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Correlation between cytomegalovirus infection and IgM anti-MAGSGPG antibodyЦassociated neuropathy.

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Correlation
between
(Iytomegalovirus Infection
add IgMv Anti-MAGISGPG
Antibody-Associated
Neuropathy
-
P
.
Nobuhiro Yuki, MD, PhD,* Takako Yamamoto, PhD,t
and Koichi Hirata, M D , PhD*
IgM anti-myelin-associated glycoprotein (anti-MAG)/sulfated glucuronyl paragloboside (SGPG) antibody is found
in some patients with chronic polyneuropathy (CP). An
antigen-driven process is considered to induce this autoantibody, but the agent has yet to be identified. It has
been reported that sera from cytomegalovirus ( C W infected patients contained anti-SGPG antibody. To clarify the mechanism of the production of the anti-MAG/
SGPG antibody, we investigated CMV DNA in sera from
26 patients with IgM anti-MAGISGPG antibody-positive
CP. Twenty-three (88%) had CMV DNA. The positive
frequency was significantly higher than the frequencies in
sera from patients with IgM anti-MAG/SGPG-negative
CP, the other disease controls, and the normal control
subjects. There were no statistical differences in the frequencies of Epstein-Barr virus DNA between anti-MAG/
SGPG-positive and anti-MAGiSGPG-negative CP and
between anti-MAG/SGPG-positive CP and each disease
control. Moreover, no herpes simplex virus 1 DNA was
detected in the sera from patients with anti-MAG/SGPGpositive CP. The strong correlation of anti-MAGISGPGpositive CP with the presence of serum CMV DNA suggests that CMV infection induces the IgM anti-MAG/
SGPG antibody.
Yuki N, Yamamoto T , Hirata K. Correlation
between cytomegalovirus infection and IgM antiMAG/SGPG antibody-associated neuropathy.
Ann Neurol 1998;44:408-410
IgM anti-myelin-associated glycoprotein (anti-MAG)/
sulfated glucuronyl paragloboside (SGPG) antibody is
found in patients with chronic polyneuropathy (CP)
who typically present with slowly progressive distal and
symmetrical sensory o r sensorimotor neuropathy that
affects the arms and legs.’ Most of these patients have
From the *Department of Neurology, Dokkyo University School of
Medicine, Tochigi, and ?Department of Clinical Pathology, Showa
University Fujigaoka Hospital, Kanagawa, Japan.
Received Dec 18, 1997. Accepted for publication Apr 2, 1998.
Address correspondence to Dr Yuki, Department of Neurology,
Dokkyo University School of Medicine, Ltakobayashi 880, Mibu,
Shimotsuga, Tochigi 32 1-0293, Japan.
408
serum IgM M protein, but some do
Systemic
administration of human anti-MAG/SGPG antibody
causes demyelinating neuropathy in the chicken,* indicative that the autoantibody is pathogenic. These
lgMs use a diverse repertoire of variable genes for both
their heavy and light chains, which show somatic mutations suggestive of an antigen-driven process.536Although the MAG/SGPG epitope has been found in
Citrobucter diversus, Proteus morguni, and Cumpylobucter
jejuni, its significance for inducing the anti-MAG/
SGPG antibody remains unknown.’.* Ogawa-Goto
and associates’ reported that sera from infants with
symptomatic congenital cytomegalovirus (CMV) infection had anti-SGPG antibody activity, which suggests
that human CMV infection produces the anti-MAG/
SGPG antibody. To gain insight into the mechanism
that generates this autoantibody, we examined whether
there is a correlation between CMV infection and IgM
anti-MAGISGPG antibody-associated neuropathy.
Materials and Methods
Sera
Serum samples were obtained from 46 patients with CP in
the progressive phase. The enzyme-linked immunosorbent
assay showed that 26 of them had high IgM anti-SGPG
antibody titers (4,000 or more). Immunoblotting confirmed
that their IgMs also reacted with MAG. All the patients with
high IgM anti-MAG/SGPG antibody titers had homogenous
clinical features.’ IgM anti-MAG/SGPG antibody titers were
lower than 1,000 in the other 20 patients with CP. We designated the former group “anti-MAG/SGPG-positive CP”
and the latter “anti-MAG/SGPG-negative CP.”
The other disease controls consisted of 20 patients with
amyotrophic lateral sclerosis (ALS), 20 with Guillain-Barrt.
syndrome (GBS), and 20 with Fisher’s syndrome (FS). Normal control (NC) serum samples were obtained from 30
healthy volunteers. IgM anti-SGPG antibody titers were all
lower than 1,000 in the patients who served as the disease
controls and N C subjects.
Detection of CMV DNA, Epstein-Burr Virus DNA,
and Herpes Simplex Virus 1 DNA by Poolyrneruse
C h i n Reuction
Serum DNAs were extracted with Glass powder (BIO 101,
Glassmik, CA). One microliter of each sample was subjected
to the polymerase chain reaction (PCR) assay to amplify
CMV, Epstein-Barr virus (EBV), and herpes simplex virus
(HSV) type 1 DNAs. Primers that amplify the DNA fragment from the immediate early gene” were used to detect
CMV DNA. T o detect EBV DNA, primers were chosen
from the 134-bp sequences in the BamHI-W fragment.’’
The specific HSV-1 primers were purchased from Iatron
(Tokyo, Japan). The PCR products were electrophoresed in
a 1.8% agarose gel, then stained with 0.5 p,g/ml ethidium
bromide, and identified by Southern blot hybridization with
an alkaline phosphatase linked to oligonucleotide probe, as
described previously.’
Copyright 0 1998 by the American Neurological Association
Table. CMV DNA, EBV DNA, und HSV-1 DNA in Patient Seru
Disease
Patients, n
Anti-MAGISGPG-positive CP
Anti-MAG/SGPG-negative CP
Amyotrophic lateral sclerosis
Guillain-Bard syndrome
Fisher’s syndrome
Normal control
26
20
20
20
20
30
CMV DNA
Positive, n (Yo)
EBV DNA
Positive, n (%)
HSV-1 DNA
Positive, n (Yo)
23 (88)
1 (5)
1 (5)
1 (5)
4 (15)
4 (20)
4 (20)
7 (35)
0 (0)
9 (45)
2 (10)
0 (0)
8 (40)
0 (0)
C M V = cytomegalovirus; EBV = Epstein-Barr virus; HSV-1 = herpes simplex virus type 1; MAG
sulfated glucuronyl paragloboside; C P = chronic polyneuropathy.
Statistical Methods
Statistical calculations were done with Statview-J 4.5 software. Differences in values were tested by the x2 test or Fisher’s exact test.
Results
Neither CMV DNA, EBV DNA, nor HSV-1 DNA
was present in sera from the NC subjects (Table).
CMV DNA was detected in 23 (88%) of 26 serum
samples from patients with anti-MAG/SGPG-positive
CP, whereas serum CMV DNA was detected in 1
(5%) patient with anti-MAG/SGPG-negative CP and
in 4 (7%) of the disease control patients with ALS,
GBS, and FS. Serum CMV DNA was significantly
more frequent in anti-MAG/SGPG-positive C P than
in anti-MAGfSGPG-negative CP patients (odds ratio,
145.7; 95% confidence intervals [CI], 25.6-822.7),
the disease controls (ALS and GBS: odds ratio, 145.7;
95% CI, 25.6-822.7; FS: odds ratio, 69.0; 95% CI
14.4-330.5), and NC (odds ratio, 409.6; 95% CI,
70.7-2,372.3)
test, each p < 0.0001). Immunoelectrophoresis detected no IgM M protein in 4 of the
26 patients with anti-MAG/SGPG-positive CP, whereas
3 of these 4 patients had CMV DNA in their sera.
Serum EBV DNA was present in 4 (15%) patients
with anti-MAG/SGPG-positive CP, 4 (20%) with
anti-MAG/SGPG-negative CP, and 19 (32%) of the
disease control patients. No statistical difference was
found in the frequency of EBV DNA positivity between the anti-MAG/SGPG-positive and anti-MAG/
SGPG-negative CP patients nor between the antiMAG/SGPG-positive CP patients and the individual
disease control patients. Moreover, serum HSV- 1
DNA was present in 9 (45%) patients with anti-MAG/
SGPG-negative CP and 11 (18%) of the disease control patients, but not in the anti-MAG/SGPG-positive
C P patients.
(x2
=
3 (15)
2 (10)
6 (30)
0 (0)
myelin-associated glycoprotein; SGPG =
MAG/SGPG-negative CP, ALS, GBS, and FS as well
as than the value for the NC subjects. In contrast, the
positive EBV DNA frequency in sera from patients
with anti-MAG/SGPG-positive CP did not differ from
the frequencies for the patients with anti-MAC2
SGPG-negative CP, ALS, GBS, and FS. In addition,
no HSV-1 DNA was detected in sera from the patients
with anti-MAG/SGPG-positive CP. These results indicate a strong correlation between anti-MAG/SGPGpositive CP and the presence of serum CMV DNA.
The detection of serum CMV DNA suggests that extracellular free virus is present in the serum during active CMV infection. We therefore assume that CMV
infection causes the induction of anti-MAG/SGPG
antibody.
The following three mechanisms can be posited for
the production of anti-MAG/SGPG antibodies by
CMV infection: ( 1 ) CMV has the MAG/SGPG
epitope on its envelope. (2) The antibodies may be
produced against altered glycoconjugate patterns of
host cells as a result of virus infection. (3) They may be
anti-idiotypic antibodies produced against antibodies to
viral attachment proteins that recognize the host cell
viral receptor. The mechanism that induces IgM antiMAGISGPG antibodies has now to be determined.
This research was supported in part by grants-in-aid from the Ono
Medical Research Foundation, the Uehara Memorial Foundation,
the Ciba-Geigy Foundation (Japan) for the Promotion of Science,
the Nakabayashi Trust for ALS Research, the Ryoich Naito Foundation for Medical Research, and a Research Grant for Neuroimmunological Diseases from the Ministry of Health and Welfare of
Japan.
We thank Dr Yumi Tagawa for the IgM anti-MAG/SGPG antibody
assay and Dr Michiaki Koga for his critical reading of our study.
References
Discussion
Eighty-eight percent of the 26 patients with antiMAG/SGPG-positive CP had serum CMV DNA. The
positive frequency of CMV DNA in their sera was statistically higher than the values in patients with anti-
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409
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Cerebrospinal Fluid
h,-lsoprostane Levels
Are Increased in
Alzheimer's Disease
T. J. Montine, MD, PhD,*t$ W. R. Markesbery, MD,$
J. D. Morrow, MD,$ and L. J. Roberts 11, MD$
Postmortem studies have associated Alzheimer's disease
(AD)with regionally increased oxidative damage to
brain. Lacking, however, is a specific marker of oxidative
damage to brain that may be measured during life. We
tested the hypothesis that cerebrospinal fluid (CSF) concentrations of F,-isoprostanes (F,-IsoPs), stable products
of arachidonate peroxidation, are increased in CSF of AD
patients. CSF from lateral ventricles (VF) was analyzed
from 11 AD patients and 11 control subjects who participated in a rapid autopsy program. VF F,-IsoP concentrations were significantly elevated in AD patients compared with control subjects (72 2 7 vs 46 k 4 pg/ml)
and were significantly linearly correlated with brain
weight (-0.3 pg/ml/g, r2 = 0.32). These results suggest
that quantification of CSF F,-IsoP concentrations may
provide a useful biomarker of central nervous system oxidative damage in AD.
Montine TJ, Markesbery WR, Morrow JD,
Roberts LJ 11. Cerebrospinal fluid F,-isoprostane
levels are increased in Alzheimer's disease.
Ann Neurol 1998;44:410-413
Regional increases in oxidative damage are a feature of
brain tissue obtained post mortem from patients with
Alzheimer's disease (AD).' However, an objective index of oxidative damage associated with AD that may
be assessed during life is lacking. Such a biomarker
could have an important impact on the ability to test
hypotheses concerning oxidative damage in AD patients by permitting repeated evaluation to follow progression of disease and to quantify response to experimental therapeutic interventions.
Lipid peroxidation is a prominent manifestation of
oxidative challenge in brain.' Recently, we have shown
From the Departments of "Medicine, *Pathology, and fPharmaco1ogy, and ?Center for Molecular Neurosciences, Vanderbilt University Medical Center, Nashville, T N ; and %Departments of Pathology and Neurology and the Sanders-Brown Center on Aging,
University of Kentucky Medical Center, Lexington, KY.
Received Dec 29, 1997, and in revised form Apr 3, 1998. Accepted
for publication Apr 7, 1998.
Address correspondence to Dr Montine, Department of Pathology,
Vanderbilt University Medical Center, C3321A Medical Center
North, Nashville, T N 37232.
410
Copyright 0 1998 by the American Neurological Association
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