JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants

PLoS Pathogens

International Multiple Sclerosis Genetics Consortium¹  Helle Bach Søndergaard¹  Annette B. Oturai²  Dorothea Buck²  Lars Alfredsson³  Christian Gieger⁴  Eva Albrecht⁴  Bernhard Hemme⁵  Izaura Lima Bomfim⁶  Ingrid Kockum⁶  Emilie Sundqvist⁶  Mohsen Khademi⁶  Tomas Olsson⁶  Anna Fogdell-Hahn⁷  Jan Hillert⁷  Jenny Link⁷  Clemens Warnke⁷ 

[1] Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark;Department of Neurology, Technische Universität München, Munich, Germany;Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany;Munich Cluster for Systems Neurology (SyNergy), Munich, Germany;Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden;The Multiple Sclerosis Research Group, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

关键词: Haplotypes;    Genome-wide association studies;    Enzyme-linked immunoassays;    Antibodies;    Variant genotypes;    Immune response;    Swedish people;    Multiple sclerosis;   

DOI  :  10.1371/journal.ppat.1004084

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY