PMID- 24763718 OWN - NLM STAT- MEDLINE DCOM- 20141210 LR - 20211021 IS - 1553-7374 (Electronic) IS - 1553-7366 (Print) IS - 1553-7366 (Linking) VI - 10 IP - 4 DP - 2014 Apr TI - JC polyomavirus infection is strongly controlled by human leucocyte antigen class II variants. PG - e1004084 LID - 10.1371/journal.ppat.1004084 [doi] LID - e1004084 AB - JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7x10(-15)) and controls (OR = 0.53, p = 2x10(-5)). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1x10(-5)). The German dataset confirmed these findings (OR = 0.54, p = 1x10(-4) and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention. FAU - Sundqvist, Emilie AU - Sundqvist E AD - Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Buck, Dorothea AU - Buck D AD - Department of Neurology, Technische Universitat Munchen, Munich, Germany. FAU - Warnke, Clemens AU - Warnke C AD - The Multiple Sclerosis Research Group, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Albrecht, Eva AU - Albrecht E AD - Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, Neuherberg, Germany. FAU - Gieger, Christian AU - Gieger C AD - Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, Neuherberg, Germany. FAU - Khademi, Mohsen AU - Khademi M AD - Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Lima Bomfim, Izaura AU - Lima Bomfim I AD - Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Fogdell-Hahn, Anna AU - Fogdell-Hahn A AD - The Multiple Sclerosis Research Group, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Link, Jenny AU - Link J AD - The Multiple Sclerosis Research Group, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Alfredsson, Lars AU - Alfredsson L AD - Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. FAU - Sondergaard, Helle Bach AU - Sondergaard HB AD - Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. FAU - Hillert, Jan AU - Hillert J AD - The Multiple Sclerosis Research Group, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. CN - International Multiple Sclerosis Genetics Consortium FAU - Oturai, Annette B AU - Oturai AB AD - Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. FAU - Hemmer, Bernhard AU - Hemmer B FAU - Kockum, Ingrid AU - Kockum I AD - Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Olsson, Tomas AU - Olsson T AD - Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. LA - eng GR - Wellcome Trust/United Kingdom GR - R01 NS049477/NS/NINDS NIH HHS/United States PT - Clinical Trial PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20140424 PL - United States TA - PLoS Pathog JT - PLoS pathogens JID - 101238921 RN - 0 (HLA-DQ beta-Chains) RN - 0 (HLA-DQB1 antigen) RN - 0 (HLA-DRB1 Chains) RN - 0 (HLA-DRB1*15 antigen) SB - IM EIN - PLoS Pathog. 2014 Sep;10(9):e1004430. Hemme, Bernhard [corrected to Hemmer, Bernhard] MH - *Alleles MH - CD4-Positive T-Lymphocytes/immunology MH - Female MH - HLA-DQ beta-Chains/*genetics/immunology MH - HLA-DRB1 Chains/*genetics/immunology MH - *Haplotypes MH - Humans MH - *JC Virus MH - Male MH - Polyomavirus Infections/*genetics/immunology MH - Scandinavian and Nordic Countries PMC - PMC3999271 COIS- Tomas Olsson has received lecture and or advisory board honoraria from BiogenIdec, Novartis, Genzyme and Merck. The same companies have provided unrestricted MS research grants. Bernard Hemmer has received lecture and advisory board honoraria from Biogenidec, Novartism Bayer, Teva, Roche, Glaxo-Smith-Kline, Chugai and Merck-Serono. Biogenidec, Novartis, Metanomics, 5Prime, Roche, Bayer and Merck-Serono have supported the Department of Neurology of the Technische Universitat Munchen with research grants. This does not alter our adherence to all PLOS policies on sharing data and materials. FIR - Barcellos, Lisa IR - Barcellos L FIR - Booth, David IR - Booth D FIR - McCauley, Jacob L IR - McCauley JL FIR - Comabella, Manuel IR - Comabella M FIR - Compston, Alastair IR - Compston A FIR - DAlfonso, Sandra IR - DAlfonso S FIR - De Jager, Philip IR - De Jager P FIR - Fontaine, Bertrand IR - Fontaine B FIR - Goris, An IR - Goris A FIR - Hafler, David IR - Hafler D FIR - Haines, Jonathan IR - Haines J FIR - Harbo, Hanne F IR - Harbo HF FIR - Hauser, Stephen L IR - Hauser SL FIR - Hawkins, Clive IR - Hawkins C FIR - Hemmer, Bernhard IR - Hemmer B FIR - Hillert, Jan IR - Hillert J FIR - Ivinson, Adrian IR - Ivinson A FIR - Kockum, Ingrid IR - Kockum I FIR - Martin, Roland IR - Martin R FIR - Martinelli Boneschi, Filippo IR - Martinelli Boneschi F FIR - Oksenberg, Jorge IR - Oksenberg J FIR - Olsson, Tomas IR - Olsson T FIR - Oturai, Annette IR - Oturai A FIR - Patsopoulos, Nikolaos IR - Patsopoulos N FIR - Pericak-Vance, Margaret IR - Pericak-Vance M FIR - Saarela, Janna IR - Saarela J FIR - Sawcer, Stephen IR - Sawcer S FIR - Spurkland, Anne IR - Spurkland A FIR - Stewart, Graeme IR - Stewart G FIR - Zipp, Frauke IR - Zipp F EDAT- 2014/04/26 06:00 MHDA- 2014/12/15 06:00 PMCR- 2014/04/24 CRDT- 2014/04/26 06:00 PHST- 2013/11/18 00:00 [received] PHST- 2014/03/03 00:00 [accepted] PHST- 2014/04/26 06:00 [entrez] PHST- 2014/04/26 06:00 [pubmed] PHST- 2014/12/15 06:00 [medline] PHST- 2014/04/24 00:00 [pmc-release] AID - PPATHOGENS-D-13-03055 [pii] AID - 10.1371/journal.ppat.1004084 [doi] PST - epublish SO - PLoS Pathog. 2014 Apr 24;10(4):e1004084. doi: 10.1371/journal.ppat.1004084. eCollection 2014 Apr.