihito Maruyama, Shun ichiro Ota, Seiji Yoshizawa, Takuya Sawabe, Naoko Himuro, Katsuhisa Miyake, Yasutaka Kimoto, Takahiko Horiuchi, Hiroki Mitoma, Hiroaki Niiro, Ayako Takamori, Yoshifumi Tada, Rituximab maintenance therapy for patients with antineutrophil cytoplasmic antibody-associated vasculitis in Japan, Modern Rheumatology, 10.1080/14397595.2020.1790778, 2020, Objectives: We examined the efficacy and safety of rituximab (RTX) maintenance therapy for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan. Methods: We conducted a retrospective study using a multi-center cohort database of vasculitis patients. All maintenance treatment courses were divided into three groups: a RTX group, a group treated with other immunosuppressant drugs (IS) and a group receiving glucocorticoid monotherapy (GC). The primary endpoint was the comparison of relapse-free survival after 1 year. We also analyzed the occurrence of severe adverse events (SAEs) to assess safety. Results: We included 123 courses of 107 patients (RTX n = 14, IS n = 64, GC n = 45). Twelve of 14 in the RTX group patients were diagnosed with granulomatosis with polyangiitis (GPA). The relapse-free survival of RTX maintenance therapy was comparable to that in the other groups (p =.122). After 1 year of treatment, the RTX group was administered lower steroid doses and one-third of them could withdraw corticosteroid. The overall incidence of SAE was 0.54/patient-year in the RTX group, 0.39/patient-year in the IS group and 0.34/patient-year in the GC group. Conclusion: RTX maintenance therapy could be effective and safe in Japanese GPA patients..
5. Shoichi Fukui, Ayako Kuwahara-Takaki, Nobuyuki Ono, Shuntaro Sato, Tomohiro Koga, Shin ya Kawashiri, Nozomi Iwanaga, Naoki Iwamoto, Kunihiro Ichinose, Mami Tamai, Hideki Nakamura, Tomoki Origuchi, Kiyoshi Migita, Yojiro Arinobu, Hiroaki Niiro, Yoshifumi Tada, Koichi Akashi, Takahiro Maeda, Atsushi Kawakami, Serum levels of fibroblast growth factor-2 distinguish Takayasu arteritis from giant cell arteritis independent of age at diagnosis, Scientific reports, 10.1038/s41598-018-36825-y, 9, 1, 2019.12, Takayasu arteritis (TAK) and giant cell arteritis (GCA) are two major variants of large vessel vasculitis, and age is a major factor in their differential diagnosis. We sought to determine whether the two diseases exist on the same spectrum. We compared the serum levels of multiple cytokines and chemokines in 25 patients with TAK, 20 patients with GCA, and sex- and age-matched healthy donors for either condition (HD-TAK and HD-GCA). To evaluate the effects of age on the levels of cytokines and chemokines, we performed multiple logistic regression analysis using the least absolute shrinkage and selection operator (LASSO) method. The levels of IL-1RA, IL-10, GM-CSF, G-CSF, FGF-2, eotaxin, and IP-10 were significantly different between TAK and GCA, but no differences were found in the levels of IL-6, IL-12(p40), IL-17, IFN-γ, and TNF-α. Significant differences in the levels of IL-1RA, IL-10, GM-CSF, eotaxin, and IP-10 were observed between the HD-TAK and HD-GCA groups. Multiple logistic regression analysis demonstrated that only FGF-2 and IP-10 could significantly distinguish the diseases when added to age. Multiple logistic analysis using factors selected by the LASSO method revealed that FGF-2 was the only significant factor to distinguish the diseases when added to age. Among numerous cytokines and chemokines analyzed, only FGF-2 could be used together with age at diagnosis to differentiate TAK and GCA. Our results suggested the importance of considering the effects of age on serum cytokines..
6. Yoshifumi Tada, Mariko Sakai, Yoshinobu Nakao, Akihito Maruyama, Nobuyuki Ono, Syuichi Koarada, Placental transfer of tocilizumab in a patient with rheumatoid arthritis, Rheumatology (United Kingdom), 10.1093/rheumatology/kez155, 58, 9, 1694-1695, 2019.09.
7. Placental transfer of tocilizumab in a patient with rheumatoid arthritis..
8. The association of airway comorbidities with the clinical phenotypes and outcomes of ANCA-associated vasculitis patients..
9. Nobuyuki Ono, Keita Kai, Akihito Maruyama, Mariko Sakai, Yuri Sadanaga, Shuichi Koarada, Takuya Inoue, Yoshifumi Tada, The relationship between type 1 IFN and vasculopathy in anti-MDA5 antibody-positive dermatomyositis patients, Rheumatology (United Kingdom), 10.1093/rheumatology/key386, 58, 5, 786-791, 2019.05, Objectives. Based on the antibody profiles of inflammatory myositis patients, we investigated the type 1 IFN (T1-IFN) signature in serum and DM skin to determine the relationship between T1-IFN and vasculopathy in anti-melanoma differentiation-associated 5 gene (MDA5) antibody-positive DM patients. Methods. We examined 47 patients with new-onset inflammatory myositis. We divided them into three groups: the anti-MDA5 antibody-positive patients (MDA5 group, n = 16), the anti-aminoacyl-tRNA synthetase antibody-positive patients (aminoacyl-tRNA synthetase group, n = 12), and the double-negative patients (n = 19). Serum T1-IFN signatures were revealed by a functional reporter assay, and we evaluated the T1-IFN signatures of skin based on Mx1 expression by immunohistochemistry. Results. The numbers of patients with classical DM, clinically amyopathic DM and interstitial lung disease were 1, 15 and 13 in the MDA5 group, 2, 3 and 11 in the aminoacyl-tRNA synthetase group, and 10, 1 and 4 in the double-negative group, respectively. The signs of vasculopathies (i.e. palmer papules, skin ulcers and mononeuritis multiplex) were identified only in the MDA5 patients. Most of the MDA5 group showed the highest serum T1-IFN signatures among the three groups. In the histological analysis of DM skin, perivascular inflammations were significant in the MDA5 group. The MDA5 group's Mx1 expression was significantly strong, distributed in blood vessels and interstitial fibroblasts, and had spread to deep dermis. Conclusion. Anti-MDA5 antibody-positive DM patients showed high T1-IFN signatures in serum and affected skin. The high T1-IFN signatures of the MDA5 antibody-positive DM patients in serum and deep vasculatures suggested that T1-IFN may have important roles in the vasculopathy of these patients..
10. The relationship between type 1 IFN and vasculopathy in anti-MDA5 antibody-positive dermatomyositis patients..
11. Yoshifumi Tada, Satomi Inokuchi, Akihito Maruyama, Rie Suematsu, Mariko Sakai, Yuri Sadanaga, Nobuyuki Ono, Yojiro Arinobu, Syuichi Koarada, Are the 2016 EULAR/ACR/PRINTO classification criteria for macrophage activation syndrome applicable to patients with adult-onset Still’s disease?, Rheumatology International, 10.1007/s00296-018-4114-1, 39, 1, 97-104, 2019.01, The objectives of this study are to determine whether the 2016 European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organization classification criteria for macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (SJIA) can be used to identify MAS in patients with adult-onset Still’s disease (AOSD). Using laboratory data from 76 AOSD patients with and without MAS, we analyzed the ability of the collective and individual constitutive elements of the 2016 MAS in SJIA criteria and additional laboratory measures to discriminate between AOSD patients with (n = 16) and without (n = 60) MAS. Cutoff values to determine the sensitivity, specificity, and predictive values were calculated from receiver operating characteristic curves, and modified classification criteria for MAS in AOSD were evaluated. The 2016 MAS in SJIA classification criteria had an overall sensitivity of 100%, specificity of 70.0%, positive predictive value of 47.1%, and negative predictive value of 100% to discriminate between AOSD patients with and without MAS based on laboratory data. Among the individual criteria, the sensitivity of triglycerides (46.7%) and the specificity of ferritin (15.0%) for MAS in AOSD were particularly low. The sensitivity and specificity for classifying MAS in AOSD patients were increased to 100 and 93%, respectively, by excluding triglycerides and changing the cutoff values for other criteria in the 2016 MAS in SJIA classification. The 2016 classification criteria for MAS in SJIA had higher sensitivity but lower specificity to identify MAS in AOSD patients compared with SJIA patients..
12. Are the 2016 EULAR/ACR/PRINTO classification criteria for macrophage activation syndrome applicable to patients with adult-onset Still's disease?.
13. Shoichi Fukui, Ayako Kuwahara-Takaki, Nobuyuki Ono, Shuntaro Sato, Tomohiro Koga, Shin-Ya Kawashiri, Nozomi Iwanaga, Naoki Iwamoto, Kunihiro Ichinose, Mami Tamai, Hideki Nakamura, Tomoki Origuchi, Kiyoshi Migita, Yojiro Arinobu, Hiroaki Niiro, Yoshifumi Tada, Koichi Akashi, Takahiro Maeda, Atsushi Kawakami, Serum levels of fibroblast growth factor-2 distinguish Takayasu arteritis from giant cell arteritis independent of age at diagnosis., Scientific reports, 10.1038/s41598-018-36825-y, 9, 1, 688-688, 2019.01, Takayasu arteritis (TAK) and giant cell arteritis (GCA) are two major variants of large vessel vasculitis, and age is a major factor in their differential diagnosis. We sought to determine whether the two diseases exist on the same spectrum. We compared the serum levels of multiple cytokines and chemokines in 25 patients with TAK, 20 patients with GCA, and sex- and age-matched healthy donors for either condition (HD-TAK and HD-GCA). To evaluate the effects of age on the levels of cytokines and chemokines, we performed multiple logistic regression analysis using the least absolute shrinkage and selection operator (LASSO) method. The levels of IL-1RA, IL-10, GM-CSF, G-CSF, FGF-2, eotaxin, and IP-10 were significantly different between TAK and GCA, but no differences were found in the levels of IL-6, IL-12(p40), IL-17, IFN-γ, and TNF-α. Significant differences in the levels of IL-1RA, IL-10, GM-CSF, eotaxin, and IP-10 were observed between the HD-TAK and HD-GCA groups. Multiple logistic regression analysis demonstrated that only FGF-2 and IP-10 could significantly distinguish the diseases when added to age. Multiple logistic analysis using factors selected by the LASSO method revealed that FGF-2 was the only significant factor to distinguish the diseases when added to age. Among numerous cytokines and chemokines analyzed, only FGF-2 could be used together with age at diagnosis to differentiate TAK and GCA. Our results suggested the importance of considering the effects of age on serum cytokines..
14. Ryoko Egashira, Takahiko Nakazono, Ken Yamaguchi, Keita Kai, Nobuyuki Ono, Mariko Yoshimura, Hiroyuki Irie, A rare case of kikuchi-fujimoto disease with diffuse lung involvement presenting a lymphatic-like distribution on thin-section computed tomography, Journal of Thoracic Imaging, 10.1097/RTI.0000000000000353, 33, 6, W51-W53, 2018.11.
15. A Rare Case of Kikuchi-Fujimoto Disease With Diffuse Lung Involvement Presenting a Lymphatic-like Distribution on Thin-section Computed Tomography..
16. Rie Suematsu, Satoko Tashiro, Nobuyuki Ono, Syuichi Koarada, Akihide Ohta, Yoshifumi Tada, Successful golimumab therapy in four patients with refractory Takayasu’s arteritis, Modern Rheumatology, 10.3109/14397595.2015.1134393, 28, 4, 712-715, 2018.07, Recent studies suggested that anti-TNF-α biological therapies are effective in treating Takayasu's arteritis (TA) refractory to conventional immunosuppressive therapy. However, the efficacy of golimumab (GLM) for TA therapy is unknown. We report four women with TA who were successfully treated with GLM. GLM was prescribed as induction therapy for three patients and as maintenance therapy for one patient. GLM showed therapeutic value and might be useful, together with other anti-TNF-α agents, in treating TA..
17. Successful golimumab therapy in four patients with refractory Takayasu's arteritis..
18. Nobuyuki Ono, Kiichi Murakami, Olivia Chan, Håkan Hall, Alisha R. Elford, Patty Yen, Thomas Calzascia, David M. Spencer, Pamela S. Ohashi, Salim Dhanji, Exposure to sequestered self-antigens in vivo is not sufficient for the induction of autoimmune diabetes, PloS one, 10.1371/journal.pone.0173176, 12, 3, 2017.03, Although the role of T cells in autoimmunity has been explored for many years, the mechanisms leading to the initial priming of an autoimmune T cell response remain enigmatic. The 'hit and run' model suggests that self-antigens released upon cell death can provide the initial signal for a self-sustaining autoimmune response. Using a novel transgenic mouse model where we could induce the release of self-antigens via caspase-dependent apoptosis. We tracked the fate of CD8+ T cells specific for the self-antigen. Our studies demonstrated that antigens released from apoptotic cells were cross-presented by CD11c+ cells in the draining lymph node. This cross-presentation led to proliferation of self-antigen specific T cells, followed by a transient ability to produce IFN-ã, but did not lead to the development of autoimmune diabetes. Using this model we examined the consequences on T cell immunity when apoptosis was combined with dendritic cell maturation signals, an autoimmune susceptible genetic background, and the deletion of Tregs. The results of our study demonstrate that autoimmune diabetes cannot be initiated by the presentation of antigens released from apoptotic cells in vivo even in the presence of factors known to promote autoimmunity..
19. Nobuyuki Ono, Kiichi Murakami, Olivia Chan, Hakan Hall, Alisha R. Elford, Patty Yen, Thomas Calzascia, David M. Spencer, Pamela S. Ohashi, Salim Dhanji, Exposure to sequestered self-antigens in vivo is not sufficient for the induction of autoimmune diabetes, PLOS ONE, 10.1371/journal.pone.0173176, 12, 3, e0173176, 2017.03, Although the role of T cells in autoimmunity has been explored for many years, the mechanisms leading to the initial priming of an autoimmune T cell response remain enigmatic. The `hit and run' model suggests that self-antigens released upon cell death can provide the initial signal for a self-sustaining autoimmune response. Using a novel transgenic mouse model where we could induce the release of self-antigens via caspase-dependent apoptosis. We tracked the fate of CD8+ T cells specific for the self-antigen. Our studies demonstrated that antigens released from apoptotic cells were cross-presented by CD11c+ cells in the draining lymph node. This cross-presentation led to proliferation of self-antigen specific T cells, followed by a transient ability to produce IFN-gamma,but did not lead to the development of autoimmune diabetes. Using this model we examined the consequences on T cell immunity when apoptosis was combined with dendritic cell maturation signals, an autoimmune susceptible genetic background, and the deletion of Tregs. The results of our study demonstrate that autoimmune diabetes cannot be initiated by the presentation of antigens released from apoptotic cells in vivo even in the presence of factors known to promote autoimmunity..
20. Daisuke Oryoji, Nobuyuki Ono, Daisuke Himeji, Kyoko Yoshihiro, Yasufumi Kai, Motohiro Matsuda, Hiroshi Tsukamoto, Akira Ueda, Sudden respiratory failure due to tracheobronchomalacia by relapsing polychondritis, successfully rescued by multiple metallic stenting and tracheostomy, Internal Medicine, 10.2169/internalmedicine.8778-16, 56, 24, 3369-3372, 2017.01, Relapsing polychondritis (RP) is a rare systemic autoimmune disease that affects cartilaginous structures. RP causes tracheobronchomalacia (TBM) by affecting the bronchial cartilage. TBM is a fatal condition characterized by excessive weakening of the walls of the trachea and bronchi. We herein report a case of a 73-year-old man who experienced sudden respiratory failure due to TBM caused by RP. Immunosuppressive treatment did not improve his respiratory failure. Multiple metallic stentings dramatically improved his severe airway symptoms. When the airway condition becomes lethal in RP patients, then metallic stenting can be a useful treatment option..
21. Yoshifumi Tada, Nobuyuki Ono, Rie Suematsu, Satoko Tashiro, Yuri Sadanaga, Yukiko Tokuda, Yukihide Ono, Yoshinobu Nakao, Akihito Maruyama, Akihide Ohta, Syuichi Koarada, The balance between Foxp3 and Ror-γt expression in peripheral blood is altered by tocilizumab and abatacept in patients with rheumatoid arthritis, BMC Musculoskeletal Disorders, 10.1186/s12891-016-1137-1, 17, 1, 2016.07, Background: The balance between Th17 cells and regulatory T (Treg) cells has been shown to play an important role in the development of rheumatoid arthritis (RA). Recent studies have shown that treatment with abatacept (ABT) or tocilizumab (TCZ) affects Th17 and Treg cell populations. Although not unanimously accepted, several reports have shown that Treg cells are decreased by ABT and increased by TCZ, and that Th17 cells are decreased by TCZ. To further investigate the effects of ABT and TCZ on the skewing of T cell populations, we analyzed the expression of master regulators genes of helper T cell lineages following ABT/TCZ treatment of RA patients. Methods: Ten patients treated with ABT and 10 patients treated with TCZ were enrolled. Total RNA was extracted from peripheral blood cells at baseline, and after 12 and 24 weeks of therapy. The expression levels of T-bet, GATA3, Foxp3 and Ror-γt were semi-quantified using real-time PCR. The relative expression levels were expressed as the ratios of two genes (T-bet/GATA3, Foxp3/GATA3, Foxp3/T-bet, Foxp3/Ror-γt, Ror-γt/T-bet, Ror-γt/GATA3), and the changes in these ratios with treatment were determined. Results: The Foxp3/Ror-γt ratio was decreased after ABT therapy (0.67 ± 0.16 at 24 weeks, P = 0.0034) but was increased after TCZ therapy (2.00 ± 1.03 at 24 weeks, P = 0.0013). In addition, the Ror-γt/GATA3 ratio was decreased after TCZ therapy (0.78 ± 0.37 at 24 weeks, P = 0.0008). Except for these ratios, no significant skewing in the expression of these factors was detected. No significant relationship between clinical response to the treatment and change in the ratios of these factors was determined. Conclusion: Treatment with TCZ or ABT differently affected the balance between Foxp3 and Ror-γt expression in the peripheral blood of patients with RA..
22. Tada Y, Ono N, Suematsu R, Tashiro S, Sadanaga Y, Tokuda Y, Ono Y, Nakao Y, Maruyama A, Ohta A, Koarada S, The balance between Foxp3 and Ror-γt expression in peripheral blood is altered by tocilizumab and abatacept in patients with rheumatoid arthritis., BMC musculoskeletal disorders, 10.1186/s12891-016-1137-1, 17, 290, 2016.07.
23. Effectiveness of Certolizumab Pegol in Treating Rheumatoid Arthritis Patients with Persistent Inflamed Residual Mono- or Oligosynovitis Resistant to Prior TNF-α Inhibitors..
24. Syuichi Koarada, Yukiko Tokuda, Yukihide Ono, Yuri Sadanaga, Satoko Tashiro, Rie Suematsu, Nobuyuki Ono, Akihide Ohta, Yoshifumi Tada, Early diagnosis and preventive strategy of corticosteroid induced osteonecrosis in systemic autoimmune diseases, Corticosteroids and Steroid Therapy New Research, 79-100, 2015.04, Osteonecrosis of femoral head (ONF) is one of the serious adverse events in the patients with systemic lupus erythematosus (SLE) associated with corticosteroid therapy. We have reported a multicenter prospective study of prevention of ONF in SLE patients on high doses of corticosteroids using anticoagulant of warfarin. In the diagnosis of ONF, plain radiography and magnetic resonance imaging (MRI) are important. Especially, in early stage of ONF, although the plain radiograph is still normal, evident changes can be seen in MRI. The treatment of ONFremains controversial. Anticoagulants may be useful to prevent ONF. Therefore, early diagnosis and prevention of ONF are critical issues especially in SLE patients. In this chapter, we present the radiological images illustrating osteonecrosis in patients with autoimmune diseases including SLE, and review the strategy to prevent ONF induced by corticosteroids..
25. Syuichi Koarada, Satoko Tashiro, Yukiko Tokuda, Yukihide Ono, Yuri Sadanaga, Rie Suematsu, Nobuyuki Ono, Akihide Ohta, Yoshifumi Tada, Persistent expression of CXCR5 on plasmablasts in IgG4-related disease, Annals of the Rheumatic Diseases, 10.1136/annrheumdis-2014-207207, 74, 4, e32, 2015.04.
26. Syuichi Koarada, Satoko Tashiro, Yukiko Tokuda, Yukihide Ono, Yuri Sadanaga, Rie Suematsu, Nobuyuki Ono, Akihide Ohta, Yoshifumi Tada, Persistent expression of CXCR5 on plasmablasts in IgG4-related disease, ANNALS OF THE RHEUMATIC DISEASES, 10.1136/annrheumdis-2014-207207, 74, 4, e32, 2015.04.
27. Nobuyuki Ono, Hiroaki Niiro, Akira Ueda, Takuya Sawabe, Hiroaki Nishizaka, Isao Furugo, Seiji Yoshizawa, Shigeru Yoshizawa, Hiroshi Tsukamoto, Chikako Kiyohara, Yoshifumi Tada, Takahiko Horiuchi, Characteristics of MPO-ANCA-positive granulomatosis with polyangiitis: a retrospective multi-center study in Japan, RHEUMATOLOGY INTERNATIONAL, 10.1007/s00296-014-3106-z, 35, 3, 555-559, 2015.03, We studied the clinico-pathological differences among PR3-ANCA-positive granulomatosis with polyangiitis (PR3-GPA), MPO-ANCA-positive GPA (MPO-GPA) and microscopic polyangiitis (MPA). ANCA-associated vasculitis (AAV) was classified using the European Medicines Agency classification. We retrospectively analyzed 38 patients with GPA and 41 with MPA treated in eight hospitals in Japan. Of the patients with GPA, 17 were positive for MPO-ANCA, and 15 for PR3-ANCA. All patients with MPA were MPO-ANCA positive. The mean ages of those with MPO-GPA were 69.6 years old, 10 years older than those with PR3-GPA. The majority (82 %) of patients with MPO-GPA were woman, a significantly greater proportion than for PR3-GPA. We also found that ear, nose and throat (ENT), nervous system involvement were significantly more common in MPO-GPA, but renal function was less impaired than those with MPA. Both PR3-GPA and MPO-GPA relapsed more frequently than MPA, but overall survival was significantly better (P < 0.01 and P < 0.05, respectively). Univariate analysis identified the following factors as predictors of a poor prognosis: MPA (P < 0.01), pulmonary UIP pattern (P < 0.005) Cr a parts per thousand yen 1.7 mg/dl (P < 0.01) and absence of ENT involvement (P < 0.05), which were characteristics of MPA. In our cohort, MPO-GPA was most likely to affect older women and was associated with otitis media, nervous system involvement, mild renal impairment and more favorable outcome. It is clinically useful to differentiate MPO-GPA from MPA and PR3-GPA in patients with AAV..
28. Nobuyuki Ono, Hiroaki Niiro, Akira Ueda, Takuya Sawabe, Hiroaki Nishizaka, Isao Furugo, Seiji Yoshizawa, Shigeru Yoshizawa, Hiroshi Tsukamoto, Chikako Kiyohara, Yoshifumi Tada, Takahiko Horiuchi, Characteristics of MPO-ANCA-positive granulomatosis with polyangiitis
a retrospective multi-center study in Japan, Rheumatology International, 10.1007/s00296-014-3106-z, 35, 3, 555-559, 2015.01, We studied the clinico-pathological differences among PR3-ANCA-positive granulomatosis with polyangiitis (PR3-GPA), MPO-ANCA-positive GPA (MPO-GPA) and microscopic polyangiitis (MPA). ANCA-associated vasculitis (AAV) was classified using the European Medicines Agency classification. We retrospectively analyzed 38 patients with GPA and 41 with MPA treated in eight hospitals in Japan. Of the patients with GPA, 17 were positive for MPO-ANCA, and 15 for PR3-ANCA. All patients with MPA were MPO-ANCA positive. The mean ages of those with MPO-GPA were 69.6 years old, 10 years older than those with PR3-GPA. The majority (82 %) of patients with MPO-GPA were woman, a significantly greater proportion than for PR3-GPA. We also found that ear, nose and throat (ENT), nervous system involvement were significantly more common in MPO-GPA, but renal function was less impaired than those with MPA. Both PR3-GPA and MPO-GPA relapsed more frequently than MPA, but overall survival was significantly better (P < 0.01 and P < 0.05, respectively). Univariate analysis identified the following factors as predictors of a poor prognosis: MPA (P < 0.01), pulmonary UIP pattern (P < 0.005) Cr ≥ 1.7 mg/dl (P < 0.01) and absence of ENT involvement (P < 0.05), which were characteristics of MPA. In our cohort, MPO-GPA was most likely to affect older women and was associated with otitis media, nervous system involvement, mild renal impairment and more favorable outcome. It is clinically useful to differentiate MPO-GPA from MPA and PR3-GPA in patients with AAV..
29. Noriaki Kawano, Shuro Yoshida, Takuro Kuriyama, Yoshihiro Tahara, Kiyoshi Yamashita, Yuri Nagahiro, Jiro Kawano, Hideki Koketsu, Atsushi Toyofuku, Tatsuya Manabe, Kiichiro Beppu, Nobuyuki Ono, Daisuke Himeji, Naoko Yokota-Ikeda, Sanshiro Inoue, Hidenobu Ochiai, Koh Hei Sonoda, Kazuya Shimoda, Fumihiko Ishikawa, Akira Ueda, Clinical features and treatment outcomes of 81 patients with aggressive type adult T-cell leukemia-lymphoma at a single institution over a 7-year period (2006-2012), Internal Medicine, 10.2169/internalmedicine.54.1953, 54, 12, 1489-1498, 2015.01, Objective Despite the remarkable advances in chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), adult T-cell leukemia-lymphoma (ATL) is still associated with a high mortality rate. It is therefore essential to elucidate the current features of ATL. Methods We retrospectively analyzed 81 patients with aggressive type ATL at our institution over a 7-year period based on Shimoyama’s diagnostic criteria. Results Eighty-one patients with a median age of 67.5 years were classified as having acute (n=47), lymphoma (n=32), or chronic type (n=2) ATL. They were initially treated by either palliative therapy (n=25) or systemic chemotherapy [n=56; cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy (n=25)/vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP)-doxorubicin, ranimustine, and prednisone (AMP)-vindesine, etoposide, carboplatin, and prednisone (VECP) therapy (VCAP-AMP-VECP) or CHOP-VMMV therapy (n=31)], and showed median survival durations of 16 and 277 days, respectively. Subsequent to the initial treatment, HSCT (n=6) was performed for certain patients, thus revealing that twothirds (n=4) relapsed, and one-third (n=2) survived for 131 days and 203 days, respectively. The relapsed ATL patients were treated with conventional salvage therapy (n=29) or anti-CC chemokine receptor 4 antibody (mogamulizumab) (n=3). The patients treated with mogamulizumab demonstrated complete response (2) and partical response (1) with short duration periods of 82 days, 83 days, and 192 days, respectively. Among the five long-term survivors (>5 years) who received chemotherapy, most showed a low and intermediate risk according to the ATL prognostic index. Conclusion In our study, the overall survival of ATL remains poor due to the advanced age of the patients at diagnosis, a high proportion of patients receiving palliative therapy, and a small proportion of long-term survivors receiving chemotherapy and undergoing HSCT. This study illustrates the current clinical features, treatment strategies, and outcomes in clinical practice..
30. Syuichi Koarada, Satoko Tashiro, Yukiko Tokuda, Yukihide Ono, Yuri Sadanaga, Rie Suematsu, Nobuyuki Ono, Akihide Ohta, Yoshifumi Tada, Subsets of RP105-negative plasmablasts in IgG4-related disease, Annals of the Rheumatic Diseases, 10.1136/annrheumdis-2014-206179, 73, 10, 2014.10.
31. Syuichi Koarada, Satoko Tashiro, Yukiko Tokuda, Yukihide Ono, Yuri Sadanaga, Rie Suematsu, Nobuyuki Ono, Akihide Ohta, Yoshifumi Tada, Subsets of RP105-negative plasmablasts in IgG4-related disease, ANNALS OF THE RHEUMATIC DISEASES, 10.1136/annrheumdis-2014-206179, 73, 10, E65-E65, 2014.10.
32. Noriaki Kawano, Akira Tasaki, Takuro Kuriyama, Yoshihiro Tahara, Shuro Yoshida, Nobuyuki Ono, Daisuke Himeji, Kiyoshi Yamashita, Yoshihiro Shibata, Toshiyuki Goto, Tomohiro Inoue, Naoko Yokota-Ikeda, Shigehiro Uezono, Akihiko Yuge, Toshihiro Nishiguchi, Tamahiro Kinjo, Yasuhiro Ogura, Kiichiro Beppu, Yuji Ueda, Mariko Kinoshita, Hiroshi Moritake, Kazuya Shimoda, Hidenobu Ochiai, Akira Ueda, Effects of recombinant human soluble thrombomodulin treatment for disseminated intravascular coagulation at a single institution-an analysis of 62 cases caused by infectious diseases and 30 cases caused by hematological diseases, Internal Medicine, 10.2169/internalmedicine.53.0715, 53, 3, 205-213, 2014.02, Objective Disseminated intravascular coagulation (DIC) is a clinical condition with high mortality that is characterized by the systemic activation of coagulation pathways resulting in multiple organ failure. Although no standard treatment for DIC has been established, recent reports have indicated that recombinant human soluble thrombomodulin (rTM) is effective against DIC. Methods To elucidate the clinical characteristics and outcomes of DIC, we retrospectively analyzed 92 DIC patients who were treated with rTM at Miyazaki Prefectural Hospital over a 4-year period (62 patients had infectious diseases and 30 patients had hematological diseases). A diagnosis of DIC was made based on the diagnostic criteria of the Japanese Association for Acute Medicine (JAAM) and Japanese Ministry of Health and Welfare (JMHW) for infectious diseases and hematological diseases, respectively. In addition to treating the underlying disease, rTM was administered for six consecutive days. Results In this study, 49 of the 92 DIC patients (53.3%) experienced resolution of DIC seven days after administration (46.8% patients with infectious disease and 66.7% with hematological disease). A higher survival rate was observed after a 28-day observation period in 69 of the 92 patients (75.0%) (72.6% of the patients with infectious disease and 80.0% of the patients with hematological disease). A lower DIC score at the initiation of rTM treatment was closely related to a higher rate of resolution of DIC. Conclusion Our findings indicate that rTM therapy is an effective, safe and feasible treatment for DIC patients. Furthermore, making an accurate and early diagnosis of DIC and providing subsequent immediate treatment with rTM may improve the resolution of DIC..
33. Clinical features and outcomes of 9 patients with immunodeficiency-associated lymphoproliferative disorders treated at a single institution..
34. Noriaki Kawano, Naoko Yokota-Ikeda, Shuro Yoshida, Takuro Kuriyama, Kiyoshi Yamashita, Yasuhiro Sugio, Shigeyoshi Makino, Nobuyuki Ono, Yasushi Inoue, Daisuke Himeji, Kieko Kodama, Shigehiro Uezono, Yoshiya Shimao, Akira Ueda, Masanori Matsumoto, Hisayo Iino, Yoshihiro Fujimura, Therapeutic modality of 11 patients with TTP in a single institution in Miyazaki from 2000 to 2011, Internal Medicine, 10.2169/internalmedicine.52.8253, 52, 17, 1883-1891, 2013.09, Objective Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disease with pathological features that are termed thrombotic microangiopathies. Since the discovery of the von Willebrand factor-cleaving protease [a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13)], it is widely known that approximately two-thirds of TTP patients have a severe deficiency of ADAMTS13 activity due to gene mutations or acquired autoantibodies to this enzyme. However, the remaining one-third of TTP patients have only moderately reduced or almost normal ADAMTS13 activity. To elucidate the clinical characteristics and outcomes of these two types of TTP, we have retrospectively analyzed the cases of acquired TTP patients treated in a single institution from 2000 to 2011. Methods Our case studies include 11 TTP patients, of which 5 were considered idiopathic and 6 had cases of TTP associated with underlying diseases such as non-Hodgkin lymphoma or connective tissue diseases. Results These patients were treated with a combination therapy of plasma exchange and steroids and with several adjunctive therapeutic regimens including the on-label use of cyclophosphamide and cyclosporine and the off-label use of high-dose steroid or immunoglobulin with rituximab. Splenectomies were not performed. As a result of these treatments, 6 out of the 7 patients with ADAMTS13 activity deficient TTP achieved a complete remission without relapse, but the remaining 4 patients with non-ADAMTS13 activity deficient TTP all died without complete remission. Conclusion We present herein the detailed clinical courses of 11 patients with TTP and address our experiences with the efficacy of various therapeutic regimens. This case-oriented study should be helpful to the physicians who directly care for TTP patients, and may provide a future direction for developing a more efficient treatment modality..
35. Daisuke Himeji, Nobuyuki Ono, Atsushi Yamanaka, Kiichiro Beppu, Yoshiya Shimao, Yukito Ichinose, Two cases of pure red cell aplasia that developed during chemotherapy for invasive thymoma, Japanese Journal of Lung Cancer, 10.2482/haigan.53.17, 53, 1, 17-24, 2013.07, Background. Thymoma is often associated with various autoimmune disease, and pure red cell aplasia occurs in 5% of thymoma patients. Pure red cell aplasia is classified into several groups, and in secondary pure red cell aplasia, it has various causes, however, there have been few reports on the association of development of pure red cell aplasia and chemotherapy. Cases. Case 1, a 36-year-old man was administrated induction chemotherapy with cisplatin and amrubicin for invasive thymoma (WHO type B2, Masaoka classification III). Thymoma decreased in size, but he suffered from severe anemia, and pure red cell aplasia was diagnosed based on data from peripheral blood examination and bone marrow aspiration. Administration of cyclosporin and corticosteroid improved his anemia. Case 2, a 45-year-old woman was given chemotherapy with cisplatin and amrubicin for invasive thymoma (WHO type B1, Masaoka classification IVa). Thymoma decreased in size, but she suffered from severe anemia, and pure red cell aplasia was diagnosed based on data from peripheral blood examination and bone marrow aspiration. Administration of cyclosporin and corticosteroid improved her anemia. Conculsion. We experienced two cases of pure red cell aplasia appeared during chemotherapy for invasive thymoma. It is important to observe the patients during or even after chemotherapy by keeping the possible appearance of pure red cell aplasia in mind..
36. Nobuyuki Ono, Kyoko Yoshihiro, Daisuke Oryoji, Motohiro Matsuda, Yoshihiro Ueki, Shigehiro Uezono, Yasufumi Kai, Daisuke Himeji, Hiroaki Niiro, Akira Ueda, Four cases of MPO-ANCA-positive vasculitis with otitis media, and review of the literature, Modern Rheumatology, 10.1007/s10165-012-0682-1, 23, 3, 554-563, 2013.05, Otitis media is one of the common organ injuries that appear during the course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We experienced four patients with myeloperoxidase (MPO)-ANCA-positive AAV with otitis media. All were elderly Japanese women. MPO-ANCA in our patients was reminiscent of microscopic polyangiitis (MPA), although chest computed tomography (CT) scans revealed characteristics of both granulomatosis with polyangiitis (GPA), showing bronchial lesions and nodule formation, and MPA, showing interstitial changes. Whether our cases should be classified as GPA or MPA is a matter of discussion. We detail their profiles, and review previous literature on MPO-ANCA-positive AAV with otitis media..
37. Nobuyuki Ono, Kyoko Yoshihiro, Daisuke Oryoji, Motohiro Matsuda, Yoshihiro Ueki, Shigehiro Uezono, Yasufumi Kai, Daisuke Himeji, Hiroaki Niiro, Akira Ueda, Four cases of MPO-ANCA-positive vasculitis with otitis media, and review of the literature, MODERN RHEUMATOLOGY, 10.1007/s10165-012-0682-1, 23, 3, 554-563, 2013.05, Otitis media is one of the common organ injuries that appear during the course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We experienced four patients with myeloperoxidase (MPO)-ANCA-positive AAV with otitis media. All were elderly Japanese women. MPO-ANCA in our patients was reminiscent of microscopic polyangiitis (MPA), although chest computed tomography (CT) scans revealed characteristics of both granulomatosis with polyangiitis (GPA), showing bronchial lesions and nodule formation, and MPA, showing interstitial changes. Whether our cases should be classified as GPA or MPA is a matter of discussion. We detail their profiles, and review previous literature on MPO-ANCA-positive AAV with otitis media..
38. Successful surgical treatment for pulmonary crystal-storing histiocytosis following the onset of gastric non-hodgkin lymphoma..
39. Noriaki Kawano, Kiichiro Beppu, Mayumi Oyama, Daisuke Himeji, Shuro Yoshida, Takuro Kuriyama, Nobuyuki Ono, Hiroyuki Masuyama, Kiyoshi Yamashita, Kenichiro Yamaguchi, Yoshiya Shimao, Koichi Oshima, Yuji Ueda, Akira Ueda, Successful surgical treatment for pulmonary crystal-storing histiocytosis following the onset of gastric non-hodgkin lymphoma., Journal of clinical and experimental hematopathology : JCEH, 10.3960/jslrt.53.241, 53, 3, 241-245, 2013, Crystal-storing histiocytosis is a rare clinical entity characterized by an increase in the number of abnormal histiocytes accompanied by accumulation of crystallized immunoglobulins. We describe the case of an 80-year-old man who presented with crystal-storing histiocytosis of the lung 13 years after receiving a diagnosis of gastric non-Hodgkin lymphoma (NHL ; clinical stage, Lugano IA). After wedge resection of the left upper lobe, the histological findings showed crystal-storing histiocytosis with CD68(+), some small to medium lymphoid cells with CD79a(+) with κ(+(weekly)) and λ(-), and some plasma cells with CD138(+), and rearrangement of the immunoglobulin heavy chain. Based on the nonrecurrent gastric NHL, small B-cell population, and failure to detect the same clone by polymerase chain reaction analysis, our case was classified as pulmonary localized crystal-storing histiocytosis without underlying lymphoproliferative or plasma cell disorder. The findings of minor B-cell populations harboring a heavy chain rearrangement with slight light-chain restriction (κ > λ) may be related to the pathogenesis of crystallogenesis and crystal-storing histiocytosis. Moreover, surgical treatment may be an effective therapeutic option for solitary crystal-storing histiocytosis..
40. Successful treatment of immunodeficiency-associated EBV-negative lymphoproliferative disorders in rheumatoid arthritis by methotrexate withdrawal and prevention of its relapse by rituximab administration..
41. Noriaki Kawano, Nobuyuki Ono, Shuro Yoshida, Takuro Kuriyama, Kiyoshi Yamashita, Kiichiro Beppu, Yoshiya Shimao, Kosuke Marutsuka, Yuji Ueda, Akira Ueda, Successful treatment of immunodeficiency-associated EBV-negative lymphoproliferative disorders in rheumatoid arthritis by methotrexate withdrawal and prevention of its relapse by rituximab administration., Journal of clinical and experimental hematopathology : JCEH, 10.3960/jslrt.52.193, 52, 3, 193-198, 2012, Immunodeficiency-associated lymphoproliferative disorders (LPD) in rheumatoid arthritis are a rare, aggressive, and life-threatening clinical entity. We describe a 60-year-old man who had rheumatoid arthritis that was treated with methotrexate. Eight months after the treatment, the case was diagnosed as Epstein-Barr virus-negative LPD (diffuse large B-cell lymphoma) with abdominal bulky mass and clinical stage IVB at high risk in the international prognostic index. Immediate withdrawal of methotrexate led the patient to achieve complete remission, and 8 subsequent courses of rituximab treatment for the prevention of relapse kept the patient disease-free for 29 months. Our case suggests that these treatments may be an effective, safe, and feasible strategy for immunodeficiency-associated LPD in rheumatoid arthritis..
42. Clinical features and outcomes of 35 disseminated intravascular coagulation cases treated with recombinant human soluble thrombomodulin at a single institution..
43. Noriaki Kawano, Shuro Yoshida, Nobuyuki Ono, Daisuke Himeji, Yuri Nagahiro, Kawano Sayaka Kawano, Kiyoshi Yamashita, Naoko Ikeda, Shigehiro Uezono, Hidenobu Ochiai, Fumiko Kawano, Ikuo Kikuchi, Fumihiko Ishikawa, Kazuya Shimoda, Akira Ueda, Koichi Akashi, Clinical features and outcomes of 35 disseminated intravascular coagulation cases treated with recombinant human soluble thrombomodulin at a single institution., Journal of clinical and experimental hematopathology : JCEH, 10.3960/jslrt.51.101, 51, 2, 101-107, 2011, Disseminated intravascular coagulation (DIC) is a clinical entity with high mortality and is characterized by multiple organ failure caused by activation of systemic intravascular coagulation. Although a standard treatment for DIC has not been established owing to the absence of randomized controlled trials, recent reports have indicated that recombinant human soluble thrombomodulin (rTM) is effective against DIC. To elucidate the clinical characteristics and outcomes of DIC, we retrospectively analyzed 35 DIC patients treated with rTM at our institution over a 2-year period (infectious disease: 21 cases; hematological disease: 14 cases). Diagnosis of DIC was based on the diagnostic criteria for DIC of the Japanese Ministry of Health and Welfare. In addition to the treatment of underlying diseases, we administered rTM for 6 consecutive days. Twenty-one (60.0%) of the DIC patients attained resolution of DIC at 7 days after administration (infectious disease: 61.9%; hematological disease: 57.1%). Furthermore, 7 of the remaining 14 DIC patients (who did not attain resolution at 7 days) attained resolution at an average of 12.1 days. Consequently, 28 (80.0%) of the 35 patients were alive with resolution of DIC after a 28-day observation period (infectious disease: 76.2%; hematological disease: 85.7%). Among them, for 7 (70%) of the 10 DIC patients with severe life-threatening bleeding symptoms without hemorrhagic shock, treatment with heparin was contraindicated; these patients were successfully treated with rTM without the progression of hemorrhage. In the majority of DIC patients, rTM administration may be an effective, safe, and feasible therapeutic modality producing a good outcome..
44. Shinji Shimoda, Hiroshi Miyakawa, Minoru Nakamura, Hiromi Ishibashi, Kentaro Kikuchi, Hiroto Kita, Hiroaki Niiro, Youjirou Arinobu, Nobuyuki Ono, Ian R. Mackay, M. Eric Gershwin, Koichi Akashi, CD4 T-cell autoreactivity to the mitochondrial autoantigen PDC-E2 in AMA-negative primary biliary cirrhosis, Journal of Autoimmunity, 10.1016/j.jaut.2008.05.003, 31, 2, 110-115, 2008.09, Approximately 5% of patients with primary biliary cirrhosis (PBC) lack characteristic anti-mitochondrial antibodies (AMA). Yet clinically AMA+ and AMA- patients are similar. Using both AMA+ and AMA- patients, we quantitated the frequency of autoreactive T cells that respond to the major CD4 T-cell epitope, PDC-E2 163-176, using limiting dilution assays and quantitation of IFN-γ, IL-10 and IL-4. Further, based on data that both PBC patients and healthy subjects have CD4+ T cells that recognize PDC-E2 163-176 but with differing costimulation requirements, assays were performed using two different antigen-presenting cell (APC) systems: either autologous peripheral blood mononuclear cells (PBMC) or HLA DR53 transfected mouse fibroblast cell lines (L-DR53). When costimulation-incompetent L-DR53 were used as APCs, the PDC-E2 CD4 T-cell frequency and capacity for IFN-γ production were equivalent in both AMA+ and AMA- patients but the frequencies of such cells were significantly lower in normals, with IL-10 production similar in all three groups. Thus, in PBC there is 'universal' autoreactive CD4+ T-cell immune responsiveness to the critical autoantigen, PDC-E2. These observations emphasize that the mitochondrial autoreactivity in PBC is a multi-lineage response and hence, AMA-negative PBC may be an anachronism that refers only to sera autoantibodies..
45. Shinji Shimoda, Hiroshi Miyakawa, Minoru Nakamura, Hiromi Ishibashi, Kentaro Kikuchi, Hiroto Kita, Hiroaki Niiro, Youjirou Arinobu, Nobuyuki Ono, Ian R. Mackay, M. Eric Gershwing, Koichi Akashi, CD4 T-cell autoreactivity to the mitochondrial autoantigen PDC-E2 in AMA-negative primary biliary cirrhosis, JOURNAL OF AUTOIMMUNITY, 10.1016/j.jaut.2008.05.003, 31, 2, 110-115, 2008.09, Approximately 5% of patients with primary biliary cirrhosis (PBC) lack characteristic anti-mitochondrial antibodies (AMA). Yet clinically AMA(+) and AMA(-) patients are similar. Using both AMA 4 and AMA- patients, we quantitated the frequency of autoreactive T cells that respond to the major CD4 T-cell epitope, PDC-E2 163-176, using limiting dilution assays and quantitation of IFN-gamma, IL-10 and IL-4. Further, based on data that both PBC patients and healthy subjects have CD4(+) T cells that recognize PDC-E2 163-176 but with differing costimulation requirements, assays were performed using two different antigen-presenting cell (APC) systems: either autologous peripheral blood mononuclear cells (PBMC) or HLA DR53 transfected mouse fibroblast cell lines (L-DR53). When costimulation-incompetent L-DR53 were used as APCs, the PDC-E2 CD4 T-cell frequency and capacity for IFN-gamma production were equivalent in both AMA and AMA- patients but the frequencies of such cells were significantly lower in normals, with IL-10 production similar in all three groups. Thus, in PBC there is 'universal' autoreactive CD4 I T-cell immune responsiveness to the critical autoantigen, PDC-E2. These observations emphasize that the mitochondrial autoreactivity in PBC is a muiti-lineage response and hence, AMA-negative PBC may be ail anachronism that refers only to sera autoantibodies. (C) 2008 Elsevier Ltd. All Fights reserved..
46. Thomas Calzascia, Marc Pellegrini, Håkan Hall, Laurent Sabbagh, Nobuyuki Ono, Alisha R. Elford, Tak W. Mak, Pamela S. Ohashi, TNF-α is critical for antitumor but not antiviral T cell immunity in mice, Journal of Clinical Investigation, 10.1172/JCI32567, 117, 12, 3833-3845, 2007.12, TNF-α antagonists are widely used in the treatment of inflammatory and autoimmune diseases, but their use is associated with reactivation of latent infections. This highlights the importance of TNF-α in immunity to certain pathogens and raises concerns that critical aspects of immune function are impaired in its absence. Unfortunately, the role of TNF-α in the regulation of T cell responses is clouded by a myriad of contradictory reports. Here, we show a role for TNF-α and its receptors, TNFR1 and TNFR2, specifically in antitumor immunity. TNF-α-deficient mice exhibited normal antiviral responses associated with strong inflammation. However, TNF-α/TNFR1-mediated signals on APCs and TNF-α/TNFR2 signals on T cells were critically required for effective priming, proliferation, and recruitment of tumor-specific T cells. Furthermore, in the absence of TNF-α signaling, tumor immune surveillance was severely abrogated. Finally, treatment with a CD40 agonist alone or in combination with TLR2 stimuli was able to rescue proliferation of TNF-α-deficient T cells. Therefore, TNF-α signaling may be required only for immune responses in conditions of limited immunostimulatory capacity, such as tumor surveillance. Importantly, these results suggest that prolonged continuous TNF-α blockade in patients may have long-term complications, including potential tumor development or progression..
47. Thomas Calzascia, Marc Pellegrini, Hakan Hall, Laurent Sabbagh, Nobuyuki Ono, Alisha R. Elford, Tak W. Mak, Pamela S. Ohashi, TNF-alpha is critical for antitumor but not antiviral T cell immunity in mice, JOURNAL OF CLINICAL INVESTIGATION, 10.1172/JCI32567, 117, 12, 3833-3845, 2007.12, TNF-alpha antagonists are widely used in the treatment of inflammatory and autoimmune diseases, but their use is associated with reactivation of latent infections. This highlights the importance of TNF-alpha in immunity to certain pathogens and raises concerns that critical aspects of immune function are impaired in its absence. Unfortunately, the role of TNF-alpha in the regulation of T cell responses is clouded by a myriad of contradictory reports. Here, we show a role for TNF-a and its receptors, TNFR1 and TNFR2, specifically in antitumor immunity. TNF-alpha/deficient mice exhibited normal antiviral responses associated with strong inflammation. However, TNF-alpha/TNFR1-mediated signals on APCs and TNF-alpha/TNFR2 signals on T cells were critically required for effective priming, proliferation, and recruitment of tumor-specific T cells. Furthermore, in the absence of TNF-a signaling, tumor immune surveillance was severely abrogated. Finally, treatment with a CD40 agonist alone or in combination with TLR2 stimuli was able to rescue proliferation of TNF-alpha-deficient T cells. Therefore, TNF-alpha signaling may be required only for immune responses in conditions of limited immunostimulatory capacity, such as tumor surveillance. Importantly, these results suggest that prolonged continuous TNF-alpha blockade in patients may have long-term complications, including potential tumor development or progression..
48. Shinji Ohno, Nobuyuki Ono, Fumio Seki, Makoto Takeda, Shinobu Kura, Teruhisa Tsuzuki, Yusuke Yanagi, Measles virus infection of SLAM (CD150) knockin mice reproduces tropism and immunosuppression in human infection, Journal of virology, 10.1128/JVI.02134-06, 81, 4, 1650-1659, 2007.02, The human signaling lymphocyte activation molecule (SLAM, also called CD150), a regulator of antigen-driven T-cell responses and macrophage functions, acts as a cellular receptor for measles virus (MV), and its V domain is necessary and sufficient for receptor function. We report here the generation of SLAM knockin mice in which the V domain of mouse SLAM was replaced by that of human SLAM. The chimeric SLAM had an expected distribution and normal function in the knockin mice. Splenocytes from the SLAM knockin mice permitted the in vitro growth of a virulent MV strain but not that of the Edmonston vaccine strain. Unlike in vitro infection, MV could grow only in SLAM knockin mice that also lacked the type I interferon receptor (IFNAR). After intraperitoneal or intranasal inoculation, MV was detected in the spleen and lymph nodes throughout the body but not in the thymus. Notably, the virus appeared first in the mediastinal lymph node after intranasal inoculation. Splenocytes from MV-infected IFNAR-/- SLAM knockin mice showed suppression of proliferative responses to concanavalin A. Thus, MV infection of SLAM knockin mice reproduces lymphotropism and immunosuppression in human infection, serving as a useful small animal model for measles..
49. Shinji Ohno, Nobuyuki Ono, Fumio Seki, Makoto Takeda, Shinobu Kura, Teruhisa Tsuzuki, Yusuke Yanagi, Measles virus infection of SLAM (CD150) knockin mice reproduces tropism and immunosuppression in human infection, JOURNAL OF VIROLOGY, 10.1128/JVI.02134-06, 81, 4, 1650-1659, 2007.02, The human signaling lymphocyte activation molecule (SLAM, also called CD150), a regulator of antigen-driven T-cell responses and macrophage functions, acts as a cellular receptor for measles virus (MV), and its V domain is necessary and sufficient for receptor function. We report here the generation of SLAM knockin mice in which the V domain of mouse SLAM was replaced by that of human SLAM. The chimeric SLAM had an expected distribution and normal function in the knockin mice. Splenocytes from the SLAM knockin mice permitted the in vitro growth of a virulent MV strain but not that of the Edmonston vaccine strain. Unlike in vitro infection, NW could grow only in SLAM knockin mice that also lacked the type I interferon receptor (IFNAR). After intraperitoneal or intranasal inoculation, MV was detected in the spleen and lymph nodes throughout the body but not in the thymus. Notably, the virus appeared first in the mediastinal lymph node after intranasal inoculation. Splenocytes from MV-infected IFNAR(-/-) SLAM knockin mice showed suppression of proliferative responses to concanavalin A. Thus, MV infection of SLAM knockin mice reproduces lymphotropism and immunosuppression in human infection, serving as a useful small animal model for measles..
50. Megan M. McCausland, Isharat Yusuf, Hung Tran, Nobuyuki Ono, Yusuke Yanagi, Shane Crotty, SAP regulation of follicular helper CD4 T cell development and humoral immunity is independent of SLAM and Fyn kinase, Journal of Immunology, 10.4049/jimmunol.178.2.817, 178, 2, 817-828, 2007.01, Mutations in SH2D1A resulting in lack of SLAM-associated protein (SAP) expression cause the human genetic immunodeficiency X-linked lymphoproliferative disease. A severe block in germinal center development and lack of long-term humoral immunity is one of the most prominent phenotypes of SAP- mice. We show, in this study, that the germinal center block is due to an essential requirement for SAP expression in Ag-specific CD4 T cells to develop appropriate follicular helper T cell functions. It is unknown what signaling molecules are involved in regulation of SAP-dependent CD4 T cell help functions. SAP binds to the cytoplasmic tail of SLAM, and we show that SLAM is expressed on resting and activated CD4 T cells, as well as germinal center B cells. In addition, SAP can recruit Fyn kinase to SLAM. We have now examined the role(s) of the SLAM-SAP-Fyn signaling axis in in vivo CD4 T cell function and germinal center development. We observed normal germinal center development, long-lived plasma cell development, and Ab responses in SLAM-/- mice after a viral infection (lymphocytic choriomeningitis virus). In a separate series of experiments, we show that SAP is absolutely required in CD4 T cells to drive germinal center development, and that requirement does not depend on SAP-Fyn interactions, because CD4 T cells expressing SAP R78A are capable of supporting normal germinal center development. Therefore, a distinct SAP signaling pathway regulates follicular helper CD4 T cell differentiation, separate from the SLAM-SAP-Fyn signaling pathway regulating Th1/Th2 differentiation..
51. Megan M. McCausland, Isharat Yusuf, Hung Tran, Nobuyuki Ono, Yusuke Yanagi, Shane Crotty, SAP regulation of follicular helper CD4 T cell development and humoral immunity is independent of SLAM and Fyn kinase, JOURNAL OF IMMUNOLOGY, 10.4049/jimmunol.178.2.817, 178, 2, 817-828, 2007.01, Mutations in SH2D1A resulting in lack of SLAM-associated protein (SAP) expression cause the human genetic immunodeficiency X-linked lymphoproliferative disease. A severe block in germinal center development and lack of long-term Immoral immunity is one of the most prominent phenotypes of SAP(-) mice. We show, in this study, that the germinal center block is due to an essential requirement for SAP expression in Ag-specific CD4 T cells to develop appropriate follicular helper T cell functions. It is unknown what signaling molecules are involved in regulation of SAP-dependent CD4 T cell help functions. SAP binds to the cytoplasmic tail of SLAM, and we show that SLAM is expressed on resting and activated CD4 T cells, as well as germinal center B cells. In addition, SAP can recruit Fyn kinase to SLAM. We have now examined the role(s) of the SLAM-SAP-Fyn signaling axis in in vivo CD4 T cell function and germinal center development. We observed normal germinal center development, long-lived plasma cell development, and Ab responses in SLAM(-/-) mice after a viral infection (lymphocytic choriomeningitis virus). In a separate series of experiments, we show that SAP is absolutely required in CD4 T cells to drive germinal center development, and that requirement does not depend on SAP-Fyn interactions, because CD4 T cells expressing SAP R78A are capable of supporting normal germinal center development. Therefore, a distinct SAP signaling pathway regulates follicular helper CD4 T cell differentiation, separate from the SLAM-SAP-Fyn signaling pathway regulating Th1/Th2 differentiation..
52. Heidi Cheung, Nien Jung Chen, Zhaodan Cao, Nobuyuki Ono, Pamela S. Ohashi, Wen Chen Yeh, Accessory protein-like is essential for IL-18-mediated signaling, Journal of Immunology, 10.4049/jimmunol.174.9.5351, 174, 9, 5351-5357, 2005.05, IL-18 is an essential cytokine for both innate and adaptive immunity. Signaling by IL-18 requires IL-18Rα, which binds specifically to the ligand and contains sequence homology to IL-1R and TLRs. It is well established that IL-1R signaling requires an accessory cell surface protein, AcP. Other accessory proteins also exist with roles in regulating TLR signaling, but some have inhibitory functions. An AcP-like molecule (AcPL) has been identified with the ability to cooperate with IL-18Rα in vitro; however, the physiological function of AcPL remains unknown. In this study, we demonstrate that IL-18 signals are abolished in AcPL-deficient mice and cells. Splenocytes from mutant mice fail to respond to IL-18-induced proliferation and IFN-γ production. In particular, Th1 cells lacking AcPL fail to produce IFN-γ in response to IL-18. AcPL-deficient neutrophils also fail to respond to IL-18-induced activation and cytokine production. Furthermore, AcPL is required for NK-mediated cytotoxicity induced by in vivo IL-18 stimulation. However, AcPL is dispensable for the activation or inhibition of IL-1R and the various TLR signals that we have examined. These results suggest that AcPL is a critical and specific cell surface receptor that is required for IL-18 signaling..
53. H Cheung, NJ Chen, ZD Cao, N Ono, PS Ohashi, WC Yeh, Accessory protein-like is essential for IL-18-mediated signaling, JOURNAL OF IMMUNOLOGY, 10.4049/jimmunol.174.9.5351, 174, 9, 5351-5357, 2005.05, IL-18 is an essential cytokine for both innate and adaptive immunity. Signaling by IL-18 requires IL-18R alpha, which binds specifically to the ligand and contains sequence homology to IL-1R and TLRs. It is well established that IL-1R signaling requires an accessory cell surface protein, AcP. Other accessory proteins also exist with roles in regulating TLR signaling, but some have inhibitory functions. An AcP-like molecule (AcPL) has been identified with the ability to cooperate with IL-18Ra in vitro; however, the physiological function of AcPL remains unknown. In this study, we demonstrate that IL-18 signals are abolished in AcPL-deficient mice and cells. Splenocytes from mutant mice fail to respond to IL-18-induced proliferation and IFN-gamma production. In particular, Th1 cells lacking AcPL fail to produce IFN-gamma in response to IL-18. AcPL-deficient neutrophils also fail to respond to IL-18-induced activation and cytokine production. Furthermore, AcPL is required for NK-mediated cytotoxicity induced by in vivo IL-18 stimulation. However, AcPL is dispensable for the activation or inhibition of IL-1R and the various TLR signals that we have examined. These results suggest that AcPL is a critical and specific cell surface receptor that is required for IL-18 signaling..
54. Dominique Davidson, Xiaochu Shi, Shaohua Zhang, Hao Wang, Mona Nemer, Nobuyuki Ono, Shinji Ohno, Yusuke Yanagi, André Veillette, Genetic evidence linking SAP, the X-linked lymphoproliferative gene product, to Src-related kinase FynT in TH2 cytokine regulation, Immunity, 10.1016/j.immuni.2004.10.005, 21, 5, 707-717, 2004.11, SAP is an adaptor mutated in X-linked lymphoproliferative disease. It plays a critical role in T helper 2 (TH2) cytokine production. This function was suggested to reflect the capacity of SAP to associate with SLAM family receptors and enable tyrosine phosphorylation signaling by these receptors through SAP-mediated recruitment of Src-related kinase FynT. Here, we addressed by genetic means the importance of the SAP-FynT interaction in normal T cell functions. By creating a mouse in which the FynT binding site of SAP was inactivated in the germ line (sapR78A mouse) and by analyzing mice lacking SAP, FynT or SLAM, evidence was obtained that the SAP-FynT cascade is indeed crucial for normal TH2 functions in vitro and in vivo. These data imply that SAP is necessary for TH2 cytokine regulation primarily as a result of its capacity to recruit FynT. They also establish a previously unappreciated role for FynT in SAP-dependent TH2 cytokine regulation..
55. D Davidson, XC Shi, SH Zhang, H Wang, M Nemer, N Ono, SJ Ohno, Y Yanagi, A Veillette, Genetic evidence linking SAP, the X-linked lymphoproliferative gene product, to Src-related kinase FynT in T(H)2 cytokine regulation, IMMUNITY, 10.1016/j.immuni.2004.10.005, 21, 5, 707-717, 2004.11, SAP is an adaptor mutated in X-linked lymphoproliferative disease. It plays a critical role in T helper 2 (T(H)2) cytokine production. This function was suggested to reflect the capacity of SAP to associate with SLAM family receptors and enable tyrosine phosphorylation signaling by these receptors through SAP-mediated recruitment of Src-related kinase FynT. Here, we addressed by genetic means the importance of the SAP-FynT interaction in normal T cell functions. By creating a mouse in which the FynT binding site of SAP was inactivated in the germ line (sap(R78A) mouse) and by analyzing mice lacking SAP, FynT or SLAM, evidence was obtained that the SAP-FynT cascade is indeed crucial for normal T(H)2 functions in vitro and in vivo. These data imply that SAP is necessary for T(H)2 cytokine regulation primarily as a result of its capacity to recruit FynT. They also establish a previously unappreciated role for FynT in SAP-dependent T(H)2 cytokine regulation..
56. Shinji Ohno, Nobuyuki Ono, Makoto Takeda, Kaoru Takeuchi, Yusuke Yanagi, Dissection of measles virus V protein in relation to its ability to block alpha/beta interferon signal transduction, Journal of General Virology, 10.1099/vir.0.80308-0, 85, 10, 2991-2999, 2004.10, Interferon (IFN)-α and -β are the main cytokines for innate immune responses against viral infections. To replicate efficiently in the hosts, viruses have evolved various countermeasures to the IFN response. The V protein of measles virus (MV) has been shown to block IFN-α/β signalling. Here, the wild-type JC-B strain of MV was shown to grow comparably in the presence and absence of IFN-α, whereas replication of the Edmonston tag strain recovered from cloned DNA was strongly suppressed in its presence. The V protein of the IC-B strain, but not the Edmonston tag strain, blocked IFN-α signalling. The V protein of the Edmonston strain from the ATCC also inhibited IFN-α signalling. There were three amino acid differences between the V proteins of the Edmonston ATCC and tag strains, and substitutions of both residues at positions 110 and 272 were required for the Edmonston ATCC V protein to lose IFN-antagonist activity. The P protein of the IC-B strain, which shares the N-terminal 231 aa residues with the V protein, also inhibited IFN-α signalling. Indeed, fragments comprising only those 231 residues of the IC-B and Edmonston ATCC V proteins, but not the Edmonston tag V protein, were able to block IFN-α signalling. However, the N-terminal region of the Edmonston tag V protein, when attached to the C-terminal region of the Edmonston ATCC V protein, inhibited IFN-α signalling. Taken together, our results indicate that both the N- and C-terminal regions contribute to the IFN-antagonist activity of the MV V protein..
57. S Ohno, N Ono, M Takeda, K Takeuchi, Y Yanagi, Dissection of measles virus V protein in relation to its ability to block alpha/beta interferon signal transduction, JOURNAL OF GENERAL VIROLOGY, 10.1099/vir.0.80308-0, 85, Pt 10, 2991-2999, 2004.10, Interferon (IFN)-alpha and -beta are the main cytokines for innate immune responses against viral infections. To replicate efficiently in the hosts, viruses have evolved various countermeasures to the IFN response. The V protein of measles virus (MV) has been shown to block IFN-alpha/beta signalling. Here, the wild-type IC-B strain of MV was shown to grow comparably in the presence and absence of IFN-alpha, whereas replication of the Edmonston tag strain recovered from cloned DNA was strongly suppressed in its presence. The V protein of the IC-B strain, but not the Edmonston tag strain, blocked IFN-alpha signalling. The V protein of the Edmonston strain from the ATCC also inhibited IFN-alpha signalling. There were three amino acid differences between the V proteins of the Edmonston ATCC and tag strains, and substitutions of both residues at positions 110 and 272 were required for the Edmonston ATCC V protein to lose IFN-antagonist activity. The P protein of the IC-B strain, which shares the N-terminal 231 aa residues with the V protein, also inhibited IFN-alpha signalling. Indeed, fragments comprising only those 231 residues of the IC-B and Edmonston ATCC V proteins, but not the Edmonston tag V protein, were able to block IFN-alpha signalling. However, the N-terminal region of the Edmonston tag V protein, when attached to the C-terminal region of the Edmonston ATCC V protein, inhibited IFN-alpha signalling. Taken together, our results indicate that both the N- and C-terminal regions contribute to the IFN-antagonist activity of the MV V protein..
58. Douglas G. Millar, Kristine M. Garza, Bernhard Odermatt, Alisha R. Elford, Nobuyuki Ono, Zihai Li, Pamela S. Ohashi, Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo, Nature medicine, 10.1038/nm962, 9, 12, 1469-1476, 2003.12, Pathogens or pathogen-associated molecular patterns can signal to cells of the innate immune system and trigger effective adaptive immunity. However, relatively little is known about how the innate immune system detects tissue injury or necrosis. Evidence suggests that the release of heat-shock proteins (HSPs) may provide adjuvant-like signals, but the ability of HSPs to promote activation or tolerance in vivo has not been addressed. In this study we show that Hsp70 promotes dendritic cell (DC) function and, together with antigen, triggers autoimmune disease in vivo..
59. DG Millar, KM Garza, B Odermatt, AR Elford, N Ono, Z Li, PS Ohashi, Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo, NATURE MEDICINE, 10.1038/nm962, 9, 12, 1469-1476, 2003.12, Pathogens or pathogen- associated molecular patterns can signal to cells of the innate immune system and trigger effective adaptive immunity. However, relatively little is known about how the innate immune system detects tissue injury or necrosis. Evidence suggests that the release of heat- shock proteins (HSPs) may provide adjuvant- like signals, but the ability of HSPs to promote activation or tolerance in vivo has not been addressed. In this study we show that Hsp70 promotes dendritic cell (DC) function and, together with antigen, triggers autoimmune disease in vivo..
60. Fumio Seki, Nobuyuki Ono, Ryoji Yamaguchi, Yusuke Yanagi, Efficient isolation of wild strains of canine distemper virus in Vero cells expressing canine SLAM (CD150) and their adaptability to marmoset B95a cells, Journal of virology, 10.1128/JVI.77.18.9943-9950.2003, 77, 18, 9943-9950, 2003.09, We have previously shown that canine signaling lymphocyte activation molecule (SLAM; also known as CD150) acts as a cellular receptor for canine distemper virus (CDV). In this study, we established Vero cells stably expressing canine SLAM (Vero.DogSLAMtag cells). Viruses were isolated in Vero.DogSLAMtag cells one day after inoculation with spleen samples from five out of seven dogs with distemper. By contrast, virus isolation with reportedly sensitive marmoset B95a cells was only successful from three diseased animals at 7 to 10 days after inoculation, and no virus was recovered from any dogs when Vero cells were used for isolation. The CDV strain isolated in Vero.DogSLAMtag cells did not cause cytopathic effects in B95a and human SLAM-expressing Vero cells, whereas the strain isolated in B95a cells from the same dog did so in canine or human SLAM-expressing Vero cells as well as B95a cells. There were two amino acid differences in the hemagglutinin sequence between these strains. Cell fusion analysis after expression of envelope proteins and vesicular stomatitis virus pseudotype assay showed that their hemagglutinins were responsible for the difference in cell tropism between them. Site-directed mutagenesis indicated that glutamic acid to lysine substitution at position 530 of the hemagglutinin was required for the adaptation to the usage of marmoset SLAM. Our results indicate that Vero cells stably expressing canine SLAM are highly sensitive to CDV in clinical specimens and that only a single amino acid substitution in the hemagglutinin can allow the virus to adapt to marmoset SLAM..
61. Shinji Ohno, Fumio Seki, Nobuyuki Ono, Yusuke Yanagi, Histidine at position 61 and its adjacent amino acid residues are critical for the ability of SLAM (CD150) to act as a cellular receptor for measles virus, Journal of General Virology, 10.1099/vir.0.19248-0, 84, 9, 2381-2388, 2003.09, Signalling lymphocyte activation molecule (SLAM, also known as CD150), a membrane glycoprotein involved in lymphocyte activation, has two extracellular immunoglobulin superfamily domains, V and C2. It has been shown previously that human SLAM is a cellular receptor for measles virus (MV) and that its V domain is necessary and sufficient for receptor function. Although mouse SLAM has functional and structural similarity to human SLAM, it hardly acts as a receptor for MV. By producing human/mouse chimeric molecules and assessing their receptor function with a vesicular stomatitis virus pseudotype assay, the region at amino acid positions 58-67 was found to be critically responsible for the difference in MV receptor function between human and mouse SLAMs. Exchange of this region allowed mouse SLAM to act as a receptor for MV, almost comparable to human SLAM. Among three amino acid differences (positions 60, 61 and 63) in this region, histidine 61 present in human SLAM was most significant, but combined substitutions with this residue and one or both of isoleucine 60 and valine 63 increased further the receptor activity of mouse SLAM. On the other hand, converse substitution at position 61 compromised receptor function of human SLAM. Thus, histidine 61 and its adjacent residues at positions 60 and 63 are critical for SLAM to act as a receptor for MV. Notably, the pseudotype assay indicated that residues at these three positions are also critical for the function of SLAM as a receptor for canine distemper virus..
62. F Seki, N Ono, R Yamaguchi, Y Yanagi, Efficient isolation of wild strains of canine distemper virus in Vero cells expressing canine SLAM (CD150) and their adaptability to marmoset B95a cells, JOURNAL OF VIROLOGY, 10.1128/JVI.77.18.9943-9950.2003, 77, 18, 9943-9950, 2003.09, We have previously shown that canine signaling lymphocyte activation molecule (SLAM; also known as CD150) acts as a cellular receptor for canine distemper virus (CDV). In this study, we established Vero cells stably expressing canine SLAM (Vero.DogSLAMtag cells). Viruses were isolated in Vero.DogSLAMtag cells one day after inoculation with spleen samples from five out of seven dogs with distemper. By contrast, virus isolation with reportedly sensitive marmoset B95a cells was only successful from three diseased animals at 7 to 10 days after inoculation, and no virus was recovered from any dogs when Vero cells were used for isolation. The CDV strain isolated in Vero.DogSLAMtag cells did not cause cytopathic effects in B95a and human SLAM-expressing Vero cells, whereas the strain isolated in B95a cells from the same dog did so in canine or human SLAM-expressing Vero cells as well as B95a cells. There were two amino acid differences in the hemagglutinin sequence between these strains. Cell fusion analysis after expression of envelope proteins and vesicular stomatitis virus pseudotype assay showed that their hemagglutinins were responsible for the difference in cell tropism between them. Site-directed mutagenesis indicated that glutamic acid to lysine substitution at position 530 of the hemagglutinin was required for the adaptation to the usage of marmoset SLAM. Our results indicate that Vero cells stably expressing canine SLAM are highly sensitive to CDV in clinical specimens and that only a single amino acid substitution in the hemagglutinin can allow the virus to adapt to marmoset SLAM..
63. S Ohno, F Seki, N Ono, Y Yanagi, Histidine at position 61 and its adjacent amino acid residues are critical for the ability of SLAM (CD150) to act as a cellular receptor for measles virus, JOURNAL OF GENERAL VIROLOGY, 10.1099/vir.0.19248-0, 84, Pt 9, 2381-2388, 2003.09, Signalling lymphocyte activation molecule (SLAM, also known as CD150), a membrane glycoprotein involved in lymphocyte activation, has two extracellular immunoglobulin superfamily domains, V and C2. It has been shown previously that human SLAM is a cellular receptor for measles virus (MV) and that its V domain is necessary and sufficient for receptor function. Although mouse SLAM has functional and structural similarity to human SLAM, it hardly acts as a receptor for MV. By producing human/mouse chimeric molecules and assessing their receptor function with a vesicular stomatitis virus pseudotype assay, the region at amino acid positions 58-67 was found to be critically responsible for the difference in MV receptor function between human and mouse SLAMs. Exchange of this region allowed mouse SLAM to act as a receptor for MV, almost comparable to human SLAM. Among three amino acid differences (positions 60,61 and 63) in this region, histidine 61 present in human SLAM was most significant, but combined substitutions with this residue and one or both of isoleucine 60 and valine 63 increased further the receptor activity of mouse SLAM. On the other hand, converse substitution at position 61 compromised receptor function of human SLAM. Thus, histidine 61 and its adjacent residues at positions 60 and 63 are critical for SLAM to act as a receptor for MV. Notably, the pseudotype assay indicated that residues at these three positions are also critical for the function of SLAM as a receptor for canine distemper virus..
64. Y Yanagi, N Ono, H Tatsuo, K Hashimoto, H Minagawa, Measles virus receptor SLAM (CD150), VIROLOGY, 10.1006/viro.2002.1471, 299, 2, 155-161, 2002.08.
65. K Hashimoto, N Ono, H Tatsuo, H Minagawa, M Takeda, K Takeuchi, Y Yanagi, SLAM (CD150)-independent measles virus entry as revealed by recombinant virus expressing green fluorescent protein, JOURNAL OF VIROLOGY, 10.1128/JVI.76.13.6743-6749.2002, 76, 13, 6743-6749, 2002.07, Wild-type measles virus (MV) strains use human signaling lymphocyte activation molecule (SLAM) as a cellular receptor, while vaccine strains such as the Edmonston strain can use both SLAM and CD46 as receptors. Although the expression of SLAM is restricted to cells of the immune system (lymphocytes, dendritic cells, and monocytes), histopathological studies with humans and experimentally infected monkeys have shown that MV also infects SLAM-negative cells, including epithelial, endothelial, and neuronal cells. In an attempt to explain these findings, we produced the enhanced green fluorescent protein (EGFP) -expressing recombinant MV (IC323-EGFP) based on the wild-type IC-B strain. IC323-EGFP showed almost the same growth kinetics as the parental recombinant MV and produced large syncytia exhibiting green autofluorescence in SLAM-positive cells. Interestingly, all SLAM-negative cell lines examined also showed green autofluorescence after infection with IC323-EGFP, although the virus hardly spread from the originally infected individual cells and thus did not induce syncytia. When the number of EGFP-expressing cells after infection was taken as an indicator, the infectivities of IC323-EGFP for SLAM-negative cells were 2 to 3 logs lower than those for SLAM-positive cells. Anti-MV hemagglutinin antibody or fusion block peptide, but not anti-CD46 antibody, blocked IC323-EGFP infection of SLAM-negative cells. This infection occurred under conditions in which entry via endocytosis was inhibited. These results indicate that W can infect a variety of cells, albeit with a low efficiency, by using an as yet unidentified receptor(s) other than SLAM or CD46, in part explaining the observed MV infection of SLAM-negative cells in vivo..
66. Koji Hashimoto, Nobuyuki Ono, Hironobu Tatsuo, Hiroko Minagawa, Makoto Takeda, Kaoru Takeuchi, Yusuke Yanagi, SLAM (CD150)-Independent measles virus entry as revealed by recombinant virus expressing green fluorescent protein, Journal of virology, 10.1128/JVI.76.13.6743-6749.2002, 76, 13, 6743-6749, 2002.06, Wild-type measles virus (MV) strains use human signaling lymphocyte activation molecule (SLAM) as a cellular receptor, while vaccine strains such as the Edmonston strain can use both SLAM and CD46 as receptors. Although the expression of SLAM is restricted to cells of the immune system (lymphocytes, dendritic cells, and monocytes), histopathological studies with humans and experimentally infected monkeys have shown that MV also infects SLAM-negative cells, including epithelial, endothelial, and neuronal cells. In an attempt to explain these findings, we produced the enhanced green fluorescent protein (EGFP)-expressing recombinant MV (IC323-EGFP) based on the wild-type IC-B strain. IC323-EGFP showed almost the same growth kinetics as the parental recombinant MV and produced large syncytia exhibiting green autofluorescence in SLAM positive cells. Interestingly, all SLAM-negative cell lines examined also showed green autofluorescence after infection with IC323-EGFP, although the virus hardly spread from the originally infected individual cells and thus did not induce syncytia. When the number of EGFP-expressing cells after infection was taken as an indicator, the infectivities of IC323-EGFP for SLAM-negative cells were 2 to 3 logs lower than those for SLAM-positive cells. Anti-MV hemagglutinin antibody or fusion block peptide, but not anti-CD46 antibody, blocked IC323-EGFP infection of SLAM-negative cells. This infection occurred under conditions in which entry via endocytosis was inhibited. These results indicate that MV can infect a variety of cells, albeit with a low efficiency, by using an as yet unidentified receptor(s) other than SLAM or CD46, in part explaining the observed MV infection of SLAM-negative cells in vivo..
67. Yusuke Yanagi, Nobuyuki Ono, Hironobu Tatsuo, Koji Hashimoto, Hiroko Minagawa, Measles virus receptor SLAM (CD150), Virology, 10.1006/viro.2002.1471, 299, 2, 155-161, 2002.01.
68. H Minagawa, K Tanaka, N Ono, H Tatsuo, Y Yanagi, Induction of the measles virus receptor SLAM (CD150) on monocytes, JOURNAL OF GENERAL VIROLOGY, 10.1099/0022-1317-82-12-2913, 82, 2913-2917, 2001.12, Wild-type strains of measles virus (MV) isolated in B95a cells use the signalling lymphocyte activation molecule (SLAM; also known as CD1 50) as a cellular receptor, whereas the Edmonston strain and its derivative vaccine strains can use both SLAM and the ubiquitously expressed CD46 as receptors. Among the major target cells for MV, lymphocytes and dendritic cells are known to express SLAM after activation, but monocytes have been reported to be SLAM-negative. In this study, SLAM expression on monocytes was examined under different conditions. When freshly isolated from the peripheral blood, monocytes did not express SLAM on the cell surface. However, monocytes became SLAM-positive after incubation with phytohaemagglutinin, bacterial lipopolysaccharide or MV. Anti-SLAM monoclonal antibodies efficiently blocked infection of activated monocytes with a wild-type strain of MV. These results indicate that SLAM is readily induced and acts as a monocyte receptor for MV..
69. H. Tatsuo, N. Ono, Y. Yanagi, Morbilliviruses use signaling lymphocyte activation molecules (CD150) as cellular receptors, Journal of virology, 10.1128/JVI.75.13.5842-5850.2001, 75, 13, 5842-5850, 2001.07, Morbilliviruses comprise measles virus, canine distemper virus, rinderpest virus, and several other viruses that cause devastating human and animal diseases accompanied by severe immunosuppression and lymphopenia. Recently, we have shown that human signaling lymphocyte activation molecule (SLAM) is a cellular receptor for measles virus. In this study, we examined whether canine distemper and rinderpest viruses also use canine and bovine SLAMs, respectively, as cellular receptors. The Onderstepoort vaccine strain and two B95a (marmoset B cell line)-isolated strains of canine distemper virus caused extensive cytopathic effects in normally resistant CHO (Chinese hamster ovary) cells after expression of canine SLAM. The Ako vaccine strain of rinderpest virus produced strong cytopathic effects in bovine SLAM-expressing CHO cells. The data on entry with vesicular stomatitis virus pseudotypes bearing measles, canine distemper, or rinderpest virus envelope proteins were consistent with development of cytopathic effects in SLAM-expressing CHO cell clones after infection with the respective viruses, confirming that SLAM acts at the virus entry step (as a cellular receptor). Furthermore, most measles, canine distemper, and rinderpest virus strains examined could any use of the human, canine, and bovine SLAMs to infect cells. Our findings suggest that the use of SLAM as a cellular receptor may be a property common to most, if not all, morbilliviruses and explain the lymphotropism and immunosuppressive nature of morbilliviruses..
70. H Tatsuo, N Ono, Y Yanagi, Morbilliviruses use signaling lymphocyte activation molecules (CD150) as cellular receptors, JOURNAL OF VIROLOGY, 10.1128/JVI.75.13.5842-5850.2001, 75, 13, 5842-5850, 2001.07, Morbilliviruses comprise measles virus, canine distemper virus, rinderpest virus, and several other viruses that cause devastating human and animal diseases accompanied by severe immunosuppression and lymphopenia. Recently, we have shown that human signaling lymphocyte activation molecule (SLAM) is a cellular receptor for measles virus. In this study, we examined whether canine distemper and rinderpest viruses also use canine and bovine SLAMs, respectively, as cellular receptors. The Onderstepoort vaccine strain and two B95a (marmoset B cell line)-isolated strains of canine distemper virus caused extensive cytopathic effects in normally resistant CHO (Chinese hamster ovary) cells after expression of canine SLAP(I, The Ako vaccine strain of rinderpest virus produced strong cytopathic effects in bovine SLAM-expressing CHO cells. The data on entry with vesicular stomatitis virus pseudotypes bearing measles, canine distemper, or rinderpest virus envelope proteins were consistent with development of cytopathic effects in SLAM-expressing CHO cell clones after infection with the respective viruses, confirming that SLAM acts at the virus entry step las a cellular receptor). Furthermore, most measles, canine distemper, and rinderpest virus strains examined could any use of the human, canine, and bovine SLAMs to infect cells, Our findings suggest that the use of SLAM as a cellular receptor may be a property common to most, if not all, morbilliviruses and explain the lymphotropism and immunosuppressive nature of morbilliviruses..
71. N. Ono, H. Tatsuo, Y. Hidaka, T. Aoki, H. Minagawa, Y. Yanagi, Measles viruses on throat swabs from measles patients use signaling lymphocytic activation molecule (CDw150) but not CD46 as a cellular receptor, Journal of virology, 10.1128/JVI.75.9.4399-4401.2001, 75, 9, 4399-4401, 2001.05, Both CD46 and signaling lymphocytic activation molecule (SLAM) have been shown to act as cellular receptors for measles virus (MV). The viruses on throat swabs from nine patients with measles in Japan were titrated on Vero cells stably expressing human SLAM. Samples from all but two patients produced numerous plaques on SLAM-expressing Vero cells, whereas none produced any plaques on Vero cells endogenously expressing CD46. The Edmonston strain of MV, which can use either CD46 or SLAM as a receptor, produced comparable titers on these two types of cells. The results strongly suggest that the viruses in the bodies of measles patients use SLAM but probably not CD46 as a cellular receptor..
72. N Ono, H Tatsuo, Y Hidaka, T Aoki, H Minagawa, Y Yanagi, Measles viruses on throat swabs from measles patients use signaling lymphocytic activation molecule (CDw150) but not CD46 as a cellular receptor, JOURNAL OF VIROLOGY, 10.1128/JVI.75.9.4399-4401.2001, 75, 9, 4399-4401, 2001.05, Both CD46 and signaling lymphocytic activation molecule (SLAM) have been shown to act as cellular receptors for measles virus (MV). The viruses on throat swabs from nine patients with measles in Japan were titrated on Vero cells stably expressing human SLAM. Samples from all but two patients produced numerous plaques on SLAM-expressing Vero cells, whereas none produced any plaques on Vero cells endogenously expressing CD46. The Edmonston strain of MV, which can use either CD46 or SLAM as a receptor, produced comparable titers on these two types of cells. The results strongly suggest that the viruses in the bodies of measles patients use SLAM but probably not CD46 as a cellular receptor..
73. N. Ono, H. Tatsuo, K. Tanaka, H. Minagawa, Y. Yanagi, V domain of human SLAM (CDw150) is essential for its function as a measles virus receptor, Journal of virology, 10.1128/JVI.75.4.1594-1600.2001, 75, 4, 1594-1600, 2001.02, Human signaling lymphocytic activation molecule (SLAM; also known as CDw150) has been shown to be a cellular receptor for measles virus (MV). Chinese hamster ovary cells transfected with a mouse SLAM cDNA were not susceptible to MV and the vesicular stomatitis virus pseudotype bearing MV envelope proteins alone, indicating that mouse SLAM cannot act as an MV receptor. To determine the functional domain of the receptor, we tested the abilities of several chimeric SLAM proteins to function as MV receptors. The ectodomain of SLAM comprises the two immunoglobulin superfamily domains (V and C2). Various chimeric transmembrane proteins possessing the V domain of human SLAM were able to act as MV receptors, whereas a chimera consisting of human SLAM containing the mouse V domain instead of the human V domain no longer acted as a receptor. To examine the interaction between SLAM and MV envelope proteins, recombinant soluble forms of SLAM were produced. The soluble molecules possessing the V domain of human SLAM were shown to bind to cells expressing the MV hemagglutinin (H) protein but not to cells expressing the MV fusion protein or irrelevant envelope proteins. These results indicate that the V domain of human SLAM is necessary and sufficient to interact with the MV H protein and allow MV entry..
74. N Ono, H Tatsuo, K Tanaka, H Minagawa, W Yanagi, V domain of human SLAM (CDw150) is essential for its function as a measles virus receptor, JOURNAL OF VIROLOGY, 10.1128/JVI.75.4.1594-1600.2001, 75, 4, 1594-1600, 2001.02, Human signaling lymphocytic activation molecule (SLAM; also known as CDw150) has been shown to be a cellular receptor for measles virus (MV). Chinese hamster ovary cells transfected with a mouse SLAM cDNA were not susceptible to MV and the vesicular stomatitis virus pseudotype bearing MV envelope proteins alone, indicating that mouse SLAR I cannot act as an MV receptor. To determine the functional domain of the receptor, we tested the abilities of several chimeric SLAM proteins to function as MV receptors. The ectodomain of SLAM comprises the two immunoglobulin superfamily domains (V and C2). Various chimeric transmembrane proteins possessing the V domain of human SLAM mere able to act as MV receptors, whereas a chimera consisting of human SLAM containing the mouse V domain instead of the human V domain no longer acted as a receptor. To examine the interaction between SLAM and MV envelope proteins, recombinant soluble forms of SLAM were produced. The soluble molecules possessing the V domain of human SLAM were shown to bind to cells expressing the MV hemagglutinin (H) protein but not to cells expressing the MV fusion protein or irrelevant envelope proteins. These results indicate that the V domain of human SLAM is necessary and sufficient to interact with the MV H protein and allow MV entry..
75. H. Minagawa, K. Tanaka, N. Ono, H. Tatsuo, Y. Yanagi, Induction of the measles virus receptor SLAM (CD150) on monocytes, Journal of General Virology, 10.1099/0022-1317-82-12-2913, 82, 12, 2913-2917, 2001.01, Wild-type strains of measles virus (MV) isolated in B95a cells use the signalling lymphocyte activation molecule (SLAM; also known as CD 150) as a cellular receptor, whereas the Edmonston strain and its derivative vaccine strains can use both SLAM and the ubiquitously expressed CD46 as receptors. Among the major target cells for MV, lymphocytes and dendritic cells are known to express SLAM after activation, but monocytes have been reported to be SLAM-negative. In this study, SLAM expression on monocytes was examined under different conditions. When freshly isolated from the peripheral blood, monocytes did not express SLAM on the cell surface. However, monocytes became SLAM-positive after incubation with phytohaemagglutinin, bacterial lipopolysaccharide or MV. Anti-SLAM monoclonal antibodies efficiently blocked infection of activated monocytes with a wild-type strain of MV. These results indicate that SLAM is readily induced and acts as a monocyte receptor for MV..
76. H. Tatsuo, N. Ono, K. Tanaka, Y. Yanagi, The cellular receptor for measles virus
SLAM (CDw 150), Uirusu. Journal of virology, 10.2222/jsv.50.289, 50, 2, 289-296, 2000.12.
77. [The cellular receptor for measles virus: SLAM (CDw 150)]..
78. Hironobu Tatsuo, Nobuyukl Ono, Kotaro Tanaka, Yusuke Yanagi, Slam (CDw150) is a cellular receptor for measles virus, Nature, 10.1038/35022579, 406, 6798, 893-897, 2000.08, Measles virus continues to be a major killer of children, claiming roughly one million lives a year. Measles virus infection causes profound immunosuppression, which makes measles patients susceptible to secondary infections accounting for high morbidity and mortality. The Edmonston strain of measles virus, and vaccine strains derived from it, use as a cellular receptor human CD46 (refs 3, 4), which is expressed on all nucleated cells; however, most clinical isolates of measles virus cromer use CD46 as a receptor. Here we show that human SLAM (signalling lymphocyte-activation molecule; also known as CDw150), a recently discovered membrane glycoprotein expressed on some Tand B cells, is a cellular receptor for measles virus, including the Edmonston strain. Transfection with a human SLAM complementary DNA enables non-susceptible cell lines to bind measles virus, support measles virus replication and develop cytopathic effects. The distribution of SLAM on various cell lines is consistent with their susceptibility to clinical isolates of measles virus. The identification of SLAM as a receptor for measles virus opens the way to a better understanding Of the pathogenesis of measles virus infection, especially the immunosuppression induced by measles virus..
79. H Tatsuo, N Ono, K Tanaka, Y Yanagi, SLAM (CDw150) is a cellular receptor for measles virus, NATURE, 10.1038/35022579, 406, 6798, 893-897, 2000.08, Measles virus continues to be a major killer of children, claiming roughly one million lives a year(1). Measles virus infection causes profound immunosuppression, which makes measles patients susceptible to secondary infections accounting for high morbidity and mortality(2). The Edmonston strain of measles virus, and vaccine strains derived from it, use as a cellular receptor human CD46 (refs 3, 4), which is expressed on all nucleated cells; however, most clinical isolates of measles virus cannot use CD46 as a receptor(5). Here we show that human SLAM (signalling lymphocyte-activation molecule; also known as CDw150), a recently discovered membrane glycoprotein expressed on some T and B cells(6), is a cellular receptor for measles virus, including the Edmonston strain. Transfection with a human SLAM complementary DNA enables non-susceptible cell lines to bind measles virus, support measles virus replication and develop cytopathic effects. The distribution of SLAM on various cell lines is consistent with their susceptibility to clinical isolates of measles virus. The identification of SLAM as a receptor for measles virus opens the way to a better understanding of the pathogenesis of measles virus infection, especially the immunosuppression induced by measles virus..
80. Hironobu Tatsuo, Kazu Okuma, Kotaro Tanaka, Nobuyiki Ono, Hiroko Minagawa, Akemi Takade, Yoshiharu Matsuura, Yusuke Yanagi, Virus entry is a major determinant of cell tropism of Edmonston and wild-type strains of measles virus as revealed by vesicular stomatitis virus pseudotypes bearing their envelope proteins, Journal of virology, 10.1128/JVI.74.9.4139-4145.2000, 74, 9, 4139-4145, 2000.05, The Edmonston strain of measles virus (MV) that utilizes the human CD46 as the cellular receptor produced cytopathic effects (CPE) in all of the primate cell lines examined. In contrast, the wild-type MV strains isolated in a marmoset B-cell line B95a (the KA and Ichinose strains) replicated and produced CPE in some but not all of the primate lymphoid cell lines. To determine the mechanism underlying this difference in cell tropism, we used a recently developed recombinant vesicular stomatitis virus (VSV) containing as a reporter the green fluorescent protein gene in lieu of the VSV G protein gene (VSVΔG*). MV glycoproteins were efficiently incorporated into VSVΔG*, producing the VSV pseudotypes. VSVΔG* complemented with VSV G protein efficiently infected all of the cell lines tested. The VSV pseudotype bearing the Edmonston hemagglutinin (H) and fusion (F) protein (VSVΔG*- EdHF) infected all cell lines in which the Edmonston strain caused CPE, including the rodent cell lines to which the human CD46 gene was stably transfected. The pseudotype bearing the wild-type KA H protein and Edmonston F protein (VSVΔG*-KAHF) infected all lymphoid cell lines in which the wild- type MV strains caused CPE as efficiently as VSVΔG*-EdHF, but it did not infect any of the cell lines resistant to infection with the KA strain. The results indicate that the difference in cell tropism between these MV strains was largely determined by virus entry, in which the H proteins of respective MV strains play a decisive role..
81. H Tatsuo, K Okuma, K Tanaka, N Ono, H Minagawa, A Takade, Y Matsuura, Y Yanagi, Virus entry is a major determinant of cell tropism of Edmonston and wild-type strains of measles virus as revealed by vesicular stomatitis virus pseudotypes bearing their envelope proteins, JOURNAL OF VIROLOGY, 10.1128/jvi.74.9.4139-4145.2000, 74, 9, 4139-4145, 2000.05, The Edmonston strain of measles virus (MV) that utilizes the human CD46 as the cellular receptor produced cytopathic effects (CPE) in all of the primate cell lines examined. In contrast, the wild-type MV strains isolated in a marmoset B-cell line B95a (the KA and Ichinose strains) replicated and produced CPE in some but not all of the primate lymphoid cell lines. To determine the mechanism underlying this difference in cell tropism, we used a recently developed recombinant vesicular stomatitis virus (VSV) containing as a reporter the green fluorescent protein gene in lieu of the VSV G protein gene (VSV Delta G*). MV glycoproteins were efficiently incorporated into VSV Delta G*, producing the VSV pseudotypes. VSV Delta G* complemented with VSV G protein efficiently infected all of the cell lines tested. The VSV pseudotype bearing the Edmonston hemagglutinin (H) and fusion (F) protein (VSV Delta G*-EdHF) infected all cell lines in which the Edmonston strain caused CPE, including the rodent cell lines to which the human CD46 gene was stably transfected. The pseudotype bearing the wild-type KA H protein and Edmonston F protein (VSV Delta G*-KAHF) infected all lymphoid cell lines in which the wild type MV strains caused CPE as efficiently as VSV Delta G*-EdHF, but it did not infect any of the cell lines resistant to infection with the KA strain. The results indicate that the difference in cell tropism between these MV strains was largely determined by virus entry, in which the H proteins of respective MV strains play a decisive role..
82. M. F. Xie, K. Tanaka, N. Ono, H. Minagawa, Y. Yanagi, Amino acid substitutions at position 481 differently affect the ability of the measles virus hemagglutinin to induce cell fusion in monkey and marmoset cells co-expressing the fusion protein, Archives of Virology, 10.1007/s007050050697, 144, 9, 1689-1699, 1999.10, Summary. The hemagglutinin (H) protein of the measles virus (MV) Edmonston strain induced cell fusion in Cos (monkey) and B95a (marmoset) cells, when co-expressed with the fusion (F) protein, whereas the H protein of the wild-type KA strain induced fusion in B95a cells, but not in Cos cells. Asparagine residue at position 481 of the KA H protein was replaced by various amino acids through site-directed mutagenesis. Substitution with tyrosine, which was found at position 481 of the Edmonston H protein, enabled the mutant KA H protein (N481Y) to induce cell fusion in Cos cells co-expressing the F protein, which could be completely blocked by anti-CD46 antibody. This mutant, however, did not cause CD46 downregulation, unlike the Edmonston H protein. The other H protein mutants (N481S, N481T, N481D, N481H, N481F) did not produce syncytia in Cos cells. On the other hand, all of the mutants retained the ability to induce cell fusion in B95a cells. Thus, while tyrosine at position 481 was indispensable for the MV H protein's interaction with CD46, the residue at this position does not appear to be critically involved in the interaction with the receptor for wild-type strains present on B95a cells..