Higher EBV response is associated with more severe gray matter and lesion pathology in relapsing multiple sclerosis patients: A case-controlled magnetization transfer ratio study
Restricted accessResearch articleFirst published online March, 2020
Higher EBV response is associated with more severe gray matter and lesion pathology in relapsing multiple sclerosis patients: A case-controlled magnetization transfer ratio study
Epstein–Barr virus (EBV) infection has been associated with higher clinical activity and risk of multiple sclerosis (MS).
Objective:
To evaluate associations between EBV-specific humoral response and magnetization transfer ratio (MTR)-derived measure in MS patients and healthy controls (HCs).
Methods:
The study included 101 MS patients (69 relapsing-remitting multiple sclerosis (RRMS) and 32 secondary-progressive multiple sclerosis (SPMS)) and 41 HCs who underwent clinical, serological, and magnetic resonance imaging (MRI) investigations. MTR values of T1 or T2 lesion volume (LV), normal-appearing (NA) brain tissue (NABT), gray matter (NAGM), and white matter (NAWM) were obtained. Enzyme-linked immunosorbent assay was used to quantify EBV antibody levels. Partial correlations corrected for MRI strength were used, and Benjamini–Hochberg–adjusted p-values < 0.05 were considered significant.
Results:
MS patients had significantly higher anti-EBV nuclear antigen-1 (EBNA-1) titer when compared to HCs (107.9 U/mL vs 27.8 U/mL, p < 0.001). Within the MS group, higher serum anti-EBNA-1 titer was significantly correlated with lower T1-LV MTR (r = –0.287, p = 0.035). Within the RRMS group, higher serum anti-EBNA-1 titer was associated with T1-LV MTR (r = –0.524, p = 0.001) and NAGM MTR (r = –0.308, p = 0.043). These associations were not present in HCs or SPMS patients.
Conclusion:
Greater EBV humoral response is associated with lower GM MTR changes and focal destructive lesion pathology in RRMS patients.
BenedictRHZivadinovR.Risk factors for and management of cognitive dysfunction in multiple sclerosis. Nat Rev Neurol2011; 7(6): 332–342. DOI: 10.1038/nrneurol.2011.61.
2.
GuanYJakimovskiDRamanathanM, et al. The role of Epstein-Barr virus in multiple sclerosis: From molecular pathophysiology to in vivo imaging. Neural Regen Res2018; 14(3): 373–386. DOI: 10.4103/1673-5374.245462.
3.
LiRPattersonKRBar-OrA.Reassessing B cell contributions in multiple sclerosis. Nat Immunol2018; 19(7): 696–707. DOI: 10.1038/s41590-018-0135-x.
4.
JakimovskiDWeinstock-GuttmanBRamanathanM, et al. Ocrelizumab: A B-cell depleting therapy for multiple sclerosis. Expert Opin Biol Ther2017; 17(9): 1163–1172. DOI: 10.1080/14712598.2017.1347632.
5.
BakerDMartaMPryceG, et al. Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis. EBioMedicine2017; 16: 41–50. DOI: 10.1016/j.ebiom.2017.01.042.
6.
MorandiEJagessarSA‘tHartBA, et al. EBV infection empowers human B cells for autoimmunity: Role of autophagy and relevance to multiple sclerosis. J Immunol2017; 199(2): 435–448. DOI: 10.4049/jimmunol.1700178.
7.
ZivadinovRCerzaNHagemeierJ, et al. Humoral response to EBV is associated with cortical atrophy and lesion burden in patients with MS. Neurol Neuroimmunol Neuroinflamm2016; 3(1): e190. DOI: 10.1212/NXI.0000000000000190.
8.
HorakovaDZivadinovRWeinstock-GuttmanB, et al. Environmental factors associated with disease progression after the first demyelinating event: Results from the multi-center SET study. PLoS ONE2013; 8(1): e53996. DOI: 10.1371/journal.pone.0053996.
9.
PoloniGMinagarAHaackeEM, et al. Recent developments in imaging of multiple sclerosis. Neurologist2011; 17(4): 185–204. DOI: 10.1097/NRL.0b013e31821a2643.
10.
SchmiererKScaravilliFAltmannDR, et al. Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain. Ann Neurol2004; 56(3): 407–415. DOI: 10.1002/ana.20202.
11.
ChenJTEasleyKSchneiderC, et al. Clinically feasible MTR is sensitive to cortical demyelination in MS. Neurology2013; 80(3): 246–252. DOI: 10.1212/WNL.0b013e31827deb99.
12.
DwyerMBergslandNHusseinS, et al. A sensitive, noise-resistant method for identifying focal demyelination and remyelination in patients with multiple sclerosis via voxel-wise changes in magnetization transfer ratio. J Neurol Sci2009; 282(1–2): 86–95. DOI: 10.1016/j.jns.2009.03.016.
13.
PolmanCHReingoldSCBanwellB, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol2011; 69(2): 292–302. DOI: 10.1002/ana.22366.
14.
KurtzkeJF.Rating neurologic impairment in multiple sclerosis: An Expanded Disability Status Scale (EDSS). Neurology1983; 33(11): 1444–1452.
15.
ZivadinovRHeininen-BrownMSchirdaCV, et al. Abnormal subcortical deep-gray matter susceptibility-weighted imaging filtered phase measurements in patients with multiple sclerosis: A case-control study. Neuroimage2012; 59(1): 331–339. DOI: 10.1016/j.neuroimage.2011.07.045.
16.
SmithSMZhangYJenkinsonM, et al. Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage2002; 17(1): 479–489.
17.
Gelineau-MorelRTomassiniVJenkinsonM, et al. The effect of hypointense white matter lesions on automated gray matter segmentation in multiple sclerosis. Hum Brain Mapp2012; 33(12): 2802–2814. DOI: 10.1002/hbm.21402.
18.
KvistadSMyhrKMHolmoyT, et al. Antibodies to Epstein-Barr virus and MRI disease activity in multiple sclerosis. Mult Scler2014; 20(14): 1833–1840. DOI: 10.1177/1352458514533843.
19.
MungerKLLevinLIO’ReillyEJ, et al. Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: A prospective study among United States military personnel. Mult Scler2011; 17(10): 1185–1193. DOI: 10.1177/1352458511408991.
20.
NielsenTRRostgaardKNielsenNM, et al. Multiple sclerosis after infectious mononucleosis. Arch Neurol2007; 64(1): 72–75. DOI: 10.1001/archneur.64.1.72.
21.
ThackerELMirzaeiFAscherioA.Infectious mononucleosis and risk for multiple sclerosis: A meta-analysis. Ann Neurol2006; 59(3): 499–503. DOI: 10.1002/ana.20820.
22.
van der MeiILucasRMTaylorBV, et al. Population attributable fractions and joint effects of key risk factors for multiple sclerosis. Mult Scler2016; 22(4): 461–469. DOI: 10.1177/1352458515594040.
23.
FarrellRAAntonyDWallGR, et al. Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI. Neurology2009; 73(1): 32–38. DOI: 10.1212/WNL.0b013e3181aa29fe.
24.
ZivadinovRZorzonMWeinstock-GuttmanB, et al. Epstein-Barr virus is associated with grey matter atrophy in multiple sclerosis. J Neurol Neurosurg Psychiatry2009; 80(6): 620–625. DOI: 10.1136/jnnp.2008.154906.
25.
VirtanenJOWohlerJFentonK, et al. Oligoclonal bands in multiple sclerosis reactive against two herpesviruses and association with magnetic resonance imaging findings. Mult Scler2014; 20(1): 27–34. DOI: 10.1177/1352458513490545.
26.
MorenoMAOr-GevaNAftabBT, et al. Molecular signature of Epstein-Barr virus infection in MS brain lesions. Neurol Neuroimmunol Neuroinflamm2018; 5(4): e466. DOI: 10.1212/NXI.0000000000000466.
27.
VeroniCSerafiniBRosicarelliB, et al. Transcriptional profile and Epstein-Barr virus infection status of laser-cut immune infiltrates from the brain of patients with progressive multiple sclerosis. J Neuroinflammation2018; 15(1): 18. DOI: 10.1186/s12974-017-1049-5.
28.
SerafiniBScorsiERosicarelliB, et al. Massive intracerebral Epstein-Barr virus reactivation in lethal multiple sclerosis relapse after natalizumab withdrawal. J Neuroimmunol2017; 307: 14–17. DOI: 10.1016/j.jneuroim.2017.03.013.
29.
MagliozziRSerafiniBRosicarelliB, et al. B-cell enrichment and Epstein-Barr virus infection in inflammatory cortical lesions in secondary progressive multiple sclerosis. J Neuropathol Exp Neurol2013; 72(1): 29–41. DOI: 10.1097/NEN.0b013e31827bfc62.
30.
SerafiniBRosicarelliBMagliozziR, et al. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol2004; 14(2): 164–174.
31.
SerafiniBRosicarelliBFranciottaD, et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med2007; 204(12): 2899–2912. DOI: 10.1084/jem.20071030.
32.
HowellOWReevesCANicholasR, et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain2011; 134(Pt9): 2755–2771. DOI: 10.1093/brain/awr182.
33.
MagliozziRHowellOWReevesC, et al. A gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol2010; 68(4): 477–493. DOI: 10.1002/ana.22230.
34.
ZurawskiJLassmannHBakshiR.Use of magnetic resonance imaging to visualize leptomeningeal inflammation in patients with multiple sclerosis: A review. JAMA Neurol2017; 74(1): 100–109. DOI: 10.1001/jamaneurol.2016.4237.
35.
AbsintaMVuoloLRaoA, et al. Gadolinium-based MRI characterization of leptomeningeal inflammation in multiple sclerosis. Neurology2015; 85(1): 18–28. DOI: 10.1212/WNL.0000000000001587.
36.
BevanRJEvansRGriffithsL, et al. Meningeal inflammation and cortical demyelination in acute multiple sclerosis. Ann Neurol2018; 84: 829–842. DOI: 10.1002/ana.25365.
37.
Lehmann-HornKKinzelSFeldmannL, et al. Intrathecal anti-CD20 efficiently depletes meningeal B cells in CNS autoimmunity. Ann Clin Transl Neurol2014; 1(7): 490–496. DOI: 10.1002/acn3.71.
38.
BhargavaPWickenCSmithM, et al. Phase 1 trial of intrathecal rituximab in progressive MS patients with evidence of leptomeningeal contrast enhancement (P3.393). Neurology2018; 90: P3393.
39.
TrappBDVignosMDudmanJ, et al. Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: A retrospective study. Lancet Neurol2018; 17: 870–884. DOI: 10.1016/S1474-4422(18)30245-X.
40.
AbsintaMSatiPFechnerA, et al. Identification of chronic active multiple sclerosis lesions on 3T MRI. AJNR2018; 39: 1233–1238. DOI: 10.3174/ajnr.A5660.
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