JC polyomavirus infection is strongly controlled by human leucocyte antigen class II variants.
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 = 7×10(-15)) and controls (OR = 0.53, p = 2×10(-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 = 1×10(-5)). The German dataset confirmed these findings (OR = 0.54, p = 1×10(-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.
Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Emilie
E
Sundqvist
Department of Neurology, Technische Universität München, Munich, Germany.
Dorothea
D
Buck
The Multiple Sclerosis Research Group, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Clemens
C
Warnke
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
Eva
E
Albrecht
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
Christian
C
Gieger
Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Mohsen
M
Khademi
Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Izaura
I
Lima Bomfim
The Multiple Sclerosis Research Group, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Anna
A
Fogdell-Hahn
The Multiple Sclerosis Research Group, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Jenny
J
Link
Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Lars
L
Alfredsson
Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Helle Bach
HB
Søndergaard
The Multiple Sclerosis Research Group, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Jan
J
Hillert
Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Annette B
AB
Oturai
Bernhard
B
Hemmer
Department of Neurology, Technische Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Bernhard
B
Hemme
Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Ingrid
I
Kockum
Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Tomas
T
Olsson
D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D059866:HLA-DQ beta-Chains / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D007577:JC Virus; D008297:Male; D027601:Polyomavirus Infections / Q000235:genetics* / Q000276:immunology; D012537:Scandinavian and Nordic Countries
D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; C507799:HLA-DRB1*15 antigen