Contributions
Abstract: P980
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - MS and infections
JC polyomavirus (JCV) infections are commonly latent and asymptomatic with a seroprevalance rate between 40-90%. When immunosuppressed, such as during treatment of multiple sclerosis (MS) patients with natalizumab, JCV reactivation may cause progressive multifocal leukoencephalopathy, an often fatal disease caused by lytic infections predominantly of oligodendrocytes. Previous studies have shown genetic associations between the human leukocyte antigen (HLA) and JCV seropositivity namely HLA-DRB1*15 and HLA-DQB1*06:03. The aim of this study is to further investigate the role of HLA and JCV serostatus and consider the genetically similar BK polyomavirus (BKV).
MS cases (n=6872) and matched healthy controls (n=5780) were sampled from several Swedish MS case-control studies. Anti-JCV antibodies for both virus capsid protein (VP1) and large T-antigen (TAg) along with anti-BKV VP1 antibodies were measured using a Luminex multiplex serology assay. HLA allele variants were imputed from previous single nucleotide polymorphism genotypes using HLA*IMP:02. JCV serostatus was determined by reference to available second-generation STRATIFY JCV values and analyzed by combined VP1/TAg epitopes or separately.
JCV seroprevalence was 73.0% and 76.1% among MS cases and controls, respectively. HLA-DRB1*15:01 showed a strong negative association with JCV serostatus in both MS cases (Odds Ratio(OR)=0.64, Probability(P)=1x10-10) and controls (OR=0.63, P=2x10-10). Additionally, HLA-DQB1*06:03 showed a positive association in MS cases (OR=1.30, P=0.005) and controls (OR=1.34, P=0.003). TAg-based JCV serostatus showed no significant association with HLA-DRB1*15:01 and HLA-DQB1*06:03. VP1-based BKV serostatus showed a strong positive association with TAg-based JCV serostatus (OR=1.27, P=2x10-74) but a similar association was not seen with VP1-based JCV serostatus.
Strong association was seen for HLA-DRB1*15:01 and HLA-DQB1*06:03 haplotypes with additional associations for HLA-DQA1*05, HLA-DRB3*01, and HLA-DPB*02. Overall HLA associations in this study supports findings from previous studies. Epitope-stratified analysis indicates major HLA associations likely originate from the viral capsid protein, known as the most immunogenic surface protein of JCV. Lastly, association between TAg-based JCV serostatus and VP1-based BKV serostatus also suggests a possible cross-reactivity between antibodies.
Disclosure: This study is supported by the PML consortium.
Jesse Huang: Nothing to Disclose
Izaura Lima: Nothing to Disclose
Angelika Michel: Nothing to Disclose
Jenny Link: Jenny Link received support from Neuro Sweden.
Mohsen Khademi: Nothing to Disclose
Clemens Warnke: Clemens Warnke has received consultancy or speaking fees from Novartis, Bayer, Biogen and Teva.
Jan Hillert: Jan Hillert has received honoraria for serving on advisory boards for Biogen and Novartis and speaker"s fees from BiogenIdec, Merck-Serono, Bayer-Schering, Teva and Sanofi-Aventis. He has served as P.I. for projects, or received unrestricted research support from, Biogen, Merck-Serono, Sanofi-Genzyme and Novartis.
Lars Alfredsson: Dr. Alfredsson received speaker´s fee from Biogene and Teva and receives research support from the Swedish Medical Research Council (Dnr 521-2012-2917), Swedish Council for Health, Working Life and Welfare (Dnr 2012-0325) and Swedish Brain Foundation.
Tim Waterboer: Nothing to Disclose
Tomas Olsson: Tomas Olsson has received lecture and/or advisory board honoraria, and unrestricted MS research grants from Astrazeneca, Biogen, Novartis , Allmiral and Genzyme.
Ingrid Kockum: Ingrid Kockum has recieved honoraria for lecture from Merck Serono.
Abstract: P980
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - MS and infections
JC polyomavirus (JCV) infections are commonly latent and asymptomatic with a seroprevalance rate between 40-90%. When immunosuppressed, such as during treatment of multiple sclerosis (MS) patients with natalizumab, JCV reactivation may cause progressive multifocal leukoencephalopathy, an often fatal disease caused by lytic infections predominantly of oligodendrocytes. Previous studies have shown genetic associations between the human leukocyte antigen (HLA) and JCV seropositivity namely HLA-DRB1*15 and HLA-DQB1*06:03. The aim of this study is to further investigate the role of HLA and JCV serostatus and consider the genetically similar BK polyomavirus (BKV).
MS cases (n=6872) and matched healthy controls (n=5780) were sampled from several Swedish MS case-control studies. Anti-JCV antibodies for both virus capsid protein (VP1) and large T-antigen (TAg) along with anti-BKV VP1 antibodies were measured using a Luminex multiplex serology assay. HLA allele variants were imputed from previous single nucleotide polymorphism genotypes using HLA*IMP:02. JCV serostatus was determined by reference to available second-generation STRATIFY JCV values and analyzed by combined VP1/TAg epitopes or separately.
JCV seroprevalence was 73.0% and 76.1% among MS cases and controls, respectively. HLA-DRB1*15:01 showed a strong negative association with JCV serostatus in both MS cases (Odds Ratio(OR)=0.64, Probability(P)=1x10-10) and controls (OR=0.63, P=2x10-10). Additionally, HLA-DQB1*06:03 showed a positive association in MS cases (OR=1.30, P=0.005) and controls (OR=1.34, P=0.003). TAg-based JCV serostatus showed no significant association with HLA-DRB1*15:01 and HLA-DQB1*06:03. VP1-based BKV serostatus showed a strong positive association with TAg-based JCV serostatus (OR=1.27, P=2x10-74) but a similar association was not seen with VP1-based JCV serostatus.
Strong association was seen for HLA-DRB1*15:01 and HLA-DQB1*06:03 haplotypes with additional associations for HLA-DQA1*05, HLA-DRB3*01, and HLA-DPB*02. Overall HLA associations in this study supports findings from previous studies. Epitope-stratified analysis indicates major HLA associations likely originate from the viral capsid protein, known as the most immunogenic surface protein of JCV. Lastly, association between TAg-based JCV serostatus and VP1-based BKV serostatus also suggests a possible cross-reactivity between antibodies.
Disclosure: This study is supported by the PML consortium.
Jesse Huang: Nothing to Disclose
Izaura Lima: Nothing to Disclose
Angelika Michel: Nothing to Disclose
Jenny Link: Jenny Link received support from Neuro Sweden.
Mohsen Khademi: Nothing to Disclose
Clemens Warnke: Clemens Warnke has received consultancy or speaking fees from Novartis, Bayer, Biogen and Teva.
Jan Hillert: Jan Hillert has received honoraria for serving on advisory boards for Biogen and Novartis and speaker"s fees from BiogenIdec, Merck-Serono, Bayer-Schering, Teva and Sanofi-Aventis. He has served as P.I. for projects, or received unrestricted research support from, Biogen, Merck-Serono, Sanofi-Genzyme and Novartis.
Lars Alfredsson: Dr. Alfredsson received speaker´s fee from Biogene and Teva and receives research support from the Swedish Medical Research Council (Dnr 521-2012-2917), Swedish Council for Health, Working Life and Welfare (Dnr 2012-0325) and Swedish Brain Foundation.
Tim Waterboer: Nothing to Disclose
Tomas Olsson: Tomas Olsson has received lecture and/or advisory board honoraria, and unrestricted MS research grants from Astrazeneca, Biogen, Novartis , Allmiral and Genzyme.
Ingrid Kockum: Ingrid Kockum has recieved honoraria for lecture from Merck Serono.