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HomeScienceFirst ReleaseLongitudinal analysis reveals high prevalence
of Epstein-Barr virus associated with multiple sclerosis
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Longitudinal analysis reveals high prevalence of Epstein-Barr virus
associated with multiple sclerosis

Kjetil Bjornevik https://orcid.org/0000-0002-2892-6986, Marianna 
Cortese https://orcid.org/0000-0002-3665-2006, Brian C. Healy https:/
/orcid.org/0000-0001-5272-2425, Jens Kuhle, Michael J. Mina https://
orcid.org/0000-0002-0674-5762, Yumei Leng https://orcid.org/
0000-0003-2512-9284, Stephen J. Elledge https://orcid.org/
0000-0001-7923-6283, David W. Niebuhr, Ann I. Scher, Kassandra L. 
Munger https://orcid.org/0000-0001-7486-9858, and Alberto Ascherio
https://orcid.org/0000-0002-0585-3294 [email protected]
Science * 13 Jan 2022 * First Release * DOI: 10.1126/science.abj8222
 

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Epstein-Barr virus and multiple sclerosis
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  * Abstract
  * Supplementary Materials
  * References and Notes

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating
disease of the central nervous system of unknown etiology. We tested
the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a
cohort comprising more than 10 million young adults on active duty in
the US military, 955 of whom were diagnosed with MS during their
period of service. Risk of MS increased 32-fold after infection with
EBV but was not increased after infection with other viruses,
including the similarly transmitted cytomegalovirus. Serum levels of
neurofilament light chain, a biomarker of neuroaxonal degeneration,
increased only after EBV seroconversion. These findings cannot be
explained by any known risk factor for MS and suggest EBV as the
leading cause of MS.

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Supplementary Materials

This PDF file includes:

Materials and Methods
Figs. S1 to S4
Tables S1 and S2
References (39-52)
Data S1
MDAR Reproducibility Checklist
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Other Supplementary Material for this manuscript includes the
following:

MDAR Reproducibility Checklist
Download (97.32 KB)
Data S1
Download (23.29 MB)
View/request a protocol for this paper from Bio-protocol.

References and Notes

1
D. S. Reich, C. F. Lucchinetti, P. A. Calabresi, Multiple sclerosis.
N. Engl. J. Med. 378, 169-180 (2018).
Crossref
PubMed
Google Scholar
2
N. L. Fransen, C.-C. Hsiao, M. van der Poel, H. J. Engelenburg, K.
Verdaasdonk, M. C. J. Vincenten, E. B. M. Remmerswaal, T. Kuhlmann,
M. R. J. Mason, J. Hamann, J. Smolders, I. Huitinga, Tissue-resident
memory T cells invade the brain parenchyma in multiple sclerosis
white matter lesions. Brain 143, 1714-1730 (2020).
Crossref
PubMed
Google Scholar
3
D. A. Thorley-Lawson, Epstein-Barr virus: Exploiting the immune
system. Nat. Rev. Immunol. 1, 75-82 (2001).
Crossref
PubMed
Google Scholar
4
E. L. Thacker, F. Mirzaei, A. Ascherio, Infectious mononucleosis and
risk for multiple sclerosis: A meta-analysis. Ann. Neurol. 59,
499-503 (2006).
Crossref
PubMed
Google Scholar
5
L. I. Levin, K. L. Munger, M. V. Rubertone, C. A. Peck, E. T.
Lennette, D. Spiegelman, A. Ascherio, Temporal relationship between
elevation of Epstein-Barr virus antibody titers and initial onset of
neurological symptoms in multiple sclerosis. JAMA 293, 2496-2500
(2005).
Crossref
PubMed
Google Scholar
6
B. Serafini, B. Rosicarelli, D. Franciotta, R. Magliozzi, R.
Reynolds, P. Cinque, L. Andreoni, P. Trivedi, M. Salvetti, A.
Faggioni, F. Aloisi, Dysregulated Epstein-Barr virus infection in the
multiple sclerosis brain. J. Exp. Med. 204, 2899-2912 (2007).
Crossref
PubMed
Google Scholar
7
M. A. Moreno, N. Or-Geva, B. T. Aftab, R. Khanna, E. Croze, L.
Steinman, M. H. Han, Molecular signature of Epstein-Barr virus
infection in MS brain lesions. Neurol. Neuroimmunol. Neuroinflamm. 5,
e466 (2018).
Crossref
PubMed
Google Scholar
8
A. Hassani, J. R. Corboy, S. Al-Salam, G. Khan, Epstein-Barr virus is
present in the brain of most cases of multiple sclerosis and may
engage more than just B cells. PLOS ONE 13, e0192109 (2018).
Crossref
PubMed
Google Scholar
9
H. Lassmann, G. Niedobitek, F. Aloisi, J. M. Middeldorp; NeuroproMiSe
EBV Working Group, Epstein-Barr virus in the multiple sclerosis
brain: A controversial issue--report on a focused workshop held in the
Centre for Brain Research of the Medical University of Vienna,
Austria. Brain 134, 2772-2786 (2011).
Crossref
PubMed
Google Scholar
10
C. L. Perdue, A. A. Eick-Cost, M. V. Rubertone, A Brief Description
of the Operation of the DoD Serum Repository. Mil. Med. 180 (Suppl),
10-12 (2015).
Crossref
PubMed
Google Scholar
11
L. I. Levin, K. L. Munger, E. J. O'Reilly, K. I. Falk, A. Ascherio,
Primary infection with the Epstein-Barr virus and risk of multiple
sclerosis. Ann. Neurol. 67, 824-830 (2010).
Crossref
PubMed
Google Scholar
12
D. H. Crawford, K. F. Macsween, C. D. Higgins, R. Thomas, K. McAulay,
H. Williams, N. Harrison, S. Reid, M. Conacher, J. Douglas, A. J.
Swerdlow, A cohort study among university students: Identification of
risk factors for Epstein-Barr virus seroconversion and infectious
mononucleosis. Clin. Infect. Dis. 43, 276-282 (2006).
Crossref
PubMed
Google Scholar
13
J. B. Dowd, A. E. Aiello, D. E. Alley, Socioeconomic disparities in
the seroprevalence of cytomegalovirus infection in the US population:
NHANES III. Epidemiol. Infect. 137, 58-65 (2009).
Crossref
PubMed
Google Scholar
14
H. H. Balfour Jr., F. Sifakis, J. A. Sliman, J. A. Knight, D. O.
Schmeling, W. Thomas, Age-specific prevalence of Epstein-Barr virus
infection among individuals aged 6-19 years in the United States and
factors affecting its acquisition. J. Infect. Dis. 208, 1286-1293
(2013).
Crossref
PubMed
Google Scholar
15
M. Lipsitch, E. Tchetgen Tchetgen, T. Cohen, Negative controls: A
tool for detecting confounding and bias in observational studies.
Epidemiology 21, 383-388 (2010).
Crossref
PubMed
Google Scholar
16
V. Grut, M. Bistrom, J. Salzer, P. Stridh, D. Jons, R. Gustafsson, A.
Fogdell-Hahn, J. Huang, N. Brenner, J. Butt, N. Bender, A. Lindam, L.
Alonso-Magdalena, M. Gunnarsson, M. Vrethem, T. Bergstrom, O.
Andersen, I. Kockum, T. Waterboer, T. Olsson, P. Sundstrom,
Cytomegalovirus seropositivity is associated with reduced risk of
multiple sclerosis-a presymptomatic case-control study. Eur. J.
Neurol. 28, 3072-3079 (2021).
Crossref
PubMed
Google Scholar
17
H. Tremlett, R. A. Marrie, The multiple sclerosis prodrome: Emerging
evidence, challenges, and opportunities. Mult. Scler. 27, 6-12
(2021).
Crossref
PubMed
Google Scholar
18
M. Khalil, C. E. Teunissen, M. Otto, F. Piehl, M. P. Sormani, T.
Gattringer, C. Barro, L. Kappos, M. Comabella, F. Fazekas, A.
Petzold, K. Blennow, H. Zetterberg, J. Kuhle, Neurofilaments as
biomarkers in neurological disorders. Nat. Rev. Neurol. 14, 577-589
(2018).
Crossref
PubMed
Google Scholar
19
B. Delcoigne, A. Manouchehrinia, C. Barro, P. Benkert, Z. Michalak,
L. Kappos, D. Leppert, J. A. Tsai, T. Plavina, B. C. Kieseier, J.
Lycke, L. Alfredsson, I. Kockum, J. Kuhle, T. Olsson, F. Piehl, Blood
neurofilament light levels segregate treatment effects in multiple
sclerosis. Neurology 94, e1201-e1212 (2020).
Crossref
PubMed
Google Scholar
20
K. Bjornevik, K. L. Munger, M. Cortese, C. Barro, B. C. Healy, D. W.
Niebuhr, A. I. Scher, J. Kuhle, A. Ascherio, Serum neurofilament
light chain levels in patients with presymptomatic multiple
sclerosis. JAMA Neurol. 77, 58-64 (2020).
Crossref
PubMed
Google Scholar
21
G. J. Xu, T. Kula, Q. Xu, M. Z. Li, S. D. Vernon, T. Ndung'u, K.
Ruxrungtham, J. Sanchez, C. Brander, R. T. Chung, K. C. O'Connor, B.
Walker, H. B. Larman, S. J. Elledge, Comprehensive serological
profiling of human populations using a synthetic human virome.
Science 348, aaa0698 (2015).
Crossref
PubMed
Google Scholar
22
M. J. Mina, T. Kula, Y. Leng, M. Li, R. D. de Vries, M. Knip, H.
Siljander, M. Rewers, D. F. Choy, M. S. Wilson, H. B. Larman, A. N.
Nelson, D. E. Griffin, R. L. de Swart, S. J. Elledge, Measles virus
infection diminishes preexisting antibodies that offer protection
from other pathogens. Science 366, 599-606 (2019).
Crossref
PubMed
Google Scholar
23
T. J. VanderWeele, P. Ding, Sensitivity analysis in observational
research: introducing the E-value. Ann. Intern. Med. 167, 268-274
(2017).
Crossref
PubMed
Google Scholar
24
S. Sawcer, G. Hellenthal, M. Pirinen, C. C. Spencer, N. A.
Patsopoulos, L. Moutsianas, A. Dilthey, Z. Su, C. Freeman, S. E.
Hunt, S. Edkins, E. Gray, D. R. Booth, S. C. Potter, A. Goris, G.
Band, A. B. Oturai, A. Strange, J. Saarela, C. Bellenguez, B.
Fontaine, M. Gillman, B. Hemmer, R. Gwilliam, F. Zipp, A. Jayakumar,
R. Martin, S. Leslie, S. Hawkins, E. Giannoulatou, S. D'alfonso, H.
Blackburn, F. Martinelli Boneschi, J. Liddle, H. F. Harbo, M. L.
Perez, A. Spurkland, M. J. Waller, M. P. Mycko, M. Ricketts, M.
Comabella, N. Hammond, I. Kockum, O. T. McCann, M. Ban, P. Whittaker,
A. Kemppinen, P. Weston, C. Hawkins, S. Widaa, J. Zajicek, S. Dronov,
N. Robertson, S. J. Bumpstead, L. F. Barcellos, R. Ravindrarajah, R.
Abraham, L. Alfredsson, K. Ardlie, C. Aubin, A. Baker, K. Baker, S.
E. Baranzini, L. Bergamaschi, R. Bergamaschi, A. Bernstein, A.
Berthele, M. Boggild, J. P. Bradfield, D. Brassat, S. A. Broadley, D.
Buck, H. Butzkueven, R. Capra, W. M. Carroll, P. Cavalla, E. G.
Celius, S. Cepok, R. Chiavacci, F. Clerget-Darpoux, K. Clysters, G.
Comi, M. Cossburn, I. Cournu-Rebeix, M. B. Cox, W. Cozen, B. A. Cree,
A. H. Cross, D. Cusi, M. J. Daly, E. Davis, P. I. de Bakker, M.
Debouverie, M. B. D'hooghe, K. Dixon, R. Dobosi, B. Dubois, D.
Ellinghaus, I. Elovaara, F. Esposito, C. Fontenille, S. Foote, A.
Franke, D. Galimberti, A. Ghezzi, J. Glessner, R. Gomez, O. Gout, C.
Graham, S. F. Grant, F. R. Guerini, H. Hakonarson, P. Hall, A.
Hamsten, H. P. Hartung, R. N. Heard, S. Heath, J. Hobart, M. Hoshi,
C. Infante-Duarte, G. Ingram, W. Ingram, T. Islam, M. Jagodic, M.
Kabesch, A. G. Kermode, T. J. Kilpatrick, C. Kim, N. Klopp, K.
Koivisto, M. Larsson, M. Lathrop, J. S. Lechner-Scott, M. A. Leone,
V. Leppa, U. Liljedahl, I. L. Bomfim, R. R. Lincoln, J. Link, J. Liu,
A. R. Lorentzen, S. Lupoli, F. Macciardi, T. Mack, M. Marriott, V.
Martinelli, D. Mason, J. L. McCauley, F. Mentch, I. L. Mero, T.
Mihalova, X. Montalban, J. Mottershead, K. M. Myhr, P. Naldi, W.
Ollier, A. Page, A. Palotie, J. Pelletier, L. Piccio, T. Pickersgill,
F. Piehl, S. Pobywajlo, H. L. Quach, P. P. Ramsay, M. Reunanen, R.
Reynolds, J. D. Rioux, M. Rodegher, S. Roesner, J. P. Rubio, I. M.
Ruckert, M. Salvetti, E. Salvi, A. Santaniello, C. A. Schaefer, S.
Schreiber, C. Schulze, R. J. Scott, F. Sellebjerg, K. W. Selmaj, D.
Sexton, L. Shen, B. Simms-Acuna, S. Skidmore, P. M. Sleiman, C.
Smestad, P. S. Sorensen, H. B. Sondergaard, J. Stankovich, R. C.
Strange, A. M. Sulonen, E. Sundqvist, A. C. Syvanen, F. Taddeo, B.
Taylor, J. M. Blackwell, P. Tienari, E. Bramon, A. Tourbah, M. A.
Brown, E. Tronczynska, J. P. Casas, N. Tubridy, A. Corvin, J.
Vickery, J. Jankowski, P. Villoslada, H. S. Markus, K. Wang, C. G.
Mathew, J. Wason, C. N. Palmer, H. E. Wichmann, R. Plomin, E.
Willoughby, A. Rautanen, J. Winkelmann, M. Wittig, R. C. Trembath, J.
Yaouanq, A. C. Viswanathan, H. Zhang, N. W. Wood, R. Zuvich, P.
Deloukas, C. Langford, A. Duncanson, J. R. Oksenberg, M. A.
Pericak-Vance, J. L. Haines, T. Olsson, J. Hillert, A. J. Ivinson, P.
L. De Jager, L. Peltonen, G. J. Stewart, D. A. Hafler, S. L. Hauser,
G. McVean, P. Donnelly, A. Compston; International Multiple Sclerosis
Genetics Consortium; Wellcome Trust Case Control Consortium 2,
Genetic risk and a primary role for cell-mediated immune mechanisms
in multiple sclerosis. Nature 476, 214-219 (2011).
Crossref
PubMed
Google Scholar
25
W. J. Jabs, M. Paulsen, H. J. Wagner, H. Kirchner, H. Kluter,
Analysis of Epstein-Barr virus (EBV) receptor CD21 on peripheral B
lymphocytes of long-term EBV- adults. Clin. Exp. Immunol. 116,
468-473 (1999).
Crossref
PubMed
Google Scholar
26
T. Olsson, L. F. Barcellos, L. Alfredsson, Interactions between
genetic, lifestyle and environmental risk factors for multiple
sclerosis. Nat. Rev. Neurol. 13, 25-36 (2017).
Crossref
PubMed
Google Scholar
27
H. Zdimerova, A. Murer, C. Engelmann, A. Raykova, Y. Deng, C. Gujer,
J. Ruhl, D. McHugh, N. Caduff, R. Naghavian, G. Pezzino, R. Capaul,
A. Zbinden, G. Ferlazzo, J. D. Lunemann, R. Martin, B. Chatterjee, C.
Munz, Attenuated immune control of Epstein-Barr virus in humanized
mice is associated with the multiple sclerosis risk factor HLA-DR15.
Eur. J. Immunol. (2020).
PubMed
Google Scholar
28
A. Ascherio, K. L. Munger, Epidemiology of multiple sclerosis: From
risk factors to prevention -- An update. Semin. Neurol. 36, 103-114
(2016).
Crossref
PubMed
Google Scholar
29
J. M. A. Wijnands, F. Zhu, E. Kingwell, Y. Zhao, C. Evans, J. D.
Fisk, R. A. Marrie, H. Tremlett, Prodrome in relapsing-remitting and
primary progressive multiple sclerosis. Eur. J. Neurol. 26, 1032-1036
(2019).
Crossref
PubMed
Google Scholar
30
W. A. Sibley, C. R. Bamford, K. Clark, Clinical viral infections and
multiple sclerosis. Lancet 1, 1313-1315 (1985).
Crossref
PubMed
Google Scholar
31
Y. Xu, K. A. Smith, A. Hiyoshi, F. Piehl, T. Olsson, S. Montgomery,
Hospital-diagnosed infections before age 20 and risk of a subsequent
multiple sclerosis diagnosis. Brain 144, 2390-2400 (2021).
Crossref
PubMed
Google Scholar
32
T. R. Nielsen, K. Rostgaard, N. M. Nielsen, N. Koch-Henriksen, S.
Haahr, P. S. Sorensen, H. Hjalgrim, Multiple sclerosis after
infectious mononucleosis. Arch. Neurol. 64, 72-75 (2007).
Crossref
PubMed
Google Scholar
33
G. N. DeLorenze, K. L. Munger, E. T. Lennette, N. Orentreich, J. H.
Vogelman, A. Ascherio, Epstein-Barr virus and multiple sclerosis:
Evidence of association from a prospective study with long-term
follow-up. Arch. Neurol. 63, 839-844 (2006).
Crossref
PubMed
Google Scholar
34
K. Messacar, T. L. Schreiner, J. A. Maloney, A. Wallace, J. Ludke, M.
S. Oberste, W. A. Nix, C. C. Robinson, M. P. Glode, M. J. Abzug, S.
R. Dominguez, A cluster of acute flaccid paralysis and cranial nerve
dysfunction temporally associated with an outbreak of enterovirus D68
in children in Colorado, USA. Lancet 385, 1662-1671 (2015).
Crossref
PubMed
Google Scholar
35
J. I. Cohen, Vaccine development for Epstein-Barr virus. Adv. Exp.
Med. Biol. 1045, 477-493 (2018).
Crossref
PubMed
Google Scholar
36
S. L. Hauser, A. Bar-Or, G. Comi, G. Giovannoni, H.-P. Hartung, B.
Hemmer, F. Lublin, X. Montalban, K. W. Rammohan, K. Selmaj, A.
Traboulsee, J. S. Wolinsky, D. L. Arnold, G. Klingelschmitt, D.
Masterman, P. Fontoura, S. Belachew, P. Chin, N. Mairon, H. Garren,
L. Kappos; OPERA I and OPERA II Clinical Investigators, Ocrelizumab
versus interferon beta-1a in relapsing multiple sclerosis. N. Engl.
J. Med. 376, 221-234 (2017).
Crossref
PubMed
Google Scholar
37
M. P. Pender, P. A. Csurhes, C. Smith, N. L. Douglas, M. A. Neller,
K. K. Matthews, L. Beagley, S. Rehan, P. Crooks, T. J. Hopkins, S.
Blum, K. A. Green, Z. A. Ioannides, A. Swayne, B. T. Aftab, K. D.
Hooper, S. R. Burrows, K. M. Thompson, A. Coulthard, R. Khanna,
Epstein-Barr virus-specific T cell therapy for progressive multiple
sclerosis. JCI Insight 3, e124714 (2018).
Crossref
PubMed
Google Scholar
38
Data for: K. Bjornevik, M. Cortese, B. C. Healy, J. Kuhle, M. J.
Mina, Y. Leng, S. J. Elledge, D. W. Niebuhr, A. I. Scher, K. L.
Munger, A. Ascherio, Data for: K. Bjornevik, M. Cortese, B. C. Healy,
J. Kuhle, M. J. Mina, Y. Leng, S. J. Elledge, D. W. Niebuhr, A. I.
Scher, K. L. Munger, A. Ascherio, Longitudinal analysis reveals high
prevalence of Epstein-Barr virus associated with multiple sclerosis,
Harvard Dataverse (2021); .
Crossref
Google Scholar
39
U.S. Department of Defense, "2019 Demographics. profile of the
miltary community" (DoD, 2019); https://
download.militaryonesource.mil/12038/MOS/Reports/
2019-demographics-report.pdf.
Google Scholar
40
M. J. Knol, J. P. Vandenbroucke, P. Scott, M. Egger, What do
case-control studies estimate? Survey of methods and assumptions in
published case-control research. Am. J. Epidemiol. 168, 1073-1081
(2008).
Crossref
PubMed
Google Scholar
41
A. D. Hislop, G. S. Taylor, D. Sauce, A. B. Rickinson, Cellular
responses to viral infection in humans: Lessons from Epstein-Barr
virus. Annu. Rev. Immunol. 25, 587-617 (2007).
Crossref
PubMed
Google Scholar
42
S. K. Dunmire, P. S. Verghese, H. H. Balfour Jr., Primary
Epstein-Barr virus infection. J. Clin. Virol. 102, 84-92 (2018).
Crossref
PubMed
Google Scholar
43
M. De Paschale, P. Clerici, Serological diagnosis of Epstein-Barr
virus infection: Problems and solutions. World J. Virol. 1, 31-43
(2012).
Crossref
PubMed
Google Scholar
44
J. B. Dowd, T. Palermo, J. Brite, T. W. McDade, A. Aiello,
Seroprevalence of Epstein-Barr virus infection in U.S. children ages
6-19, 2003-2010. PLOS ONE 8, e64921 (2013).
Crossref
PubMed
Google Scholar
45
J. M. Grimm, D. O. Schmeling, S. K. Dunmire, J. A. Knight, B. D.
Mullan, J. A. Ed, R. C. Brundage, K. A. Hogquist, H. H. Balfour Jr.,
Prospective studies of infectious mononucleosis in university
students. Clin. Transl. Immunology 5, e94 (2016).
Crossref
PubMed
Google Scholar
46
W. Henle, G. Henle, J. Andersson, I. Ernberg, G. Klein, C. A.
Horwitz, G. Marklund, L. Rymo, C. Wellinder, S. E. Straus, Antibody
responses to Epstein-Barr virus-determined nuclear antigen (EBNA)-1
and EBNA-2 in acute and chronic Epstein-Barr virus infection. Proc.
Natl. Acad. Sci. U.S.A. 84, 570-574 (1987).
Crossref
PubMed
Google Scholar
47
G. Disanto, C. Barro, P. Benkert, Y. Naegelin, S. Schadelin, A.
Giardiello, C. Zecca, K. Blennow, H. Zetterberg, D. Leppert, L.
Kappos, C. Gobbi, J. Kuhle; Swiss Multiple Sclerosis Cohort Study
Group, Serum Neurofilament light: A biomarker of neuronal damage in
multiple sclerosis. Ann. Neurol. 81, 857-870 (2017).
Crossref
PubMed
Google Scholar
48
J. Kuhle, C. Barro, U. Andreasson, T. Derfuss, R. Lindberg, A.
Sandelius, V. Liman, N. Norgren, K. Blennow, H. Zetterberg,
Comparison of three analytical platforms for quantification of the
neurofilament light chain in blood samples: ELISA,
electrochemiluminescence immunoassay and Simoa. Clin. Chem. Lab. Med.
54, 1655-1661 (2016).
Crossref
PubMed
Google Scholar
49
J. Kuhle, K. Plattner, J. P. Bestwick, R. L. Lindberg, S. V.
Ramagopalan, N. Norgren, A. Nissim, A. Malaspina, D. Leppert, G.
Giovannoni, L. Kappos, A comparative study of CSF neurofilament light
and heavy chain protein in MS. Mult. Scler. 19, 1597-1603 (2013).
Crossref
PubMed
Google Scholar
50
J. Gaiottino, N. Norgren, R. Dobson, J. Topping, A. Nissim, A.
Malaspina, J. P. Bestwick, A. U. Monsch, A. Regeniter, R. L.
Lindberg, L. Kappos, D. Leppert, A. Petzold, G. Giovannoni, J. Kuhle,
Increased neurofilament light chain blood levels in neurodegenerative
neurological diseases. PLOS ONE 8, e75091 (2013).
Crossref
PubMed
Google Scholar
51
H. B. Larman, Z. Zhao, U. Laserson, M. Z. Li, A. Ciccia, M. A. M.
Gakidis, G. M. Church, S. Kesari, E. M. Leproust, N. L. Solimini, S.
J. Elledge, Autoantigen discovery with a synthetic human peptidome.
Nat. Biotechnol. 29, 535-541 (2011).
Crossref
PubMed
Google Scholar
52
R. Vita, S. Mahajan, J. A. Overton, S. K. Dhanda, S. Martini, J. R.
Cantrell, D. K. Wheeler, A. Sette, B. Peters, The Immune Epitope
Database (IEDB): 2018 update. Nucleic Acids Res. 47 (D1), D339-D343
(2019).
Crossref
PubMed
Google Scholar

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Copyright (c) 2022, American Association for the Advancement of
Science.

Submission history

Received: 3 June 2021
Accepted: 2 December 2021
Published in print: 21 January 2022

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Acknowledgments

We thank M. Rubertone and A. Cost of the Armed Forces Health
Surveillance Center, Silver Spring, MD, for control and sample
identification and retrieval; N. Howard, Department of the Navy,
Secretary of the Naval Council of Review Boards, Washington, DC, for
MS case identification in the US Navy and Marines; D. Armitage, US
Army Physical Disability Agency, Washington, DC, and L. Kent, SAIC,
US Army Physical Disability Agency, Washington, DC, for MS case
identification in the US Army; L. R. Hodge, US Air Force Personnel
Center, San Antonio, TX, for MS case identification in the US Air
Force; S. Bernstein, Uniformed Services University of the Health
Sciences, Bethesda, MD, for project coordination and management; D.
Leppert, University of Basel, Basel, Switzerland, for serum
neurofilament measurements and interpretation of results. The views
expressed are those of the authors and should not be construed to
represent the positions of the Department of the Army, Department of
the Navy, Department of Defense, Department of the Air Force, or
Uniformed Services University of the Health Sciences. Funding: This
work was supported by grants NS046635, NS042194, and NS103891 from
the National Institute of Neurological Disorders and Stroke, National
Institutes of Health (NIH); National Multiple Sclerosis Society award
PP-1912-35234 and German Research Foundation (DFG) research
fellowship CO 2129/1-1 to M.C.; and NIH Directors Early Independence
Award DP5-OD028145 to M.J.M.. S.J.E is an investigator with the
Howard Hughes Medical Institute. The content is solely the
responsibility of the authors and does not necessarily represent the
official views of the NIH. Author contributions: Conceptualization:
K.B., M.C., K.L.M., A.A.; Data curation: D.W.N., A.I.S.;
Investigation: J.K, M.J.M., Y.L., S.J.E.; Writing: K.B., M.C.,
K.L.M., A.A., B.C.H., J.K., M.J.M., Y.L., S.J.E., D.W.N., A.I.S.
Statistical analysis: K.B., M.C., B.C.H.; Supervision: K.L.M., A.A.
Competing interests: B.C.H. has received research support from
Analysis Group, Celgene (Bristol-Myers Squibb), Verily Life Sciences,
Merck-Serono, Novartis, and Genzyme. J.K. has received speaker fees,
research support, travel support, and/or served on advisory boards of
the Swiss MS Society, Swiss National Research Foundation
(320030_189140/1), University of Basel, Progressive MS Alliance,
Bayer, Biogen, Celgene, Merck, Novartis, Octave Bioscience, Roche,
and Sanofi. M.J.M. is on the advisory board of ImmuneID and an
adviser to Detect and Quantum-SI. S.J.E. is a founder of TSCAN
Therapeutics, MAZE Therapeutics, Mirimus, and ImmuneID., S.J.E.
serves on the scientific advisory board of Homology Medicines, TSCAN
Therapeutics, MAZE, and ImmuneID, and is an adviser for MPM, none of
which affect this work. S.J.E is an inventor on a patent application
filed by the Brigham and Women's Hospital (US20160320406A) that
covers the use of the VirScan library to identify pathogen antibodies
in the blood. K.B., Y.L., A.I.S., D.W.N., A.A., K.L.M., and M.C.
declare no competing interests. Data and materials availability: All
data needed to evaluate the conclusions in this study are present in
the main paper or the supplementary materials and have been deposited
at the Harvard Dataverse (38).

Authors

Affiliations

Kjetil Bjornevik^+ https://orcid.org/0000-0002-2892-6986
Department of Nutrition, Harvard T. H. Chan School of Public Health,
Boston, MA, USA.
View all articles by this author
Marianna Cortese^+ https://orcid.org/0000-0002-3665-2006
Department of Nutrition, Harvard T. H. Chan School of Public Health,
Boston, MA, USA.
View all articles by this author
Brian C. Healy https://orcid.org/0000-0001-5272-2425
Partners Multiple Sclerosis Center, Brigham and Women's Hospital,
Boston, MA, USA.
Department of Neurology, Harvard Medical School, Boston, MA, USA.
Biostatistics Center, Massachusetts General Hospital, Boston, MA,
USA.
View all articles by this author
Jens Kuhle
Neurologic Clinic and Policlinic, MS Center and Research Center for
Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University
Hospital Basel, University of Basel, Basel, Switzerland.
View all articles by this author
Michael J. Mina https://orcid.org/0000-0002-0674-5762
Division of Genetics, Brigham and Women's Hospital, Howard Hughes
Medical Institute, Department of Genetics, and Program in Virology,
Harvard Medical School, Boston, MA, USA.
Center for Communicable Disease Dynamics, Department of Epidemiology,
and Department of Immunology and Infectious Diseases, Harvard T. H.
Chan School of Public Health, Boston, MA, USA.
Department of Pathology, Brigham and Women's Hospital, Harvard
Medical School, Boston, MA, USA.
View all articles by this author
Yumei Leng https://orcid.org/0000-0003-2512-9284
Division of Genetics, Brigham and Women's Hospital, Howard Hughes
Medical Institute, Department of Genetics, and Program in Virology,
Harvard Medical School, Boston, MA, USA.
View all articles by this author
Stephen J. Elledge https://orcid.org/0000-0001-7923-6283
Division of Genetics, Brigham and Women's Hospital, Howard Hughes
Medical Institute, Department of Genetics, and Program in Virology,
Harvard Medical School, Boston, MA, USA.
View all articles by this author
David W. Niebuhr
Department of Preventive Medicine and Biostatistics, Uniformed
Services University of the Health Sciences, Bethesda, MD, USA.
View all articles by this author
Ann I. Scher
Department of Preventive Medicine and Biostatistics, Uniformed
Services University of the Health Sciences, Bethesda, MD, USA.
View all articles by this author
Kassandra L. Munger^++ https://orcid.org/0000-0001-7486-9858
Department of Nutrition, Harvard T. H. Chan School of Public Health,
Boston, MA, USA.
View all articles by this author
Alberto Ascherio^++,* https://orcid.org/0000-0002-0585-3294
[email protected]
Department of Nutrition, Harvard T. H. Chan School of Public Health,
Boston, MA, USA.
Department of Epidemiology, Harvard T. H. Chan School of Public
Health, Boston, MA, USA.
Channing Laboratory, Department of Medicine, Brigham and Women's
Hospital, and Harvard Medical School, Boston, MA, USA.
View all articles by this author

Funding Information

National Institutes of Health: DP5-OD028145
National Institute of Neurological Disorders and Stroke: NS046635
National Institute of Neurological Disorders and Stroke: NS042194
National Institute of Neurological Disorders and Stroke: NS103891
National Multiple Sclerosis Society: PP-1912-35234
German Research Foundation:

Notes

+
These authors contributed equally to this work.
++
These authors contributed equally to this work.
*Corresponding author. E-mail: [email protected]

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