Date Published: April 24, 2014
Publisher: Public Library of Science
Author(s): Emilie Sundqvist, Dorothea Buck, Clemens Warnke, Eva Albrecht, Christian Gieger, Mohsen Khademi, Izaura Lima Bomfim, Anna Fogdell-Hahn, Jenny Link, Lars Alfredsson, Helle Bach Søndergaard, Jan Hillert, Annette B. Oturai, Bernhard Hemme, Ingrid Kockum, Tomas Olsson, Walter J. Atwood.
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.
Progressive multifocal leukoencephalopathy (PML) was first described neuropathologically during the fifties by Karl Erik Åström . It took until 1971 when JC virus (JCV) was isolated from brain tissue of a patient with PML, since then JCV was accepted as the causative agent of PML . PML used to be a rare demyelinating disease of the central nervous system, mainly seen in patients with lymphoproliferative disease or AIDS. Now several different drugs that interfere with immune functions, such as natalizumab, efalizumab, mycophenolate mofetil, fumaric acid, rituximab, tacrolimus, and possibly azathioprine, cyclosporine and cyclophosphamide have been associated with an increased risk of developing PML. For natalizumab and efalizumab the strongest associations were seen in patients without an underlying disease that predispose for PML itself –. Thus, it is of major importance to develop measures to prevent or treat the condition, including understanding of factors allowing persons to acquire the virus, as carriers, a requisite for later risk for PML.
Clinical characteristics and demographic data of the included patients and controls are displayed in table 1. Anti-JCV antibody status and levels were determined in the same laboratory for all individuals with an ELISA based method .
We here demonstrate a host genetic HLA complex mediated influence on anti-JCV antibody status and anti-JCV antibody levels as surrogate for the susceptibility of the infection with JCV or the activity of the infection with JCV, respectively.