Antibodies to Epstein-Barr virus and neurotropic viruses in multiple sclerosis and optic neuritis

Heiden, Julie; Trier, Nicole Hartwig; Draborg, Anette Holck; Benros, Michael E.; Zinkevičiūtė, Rūta; Petraitytė-Burneikienė, Rasa; Čiplys, Evaldas; Slibinskas, Rimantas; Frederiksen, Jette Lautrup

doi:10.1016/j.jneuroim.2020.577314

Cited by 7 publications

(7 citation statements)

References 35 publications

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“…A review of nine studies on MS found a positive intrathecal antibodies index against EBNA1 in 9.7% of persons with MS, which is markedly lower than the presence of intrathecally enriched antibodies against representative measles (56%), varicella (51%), rubella (57%), and herpes-1 (27%) antigens (Ruprecht et al, 2018). However, one study did report an increased antibody index for EBNA1 (Houen et al, 2020). Two mechanisms could relate the migration of the polyspecific antibody reaction to the intrathecal compartment in MS to a previous primary EBV infection.…”

Section: Discussionmentioning

confidence: 98%

Follow-up after infectious mononucleosis in search of serological similarities with presymptomatic multiple sclerosis

Jons¹,

Berg

Sundström

et al. 2021

Multiple Sclerosis and Related Disorders

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Background: : A two-to three-fold increase in the risk of multiple sclerosis (MS) after infectious mononucleosis (IM) has been observed in cohort and case control studies. However, this association has not been investigated prospectively from IM. It remains to be determined whether long-term immunospecific sequelae with features consistent with presymptomatic MS occur after IM. Methods: : Sera were obtained from individuals with acute IM from 2003-2007 (n = 42) and from the same individuals at a follow-up (FU) study approximately 10 years after IM. These were assayed for antibodies against a variety of Epstein-Barr virus (EBV) antigens, including gp350, a novel recombinant glycoprotein from the EBV envelope. Similarly, single-protein antigens were used to assess measles and varicella-zoster reactivity (Ncore and varicella-zoster glycoprotein E [VZVgE]). The FU study also included cerebrospinal fluid (CSF) samples from 21 of these individuals to test for IgG antibodies against the same viral antigens. As controls, CSF and serum samples were obtained from 15 EBV-seropositive volunteers who denied a history of IM, and serum samples were obtained from 24 EBV-seropositive blood donors. Anti-gp350, anti-Ncore and anti-VZVgE IgG levels were also analysed in sera and CSF samples from 22 persons with MS.Results: : The FU assays showed higher anti-gp350 IgG (p = 0.007, univariate) than among healthy controls, with no difference in serum anti-VCA or anti-EBNA1 IgG levels and no difference in anti-gp350 in the CSF samples. Anti-Ncore IgG and anti-VZVgE were higher in acute IM samples (p < 0.001 and p < 0.0001, respectively) than at FU, although anti-Ncore remained heightened in an age-adjusted analysis at FU (p = 0.014) compared to the control group. In the MS group, the serum anti-gp350 and anti-Ncore IgG levels were significantly higher than among the control group, but the anti-VZVgE levels were not. The CSF anti-gp350 and VZVgE levels were slightly higher among persons with MS than among the control group, whereas anti-Ncore IgG was markedly higher in persons with MS than in the control group. Conclusion: : In the present study IM showed certain similarities with MS. Increased anti-gp350 reactivity persisted more than a decade after IM, reminiscent of the established increased anti-EBV reactivity in presymptomatic MS. Acute IM was associated with increased anti-measles and anti-VZV immunoreactivity, similar to the MRZ reaction in MS, with some evidence suggesting that this measles reactivity persisted after a decade.

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Section: Discussionmentioning

confidence: 98%

Follow-up after infectious mononucleosis in search of serological similarities with presymptomatic multiple sclerosis

Jons¹,

Berg

Sundström

et al. 2021

Multiple Sclerosis and Related Disorders

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“…EBV AIs are also elevated, however, not necessarily to the same extent as other AIs, despite the presence of high levels of Abs to EBV in serum of MS patients (15,124). Interestingly, there is a high degree of correlation between Ab concentrations in serum and in CSF for most or all of the virus Abs described above (15). Since the elevated CSF levels are not caused by diffusion from serum to CSF and since there is a highly significant correlation between serum and CSF Ab levels, the only likely explanation is that there has been or is a continuous influx of Ab-producing B cells from blood to CSF, most likely in the form of B cell blasts which have differentiated to plasma cells concomitantly in the periphery and in the CNS.…”

Section: Ebv and Msmentioning

confidence: 89%

“…In MS, much evidence indicates a role for EBV and specifically that EBV-infected B cells have entered the CNS at some point of disease development ( Table 1) (11)(12)(13)(14)(15)(16). EBV AIs are also elevated, however, not necessarily to the same extent as other AIs, despite the presence of high levels of Abs to EBV in serum of MS patients (15,124). Interestingly, there is a high degree of correlation between Ab concentrations in serum and in CSF for most or all of the virus Abs described above (15).…”

Section: Ebv and Msmentioning

confidence: 99%

“…This may simply reflect a viral Aginduced reactivation and stimulation of EBV-infected B cells with specificity for the virus(es) in question (i.e., a secondary role for these viruses), or it may reflect a more active role of the viruses. The virus Ab profile varies much between individual patients, thus favoring a primary role of EBV and a secondary role of other viruses (15). Interestingly, CMV seropositivity appears to afford some protection against MS development (30,135).…”

Section: Ebv and Msmentioning

confidence: 99%

“…These criteria include detection of active inflammatory foci in the CNS as seen by positron emission tomography (PET) and magnetic resonance imaging (MRI) and intrathecal production of immunoglobulins (Igs), measured as an elevated cerebrospinal fluid (CSF)/serum IgG index, as a free light chain index or as the occurrence of oligoclonal bands (OCBs) of IgG in CSF (6)(7)(8)(9)(10). Each oligoclonal band is a result of intrathecal antibody (Ab) synthesis by single B cell clones and therefore, specific CSF/ serum Ab indices (AIs) may also be elevated, e.g., Abs to various viruses, corresponding to the specificity of some of the OCBs (11)(12)(13)(14)(15). Accordingly, the OCB Abs show evidence of antigen (Ag) exposure, somatic hypermutation and affinity maturation (16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

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Epstein-Barr Virus and Multiple Sclerosis

2020

Self Cite

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Multiple sclerosis (MS) is a neurologic disease affecting myelinated nerves in the central nervous system (CNS). The disease often debuts as a clinically isolated syndrome, e.g., optic neuritis (ON), which later develops into relapsing-remitting (RR) MS, with temporal attacks or primary progressive (PP) MS. Characteristic features of MS are inflammatory foci in the CNS and intrathecal synthesis of immunoglobulins (Igs), measured as an IgG index, oligoclonal bands (OCBs), or specific antibody indexes. Major predisposing factors for MS are certain tissue types (e.g., HLA DRB1*15:01), vitamin D deficiency, smoking, obesity, and infection with Epstein-Barr virus (EBV). Many of the clinical signs of MS described above can be explained by chronic/recurrent EBV infection and current models of EBV involvement suggest that RRMS may be caused by repeated entry of EBV-transformed B cells to the CNS in connection with attacks, while PPMS may be caused by more chronic activity of EBV-transformed B cells in the CNS. In line with the model of EBV’s role in MS, new treatments based on monoclonal antibodies (MAbs) targeting B cells have shown good efficacy in clinical trials both for RRMS and PPMS, while MAbs inhibiting B cell mobilization and entry to the CNS have shown efficacy in RRMS. Thus, these agents, which are now first line therapy in many patients, may be hypothesized to function by counteracting a chronic EBV infection.

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Antibodies to expanded virus antigen panels show elevated diagnostic sensitivities in multiple sclerosis and optic neuritis

Gåsland¹,

Trier²,

Kyllesbech³

et al. 2023

Immunology Letters

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Antibodies to Epstein-Barr virus and neurotropic viruses in multiple sclerosis and optic neuritis

Cited by 7 publications

References 35 publications

Follow-up after infectious mononucleosis in search of serological similarities with presymptomatic multiple sclerosis

Follow-up after infectious mononucleosis in search of serological similarities with presymptomatic multiple sclerosis

Epstein-Barr Virus and Multiple Sclerosis

Antibodies to expanded virus antigen panels show elevated diagnostic sensitivities in multiple sclerosis and optic neuritis

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