Jpn. J. Infect. Dis., 52, 198‑200, 1999

Imvited Minireyiew
Multiple Sclerosis and Measles ⅥmsYoshiro Ohara*

Department of Microbiology, Kanazawa Medical University
Uchinada‑machi, Kahoku‑gun, Ishikawa 920‑0293, Japan(Received November 12, 1999)

SUMMARY: Epidemiological studies suggest that patients with multiple sclerosis (MS) are exposed to some
infectious a.gent(S) before puberty･ The p.resence of virus‑induced demyelination in animal models indicates that●demyelinatlOn Can occur followlng the trlgger Of a virus infection. Data regarding the immunologlCal abnormali‑ties to measles virus (MV) and the presence of neurological complications induced by MV infection suggest thatMV may be a caTsative agent of the demyelination observed in MS･ Numerous virologlPal studies (e･g･, morph0‑
logical observat10n, Virus isolation, and the search for the MV gene) have been performed, though definite
evidence identifying MV as the causative agent has not yet been obtained.
●1. 1mtroduction

Multiple sclerosis (MS) is a representative human demyeli‑
natlng disease･ The disorder occurs most frequently in young
adults, generally with periodic exacerbations and remissions.

The intervals of exacerbation and remission are indefinite,
however, the course of the disease is generally progressive.

Demyelination and sclerotic lesions at more than two distinct●sites in the white matter characterize the neuropathologlCal

findings of MS (Figure). The first case of MS was reported
by Charles Prosper Ollivier in 1824, and Charcot described

the clinical features of MS as a discrete and diagnosable entity
in 1868(1).

The exact pathomechanisms of MS have not been fully
Figure･ Demyelinadon inthe brain stem of a patient withmultiple sclerosis･
Scattered demyelinating lesions are observed (Kldver‑Barrera stain

clarified, however, accumulated data suggest that immun0‑●10glCal abnormalities play an important role in susceptiblity(original magnification x 2･5); Courtesy of Professor Genjiro Hirose,

to MS. EpidemiologlCal studies have indicated that infectious
agents play a role in induclng these immunologlCal abnomali‑ties･ Here, I review the reasons why measles virus (MV) issuspected to be a causative agent of MS, and is thought to be●●

Department of Neurology, Kanazawa MedicalUniversity)･●cDNAs were constructed. These studies provided the oppoトtunities fわr molecular genetic studies to elucidate of TMEV

induced demyelination. Data from the animal models demon‑

involved in its pathogenesis.

strate that viruses can cause demyelination in their hosts
either directly an〟or indirectly･ In those animal models, both

2. Data from experimental animal models indicate theviral genomic and host factors are considered to influence

presence of virus･induced demyelinationdemyelination since some strains of virus are more likely to●One reason that many Investigators believe infectious

result in demyelination and some mouse strains have been

agent(S) are involved in the pathogenesis of MS is that there

shown to be more sensitive to demyelination than others. The

are several animal models of virus‑induced demyelination indata obtained from these animal models are valuable to an

the central nervops system (CNS) (Table)･ In these animal

understanding of the mechanisms of demyelination in MS･models, pathologlCal features of demyelination with inflam‑
Table･ Experimental animal models of virus‑induced demyelination

matory cell infiltration are reminiscent of those found in MS.
Among these models, the demyelinating disease induced byVirus group Natural host

Theiler's murine encephalomyelitis virus (TMEV) infection

Theiler's murine

in the spinal cords of mice has been extensively studied (2,Picomavirus Mice

encephalomyeliti s virus

3). In the late 1980S, the entire nucleotide and predicted amino

Canine distemper virus

Paramyxov i ms Dogsacid sequences were determined, and fulHength infectiousJHM strain or mouse

Coronavirus Mice, Rats

hepatitis virus

Retrov i ms Sheep

Visna virus*Co汀eSpOnding author: Tel: +81‑76‑286‑221 1 ext. 301 1, Fax:
+8ト76‑286‑396 1 , E‑mail: ohara@kanazawa‑ned.ac.Jp

3. EpidemiologiCaldata suggest an infectious agent isinvolved in the pathogenesis of multiple sclerosis

ThisarticleisanⅠnvitedMinireviewbasedonalecture

presentedatthe9thSymposiumoftheNationalⅠnstituteof●EpidemiologlCal data overthe past 50 years strongly indicate

InfectiousDiseases,Tokyo,21May1999.

that MS is related to environmental exposure in childhood･198

The geographicaldistribution of MS patients is very specific･Generally, MS increases in frequency with latitude in bothof the total IgG, whereas it is 30‑60% of the total in CSF ofpatients with SSPE (12). In addition, Oligoclonal bands inthe no仙ern and southem hemlSpheres･ At the equator, MS is

SSPE can be absorbed out with MV preparations althoughrare, while the incidence of MS in the northem United States,

those in MS cannot.

●southem Canada, Northem Europe is 30‑80 casesper 100,000,2) MorphologiCalstudies■decreaslng tO 6‑20 cases per 100,000 in most of Southern

Several investigators have found measles virus‑like orEurope andthe southem United States. The number is evenlower, with rates of 1‑4 cases per 100,000, in Asia, Africa,and on the Caribbean coasts. In South Africa, the prevalence
rate of MS among Immigrants Who were bom in North Europe●●paramyxovirus‑like structures by electron microscopy ln

autopsied MS brains (1 3‑ 15); these include intranuclear andcytoplasmic tubular structures, intranuclear dense strands,●cytoplasmic membrane‑bound twisted tubules, etc. However,

was found to be 49per loo,000 in comparison with a preva‑
lence of I lper loo,000 among native‑bom English‑Speaking
white South Africans (4). The risk of developing MS wassuch structures have not been positively stained by immuno‑

electron microscopy using an antibody specific for MV ( 15).
In addition, such structures have been reported in other neur0‑

reduced to less than one third of that expectedrisk among

10gical diseases such as Guillain‑Barri syndrome, herpeticヽ●those who immigrated under the age of 15 or 16. This suggests

encephalitis, lipidosis, etc. (15).

0that exposure before puberty to some environmental factor(S),3) Virus isolations

possibly an infectious agent, could play an important role in

There are a variety of repo咋ys regarding vlruS isolation from●●MS brains. However, the number of reports of MV isolationfrom MS brains is limited. Field et al. reported that explantsof an MS patient's brain developed cytopathic changes in
LLC‑MK2 Cells, which were neutralized by rabbit anti‑MV●

the pathogenesis of MS. However, data on immlg柁mtS mOVlngfrom low‑ to highィisk areas are less complete (5).

4. Post･measles encephalomyelitis

serum (16). However, the authors allowed the possibility ofThe presence of post‑MV infection neurologicalcomplica‑

laboratory contamination.Asnoted above, MV can inducetions, including a＼demyelinating disease, suggests a possible

hypererglC enCephalitis without invading the CNS. The

relationship between MVand MS･ These neurologlCal compli‑

findings prompted a search for the presence of MV outsidethe
CNS. Pertschuk et al. reported that MVantigen was identified●●cations are divided into three distinct categories: measles■

inclusion‑txxly encephaliti s, subacute scleroslng PanenCePhaliti s

by immuno‑fluorescence in epithelialand lamina‑propna cells(SSPE), and postinfectious encephalomyelitis (PIE) (6). The
neuropathologlCal findings seen in PIE include perivascularof the jejunum of 24 MS patients, but in none of 20 controls●(17). In addition, MV was recovered by cocultivation or●●

inflammation and demyelination. The pathologlCal findings●cell‑fusion techniques from Jqunal biopsy specimens from 6MS patients (18). Although these findings were partly
confined in some Japanese MS patients (19), attempts byother laboratories to confirmthese results failed (20, 21 ).

●resembling those seen in experimental allerglC enCePhal0‑

myelitis suggest that PIE isanautoimmune (hyperergic) disease(7, 8). Interestingly, the vims has rarely been recovered from4) Search for measles virus genes

the brain in PIE (6). Therefわre, MV is considered to be able

By an in situ hybridization technique, MV‑Specific RNA
has been found in two foci in one of four cases of MS (22).
Cosby et al･ detected the MV nucleocapsid pmtein gene in
two of eight MS cases, but they also found it in one control

to induce demyelination without invading the CNS.

5. Multiple sclerosis and measles virus
1) Serological studies(23). Interestingly, Katayama et al. detected a portion of theBased on the above‑described data, Adams and Imagawa

MV mRNA encoding nucleoprotein (NP) sequence in 1 1 oftested the hypothesis that MV might act as a causative agent
for MS, and carried out serologlCal studies on complement‑
fixing and neutralization antibody titers to MV in the sera ofMS patients (9). They found that 36% and 31% of MS sera

61 brain tissue samples obtained from administrative autopsy●cases, who apparently had not suffered from SSPE (24)･ These

data suggest that MV can persist in human brains without
relating to MS. Other studies have failed to detect any MV

showed significantly hightiters in MV neutralization andgenes in MS brains (25, 26)･

complement‑fixation tests, respectively. In contrast, only 1 4%and 12% of control sera were positive fわr these respective

6. Future prospects

tests･ In addition, over 75% of MS cerebrospinal fluid (CSF)
showed positive neutralization titers while no control CSF

The recent identification of the human MV receptor, CD46,

showed a positive titer. After this report, a number of studies

and the subsequent generation of a transgenic mouse model

examlrung antibody titers to various viruses in MS were

have provided a new system for the study of MV CNS infec‑

camied out･ Althoughover 70% of MS CSF showed positive

tions (27, 28). Studies of this model have demonstrated that●●antibody titers agalnSt MV MS CSF demonstrated positive

MV suppresses humoral and cellular immune responses･ In

antibody 一iters to other viruses as well (10). These results

addition, MV was fわund to replicate pnmarily in neurons,●●

suggest that CSF antibody titers are not specific to MV. Of

then spread to distal sites by a又onal transport･ Althoughnote, highserumantitxxhes to MV have been found in disorders

demyelination has not yet been reported, further studies mayother thanMS, such as lupus erythematosus, Reiter's syndrome,

clarify the relationship hBtWeen MVand demyelinating disease･and chronic liver disease (1 1).
The presence of olig∝lonal bands (olig∝lonally distributed

7. Conclusions

IgG) in the CSF is a characteristic feature of MS･ Oligoclonal

EpidemiologlCal studies suggest that patients with MS are
exposed to an infectious agent(S) before puberty･ MV infec‑●

bands in the CSF result from the expanslOn Of several clonesof B‑cells, and consist of immunoglobulin which is directed●●to slngle, specific, Or several discrete antigens in the CNS.

tions pr∝luce immunologlCal abnormalities and demyelinat‑

MV‑Specific IgG in the CSF of MS patients is less than 5%

1ng disease, ralSlng the possibility that MV may a causative
●199●

●

agent of MS･ In splte Of numerous virologlCal studies, nodefinite evidence has yet identified MV as the causative agentof MS. However, the failure to isolate or detect MV in MS

14. Watanabe, I. and Okazaki, H. (1973): Virus‑like structure
in multiple sclerosis. Lancet, ⅠⅠ, 569‑570.

15. Dubois‑Dalcq, M., Schumacher, G. and Sever, ∫.し.

patients does not completely rule out a relationship between(1973): Acute multiple sclerQsis: electron‑microscopic

MV and MS.

evidence for and agalnSt a Vlral agent in the plaques.

●Lancet, ⅠⅠ, 1408‑1411.
16. Field, E. ∫., Cowshall, S., Narang, H. K. andBell,T. M.

Acknowledgments(1972): Viruses in multiple sclerosis? Lancet, ⅠⅠ, 280‑

This work was supported by a grant for Project Research281.

17. Pertschuk, L. P., Cook, A. W., Gupta, J. K., Broome, J.

from Kanaawa Medical Umiversity(朔‑7)and a grant for theScience Research Promotion Fund (1999)from the Promotion

D., Vuletin, ∫. C., Kin, D. S., Brigati, D. ∫., Rainford, E.

and Mutual Corporation for Private Schools of Japan･A. and Nidsgorski, F (1977): J亘iunal immunopathology

in amyotrophic lateral sclerosis and multiple sclerosis.

'REFERENCES

Identification of viral antigens byb immunofluorescence.
Lancet, Ⅰ, 1､119‑1■123.

1. Ebers, G. C. (1998): Introduction: a historical overview.

18. Prasad, I., Broome, J. D., Pertschuk, L P., Gupta, J. andp･ I‑4･ In Paty, D･ W･ and Ebers, G. C. (eds.), Multiple

Cook, A. W. (1977): Recovery of paramyxovirus fromsclerosis･ F A･ Davis Co･, Philadelphia･

the jejunum of patients with multiple sclerosis. Lancet,2･ Ohara,Y and 及oos, 良. (1987): The antibody response inⅠ, 1117‑1119.

Theiler's virus infection: new perspectives on multiple

19. Ebina, T., Tsukamoto, T., Suzuki, H., Takase, S., Itahara,sclerosis･ p･ 156‑179･ In Melnick, J. L. (ed.), Progress in
Medical Virology･ vol･34･ S･ Karger, Basel･3･ Obuchi, M･h･ and Ohara, Y･ (1998): Theiler's muri.ne

20. Kingston, D., Shiner, M., Lange, L S., Mertin, ∫. andencephalomyelitis virus and mechanisms of its persIS‑Meade, C. (1977): Measles antigen inj亘iunal mucosa intence･ Neuropathology, 18, 13‑18.
4･ Dean, G･ andKurtzke, J･ F･ (1971): Ontheriskofmultiple

21. WbycleChowska, ∫.し., Madden, D. L and Sever, ∫.し.

K. and lshida, N. (1979): Measles virus in j亘iunum ofpatients with multiple sclerosis. Lancet, Ⅰ, 99･multiple sclerosis. Lancet, Ⅰ, 1313.
●sclerosis according to age at immlgration to South Africa･(1977): Absence of measles‑virus antigen in jejunum ofBr. Med. ∫., 3, 725‑729.

multiple‑sclerosis patients. Lancet, ⅠⅠ, 1046‑ 1049.

22. Haase, A. T., Ventura, P., Gibbs, C. J. and Tourtellotte, W.
W (198 1): Measles vims nucleotide sequences: detection

5･ Detels, R･, Brody, ∫. A. and Edgar,A. H. (1972): Multiple

sclerosis among Americans, Japanese and Chinese

mlgrantS tO Califomia and Washington. J. Chron. Dis.,by hybridization in situ. Science, 212, 672‑674.

6･ Griffin, D･ E. (1997): Measles. p.47156. In Scheld, W.

23. Cosby, S. L., McQuaid, S.,Taylor, M. J., Bailey, M., mma,
B. K., Martin, S. J. andAllen, I. V. (1989): Examination

M., Whitley, 良. ∫. and Durak, D. T. (eds.), Infections ofof eight cases of multiple sclerosis and 56 meurologlCal

25, 3‑10.

●●●

the Central Nervous System･ ュnd ed･ LipplnCOtt‑Ravin,and non‑neurologlCal controls for genomic sequences ofPhiladelphia.

measles virus, canine distemper virus, simian virus 5 and7･ Koprowski, H･ (1960): The role ofhyperergy in measles

rubella virus. ∫. Gen. Viro1., 70, 2027‑2036.

24. Katayama, Y., Hotta, H., Nishimura, A., Tatsuno, Y･ andencephalitis. Am. ∫. Dis. Child., 103, 273‑278.
8･ Johnson, R･ T･, Grimm, D. E., Hirsch, 良.し., Wblinsky, ∫.

Homma, M. (1995): Detection of measles virus nucle‑

S･, Roedenbeck, S･, de Soriano, I･ L and Vaisberg, A･oprotein mRNA in autopsied brain tissues･ J･ Gen･ Virol･,76, 3201‑3204.

(1984): Measles encephalomyelitis ‑clinical and immu‑●nologlCal studies. N. Engl. ∫. Med., 310, 137‑141.

25. Stevens, ∫. G., Batone,VB., Ellison, G. W and Myers, L9･ Adams, J･ M･ and lmagaYa, D･ T･ (1962): Measles anti‑W. ( 1 980): No measles virus genetic information detectedbodies in multiple sclerosIS･ Proc･ Soc° Exp･ Biol･ Med･,in multiple sclerosis‑derived brain. Ann. Neuro1., 8, 625‑

111, 562‑566.

627.

10. Salmi, A., Reunanen, M., Ilonen, ∫. and Panelius, M.

26. Godec, M. S.,Asher, D. M., Murray, 良. S., Shin, M.し.,(1983): Intrathecal antibody synthesis to virus antigens

Greenham, L. W., Gibbs, C. J., Jr. and Gajdusek, D. C.

in multiple sclerosis. Clin. Exp. Immuno1., 52, 24ト249.

(1992): Absence of measles, mumps, and mbella viral

1 1 ･ Johnson, R･ T･ (1985): Viral aspects of multiple sclerosis.

genomic sequences from multiple sclerosis brain tissue

p･ 319‑336. In Vinken, P. J., Bruyn, G. W. and Klawans,by polymerase chain reaction･ Ann･ Neurol･, 32, 401 ‑404･

H･し. (eds.), Handbook of Clinical Neurology. γol. 47.

27. Rall, G. F, Manchester, M., Daniels, L 良., Callahan, E.

EIsevier Science Publishers, Amsterdam.

M., Belman, A. 良. and Oldstone, M. B. A. (1997): A

12. Metha, P. D., Thormar, H. andWisniewski, H. M. (1980):

transgenic mouse model for measles virus infection ofQuantitation of measles‑specific IgG. Its presence in CSF

the brain. Proc. Natl. Acad. S°i. USA, 94, 4659‑4663.

28. Oldstone, M. B. A.,Lewicki, H., Thomas, D., Tishon,A.,and brain extracts of patients with multiple sclerosis.

Arch. Neuro1., 37, 607‑609.

Dales, S., Patterson, ∫., Manchester, M., Homann, D.,

Naniche, D. and Holz, A. (1999): Measles virus infection

1 3･ mneas, J･ (1972): Pammyx.oviruS‑like particles ass∝iated●with acute demyelination ln Chronic relapslng multiple

in a transgenic model: virus‑induced immunosuppression

sclerosis. Science, 178, 760‑763.

and central nervous system disease. Cell, 98, 629‑640･200