Combining HLA-DR risk alleles and anti-Epstein-Barr virus antibody profiles to stratify multiple sclerosis risk

Strautins, K.; Tschochner, M.; James, Ian; Choo, L.; Dunn, David S.; Fabis-Pedrini, Marzena J.; Kermode, Allan G.; Carroll, William M.; Nolan, David

doi:10.1177/1352458513498829

Cited by 13 publications

(14 citation statements)

References 28 publications

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“…IgG reactive with EBV viral capsid antigen (EBV-VCA) was detected using a commercial kit (DiaSorin, Vercelli, Italy). Plasma was diluted 1 : 1075 [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

The Use of Humoral Responses as a Marker of CMV Burden in HIV Patients on ART Requires Consideration of T-Cell Recovery and Persistent B-Cell Activation

et al. 2014

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Objectives. Elevated humoral responses to cytomegalovirus (CMV) associate with increased risk of cardiovascular disease (CVD) in HIV patients on antiretroviral therapy (ART). To better understand the persistence of CMV humoral responses in relation to CVD, we determined trends in CMV antibody levels over the first 10 years on ART. Design. We describe longitudinal analyses of plasma from 13 HIV patients commencing ART with <210 CD4 T-cells/µL and 27 controls. Antibodies reactive with CMV (fibroblast lysate, gB and IE-1 antigens), EBV-VCA, and HIVgp41 were quantitated. B-cell activation was assessed via total IgG and sBAFF. Inflammation was assessed via sTNF-RI and sCD14. Results. Amongst CMV seropositive HIV patients, levels of antibody reactive with CMV (P = 0.03) and EBV-VCA (P = 0.02) peaked after 1 year on ART. Levels of total IgG, sCD14, and sTNF-RI declined to approximate those in controls after 10 years, but sBAFF (P = 0.0002), EBV-VCA (P = 0.001), and CMV (P = 0.0004) antibodies remained elevated. A strong correlation between sBAFF and CMVgB antibody was seen at 10 years (R = 0.93, P = 0.0009) and verified in a second cohort. Conclusions. CMV antibody titres peak on ART and remain high. A correlation between CMV antibody and sBAFF suggests a role for HIV-induced B-cell pathology that may affect its use as a marker of CMV burden.

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“…IgG reactive with EBV viral capsid antigen (EBV-VCA) was detected using a commercial kit (DiaSorin, Vercelli, Italy). Plasma was diluted 1 : 1075 [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

The Use of Humoral Responses as a Marker of CMV Burden in HIV Patients on ART Requires Consideration of T-Cell Recovery and Persistent B-Cell Activation

et al. 2014

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“…The risk of MS increases positively with levels of circulating anti-EBNA antibodies (Ascherio et al 2001; DeLorenze et al 2006; Levin et al 2005; Sundstrom et al 2004.) The ability to discriminate MS cases and controls was substantially enhanced by the inclusion of quantitative measures of the anti-EBNA-1 response to EBV infection (Strautins et al 2014). Interestingly, the strong genetic association of MS with particular human leukocyte antigen (HLA) alleles primarily reflects the association with anti-EBV responses (Rubicz et al 2013).…”

Section: Clinical Manifestations Of Primary Ebv Infectionmentioning

confidence: 99%

Infectious Mononucleosis

Dunmire

Hogquist

Balfour

2015

Current Topics in Microbiology and Immunology

171

203

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Infectious mononucleosis is a clinical entity characterized by sore throat, cervical lymph node enlargement, fatigue and fever most often seen in adolescents and young adults and lasting several weeks. It can be caused by a number of pathogens, but this chapter only discusses infectious mononucleosis due to primary Epstein-Barr virus (EBV) infection. EBV is a γ-herpesvirus that infects at least 90% of the population worldwide. The virus is spread by intimate oral contact among teenagers and young adults. How preadolescents acquire the virus is not known. A typical clinical picture with a positive heterophile test is usually sufficient to make the diagnosis, but heterophile antibodies are not specific and do not develop in some patients. EBV-specific antibody profiles are the best choice for staging EBV infection. In addition to causing acute illness, there can also be long-term consequences as the result of acquisition of the virus. Several EBV related illnesses occur including certain cancers and autoimmune diseases, as well as complications of primary immunodeficiency in persons with the certain genetic mutations. A major obstacle to understanding these sequelae has been the lack of an efficient animal model for EBV infection, although progress in primate and mouse models has recently been made. Key future challenges are to develop protective vaccines and effective treatment regimens.

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“…Both serological [ 27 , 31 , 32 ] and CD4 T cell responses [ 33 ] directed against EBNA-1 have been associated with multiple sclerosis, with further evidence that EBNA-1-specific antibodies differentiate disease-discordant identical twins [ 34 ]. Several groups have demonstrated higher EBV seroprevalence in MS patients compared to controls and it has further been demonstrated that EBV infection late in life, in particular if manifested as infectious mononucleosis, increases a person’s MS risk [ 27 , 35 , 36 ]. A recent study has also explored the use of Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis, with promising preliminary results [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

Identifying Patient-Specific Epstein-Barr Nuclear Antigen-1 Genetic Variation and Potential Autoreactive Targets Relevant to Multiple Sclerosis Pathogenesis

et al. 2016

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BackgroundEpstein-Barr virus (EBV) infection represents a major environmental risk factor for multiple sclerosis (MS), with evidence of selective expansion of Epstein-Barr Nuclear Antigen-1 (EBNA1)-specific CD4+ T cells that cross-recognize MS-associated myelin antigens in MS patients. HLA-DRB1*15-restricted antigen presentation also appears to determine susceptibility given its role as a dominant risk allele. In this study, we have utilised standard and next-generation sequencing techniques to investigate EBNA-1 sequence variation and its relationship to HLA-DR15 binding affinity, as well as examining potential cross-reactive immune targets within the central nervous system proteome.MethodsSanger sequencing was performed on DNA isolated from peripheral blood samples from 73 Western Australian MS cases, without requirement for primary culture, with additional FLX 454 Roche sequencing in 23 samples to identify low-frequency variants. Patient-derived viral sequences were used to predict HLA-DRB1*1501 epitopes (NetMHCII, NetMHCIIpan) and candidates were evaluated for cross recognition with human brain proteins.ResultsEBNA-1 sequence variation was limited, with no evidence of multiple viral strains and only low levels of variation identified by FLX technology (8.3% nucleotide positions at a 1% cut-off). In silico epitope mapping revealed two known HLA-DRB1*1501-restricted epitopes (‘AEG’: aa 481–496 and ‘MVF’: aa 562–577), and two putative epitopes between positions 502–543. We identified potential cross-reactive targets involving a number of major myelin antigens including experimentally confirmed HLA-DRB1*15-restricted epitopes as well as novel candidate antigens within myelin and paranodal assembly proteins that may be relevant to MS pathogenesis.ConclusionsThis study demonstrates the feasibility of obtaining autologous EBNA-1 sequences directly from buffy coat samples, and confirms divergence of these sequences from standard laboratory strains. This approach has identified a number of immunogenic regions of EBNA-1 as well as known and novel targets for autoreactive HLA-DRB1*15-restricted T cells within the central nervous system that could arise as a result of cross-reactivity with EBNA-1-specific immune responses.

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Combining HLA-DR risk alleles and anti-Epstein-Barr virus antibody profiles to stratify multiple sclerosis risk

Cited by 13 publications

References 28 publications

The Use of Humoral Responses as a Marker of CMV Burden in HIV Patients on ART Requires Consideration of T-Cell Recovery and Persistent B-Cell Activation

The Use of Humoral Responses as a Marker of CMV Burden in HIV Patients on ART Requires Consideration of T-Cell Recovery and Persistent B-Cell Activation

Infectious Mononucleosis

Identifying Patient-Specific Epstein-Barr Nuclear Antigen-1 Genetic Variation and Potential Autoreactive Targets Relevant to Multiple Sclerosis Pathogenesis

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