Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Tomohiro Morio is active.

Publication


Featured researches published by Tomohiro Morio.


Cell | 2008

Tyrosine Kinases Btk and Tec Regulate Osteoclast Differentiation by Linking RANK and ITAM Signals

Masahiro Shinohara; Takako Koga; Kazuo Okamoto; Shinya Sakaguchi; Kimiko Arai; Hisataka Yasuda; Toshiyuki Takai; Tatsuhiko Kodama; Tomohiro Morio; Raif S. Geha; Daisuke Kitamura; Tomohiro Kurosaki; Wilfried Ellmeier; Hiroshi Takayanagi

Certain autoimmune diseases result in abnormal bone homeostasis, but association of immunodeficiency with bone is poorly understood. Osteoclasts, which derive from bone marrow cells, are under the control of the immune system. Differentiation of osteoclasts is mainly regulated by signaling pathways activated by RANK and immune receptors linked to ITAM-harboring adaptors. However, it is unclear how the two signals merge to cooperate in osteoclast differentiation. Here we report that mice lacking the tyrosine kinases Btk and Tec show severe osteopetrosis caused by a defect in bone resorption. RANK and ITAM signaling results in formation of a Btk(Tec)/BLNK(SLP-76)-containing complex and PLCgamma-mediated activation of an essential calcium signal. Furthermore, Tec kinase inhibition reduces osteoclastic bone resorption in models of osteoporosis and inflammation-induced bone destruction. Thus, this study reveals the importance of the osteoclastogenic signaling complex composed of tyrosine kinases, which may provide the molecular basis for a new therapeutic strategy.


Nature | 2010

I[kgr]B[zgr] regulates TH17 development by cooperating with ROR nuclear receptors

Kazuo Okamoto; Yoshiko Iwai; Masatsugu Oh-hora; Masahiro Yamamoto; Tomohiro Morio; Kazuhiro Aoki; Keiichi Ohya; Anton M. Jetten; Shizuo Akira; Tatsushi Muta; Hiroshi Takayanagi

Interleukin (IL)-17-producing helper T (TH17) cells are a distinct T-cell subset characterized by its pathological role in autoimmune diseases. IL-6 and transforming growth factor-β (TGF-β) induce TH17 development, in which the orphan nuclear receptors, RORγt and RORα, have an indispensable role. However, in the absence of IL-6 and TGF-β, the ectopic expression of RORγt or RORα leads to only a modest IL-17 production. Here we identify a nuclear IκB family member, IκBζ (encoded by the Nfkbiz gene), as a transcription factor required for TH17 development in mice. The ectopic expression of IκBζ in naive CD4+ T cells together with RORγt or RORα potently induces TH17 development, even in the absence of IL-6 and TGF-β. Notably, Nfkbiz-/- mice have a defect in TH17 development and a resistance to experimental autoimmune encephalomyelitis (EAE). The T-cell-intrinsic function of IκBζ was clearly demonstrated by the resistance to EAE of the Rag2-/- mice into which Nfkbiz-/- CD4+ T cells were transferred. In cooperation with RORγt and RORα, IκBζ enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. This study provides evidence for the transcriptional mechanisms underlying TH17 development and points to a molecular basis for a novel therapeutic strategy against autoimmune disease.


The Journal of Infectious Diseases | 2003

Prognostic Factors for Chronic Active Epstein-Barr Virus Infection

Hiroshi Kimura; Tsuneo Morishima; Hirokazu Kanegane; Shouichi Ohga; Yo Hoshino; Akihiko Maeda; Shosuke Imai; Motohiko Okano; Tomohiro Morio; Shumpei Yokota; Shigeru Tsuchiya; Akihiro Yachie; Shinsaku Imashuku; Keisei Kawa; Hiroshi Wakiguchi

Chronic active Epstein-Barr virus infection (CAEBV) is a high-mortality and high-morbidity disease. To clarify the prognostic factors, a national survey was performed in Japan, and data for 82 patients who met the criteria for CAEBV were analyzed. Of these 82 patients, 47 were alive and 35 had already died. Multivariate analysis revealed that thromobocytopenia and age at disease onset were correlated with mortality. The probability of 5-year survival was 0.45 for older patients (onset age, > or = 8 years), 0.94 for younger patients (P<.001), 0.38 for patients with thrombocytopenia (platelet count < 12 x 10(4) platelets/microL at diagnosis), and 0.76 for patients without thrombocytopenia (P=.01). Furthermore, patients with T cell infection by EBV had shorter survival times than patients with natural killer cell infection (probability of 5-year survival, 0.59 vs. 0.87; P<.009). Patients with CAEBV with late onset of disease, thrombocytopenia, and T cell infection had significantly poorer outcomes.


British Journal of Ophthalmology | 2008

Use of multiplex PCR and real-time PCR to detect human herpes virus genome in ocular fluids of patients with uveitis

Sunao Sugita; Norio Shimizu; Ken Watanabe; Miki Mizukami; Tomohiro Morio; Yoshiharu Sugamoto; Manabu Mochizuki

Aim: To measure the genomic DNA of human herpes viruses (HHV) in the ocular fluids and to analyse the clinical relevance of HHV in uveitis. Methods: After informed consent was obtained, a total of 111 ocular fluid samples (68 aqueous humour and 43 vitreous fluid samples) were collected from 100 patients with uveitis. The samples were assayed for HHV-DNA (HHV1–8) by using two different polymerase chain reaction (PCR) assays, qualitative PCR (multiplex PCR) and quantitative PCR (real-time PCR). Results: In all of the patients with acute retinal necrosis (n = 16) that were tested, either the HSV1 (n = 2), HSV2 (n = 3), or VZV (n = 11) genome was detected. In all patients, high copy numbers of the viral DNA were also noted, indicating the presence of viral replication. In another 10 patients with anterior uveitis with iris atrophy, the VZV genome was detected. When using multiplex PCR, EBV-DNA was detected in 19 of 111 samples (17%). However, real-time PCR analysis of EBV-DNA indicated that there were only six of the 19 samples that had significantly high copy numbers. The cytomegalovirus (CMV) genome was detected in three patients with anterior uveitis of immunocompetent patients and in one immunocompromised CMV retinitis patient. In addition, one patient with severe unilateral panuveitis had a high copy number of HHV6-DNA. There was no HHV7- or HHV8-DNA detected in any of the samples. Conclusions: A qualitative multiplex PCR is useful in the screening of viral infections. However, the clinical relevance of the virus infection needs to be evaluated by quantitative real-time PCR.


Blood | 2010

X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options

Michael H. Albert; Tanja C. Bittner; Shigeaki Nonoyama; Lucia Dora Notarangelo; Siobhan O. Burns; Kohsuke Imai; Teresa Espanol; Anders Fasth; Isabelle Pellier; Gabriele Strauss; Tomohiro Morio; Benjamin Gathmann; Jeroen G. Noordzij; Cristina Fillat; Manfred Hoenig; Michaela Nathrath; Alfons Meindl; Philipp Pagel; Uwe Wintergerst; Alain Fischer; Adrian J. Thrasher; Bernd H. Belohradsky; Hans D. Ochs

A large proportion of patients with mutations in the Wiskott-Aldrich syndrome (WAS) protein gene exhibit the milder phenotype termed X-linked thrombocytopenia (XLT). Whereas stem cell transplantation at an early age is the treatment of choice for patients with WAS, therapeutic options for patients with XLT are controversial. In a retrospective multicenter study we defined the clinical phenotype of XLT and determined the probability of severe disease-related complications in patients older than 2 years with documented WAS gene mutations and mild-to-moderate eczema or mild, infrequent infections. Enrolled were 173 patients (median age, 11.5 years) from 12 countries spanning 2830 patient-years. Serious bleeding episodes occurred in 13.9%, life-threatening infections in 6.9%, autoimmunity in 12.1%, and malignancy in 5.2% of patients. Overall and event-free survival probabilities were not significantly influenced by the type of mutation or intravenous immunoglobulin or antibiotic prophylaxis. Splenectomy resulted in increased risk of severe infections. This analysis of the clinical outcome and molecular basis of patients with XLT shows excellent long-term survival but also a high probability of severe disease-related complications. These observations will allow better decision making when considering treatment options for individual patients with XLT.


British Journal of Haematology | 2003

Common cytological and cytogenetic features of Epstein-Barr virus (EBV)-positive natural killer (NK) cells and cell lines derived from patients with nasal T/NK-cell lymphomas, chronic active EBV infection and hydroa vacciniforme-like eruptions

Yu Zhang; Hiroshi Nagata; Tatsuro Ikeuchi; Hiroyuki Mukai; Michiko K. Oyoshi; Ayako Demachi; Tomohiro Morio; Hiroshi Wakiguchi; Nobuhiro Kimura; Norio Shimizu; Kohtaro Yamamoto

Summary. In this study, we describe the cytological and cytogenetic features of six Epstein‐Barr virus (EBV)‐infected natural killer (NK) cell clones. Three cell clones, SNK‐1, ‐3 and ‐6, were derived from patients with nasal T/NK‐cell lymphomas; two cell clones, SNK‐5 and ‐10, were isolated from patients with chronic active EBV infection (CAEBV); and the other cell clone, SNK‐11, was from a patient with hydroa vacciniforme (HV)‐like eruptions. An analysis of the number of EBV‐terminal repeats showed that the SNK cell clones had monoclonal EBV genomes identical to the original EBV‐infected cells of the respective patients, and SNK cells had the type II latency of EBV infection, suggesting that not only the cell clones isolated from nasal T/NK‐cell lymphomas but also those isolated from CAEBV and HV‐like eruptions had been transformed by EBV to a certain degree. Cytogenetic analysis detected deletions in chromosome 6q in five out of the six SNK cell clones, while 6q was not deleted in four control cell lines of T‐cell lineage. This suggested that a 6q deletion is a characteristic feature of EBV‐positive NK cells, which proliferated in the diseased individuals. The results showed that EBV‐positive NK cells in malignant and non‐malignant lymphoproliferative diseases shared common cytological and cytogenetic features.


Journal of Immunology | 2009

Impaired CD4 and CD8 Effector Function and Decreased Memory T Cell Populations in ICOS-Deficient Patients

Naomi Takahashi; Kenji Matsumoto; Hirohisa Saito; Toshihiro Nanki; Nobuyuki Miyasaka; Tetsuji Kobata; Miyuki Azuma; Sang-Kyou Lee; Shuki Mizutani; Tomohiro Morio

Interaction of ICOS with its ligand is essential for germinal center formation, T cell immune responses, and development of autoimmune diseases. Human ICOS deficiency has been identified worldwide in nine patients with identical ICOS mutations. In vitro studies of the patients to date have shown only mild T cell defect. In this study, we report an in-depth analysis of T cell function in two siblings with novel ICOS deficiency. The brother displayed mild skin infections and impaired Ig class switching, whereas the sister had more severe symptoms, including immunodeficiency, rheumatoid arthritis, inflammatory bowel disease, interstitial pneumonitis, and psoriasis. Despite normal CD3/CD28-induced proliferation and IL-2 production in vitro, peripheral blood T cells in both patients showed a decreased percentage of CD4 central and effector memory T cells and impaired production of Th1, Th2, and Th17 cytokines upon CD3/CD28 costimulation or PMA/ionophore stimulation. The defective polarization into effector cells was associated with impaired induction of T-bet, GATA3, MAF, and retinoic acid-related orphan nuclear hormone receptor (RORC). Reduced CTLA-4+CD45RO+FoxP3+ regulatory T cells and diminished induction of inhibitory cell surface molecules, including CTLA-4, were also observed in the patients. T cell defect was not restricted to CD4 T cells because reduced memory T cells and impaired IFN-γ production were also noted in CD8 T cells. Further analysis of the patients demonstrated increased induction of receptor activator of NF-κB ligand (RANKL), lack of IFN-γ response, and loss of Itch expression upon activation in the female patient, who had autoimmunity. Our study suggests that extensive T cell dysfunction, decreased memory T cell compartment, and imbalance between effector and regulatory cells in ICOS-deficient patients may underlie their immunodeficiency and/or autoimmunity.


Blood | 2016

Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

Julie Toubiana; Satoshi Okada; Julia Hiller; Matías Oleastro; Macarena Lagos Gomez; Juan Carlos Aldave Becerra; Marie Ouachée-Chardin; Fanny Fouyssac; Katta M. Girisha; Amos Etzioni; Joris M. van Montfrans; Yildiz Camcioglu; Leigh Ann Kerns; Bernd H. Belohradsky; Stéphane Blanche; Aziz Bousfiha; Carlos Rodríguez-Gallego; Isabelle Meyts; Kai Kisand; Janine Reichenbach; Ellen D. Renner; Sergio D. Rosenzweig; Bodo Grimbacher; Frank L. van de Veerdonk; Claudia Traidl-Hoffmann; Capucine Picard; László Maródi; Tomohiro Morio; Masao Kobayashi; Desa Lilic

Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guérin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.


The Journal of Pediatrics | 2009

Identification of Severe Combined Immunodeficiency by T-Cell Receptor Excision Circles Quantification Using Neonatal Guthrie Cards

Yoichi Morinishi; Kohsuke Imai; Noriko Nakagawa; Hiroki Sato; Katsuyuki Horiuchi; Yoshitoshi Ohtsuka; Yumi Kaneda; Takashi Taga; Hiroaki Hisakawa; Ryosuke Miyaji; Mikiya Endo; Tsutomu Oh–ishi; Yoshiro Kamachi; Koshi Akahane; Chie Kobayashi; Masahiro Tsuchida; Tomohiro Morio; Yoji Sasahara; Satoru Kumaki; Keiko Ishigaki; Makoto Yoshida; Tomonari Urabe; Norimoto Kobayashi; Yuri Okimoto; Janine Reichenbach; Yoshiko Hashii; Yoichiro Tsuji; Kazuhiro Kogawa; Seiji Yamaguchi; Hirokazu Kanegane

OBJECTIVE To assess the feasibility of T-cell receptor excision circles (TRECs) quantification for neonatal mass screening of severe combined immunodeficiency (SCID). STUDY DESIGN Real-time PCR based quantification of TRECs for 471 healthy control patients and 18 patients with SCID with various genetic abnormalities (IL2RG, JAK3, ADA, LIG4, RAG1) were performed, including patients with maternal T-cell engraftment (n = 4) and leaky T cells (n = 3). RESULTS TRECs were detectable in all normal neonatal Guthrie cards (n = 326) at the levels of 10(4) to 10(5) copies/microg DNA. In contrast, TRECs were extremely low in all neonatal Guthrie cards (n = 15) and peripheral blood (n = 14) from patients with SCID, including those with maternal T-cell engraftment or leaky T cells with hypomorphic RAG1 mutations or LIG4 deficiency. There were no false-positive or negative results in this study. CONCLUSION TRECs quantification can be used as a neonatal mass screening for patients with SCID.


British Journal of Haematology | 2006

Outcome in patients with Wiskott–Aldrich syndrome following stem cell transplantation: an analysis of 57 patients in Japan

Ryoji Kobayashi; Tadashi Ariga; Shigeaki Nonoyama; Hirokazu Kanegane; Shigeru Tsuchiya; Tomohiro Morio; Hiromasa Yabe; Yoshihisa Nagatoshi; Keisei Kawa; Ken Tabuchi; Masahiro Tsuchida; Toshio Miyawaki; Shunichi Kato

A total of 57 patients with Wiskott–Aldrich syndrome (WAS) were studied after undergoing stem cell transplantation (SCT) in Japan between January 1985 and December 2004. Eleven patients received transplants from human leucocyte antigen (HLA)‐matched related donors, 10 from HLA‐mismatched related donors, 21 from unrelated bone marrow donors, and 15 from unrelated cord blood donors. Nine of the 57 patients rejected the initial graft. The overall 5‐year survival rate was 73·7% and the 5‐year failure‐free survival rate was 65·7% (failure was defined as rejection or death). The overall 5‐year survival rates for patients receiving bone marrow and cord blood from unrelated donors were both 80·0%. Based on univariate analysis, the factors associated with poor survival were: transplantation from an HLA‐mismatched related donor, patient age of more than 5 years at the time of transplantation, and a conditioning regimen other than busulfan and cyclophosphamide (BU‐CY) or busulfan, cyclophosphamide and antithymocyte globulin (BU‐CY‐ATG). In a multivariate analysis, a conditioning regimen other than BU‐CY and BU‐CY‐ATG was the only independent factor associated with transplantation failure. Given the improved outcome for WAS patients following transplantation from an unrelated donor, we conclude that patients with WAS should receive SCT as soon as possible after diagnosis.

Collaboration


Dive into the Tomohiro Morio's collaboration.

Top Co-Authors

Avatar

Kohsuke Imai

National Defense Medical College

View shared research outputs
Top Co-Authors

Avatar

Masatoshi Takagi

Tokyo Medical and Dental University

View shared research outputs
Top Co-Authors

Avatar

Shuki Mizutani

Tokyo Medical and Dental University

View shared research outputs
Top Co-Authors

Avatar

Hirokazu Kanegane

Tokyo Medical and Dental University

View shared research outputs
Top Co-Authors

Avatar

Norio Shimizu

Tokyo Medical and Dental University

View shared research outputs
Top Co-Authors

Avatar

Shigeaki Nonoyama

National Defense Medical College

View shared research outputs
Top Co-Authors

Avatar

Masayuki Nagasawa

Tokyo Medical and Dental University

View shared research outputs
Top Co-Authors

Avatar

Michiko Kajiwara

Tokyo Medical and Dental University

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Noriko Mitsuiki

Tokyo Medical and Dental University

View shared research outputs
Researchain Logo
Decentralizing Knowledge