Elevated Epstein–Barr virus‐encoded nuclear antigen‐1 immune responses predict conversion to multiple sclerosis

Abstract

Objective-The aims of the study were to determine the immune responses to candidate viral triggers of multiple sclerosis (MS) in patients with clinically isolated syndromes (CIS), and to evaluate their potential value in predicting conversion to MS.Methods-Immune responses to Epstein-Barr virus (EBV), human herpesvirus 6, cytomegalovirus (HCMV), and measles were determined in a cohort of 147 CIS patients with a mean follow-up of 7 years and compared with 50 demographically matched controls.Results-Compared to controls, CIS patients showed increased humoral (p<0.0001) and cellular (p=0.007) immune responses to the EBV-encoded nuclear antigen-1 (EBNA1), but not to other EBV-derived proteins. IgG responses to other virus antigens and frequencies of T cells specific for HCMV and influenza virus gene products were unchanged in CIS patients. EBNA1 was the only viral antigen towards which immune responses correlated with number of T2 lesions (p=0.006) and number of Barkhof criteria (p=0.001) at baseline, and with number of T2 lesions (p=0.012 both at 1 and 5 years), presence of new T2 lesions (p=0.003 and p=0.028 at 1 and 5 years), and EDSS (p=0.015 and p=0.010 at 1 and 5 years) during follow-up. In a univariate Cox regression model, increased EBNA1-specific IgG responses predicted conversion to MS based on McDonald criteria [hazard ratio (95% confidence interval), 2.2 (1.2-4.3); p=0.003].Interpretation-Our results indicate that elevated immune responses towards EBNA1 are selectively increased in CIS patients and suggest that EBNA1-specific IgG titers could be used as a prognostic marker for disease conversion and disability progression.

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

“…From a practical point of view, even if a vaccine against EBV is developed [Sokal et al 2007], its efficacy in preventing autoimmune diseases (including MS) or even its total inocuity could be difficult to evaluate. By contrast, given the extreme rarity of MS in EBV-seronegative patients, the serological test may be useful in certain difficult diagnostic circumstances since a negative test result, at least in adults, or low anti-EBNA titres could constitute an argument against MS [Lünemann et al 2010]. Accordingly, even if the simple encounter with EBV remains in the great majority of cases a banal infection without apparent deleterious long-term consequences, it could also, in some cases, be the first event triggering a long-lasting deleterious immunological cascade, worsened both by a late primo infection occurrence with symptomatic infectious mononucleosis and by the persistence of a high anti-EBNA1 level, [Gale and Martyn, 1995;Alonso and Hernan, 2008;Simpson et al 2011;Sloka et al 2011a], at a continental level [Kurtzke, 1995;Puggliatti et al, 2006], in large countries, such as the United States [Acheson et al 1960;Kurtzke et al 1985, Kurtzke, 2008, the former Soviet Union [Boiko et al 1995] and Australia [van der Mei et al 2001;Taylor et al 2010] and even in comparatively smaller countries, such as New Zealand [Taylor et al 2008] and France, at least in farmers [Vukusic et al 2007].…”

Environmental triggers of multiple sclerosis

“…In patients with clinically isolated syndromes (CIS), antibody responses towards EBNA1 were shown to be elevated compared to healthy EBV carriers and were predictive for conversion to clinically definite MS [24].…”

Rola infekcji wirusem Epstein-Barr’a w rozwoju autoimmunologicznych chorób tarczycy

“…EBV infection is also known to be involved in the development of different autoimmune diseases. Several studies brought evidence for the connection of EBV infection and multiple sclerosis [8,9] and even suggested a prognostic role of elevated anti-EBV antibody titres in MS development [10]. Toussirot et al demonstrated serological differences in patients with systemic lupus erythematodes and rheumatoid arthritis in comparison to healthy controls, and confirmed the presence of viral DNA and RNA in disease targeted tissue in patients with rheumatoid arthritis and Sjögren syndrome [11].…”