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Increased prevalence and titer of Epstein-Barr virus antibodies in patients with multiple sclerosis.

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Increased Prevalence and Titer of
Epstein-Barr Virus Antibodies in Patients
with Multiple Sclerosis
Giro V. Sumaya, MD, MPH,"? Lawrence W. Myers, MD,$ George W. Ellison, MD,S and Yasmin Ench, BS"
The prevalence and titer of serum antibodies to several Epstein-Barr virus (EBV) antigens were compared among
patients with multiple sclerosis, healthy siblings of multiple sclerosis patients, patients with other neurological diseases, and healthy non-blood-related subjects. Serum-cerebrospinal fluid (serum-CSF) pairs were available on a selected number of multiple sclerosis and control subjects. An increased antibody response to EBV antigens was noted
rather consistently in the sera of the multiple sclerosis group in comparison with the control groups. A greater number
of reduced ratios of serum: CSF IgG antibody to EBV-capsid antigen and antibody to EBV-early antigen components
than to adenovirus, a reference or control virus, were found in the multiple sclerosis group. Reduced ratios of these
EBV antibodies were detected more frequently or showed a trend in this direction in multiple sclerosis patients
compared with the group with other neurological diseases. Our findings extend the results of an earlier report and
strengthen the association between EBV and multiple sclerosis.
Sumaya CV, Myers LW, Ellison GW, Ench Y Increased prevalence and titer of Epstein-Barr virus
antibodies in patients with multiple sclerosis. Ann Neurol 17:371-377, 1985
Several investigations have suggested an association
between Epstein-Barr virus (EBV), which is a herpes
group virus, and multiple sclerosis. Significantly higher
titers of antibody to the capsid antigen of this virus
have been found in multiple sclerosis patients compared with control subjects 13, 311. Fraser and colleagues 171 demonstrated the tendency for spontaneous EBV transformation of lymphocytes in active
multiple sclerosis. Moreover, EBV-associated demyelination of the central nervous system has been observed C11.
To elucidate further the association of EBV with this
disease, we have now determined titers to several
distinct EBV antigens in sera and cerebrospinal fluid
(CSF) from patients with multiple sclerosis. These
values were compared with those from several groups
of control subjects. The antibody response to a reference virus was also used to determine if EBV antibodies were disproportionately increased in the CSF.
generation, epilepsy, cervical spondylosis, hydrocephalus),
and 104 healthy non-blood-related subjects. The age and
gender distributions of the four groups were comparable
(Table l), except the female-to-male ratio was reversed for
the group with other neurological diseases in contrast to each
of the other three groups. The healthy non-blood-related
subjects were matched for age (within 3 years) and sex with
the multiple sclerosis group. Serum-CSF pairs were available
initially on 28 multiple sclerosis patients and 16 persons with
other neurological diseases. Later in the study, serum-CSF
pairs became available on an additional 15 multiple sclerosis
patients and 5 persons with other neurological diseases.
Written informed consents were obtained on all subjects
prior to their participation.
Eight multiple sclerosis patients had received steroids or
other immunosuppressive medications within six months of
serum-CSF collection. Another 8 patients with only a serum
sample available had also received these drugs within this
period. Twenty-eight percent of multiple sclerosis patients
with a serum-CSF pair had a concurrent pleocytosis with at
least 5 cells or more per cubic millimeter.
Patients and Methods
Serology
Study Group
Sera were tested in 104 subjects with clinically definite multiple sclerosis [26, 281, 26 healthy siblings of multiple sclerosis patients, 45 adults with other neurological diseases (i.e.,
muscular dystrophy, cerebral infarction, spinal cerebellar de-
The coded sera and CSF from patients and control subjects
were stored at -20°C until tested.
From the *Departments of Pediatrics and TPathology, The University of Texas Health Science Center at San Antonio, San Antonio,
Of
and the Reed
TX 78284 and the
Neurologic Research Center, UCLA School of Medicine Los
Angeles, CA 90024.
Received Mar 5 , 1984, and in revised form Sept 19. Accepted for
publication Oct 1, 1984.
Antibody titrations were performed
to the following structural and nonstructural antigens of
EPSTEIN-BARR VIRUS.
Address reprint requests to Dr Sumaya, Department of Pediatrics,
at sari ~
~
The University of Texas Health Science center
7703 Floyd Curl Dr, San Antonio, TX 78284.
37 1
~
~
Table I . Composition of the Study Groups, Multiple Scle?.oJzs Patients versus Controls
Study Groups
Variables
Age (yr)
Mean
Median
Range
Female-to-male ratio
Multiple
Sclerosis
( N = 104)
Healthy NonBlood-Related
Subjects
(N = 104)
Multiple
Sclerosis
Siblings
( N = 26)
Other
Neurological
Diseases
(N = 45)
44
44
43
23-66
1.6
43
20-64
1.6
46
43
23-67
47
47
18-75
0.5
EBV: capsid antigen, early antigen, and nuclear antigen [14}.
EBV-early antigen has two components that are differentiated by their immunofluorescent staining: diffuse (D)and
restricted (R); the antibody response in individual persons is
directed predominantly to one of these components. Serum
IgM and IgG antibodies to EBV-capsid antigen and antibodies to EBV-early antigen components develop early
after an acute EBV infection. The IgM response to EBVcapsid antigen and antibody response to EBV-early antigen
components are characteristically transient while the IgG response to EBV-capsid antigen is lifelong. Antibodies to
EBV-early antigen components, however, are found in a
small number of normal individuals and in increased rates in
patients with various malignant o r immune disorders { 151.
Serum antibodies to EBV-nuclear antigen are late in onset
after an acute EBV infection and remain in the serum for the
lifetime of the patient. The status of EBV antibodies in the
CSF of patients with acute EBV infections has not been
adequately studied.
Antibodies to the different antigens were determined by
standard indirect immunofluorescent techniques using fluorescein isothiocyanate conjugates obtained from Accurate
Chemical and Scientific Corporation, Westbury, NY (except
for the IgM antibody test). IgM antibodies to EBV-capsid
antigen were determined by the method described by
Sumaya 1301. In brief, smears of the P3HR-1 line of Burkitt's lymphoma cells were fixed in acetone and incubated at
37°C for I hour with the test specimens that had been previously absorbed with Staphylococcus aureus Cowan strain. The
latter removed most of the IgG from the specimen. The
smears were then washed with phosphate-buffered saline solution, overlaid with fluorescein isothiocyanate-conjugated
rabbit antihuman IgM, and incubated again at 37°C for 45
minutes. The smears were then washed and examined under
ultraviolet illumination.
IgG antibodies to EBV-capsid antigen wefe determined
on P3HR- 1 cell smears that were serially incubated with the
test specimens and then with fluorescein isothiocyanateconjugated rabbit antibodies to human I g G {12, 131.
Antibodies to D and R components of EBV-early complex were titrated in a similar fashion as IgG antibodies to
EBV-capsid antigen using Raji cells (a Burkitt's lymphoma
line normally free of EBV-capsid antigen- and EBV-early
antigen-producing cells) [I 51 which have been activated by
5-iodo-2'-deoxyuridine [171.
372 Annals of Neurology Vol 17 N o 4
April 1985
1.6
Antibodies to EBV-nuclear antigen were determined according to the method described by Reedman and Klein
[24] with modifications developed by Henle and associates
Ell). Raji cells are successively overlaid with the test specimen, serum from an individual with no antibodies to EBV
(source of complement), and finally fluorescein isothiocyanate-conjugated goat antibodies to B [C/B[A globulins.
Negative control testing was performed on Molt 4 cell
smears.
To minimize technical differences in comparing serum with CSF antibody levels between EBV and
the reference virus, titration of antibodies to adenovirus was
also performed by an indirect immunofluorescent method
[25]. In summary, adenovirus type 7 obtained from the Microbiology Section, Center for Disease Control, Atlanta,
GA, was propagated on HEp-2 cell cultures until approximately 50% of the cell monolayer showed evidence of
a cytopathogenic effect. The cells were then trypsinized,
mixed with uninfected HEp-2 cells, and fixed onto a slide
with acetone. Following this, the fixed cell smears were sequentially reacted with the test specimen and fluorescein
isothiocyanate-conjugatedrabbit antihuman IgG.
CSF was tested undiluted, then in a dilution ratio of 1: 2.5,
and so on in increasing twofold dilutions. The minimal serum
dilution tested was 1:10. The titers are herein expressed as
reciprocals of the dilution used. All serum and CSF specimens were tested in two separate determinations. In the
event of a titer difference of one dilutional step on retesting
(overall rate, 0.12), the higher titer was used. Greater titer
differences on retesting were not observed. In a few subjects
there was not enough serum available to perform all of the
antibody determinations.
ADENOVIRUS.
Quantitation of IgG and albumin in the serum and CSF was performed by standard techniques using single radial immunodiffusion plates (Calbiochem-Behring Corp, La Jolla, CA).
ALBUMIN AND IgG LEVELS.
SERUM : CSF RATIOS. Serum :CSF ratios were calculated in
patients with a detectable CSF antibody titer and those with a
serum titer of at least 160 o r greater in the absence of CSF
antibodies f22). A reduced serum :CSF ratio was defined as
one that was equal to or less than 128 [4]. The reference
A Anti (IgGtCapsid Antigen
......
L:::
.......
...
. ..
.........
..
.......
& 160
.t
t-
I....
n
...
.....
.......
......
"
B Anti -Nuclear Antigen
".....
..
axx.
I.."
"..
...
.......
.......
.......
C L T
."...
2 0 b
"..
......
....:*
:&&
.....
.......
..._
::
*
.."..
......:
...
.......
.......
.......
.....
......
.......
25
~2 5
C Anti - D (Early Antigen)
320
I60
T"'
320
****
I60
t.=
-6 8 0 1 Z : z
....
.....
"..
..".
....
."
1
-.
80 --..
...
40 -ilinn
.....,.
20 -::.""
:::x..
.....
MS
HNBR
Siblings
OND
MS
HNBR
Antibody titers to several Epstein-Barr virus antigens in serum
of 104 multiple sclerosis (MS) patients, 104 healthy non-bloodrelated subjects (HNBR), 26 healthy siblings of multiple sclerosis patients, and 45 individuals with other neurological diseases
(OND). The straight line in each column corresponds t o the
geometric mean titer. Tofigure this mean, antibody titers of less
than 10 or less than 2.5 to the appropriate antigen were considered as 5 and 1.25, respectively. Two sera with concurrent
nonspecific antibodies to nuclear antigen were not included in B.
In a fwsubjects there was not enough serum available t o perform all of the antibody determinations. (See text for I g M antibody titers to EpItein-Baw virus capsid antigen.)
virus has no known relevance to multiple sclerosis. The rate
of reduced ratios of serum:CSF antibodies to EBV was compared between multiple sclerosis patients and the group with
other neurological diseases and also with ratios of antibodies
to the reference virus. A comparison of albumin levels in
serum and CSF was performed as a measure of blood-brain
permeability and correlated with the serum :CSF antibody
ratios. Immunoglobulin production in the central nervous
system was also assessed by comparing the level of total IgG
to albumin in the CSF. A value of at least 13.0 or greater
was considered indicative of disproportionately increased
immunoglobulin in the CSF [20}. The serum-CSF pairs that
became available later in the study were included only in the
analysis of serum: CSF antibody ratios.
...
........."
.... ......
-
Siblings
OND
Prevalence results were analyzed by the chisquare method or, if numbers were small, Fisher's exact text
for 2 x 2 contingency table. Antibody titer differences were
determined by Student's t test.
STATISTICS.
Results
Overall, the prevalence and height of titers of IgG
antibody to EBV-capsid antigen, antibodies to the D
component of EBV-early antigen, and to EBVnuclear antigen in sera of the multiple sclerosis patients were usually higher or, in the remaining few
cases, similar to those found in the other three groups
used as controls (Figure). Further breakdown of these
findings by specific antibody responses showed that the
multiple sclerosis group had a significantly greater
prevalence of serum containing IgG antibodies to
EBV-capsid antigen including sera with higher titers
(3320), 104 (100%) and 57 (54.8%), respectively,
than healthy siblings, 2 3 (88.5%) (p 0.007) and 8
(30.8%) ( p < 0.05), respectively (see Figure, A). A
higher geometric mean titer (GMT) of this antibody,
212, was also present in sera from the multiple sclerosis group compared with healthy non-blood-related
subjects, 129 ( p < 0.025), and healthy siblings, 110 ( p
< 0.025). T h e total number of sera with antibodies to
the D component of EBV-early antigen and of sera
Sumaya et al: Epstein-Barr Virus in MS
373
Table 2. Ratios of Serum:CSF IgG Antibody Titers to Epstein-Barr Virus-Capsid Antigen and Adenovirw,
along with Indicators of Blood-Brain Permeability and Central Neruous System IgG Production
Virus Group
Epstein-Bar virus
No. of serum-CSF pairs (patients)"
No. with reduced serum:CSF antibody titerb
Serum albumin: CSF albumin (mean ? SD)'
No. with elevated CSF I&: CSF albumin',d
Adenovirus (reference virus)
No. of serum-CSF pairs (patients)"
No. with reduced serum:CSF titer
Mean serum albumin : CSF albumin'
No. with elevated CSF IgG:CSF albumin
~~
Multiple Sclerosis
39
32 (82.1 %)
189 ( r 104.2)
20138 (52.6%)
20
4 (20.0%)
179.5 (64.7)
7 (35.0%)
Other Neurological
Diseases
16
6 (37.5%)
249 ( k 6 1 . 2 )
3/15 (20.0%)
8
1(12.5%)
244 ( ? 70.6)
0
~
"The serum-CSF pairs analyzed were those from patients who had detectable CSF antibody or, if lacking CSF antibody, had a serum antibody
titer 3 160 f22).
bA ratio of serum:CSF titer of anribody of G 128 was considered reduced or subnormal 14). Patients with serum titers 3 160 but whose CSF
lacked these antibodies were considered to have a normal ratio.
'Several sera or CSF specimens were exhausted before albumin levels were obtained.
dElevated CSF 1gG:CSF albumin, 3 13.0% [20).
with higher levels of this antibody ( 2 4 0 ) was greater
in the multiple sclerosis group, 47 (45.2%) and
35 (33.7%), respectively, than in healthy non-bloodrelated subjects, 16 (16.2%) ( p < 0.0005) and 11
(11.1%) ( p < 0.0005), respectively, and the other
neurological disease group, 7 (15.6%) ( p < 0.005) and
7 (15.6%) ( p < 0.025), respectively (see Figure, C).
The GMT of this serum antibody was greater in multiple sclerosis patients, 15.0, than the same latter two
control groups, 7.2 ( p < 0.0005) and 8.2 ( p < 0.01),
respectively. The prevalence rates and GMT of serum
antibody to the R component of EBV-early antigen in
the multiple sclerosis group were similar to those in
the three control groups (see Figure, D). The multiple
sclerosis group had a greater number of sera containing
antibody to EBV-nuclear antigen, 102 (98.1%), than
did healthy siblings, 23 (88.5%) ( p < 0.025) (see Figure, B). The multiple sclerosis group also had a greater
number of sera with higher levels ( 3 8 0 ) of this antibody, 51 (49.0%), than did the group with other
neurological diseases, 13 (29.5%) (p < 0.05). The
GMT of this antibody was significantly higher in sera
of multiple sclerosis patients, 50.8, than that of healthy
non-blood-related persons, 19.7 ( p < 0.005), and subjects with other neurological diseases, 24.5 ( p < 0.01).
IgM antibody to EBV-capsid antigen was detected
in the serum of one multiple sclerosis patient and one
healthy non-blood-related individual (not shown in
Figure). The presence of a nonelevated titer of antibody to EBV-capsid antigen and a significant level of
antibody to EBV-nuclear antigen suggested that these
2 persons were having a response to reactivated and
not to acute primary EBV infection. A concurrent CSF
specimen was not available on the multiple sclerosis
patient.
374 Annals of Neurology Vol 17 No 4 April 1985
There were no significant differences in prevalence
or height of titer of the various EBV antibodies tested
among the three control groups except in two instances. Siblings had a greater GMT and, as a corollary,
a greater frequency of titers ( 2 8 0 ) of antibody to
EBV-nuclear antigen, 40.0 and 46.2%, respectively,
versus healthy non-blood-related subjects, 19.7 ( p <
0.01) and 22.5% ( p < 0.025), respectively. The
neurological disease group also had a greater frequency of sera with titers of IgG antibody of 320 or
greater to EBV-capsid antigen, 22 (48.9%), than did
healthy non-blood-related subjects, 30 (29.1%) ( p <
0.025). The GMTs of the latter two groups, however,
were not significantly different.
Thirty-nine of 43 serum-CSF pairs available on patients with multiple sclerosis had either IgG antibody
to EBV-capsid antigen detectable in the CSF (35 patients) or a serum antibody titer of at least 160 without
detectable CSF antibodies ( 4 patients) (Table 2 ) and
thus were capable of being analyzed for ratio determinations. A reduced serum:CSF ratio was found in 32
(82.1%) of these patients. All but 3 of the 35 patients
with CSF antibody had a corresponding serum antibody titer of at least 160 or greater. From 20 patients
with adenovirus antibody present in the CSF or with a
serum antibody titer of at least 160 or more, only 4
(20.0%) had a reduced serum:CSF ratio. This is a
significantly lower rate of reduced ratios compared
with that for IgG antibody to EBV-capsid antigen ( p
< 0.0005). Reduced ratios of serum:CSF antibody to
EBV-early antigen (either D or R component) and to
EBV-nuclear antigen were noted in 10 (90.9%) of 11
and 2 (20.0%) of 10 patients, respectively, whose sera
contained the corresponding antibody at a titer of at
least 160 or who had detectable CSF antibody. The
rate of reduced ratios for antibody to EBV-early antigen was greater than that for the reference antibody ( p
< 0.005). The reduced ratios were divided equally
between responses to D and R components. All patients with reduced senun:CSF ratios of antibody to
EBV-early antigen and EBV-nuclear antigen also had
reduced ratios of IgG antibody to capsid antigen. The
values for mean serum:CSF albumin and the proportion of elevated CSF 1gG:CSF albumin ratios were
similar for both “subgroups,” i.e., those with EBV antibody responses and reference virus antibody responses. This was expected since both subgroups were
derived from the same patient group.
The number of persons in the other neurological
diseases category with reduced ratios of serum: CSF
IgG antibody titers to EBV-capsid antigen was not
significantly different from the number in the same
disease group with reduced ratios to the reference virus (see Table 2). The proportion of persons in the
other neurological diseases group with reduced
serum:CSF ratios of IgG antibody EBV-capsid antigen, 6 of 16 (37.5%), was significantly less than that
found in the multiple sclerosis group ( p < 0.005).Two
of 5 patients with other neurological diseases and with
analyzable ratios of serum :CSF antibody to EBVearly antigen components had reduced values. These
results were almost significantly less than those for
multiple sclerosis patients ( p 0.06). Both patients with
reduced ratios to EBV-early antigen also had reduced
ratios of IgG antibody to EBV-capsid antigen. The
patients from the other neurological diseases category
with reduced antibody ratios had the following conditions: epilepsy (3), cervical spondylosis (l),a transient
ischemic attack (l),and spinocerebellar atrophy (1).
The greater frequency of elevated CSF 1gG:CSF
albumin ratios in the entire multiple sclerosis group,
20 of 38 (52.6%) compared with 3 of 15 (20.0%)
for the group with other neurological diseases ( p <
0.025), suggests that increased central nervous system
antibody production may have accounted for the differences in the number of reduced ratios of IgG antibody to EBV-capsid antigen between these two
groups. The trend towards increased blood-brain permeability found in the multiple sclerosis patients, mean
serum albumin:CSF albumin ratio of 189 versus 249
for the other neurological diseases group (0.05 < p <
O.l), also may have contributed to these differences in
numbers of reduced ratios.
An analysis within the multiple sclerosis group
showed that 19 of 31 patients (61.3%) with reduced
serum:CSF ratios of IgG antibody to EBV-capsid
antigen versus only 1 of 7 patients (14.3%) with a
nonreduced ratio had an elevated CSF IgG :CSF albumin ratio ( p < 0.05). Seven of 10 multiple sclerosis
patients (70%) with reduced serum: CSF ratios of antibodies to EBV-early antigen had elevated CSF
1gG:CSF albumin ratios. The single patient with a
nonreduced serum :CSF ratio to EBV-early antigen
had a normal CSF 1gG:CSF albumin ratio. No differences in mean serum albumin:CSF albumin ratios
could be discerned between those with and those without the reduced antibody ratios.
There was no significant association among the prevalence and height of EBV antibody titers and age, sex,
recent immunosuppressive medication, or the clinical
stage of multiple sclerosis. There was also no relationship between the above factors or pleocytosis and the
rate of reduced serum: CSF ratios for EBV antibodies.
Discussion
This study provides further evidence of an association
between EBV and multiple sclerosis. Increased prevalence and titer of antibody responses to several EBV
antigens were documented more consistently in sera
of patients with this disease than in controls. The
significant number of multiple sclerosis patients with
reduced ratios (S128) of serum:CSF IgG antibody
titers to EBV-capsid antigen and to EBV-early antigen, in comparison with the results from a reference
virus and with the other neurological diseases group,
suggests that EBV antibody may be produced in the
central nervous system. This assumption was supported by the greater frequency of elevated CSF IgG
concentrations in comparison with CSF albumin levels
found in multiple sclerosis patients than in those with
other neurological diseases. Moreover, multiple sclerosis patients with these reduced antibody ratios, in contrast to those without reduced ratios, also had disproportionately elevated CSF IgG concentrations. The
above findings confirm and extend the serological results of prior studies C3, 311. The higher GMT of IgG
antibody to EBV-capsid antigen in sera of the multiple sclerosis and non-blood-related control group in
the present study compared with our prior report ( 3 11
may have been due to differences in antigen preparations.
Multiple sclerosis patients exhibited an increased
antibody response to a broad spectrum of EBV antigens, including EBV-nuclear antigen, a situation similar to that of individuals with Burkitt’s lymphoma and
nasopharyngeal carcinoma, two tumors closely linked
etiologically with EBV [ 171. The reason for the preferential increased serum response to the D component
instead of the R component of EBV-early antigen in
our multiple sclerosis patients is unclear. However,
preferential antibody responses to early antigen components have been noted in other EBV-associated diseases 1157. The reason for the few instances of an
increased EBV antibody response in a control group
similar to that in the multiple sclerosis group is unclear. However, a consistent increased responsiveness
to the several EBV antigens tested was lacking in these
Sumaya et al: Epstein-Barr Virus in MS
375
control groups. None of the disorders in the group
with other neurological diseases have been included
thus far among those previously reported to be linked
with EBV [6, lo}.
To minimize potential titer differences related to
technical factors, a single large lot of appropriate cell
smears (antigen) was used for the antibody determinations. Serum controls with prior known titers were
included in each determination. There is no known
seasonal variation in EBV antibody titers.
There are several plausible reasons for the increased
antibody response to EBV antigens produced by multiple sclerosis patients. A defect in immunoregulation,
possibly deficient suppressor T cell activity {S) or possibly a relative B cell unresponsiveness to activated
suppressor T cells {9), may have produced the heightened antibody response to EBV antigens. The defect,
or defects, could also permit an increase in the number
of EBV-containing B cells in the peripheral blood of
multiple sclerosis patients. This, in turn, may account
for the increased rate of viral replication and unlimited
lymphoproliferation (EBV transformation) that occurs
when lymphocytes from these patients are propagated
in vitro 17).
A genetic predisposition to produce increased
amounts of antibodies could also be used to explain
the elevated antibody titers to EBV, or other viruses,
found in multiple sclerosis. Some association between
increased EBV antibody titers and histocompatibility
types in normal populations {2) and in patients with
multiple sclerosis 251 has been reported. However, the
current study which included healthy siblings of multiple sclerosis patients did not support a hereditary basis
for the increased EBV antibody response in the multiple sclerosis subjects.
EBV is known to behave like a polyclonal B cell
mitogen, and EBV-transformed lymphocytes themselves activate other B lymphocytes [23, 27). It is conceivable then that reactivation of this virus, in concert
with abnormal T and B cell interactions, may be at
least partially responsible for the elevated antibody titers to a variety of viruses that have been reported in
patients with multiple sclerosis C20, 22).
There are other features of EBV that support an
association with multiple sclerosis. After the initial infection, the virus remains latent probably for life 1.21).
Reactivation of EBV appears to occur in adulthood,
predominantly in an asymptomatic fashion [29], but
there is still an incomplete understanding of other consequences of the reactivation phenomenon. EBV already has been closely associated with several acute
and even chronic neurological diseases 16, 10). The
specific antigenic determinants to which the characteristic oligoclonal IgG bands in the CSF of multiple sclerosis patients are directed are unknown {IS), but testing against EBV has not been performed. Oligoclonal
376 Annals of Neurology Vol 17 No 4 April 1985
IgG bands have been detected recently in the CSF of
patients with central nervous system involvement by
African Burkitt’s lymphoma [33), a tumor highly associated with EBV [17). This virus, moreover, has the
potential for stimulating autoantibody formation { 16,
32) and for producing a demyelinating process 111,
although a direct linkage of these two phenomena, that
is, the formation of antimyelin antibodies, has not been
demonstrated.
Since EBV is a common agent and most persons do
not appear to have deleterious effects from latent infections with this virus, the potential role of EBV in
multiple sclerosis may be that of a triggering agent or
cofactor-the other necessary and possibly more important component, or components, being particular
genetic or deficient immunological markers, or both. It
may well be that the increased antibody response to
EBV antigens by patients with multiple sclerosis is
merely an indirect result of the underlying factors involved in the pathogenesis of this disease. Nonetheless, investigations to increase our understanding of
the association of EBV with multiple sclerosis are warranted.
This study was supported by a grant from the Kroc Foundation and
by U.S. Public Health Service Grants NS 88711 from the National
Institute of Neurologic and Communicative Disorders and Stroke,
CA 25686 from the National Cancer Institute, and AI 15646 from
the National Institute of Allergy and Infectious Diseases.
M. Holevoet, RN, assisted in the collection of serum specimens and
in the characterization of the patient population.
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