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

Daniel Jons; Linn Persson Berg; Peter Sundström; Sara Haghighi; Markus Axelsson; Måns Thulin; Tomas Bergström; Oluf Andersen

doi:10.1016/j.msard.2021.103288

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

Mult Scler Relat Disord. 2021 Nov:56:103288. doi: 10.1016/j.msard.2021.103288. Epub 2021 Sep 28.

Authors

Daniel Jons¹, Linn Persson Berg², Peter Sundström³, Sara Haghighi⁴, Markus Axelsson⁵, Måns Thulin⁶, Tomas Bergström², Oluf Andersen⁷

Affiliations

¹ Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gröna Stråket 11, 3tr, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden; Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden and Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.
² Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, the Sahlgrenska Academy, Gothenburg, Sweden and Department of Clinical Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
³ Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
⁴ Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden and Department of Medical Specialists, Institute of Neurology, Motala Hospital, Motala, Sweden.
⁵ Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden and Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁶ School of Mathematics and Maxwell Institute for Mathematical Sciences, University of Edinburgh, UK.
⁷ Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gröna Stråket 11, 3tr, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden; Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden and Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address: Oluf.andersen@neuro.gu.se.

PMID: 34634626
DOI: 10.1016/j.msard.2021.103288

Abstract

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.

Keywords: Epstein-Barr virus; Infectious mononucleosis; Measles; Multiple sclerosis; Recombinant antigen; Varicella-zoster virus.

MeSH terms

Antibodies, Viral
Epstein-Barr Virus Infections*
Follow-Up Studies
Herpesvirus 4, Human
Humans
Infectious Mononucleosis* / diagnosis
Multiple Sclerosis* / diagnosis

Substances

Antibodies, Viral