The 5th MS Summer College in Tokyo (4–5 August 2018) Tolerance and Neuroimmunology

Day 1: 4 August 2018. Opening Remark and Introduction 13.00–13.10 Makoto Matsui (Kanazawa Medical University, Ishikawa, Japan) (1) Panel Discussion 13.10–15.50 Theme: Mucosal immunity and immune tolerance relevant to MS Chair: Makoto Matsui (Kanazawa Medical University, Ishikawa, Japan) and Takashi Yamamura (National Center of Neurology and Psychiatry, Tokyo, Japan) Commentator: Sachiko Miyake (Juntendo University, Tokyo, Japan) Gut multi-ecosystem of epithelial cells, immune cells and commensal microbiota for the balancing act between elimination and symbiosis Hiroshi Kiyono (Institute of Medical Science, Tokyo University, Tokyo, Japan) TGF-β3-expressing CD4 + CD25 − LAG3 + regulatory T cells control humoral immune responses Kazuhiko Yamamoto (RIKEN Center for Integrative Medical Sciences, Yokohama, Japan) Mucosal tolerance therapy in humans: Past and future Howard Weiner (Harvard Medical School, Boston, USA) (2) Poster presentation and coffee break 16.00–16.50 Chair: Kazuya Takahashi (Iou Hospital, Kanazawa, Japan) (P-1) Immune cell population change after fingolimod withdrawal Yusei Miyazaki,1 Masaaki Niino,1 Toshiyuki Fukazawa,2 Eri Takahashi,1 Kazunori Sato2 and Seiji Kikuchi1 (1Hokkaido Medical Center, 2Sapporo Neurology Hospital, Sapporo, Japan) (P-2) Case of a difficult diagnosis due to the absence of supratentorial lesions in the early stage of the disease Baku Hashimoto, Satoru Tanaka, Akihiro Kubota, Shoko Izaki, Satoru Oji, Hikoaki Fukaura and Kyoichi Nomura (Saitama Medical University, Saitama Medical Center, Saitama, Japan) (P-3) Drug-induced progressive multifocal leukoencephalopathy in multiple sclerosis 2018 Motohiro Yukitake (Kouhoukai Takagi Hospital, Fukuoka, Japan) (P-4) Clinical spectrum of 363 cases of demyelinating disease with myelin oligodendrocyte glycoprotein antibody in Japan Kimihiko Kaneko,1,2 Douglas Kazutoshi Sato,2,3,4 Ryo Ogawa,2 Yoshiki Takai,2 Shuhei Nishiyama,2 Toshiyuki Takahashi,2,5 Tatsuro Misu,2 Hiroshi Kuroda,2 Ichiro Nakashima,2,6 Kazuo Fujihara2,7,8 and Masashi Aoki2 (1Department of Neurology, NHO Miyagi Hospital, Miyagi, 2Department of Neurology, Tohoku University, Sendai, Japan; 3Department of Neurology, São Paulo University, São Paulo, 4Brain Institute and Hospital Sao Lucas Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil; 5Department of Neurology, NHO Yonezawa Hospital, Yamagata, 6Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, 7Department of Multiple Sclerosis Therapeutics, Fukushima Medical University, Fukushima, 8Multiple Sclerosis and Neuromyelitis Optica Center, Tohoku Research Institute for Neuroscience, Fukushima, Japan) (P-5) Clinical features of late-onset neuromyelitis optica spectrum disorders in a Japan cohort Akihiro Nakajima, Etsuji Saji, Takahiro Wakasugi, Fumihiro Yanagimura, Kaori Yanagawa, Osamu Onodera and Izumi Kawachi (Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan) (P-6) Longitudinally extensive transverse myelitis as neurosarcoidosis accompanied by duropathy Yasuyuki Takai, Yoko Warabi, Yoko Sunami, Natsuki Miyakoshi and Eiji Isozaki (Tokyo Metropolitan Neurological Hospital, Tokyo, Japan) (P-7) Case of trigeminal neuralgia stabilized using mandibular nerve block and natalizumab in a patient with multiple sclerosis Ryohei Norioka,1 Yoko Warabi,1 Aki Murayama,1 Asuka Funai,1 Hiroaki Matayoshi,2 Akihiro Kawata1 and Eiji Isozaki1 (1Department of Neurology, Tokyo Metropolitan Neurological Hospital, 2Department of Anesthesiology, Tokyo Metropolitan Neurological Hospital; Tokyo, Japan) (P-8) Investigation of anti-John Cunningham virus antibody index in Japanese patients with multiple sclerosis Shinji Aoyama, Masahiro Mori, Akiyuki Uzawa, Tomohiko Uchida, Hiroki Masuda, Ryohei Ohtani and Satoshi Kuwabara (Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan) (3) Oral presentation 16.40–17.40 Chairs: Jin Nakahara (Keio University, Tokyo, Japan), Izumi Kawachi (Niigata University, Niigata, Japan) (O-1) Brain volume decrease of the patients with multiple sclerosis investigated by 3TMR scanner: 4-year observation study Takahiro Nakayama, Takuya Sasaki, Mizuki Kitamura and Ichiro Imafuku (Department of Neurology, Yokohama Rosai Hospital, Yokohama, Japan) (O-2) Serum glial fibrillary acidic protein and neurofilament light chain as potential biomarkers for disease activity and disability progression in neuromyelitis optica spectrum disorders Mitsuru Watanabe,1 Yuri Nakamura,2 Zuzanna Michalak,3 Fumie Hayashi,1 Christian Barro,3 Noriko Isobe,2 Takuya Matsushita,1 Ryo Yamasaki,1 Jens Kuhle3,4 and Jun-ichi Kira1,4 (1Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 2Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 3Neurology, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, Basel, Switzerland; 4shared last authors) (O-3) Inverse vaccination for multiple sclerosis in control of the disease activity: Superior dominant peptide restricts the reactivity to disease-associated antigens and promotes tissue-repair capacity by sequential induction of stabilized antigen-specific hybrid regulatory T cells Youwei Lin1, 2 and Takashi Yamamura1 (1Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 2Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan) (O-4) Long-term use of interferon-β in multiple sclerosis induces an increase of Vδ1–Vδ2–Vγ9– γδ T cells, which is associated with better outcome Guzailiayi Maimaitijiang,1 Mitsuru Watanabe,1 Koji Shinoda,1 Yuri Nakamura,2 Katsuhisa Masaki,1 Takuya Matsushita,1 Ryo Yamasaki,1 Yasunobu Yoshikai3 and Jun-ichi Kira1 (1Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 2Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan) (O-5) Blood–brain barrier activation is associated with the clinical phenotype in neuromyelitis optica spectrum disorder Fumitaka Shimizu, Yuka Hamamoto, Yukio Takeshita, Yasuteru Sano, Toshihiko Maeda, Susumu Fujikawa, Masaya Honda and Takashi Kanda (Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan) (4) Lecture 1 17.40–18.40 Chair: Seiji Kikuchi (Hokkaido Medical Center, Sapporo, Japan) (L-1) Multiple sclerosis update: East and West Allan Kermode (Sir Charles Gairdner Hospital, Western Australia, Australia) (5) Lecture 2 18.40–19.10 Chair: Takuya Matsushita (Department of Neurology, Kyushu University, Fukuoka, Japan) (L-2) Imaging differences between multiple sclerosis and neuromyelitis optica spectrum disorder Yukio Miki (Osaka City University, Osaka, Japan) Meeting Dinner 19.10–20.40 Day 2: 5 August 2018 (6) Lecture 3 09.00–09.45 Chair: Yuji Nakatsuji (Toyama University, Toyama, Japan) (L-3) How to use the 2017 Japanese guidelines in diagnosis and treatments of multiple sclerosis Masaaki Niino (Hokkaido Medical Center, Sapporo, Japan) (7) Lecture 4 09.45–10.30 Chair: Katsuichi Miyamoto (Kindai University, Osaka, Japan) (L-4) Role of diet and gut microbiota in multiple sclerosis and neuromyelitis optica Tatsusada Okuno (Osaka University, Osaka, Japan) (8) Case study 10.40–12.10 ① Difficult to diagnose Chair: Yuko Shimizu (Tokyo Women's Medical University, Tokyo, Japan) Speaker: Noriko Isobe (Kyushu University, Fukuoka, Japan) ② Difficult to treat Chair: Yoko Warabi (Tokyo Metropolitan Neurological Hospital, Tokyo, Japan) Speaker: Hiroshi Kuroda (Tohoku University, Sendai, Japan) (9) Closing remark 12.10–12.20 Yuji Nakatsuji (Toyama University, Toyama, Japan) The 5th Annual Meeting of the Multiple Sclerosis (MS) Summer College was held at the Roppongi Academyhills in Tokyo, Japan, on 4 and 5 August 2018. Professor Makoto Matsui, the president of this summer college, from Kanazawa Medical University, presented the opening remarks (Fig. 1). He introduced the main theme of the meeting “Tolerance and Neuroimmunology”. The theme is classic, but revives a hot topic in the recent immunological field. Outstanding guest speakers from the USA, Australia and Japan gave spectacular seminars, and more than 116 participants from all over Japan participated in this meeting. I would like to report some of the topics during 2 days. In the Panel Discussion section, three guest speakers talked under the theme of “Mucosal Immunity and Immune Tolerance relevant to MS.” The first speaker, Professor Hiroshi Kiyono of the Institute of Medical Science, Tokyo University, gave a lecture about harmonized biological components including epithelial–mesenchymal cells, mucosal immunocompetent cells and commensal microbiota, which form the “gut multi-immunological ecosystem”. They found that commensal bacteria, Alcaligenes, can create intratissue cohabitation niches in Peyer's patches. These intratissue commensal bacteria enter Peyer's patches through M cells. From these findings, Professor Kiyono suggested the presence of commensal bacteria-mediated homeostatic inflammatory conditions within Peyer's patches. It is assumed that the gut multi-immunological ecosystem is a key element of the creation and regulation of a healthy environment of the intestinal tract for the balancing act between elimination and symbiosis.1 The next speaker, Professor Kazuhiko Yamamoto from RIKEN Center for Integrative Medical Sciences, presented data about early growth response gene 2-controlled CD4+CD25−LAG3+ regulatory T cells (LAG3+ Treg). LAG3 is a CD4-related molecule that binds to major histocompatibility complex class II, and the binding induces immunoreceptor tyrosine-based activation motif-mediated inhibitory signaling. These LAG3+ Treg produce high levels of interleukin-10 and are suppressive in a murine model of colitis in an interleukin-10-dependent manner. LAG3+ Treg produces high amounts of transforming growth factor-β3, and suppress B-cell development and antibody production.2 The third speaker, Professor Howard Weiner from Harvard Medical School, gave a lecture under the title of “Mucosal tolerance therapy in humans: Past and future” (Fig. 2). The route of mucosal administration can determine the type of Treg induced, with the oral route inducing transforming growth factor-β type Treg and the nasal route inducing interleukin-10-secreting Treg, which is driven by unique dendritic cells located in these mucosal sites. Whereas the past clinical trials of oral tolerance to autoantigens in humans were negative, Professor Weiner presented new approaches to mucosal tolerance being planned. Oral or nasal anti-CD3 monoclonal antibody induces Treg at the mucosal surface, and these cells travel systemically to suppress inflammatory diseases, including models of MS, diabetes, lupus, arthritis and colitis.3 Professor Weiner said that trials of nasal anti-CD3 are planned for patients with progressive MS, and understanding of the mucosal immune system tolerance has the potential to be successfully applied to patients with a wide variety of diseases. The next session was a poster presentation. Each presenter provided a brief oral presentation followed by a discussion in front of each poster (Fig. 3). There were eight posters that consisted of a variety of themes, including diagnosis, clinical features, disease-modifying drug-related adverse effects in MS and neuromyelitis optica spectrum disorder (NMOSD). In these, Dr Shinji Aoyama from Chiba University presented the data of anti-John Cunningham virus antibody index in Japanese patients. Approximately 70% of Japanese MS patients are anti-John Cunningham antibody-positive, and older age correlates with a higher John Cunningham antibody index; therefore, age might be a risk factor for progressive multifocal leukoencephalopathy. He won the Scientific Award. The third session was an oral presentation. Five presenters talked about their research in the neuroimmunological field. Of those, Dr Mitsuru Watanabe from Kyushu University won the Presidential Award, and Dr Fumitaka Shimizu won the School Board Presidential Award. Dr Watanabe showed that glial fibrillary acidic protein and neurofilament light chain (NfL) had an association between cerebrospinal fluid and serum levels, and serum glial fibrillary acidic protein and serum NfL levels were higher in NMOSD patients than in healthy controls. Serum NfL levels in patients in the remission phase of NMOSD were positively correlated with annualized relapse rates. Then he suggested that both serum glial fibrillary acidic protein and serum NfL could be potential biomarkers for disease activity and disability in NMOSD. Dr Shimizu showed that immunoglobulin G in the longitudinally extensive transverse myelitis group showed a significantly increased induction in nuclear translocation of nuclear factor-κB p65, compared with those from the optic neuritis group and healthy control group. A significant correlation was observed between the amounts of nuclear factor-κB nuclear-positive cells and the clinical marker of blood–brain barrier disruption, including gadolinium enhancement in spinal magnetic resonance imaging and the cerebrospinal fluid/serum albumin ratio. The last session on the first day was lectures by two invited speakers. Professor Allan Kermode from Sir Charles Gairdner Hospital in Australia overviewed MS and NMOSD across multiple domains: epidemiology, genetics, immunology, biomarkers, imaging and therapeutics, sometimes comparing East and West. The prevalence of MS has been increasing, particularly in women, especially in the Asian region. Migration of Hong Kong Chinese to Vancouver has added further weight to older European migration studies, reinforcing the pre-eminence of environmental factors in MS risk, such as ultraviolet radiation, vitamin D and Epstein–Barr virus infection. Professor Yukio Miki from Osaka City University gave a seminar about imaging differences between MS and NMOSD. Characteristic magnetic resonance findings in MS, as opposed to NMOSD, include ovoid lesions, subcallosal striations, isolated U-fiber lesions, cortical lesions and peripheral spinal cord lesions. A recent multi-institutional study in Japan confirmed that periventricular white matter lesions, ovoid lesions, T1-black hole lesions, callosal-septal interface lesions and isolated U-fiber lesions are more frequently present in MS than in NMOSD.4 In the first session, two invited speakers gave seminars. Dr Masaaki Niino, Hokkaido Medical Center, explained how to use the 2017 Japanese guidelines in the diagnosis and treatment of MS by citing an appropriate case. The new guidelines for the management of MS and NMO consisted of three major parts: the general discussion session regarding the diseases and the two detailed discussion sections. He said that the new guidelines would help to diagnose and choose treatments for patients with MS and NMO. Dr Tatsusada Okuno from Osaka University talked about the increase in the prevalence of MS in terms of microbiota in accordance with the changes in food habits. Regarding NMO, its microbiome has been reported to have distinct features in comparison with healthy controls and MS. He reviewed the current advances in the research of food habit and microbiota in MS and NMO in terms of intestinal immunity and immune-metabolic interactions. The next session was a case study session. Dr Noriko Isobe from Kyushu University presented a case that was difficult to diagnose. All the participants responded to difficult clinical questions regarding diagnosis using an answer pad. The second case, which was difficult to treat, was presented by Dr Hiroshi Kuroda from Tohoku University and chaired by Dr Yoko Warabi. All the participants responded to difficult questions regarding medication using an answer pad. The 6th annual meeting of the MS Summer College will be held by Professor Kira as the President next summer in 2019. None declared.

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