PMID- 32646493 OWN - NLM STAT- MEDLINE DCOM- 20210524 LR - 20210524 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 17 IP - 1 DP - 2020 Jul 9 TI - Two susceptible HLA-DRB1 alleles for multiple sclerosis differentially regulate anti-JC virus antibody serostatus along with fingolimod. PG - 206 LID - 10.1186/s12974-020-01865-7 [doi] LID - 206 AB - BACKGROUND: Progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) is a rare but serious complication of some disease-modifying drugs used to treat multiple sclerosis (MS). Japanese MS patients treated with fingolimod were reported to be 10 times more likely to develop PML than equivalent patients in other countries. The strongest susceptibility human leukocyte antigen (HLA) class II alleles for MS are distinct between races (DRB1*15:01 for Caucasians and DRB1*04:05 and DRB1*15:01 for Japanese); therefore, we investigated whether HLA class II alleles modulate anti-JCV antibody serostatus in Japanese MS patients with and without fingolimod. METHODS: We enrolled 128 Japanese patients with MS, in whom 64 (50%) were under fingolimod treatment at sampling, and examined the relationship between HLA class II alleles and anti-JCV antibody serostatus. Serum anti-JCV antibody positivity and index were measured using a second-generation two-step assay and HLA-DRB1 and -DPB1 alleles were genotyped. RESULTS: HLA-DRB1*15 carriers had a lower frequency of anti-JCV antibody positivity (57% vs 78%, p = 0.015), and lower antibody index (median 0.42 vs 1.97, p = 0.037) than non-carriers. Among patients without HLA-DRB1*15, DRB1*04 carriers had a higher seropositivity rate than non-carriers (84% vs 54%, p = 0.030), and DPB1*04:02 carriers had a higher anti-JCV antibody index than non-carriers (3.20 vs 1.34, p = 0.008) although anti-JCV antibody-positivity rates did not differ. Patients treated with fingolimod had a higher antibody index than other patients (1.46 vs 0.64, p = 0.039) and treatment period had a positive correlation with antibody index (p = 0.018). Multivariate logistic regression analysis revealed that age was positively associated, and HLA-DRB1*15 was negatively associated with anti-JCV antibody positivity (odds ratio [OR] = 1.06, p = 0.006, and OR = 0.37, p = 0.028, respectively). Excluding HLA-DRB1*15-carriers, DRB1*04 was an independent risk factor for the presence of anti-JCV antibody (OR = 5.50, p = 0.023). CONCLUSIONS: HLA-DRB1*15 is associated with low anti-JCV antibody positive rate and low JCV antibody index, and in the absence of DRB1*15, DRB1*04 carriers are associated with a high antibody positive rate in Japanese, suggesting the effects of two susceptible HLA-DRB1 alleles on anti-JCV antibody serostatus differ. FAU - Watanabe, Mitsuru AU - Watanabe M AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. FAU - Nakamura, Yuri AU - Nakamura Y AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. AD - Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital, International University of Health and Welfare, 2-6-11 Yakuin, Chuo-ku, Fukuoka, 810-0022, Japan. AD - School of Pharmacy at Fukuoka, International University of Health and Welfare, 137-1 Enokizu, Okawa, 831-8501, Japan. FAU - Isobe, Noriko AU - Isobe N AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. AD - Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. FAU - Tanaka, Masami AU - Tanaka M AD - Kyoto MS Center, Kyoto Min-Iren-Chuo Hospital, 2-1 Uzumasatsuchimoto-cho, Ukyo-ku, Kyoto, 616-8147, Japan. AD - Department of Neurology, Kaikoukai Jyousai Hospital, 1-4 Kitabatake, Nakamura-ku, Nagoya, 453-0815, Japan. FAU - Sakoda, Ayako AU - Sakoda A AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. AD - Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital, International University of Health and Welfare, 2-6-11 Yakuin, Chuo-ku, Fukuoka, 810-0022, Japan. FAU - Hayashi, Fumie AU - Hayashi F AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. FAU - Kawano, Yuji AU - Kawano Y AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. AD - Department of Neurology, National Hospital Organization Omuta National Hospital, 1044-1 Oaza, Tachibana, Omuta, 837-0911, Japan. FAU - Yamasaki, Ryo AU - Yamasaki R AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. FAU - Matsushita, Takuya AU - Matsushita T AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. FAU - Kira, Jun-Ichi AU - Kira JI AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. kira@neuro.med.kyushu-u.ac.jp. AD - Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital, International University of Health and Welfare, 2-6-11 Yakuin, Chuo-ku, Fukuoka, 810-0022, Japan. kira@neuro.med.kyushu-u.ac.jp. AD - Translational Neuroscience Center, Graduate School of Medicine, and School of Pharmacy at Fukuoka, International University of Health and Welfare, 137-1 Enokizu, Okawa, 831-8501, Japan. kira@neuro.med.kyushu-u.ac.jp. LA - eng GR - 19K07995/Japan Society for the Promotion of Science/ GR - 18H06214/Japan Society for the Promotion of Science/ GR - 16H02657/Japan Society for the Promotion of Science/ GR - 19H01045/Japan Society for the Promotion of Science/ GR - 16K09694/Japan Society for the Promotion of Science/ GR - 19K21317/Japan Society for the Promotion of Science (JP)/ GR - 18K07529/Japan Society for the Promotion of Science (JP)/ GR - 19K07997/Japan Society for the Promotion of Science (JP)/ GR - H29-Nanchitou (Nan)-Ippan-043/Ministry of Health, Labour and Welfare/ PT - Journal Article DEP - 20200709 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Biomarkers) RN - 0 (HLA-DRB1 Chains) RN - 0 (Immunosuppressive Agents) RN - G926EC510T (Fingolimod Hydrochloride) SB - IM MH - Adult MH - Aged MH - *Alleles MH - Biomarkers/blood MH - Female MH - Fingolimod Hydrochloride/pharmacology/*therapeutic use MH - Genetic Predisposition to Disease/genetics MH - HLA-DRB1 Chains/*blood/genetics MH - Humans MH - Immunosuppressive Agents/pharmacology/*therapeutic use MH - JC Virus/*metabolism MH - Male MH - Middle Aged MH - Multiple Sclerosis/*blood/drug therapy/genetics PMC - PMC7350631 OTO - NOTNLM OT - Fingolimod OT - Human leukocyte antigen (HLA) OT - JC virus OT - Multiple sclerosis OT - Progressive multifocal leukoencephalopathy COIS- MW received speaker honoraria and consultant fees from Novartis Pharma and received a research grant from JSPS KAKENHI (grant no. 19 K07995). YN received a grant and salary from Mitsubishi Tanabe Pharma, Bayer Yakuhin, Ltd. and Japan Blood Products Organization, received speaker honoraria from Novartis Pharma, and received a grant from JSPS KAKENHI (grant nos. 18H06214 and 19 K21317). NI received grant support from Mitsubishi Tanabe Pharma, Osoegawa Neurology Clinic, Bayer Yakuhin, Ltd. and Japan Blood Products Organization, and received a research grant from JSPS KAKENHI (grant no. 18 K07529). AS received grant support from Yazuya. YK received a grant from JSPS KAKENHI (grant no. 19 K07997). RY received honoraria from Biogen Japan and received a research grant from JSPS KAKENHI (grant no. 16 K09694). TM received speaker honoraria payments from Mitsubishi Tanabe Pharma, Takeda Pharmaceutical Company, and Biogen Japan. JK received consultant fees, speaking fees and/or honoraria from Novartis Pharma, Mitsubishi Tanabe Pharma, Boehringer Ingelheim, Teijin Pharma, Takeda Pharmaceutical Company, Otsuka Pharmaceutical, Astellas Pharma, Pfizer Japan, Sumitomo Dainippon Pharma, and Eisai, and is supported by grants from JSPS KAKENHI (grant nos. 16H02657 and 19H01045) and Health and Labour Sciences Research Grants on Intractable Diseases (H29-Nanchitou (Nan)-Ippan-043). MT and FH declare that they have no competing interests. EDAT- 2020/07/11 06:00 MHDA- 2021/05/25 06:00 PMCR- 2020/07/09 CRDT- 2020/07/11 06:00 PHST- 2020/02/29 00:00 [received] PHST- 2020/06/04 00:00 [accepted] PHST- 2020/07/11 06:00 [entrez] PHST- 2020/07/11 06:00 [pubmed] PHST- 2021/05/25 06:00 [medline] PHST- 2020/07/09 00:00 [pmc-release] AID - 10.1186/s12974-020-01865-7 [pii] AID - 1865 [pii] AID - 10.1186/s12974-020-01865-7 [doi] PST - epublish SO - J Neuroinflammation. 2020 Jul 9;17(1):206. doi: 10.1186/s12974-020-01865-7.