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Effects of gangliosides on the expression of autoimmune demyelination in the peripheral nervous system.

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Effects of Ganghosides on the Expression
of Autoimmune Demyelination in the
Peripheral Nervous System
Diego Ponzin, MS,*t Anna Maria Menegus, PhD,? Gunther Kirschner, PbD,? M. Grazia Nunzi, PhD,?
Mario G. Fiori, MD,t and Cedric S. Raine, PhD, DSc, FRCPath*
TOtest whether gangliosides (GA) q i g h t exert neuritogenic effects in vivo, experimental allergic neuritis (EAN) was
studied clinically, neuropathologically, and immunologically in Lewis rats immunized with bovine peripheral nerve,
and GA alone,
P, myelin pfotein, P2myelin protein plus two different doses of GA, P, with galactocerebroside (GC),
each emulsified in adjuvant. A14 except the GA-treated group developed signs of EAN between days 11 and 14 after
the injection. Rats immspized with P, alone were the most severely affected. Rats given Pz plus GA and those
given P? plus GC displayed a significantly lower clinical score. Histological analysis revealed a comparable degree of
inflammation of the peripheral nervous system and demyelination in the spinal nerve roots of bovine peripheral nerveand P,-immunized rats. The P, plus Glq and P, plus GC groups revealed similar degrees of pathology in the spinal
nerve roots but the latter group stood apart from the rest in that it showgd widespread peripheral nervous system
changes extending distally into the sciatic nerve. Serological analysis demonstrated that P, and GC, but not GA,
elicited antibody (I&) responses, but there was no correlation between antibody titer and clinical or histological
involvement. The present data fail to support an enhancing role for gangliosides in the expression of EAN and, by
extrapolation, in the Guillain-Bard syndrome, for which EAN serves as the laboratory model, and in which suggestions
haye been mads that antibodies to GA may have pathogenetic significance.
Ponzin D, Menegus AM, lrschner G, Nunzi MG, Fiori MG, Raine CS. Effects of gangliosides on the
expression of autoimmune demyelination in the peripheral nervous system. A n n Neurol 1991;30:678-685
In the central nervous system (CNS), autoimmune demyelination has been shown to be augmented by the
incorporation of certain myelin glycolipids (e.g., galactocerebroside [GCI) into the inochting emulsion
11-31. This effect has been attributed to myelin glycolipids acting as haptens in the generation of myelinolytic antibodies operating in concert with the T cellsensitiziqg antigen, myelin basic protein (MBP) 121. In
the peripheral nervous system (PNS), a similar pathological scpario involving the PNS myelin proteiu P,,
and glycolipids has been implicated in experimental
allergic neuritis (EAN), but the mechanisms underlying
the inflammatory events remain to be elucidated {4}.
Whether other myelin components may be operative
in autoimmune demyelination in the PNS has yet to
be assessed. In this regard, glycoconjugates, including
neutral and acidic glycolipids, occurring naturally in
both neuronal membranes and myelin 15-71, have
been suggested to be causally related to specific monoclonal antibodies in a number of human autoimmune
neuropathies [8-141. Polyclonal antiganglioside antibodies have been described in a variety of neurological
Materials and Methods
Thirty-six adult male Lewis rats (Charles River, Wilmington,
MA), were used. Animals weighed between 250 and 300
From the *Departments of Neuropathology and Neuroscience, Albert Einstein College of Medicine, The Bronx, NY, and tFidia Research Laboratories, Abano Terme, Itdy.
Address correspondence to Dr Raine, Dept. of Pathology (Neuropathofogy), Alberr Einstein College of Medicine, 1300 Morris Park
Avenue, Bronx, NY 10461.
conditions with suspected immunological involvement
(e.g., amyotrophic lateral sclerosis, multiple sclerosis,
Guillain-Barre syndrome) [l5-20). While the specificity and significance of these antibodies remain unclear, recent communications to this journal raised
the possibility that under certain conditions, antibodies
to gangliosides (GAS) may have a pathogenetic role
in some peripheral neuropathies, in particular, the
Guillain-Barre syndrome 12 1-23].
To investigate the latter possibility, the present study
was undertaken to determine whether purified GAS,
delivered either alone or in combination with the major neuritogen in EAN, P, protein, may affect the expression of immune-mediated demyelination in the
PNS. The relative effects of GC, which is known to
augment immune demyelination [l, 27, were studied
for comparison.
Received Oct 29, 1990, and in revised form Feb 27 and May 2,
1991. Accepted for publication May 2, 1991.
Copyright 0 1991 by fhe American Neurological Association
3 or 4 per cage, and were fed
standard chow and water ad libitum.
gm, were housed in groups of
lnocula and Animal Groups
Freshly dissected intradural spinal roots were homogenized 1: 1 in saline
solution. Aliquots of the suspension were emulsified with
equal volumes of complete Freund‘s adjuvant (CFA) containing 10 mg Mycobactm’urn tuberculosis per milliliter. Five
rats were subcutaneously injected with 0.2 mi of the emulsion into the dorsum of each hindfoot. In this way, animals
received about 200 pg of P, protein, a known neuritogenic
dose 143.
Bovine P, was purified
from spinal root myelin as previously described [24}. Five
rats were given one inoculation containing 0.2 mg P, in 0.1
ml saline solution emulsified in CFA.
GC GROUP). G C (Supelco, Bellefonte, PA) was prepared as a micelle preparation
with lysolecithin and bovine serum albumin 111. Four animals
were given a dosc of 0.2 ml, made up of 0.1 ml containing
1 rng GC plus 0.2 mg P,, and 0.1 ml CFA. The ratio between
GC and P, was similar to that used previously for experimental allergic encephalomyelitis (EAE) {l], except that the concentration of P, in PNS myelin was estimated to be about
half that of MBP in CNS myelin.
GA GROUP). A highly purified
bovine brain G A mixture comprising 21% GM,, 40% GD,,,
16% GD,,, 19% GTIb, 2% GD,, and 2% G Q l b (FIDIA
S.p.A, Abano Terme, Italy) was dissolved in saline solution.
P, was added so that 0.1 ml contained either 0.2 mg P, plus
0.02 mg GA (P2 GA(a) group), where the P2/GA ratio
was similar to that found in intact PNS myelin [6], or 0.2
mg P, plus 1 mg GA (P,
GA(b) group), with GA at a
concentration known to elicit a delayed-type hypersensitivity
response 1251. The two GA solutions were emulsified with
equal volumes of CFA and delivered to two groups of 4 rats,
as described above.
Two groups of 3 and 7 rats received 0.02 mg (GA(a)) and 1 mg (GA(b)) of the G A mixture, respectively. This was emulsified in CFA and delivered
as described above.
alone in CFA because this compound has been shown in
several studies not to elicit neuropathological changes after
single inoculation [I, 2, 4}.
Four rats received
0.2 ml CFA emulsitied 1:1 in saline solution.
Clinical Evaluation
Animals were observed daily and weighed from day 8 after
injection onward. Clinical signs were evaluated using a
5-point scale: 0 = normal, 1 = limp tail, 2 = slight paraparesis, 3 = one leg paralyzed, 4 = paresis of both hind and/or
front limbs, 5 = moribund or dead. Scoring was carried out
by two independent, blinded observers. Rats were anesthetized and perfused with fixative 48 hours after disease onset.
Animals failing to develop signs were sampled 15 days after
injection. Comparisons between groups were made by analysis of variance with orthogonal contrasts.
Animals were perfused with cold 2.5% glutaraldehyde in phosphate buffer [l, 2). Spinal cord, proximal
segments of L5, L6, and S1 ventral and dorsal roots and
corresponding dorsal root ganglia, plus both sciatic nerves
were dissected, thinly sliced, postfixed in chrome osmium,
dehydrated, and embedded in epoxy resin (Epon 812). Slides
containing a total of 8 to 10 semithin (1-pm) sections of the
entire root or nerve were stained with toluidine blue and
evaluated in a blinded fashion by at least three independent
observers. The index for inflammation was: 0 = none; 1 =
a few scattered inflammatory cells; 2 = numerous scattered
cells, an occasional perivascular cuff; 3 = many perivascular
cuffs; 4 = confluent perivascular cuffs; 5 = extensive perivascular cuffing with involvement of the entire nerve. The
index for demyelination was: 0 = none, 1 = a few scattered
naked axons, 2 = small groups of naked axons, 3 = larger
groups of demyelinated axons, 4 = confluent foci of demyelination, 5 = widespread demyelination.
From each animal, mean values were determined for both
ventral and dorsal roots and sciatic nerves, and were pooled
for each experimental group. Comparisons between groups
were made by analysis of variance with orthogonal contrast.
Prior to sampling, rats were bled
from the heart and serum samples stored at - 20°C. For the
detection of antibodies against P,, GA, and GC, an enzymelinked immunosorbent assay (ELISA) was employed 126,
For anti-GA antibody assays, 750 ng of GM,, GD,,, GD,,,
or GT,, was diluted in ethanol and water in a 1 :1 ratio and
added to each well of a flat-bottom microtiter plate (Flow
Labs, McLean, VA). Incubation was carried out at room
temperature for 90 minutes, and nonspecific binding was
blocked for 90 minutes with 2% bovine serum albumin in
phosphate-buffered saline (PBS) (Flow Labs). After washing
with buffer, 50 pl of serum diluted 1: 100 to 1:6,400 in
2% bovine serum albumin in PBS was added and the plate
incubated overnight at 4°C. After washing, 50 pl of horseradish peroxidase-conjugated goat anti-rat IgG (Sigma, St Louis,
MO) or IgM (Cappel, West Chester, PA), diluted 1: 1,000,
was added for 2 hours at room temperature and then washed.
Antibodies were detected by adding 50 ~1 of orthophenylanine-diamine reagent (Sorin, Vercelli, Italy). Absorbance was read at 492 nm on a Titertek Multiskan ELISA
reader (Flow Labs).
For anti-P, and anti-GC antibody assays, 100 pl of a solution of P, in PBS (1 pg/ml) or GC in ethanol (10 pg/ml)
was added to each well. Incubation was performed at 4°C
overnight (P,) or at room temperature for 120 minutes (GC).
Nonspecific binding was blocked with 1% polyvinylpyrrolidone for 20 minutes at room temperature and then 100 pl
of serum diluted 1: 100 to 1:25,600 in PBS plus 0.05%
Tween 20 (Sigma) was added and the plate incubated overnight at 4°C. Detection of antibodies was then performed as
described above.
Ponzin et al: Gangliosides and EAN 679
Table 1. Prodtlction of Experimental Allergic Neuritis in Lewis Rats with DIZfferentAntigensa
Day of Onsetb
(after Inoculation)
Complete Freund's adjuvant
11.2 k
13.2 k
12.5 ?
11.7 k
+ GC
+ GA(a)
+ GA(b)
Clinical Disease
* 0.0
Mean Scoreb
2.3 k 0.5
3.6 0.2
2.1 k 0.3
1.5 2 0.2
1.7 k 0.1
"P, and glycolipids were mixed together and emulsified with complete Freund's adjuvant containing 10 mgiml of Mycobarterium tabercalosis.
Two-tenths milliliters of this mixture was injected subcutaneously in the dorsum of the posterior feet.
bValues are mean 5 standard crror.
bovine peripheral nerve; P2
bovine P, protein; G C
galactocerebroside; GA
The results are presented as mean optical densities (OD)
1 standard deviation, and were obtained at 1: 100 (GA,
P,, GC) and 1:3,200 (P2).Control values were determined
from the sera of 15 normal Lewis rats from the same source.
A positive result was 1 OD greater than 2 standard deviations
above the mean OD for control animals analyzed in the same
experiment. Data on all P,-treated groups were compared by
Scheffe's multiple comparisons test.
Clinical Finding
BPN-inoculated rats presented with neurological signs
on day 11 after injection (Table 1). For neuropathology, 4 rats were sampled 48 hours after disease onset
when they showed mild to severe paraparesis (clinical
score, 1 to 4),and 1 was taken 5 days after onset, when
the clinical course had stabilized at grade 3.
The P, group developed significantly more severe
signs than the BPN and the P,
GA groups (p <
0.01). In these rats, signs began between days 11 and
13 after injection and, after 48 hours, reached a clinical
level of 3 to 4. GC + P, animals became sick between
days 12 and 14 after injection. At the time of death
(48 hours later), neurological signs were less severe
than those of the P,-injected group (grades 1 to 3, p
< 0.01). GA-sensitized rats presented with different
clinical pictures. When GA was given alone in CFA
(both doses), no neurological signs developed. Between days l l and 14, all rats in the P,
GA groups
developed clinical signs similar to but less severe than
those from P,-inoculated rats (clinical score 1 to 2 ) .
In all groups, most rats developed an adjuvant arthritis with a time course overlapping that of the neurological syndrome. This was taken into account by not including the hindfeet stiffness and increased sensitivity
in the evaluation of the clinical score. In addition, all
animals displayed an abrupt overnight decrease in body
weight that preceded or accompanied neurological
signs. This reduction was even apparent in nonsymptomatic rats immunized with CFA alone or GA +
PNS tissue from all animal groups was examined.
Mean histological scores for ventral roots, dorsal roots,
and sciatic nerves from all animals sampled (48 hours
after onset) are detailed in Figure 1. Readings from all
levels of either ventral or dorsal roots were pooled
since there was no clear difference. Dorsal roots were
usually more involved than were ventral roots. With
regard to inflammation (see Fig 1, upper panel), there
was no difference between groups except for the P, +
GC group, in which significantly fewer inflammatory
cells were found in ventral roots (p < O.O1), in comparison to rats treated with P, alone. The P,
GC group
was unusual in that animals showed inflammatory cells
in the sciatic nerve as an early event (' < 0.001). One
animal in the P, + GA group showed some inflammatory cells in the sciatic nerve. The one animal from the
BPN group that was killed at a later time point, when
the clinical score had stabilized at grade 3, demonstrated ventral and dorsal roots to be equally affected
and some inflammatory cells in the sciatic nerve.
With regard to demyelination (see Fig 1, lower
panel), there was no difference between the groups,
except for the P, + GC group in which demyelination
was also found in the sciatic nerve (p < 0.001). In the
single animal sampled later in the BPN group, dernyelination was also evident in the sciatic nerve.
Comparison of the various groups confirmed the
presence of relatively uniformly myelinated nerve fibers in spinal nerve roots and sciatic nerve of normal
animals, the endoneurium containing no infiltrating
cells. In GA-inoculated animals, the PNS (Figs 2A and
2B) was normal. CFA controls also showed no PNS
changes. In BPN-sensitized rats, lesions typical of
680 Annals of Neurology Vol 30 No 5 November 1991
sciatic nerve was involved (i.e., within 48 hours of onset) and perivascular cuffing was more marked. Axonal
loss occurred in all groups but was more apparent in
animals treated with P, plus GC. Animals inoculated
with P, plus GA ((a) and (b)) presented with milder
lesions than did the BPN and P, groups (see Fig 2F).
Spinal cord changes were not seen, but on occasion,
infiltration of a few mononuclear cells into the leptomeningeal space was seen in neurologically afflicted
animals. However, these cells did not invade CNS parenchyma.
5 1
Fig 1. Comparative histopathology of experimental allergic neuritis groups. Average infEammation (upper panel) and demyelination (lower panel) of ventral roots (white bars), dorsal
roots (shaded bars), and sciatic nerves (black bars) 2 standard
errors. See Materials and Methods fir a description of the
groups and of the scoring system. Note the uniformity in disease
expression in all groups except the one that was inoculated with
P2 and galactocerebroside (Pz GC) where there is a distal
shift in PNS involvement. BPN = bovine peripheral nerve;
GA = galactoside.
acute EAN were encountered and were invariably centered on blood vessels. The endoneurial space was increased and contained infiltrating cells, some perivascular cuffing was apparent, and nerve fibers at various
stages of demyelination were evident (see Fig 2C). Demyelination invariably occurred in association with infiltrating macrophages, some of which could be seen
within the Schwann cell tube. Infiltration by polymorphonuclear leukocytes occurred and was common in
all groups. P,-induced EAN was essentially identical to
BPN-induced disease (see Fig 2D). In animals sensitized with P, plus GC, spinal nerve root lesions were
qualitatively similar to those of the BPN and P, groups
but sciatic nerves were extensively infiltrated (see Fig
2E). Therefore, EAN was more widespread when G C
was combined with P,, and there was a shift in the
pathology from radicular to more distal regions. The
P, + GC group represented the only group in which
No 1gM response was found against any of the antigens. Sera from the groups inoculated with CFA or
GA contained no IgM or IgG response against P,, GA,
or GC (Table 2). Antibody reactivity is shown for GM,
only because it was representative of results from the
other three GAS tested.
P,- and BPN-sensitized rats developed antibodies
against P,. The lowest P, response was seen in sera
from BPN rats, whereas rats treated with P, or P2 plus
GA(a) developed higher responses. For this reason,
readings from the higher dilution tested are also
shown, where the OD response was linear. Somewhat
lower values, not statistically significant, were found in
rats injected with P, plus G C or P, plus GA(b), even
though some variation among individuals was found.
Antibodies against the four main GAS in the mixture
were not demonstrable in most animals. A borderline
positive response was seen in 1 rat from the P, +
GA(a) group and 2 from the P, + GA(b) group. Only
the P, + GC group displayed a positive antibody response against GC at the time point tested (48 hours
after onset). A borderline positive response was seen
in the sera of 2 rats from the P,
GA(b) group.
Taken together, the ELISA findings showed no significant correlation between humoral response and disease findings.
On the basis of suggestions that GAS might serve as
pathogens in PNS disease 121-231, the present study
investigated whether GAS possess the ability to enhance immune-mediated tissue damage in a model of
EAN in the Lewis rat. Such an augmentation effect had
previously been shown with G C in EAE El-31. These
latter studies on EAE concluded that tissue damage was
the result of an initial T-cell response to MBP and a
B-cell response to G C 111. In support of this, demyelination was observed in the rabbit retina after the introduction into the vitreous of anti-GC antiserum plus
cytokines [2]. In contrast to the situation with MBP in
EAE, sensitization to P, is sufficient to elicit full-blown
EAN with infhnmation and demyelination [28, 291.
However, the incorporation of G C into the protocol
Ponzin et al: Gangliosides and EAN 681
Annals of Neurology Vol 30 No 5
November 1991
Table 2.Antibody Reactivity by Enzyme-Linked lmmunosorbent Assay"
IgG Anti-P,
(1: 100)
Normal control
109 i 42
119 67
291 2 130
1,031 i 140
2,645 +- 63
2,102 i 142
2,113 80
2,273 232
Complete Freund's adjuvant
P2 + GC
P2 + GA(a)
P, + GA(b)
(1 :3,200)
IgG Anti-GM,
( 1 : 100)
IgG Anti-GC
54 2 17
41 t 18
43 2 16
53 2 32
65 2 12
85 20
50 & 15
109 2 54
125 ? 66
112 i 67
90 26
102 2 20
114 -t 37
216 & 71
146 & 65
420 2 173
221 58
52 ? 19
1,049 ? 302
452 2 176
1,570 ? 309
435 ? 346
aVdues are mean optical densities ( x lo3)2 standard deviation. Numbers in parentheses indicate the dilution of the sera Each s e w sample
was assayed in triplicate at the different dilutions. Mean values and standard deviations represent interanimd values. The intra-assay variatiqn
was approximately 10%.
GA = gangliosides; BPN
bovine peripheral nerve; GC
has been shown to augment tissue damage in the spinal
nerve roots {4] and, in the present case, caused an
early, distal involvement of the sciatic nerve. Sciatic
nerve is usually not involved until later time points and
the occurrence of pathology at this level in the present
animals may be related to the low levels of circulating
antibody to GC. Intraneural injection of anti-GC antiserum alone has been shown to be sufficient to produce demyelinated lesions of peripheral nerve {30].
2. (A) Ganglioside (GA(b))-sensitizedrat,
4 Fig
resin section. Transverse section o f an LS ventral root from a rat
displaying no clinical disease reveals normal nerve fibers and no
injammatory changes. (B) Sciatic nerve of the same animal as
A. Note the normal appearance of the nerve. (C) Bovine peripheral nerve (BPN)-inoculated rat, 1-pm epoxy wsin section. Detail from a transverse section o f an L6 ventral root from a rat
displaying clinical signs. The entire section was scoved 3 for inflammation and 4 f i r LmyeLination. Note the injammuto y
cells surrounding a x o m undergoing akmyelination. ( D ) Pzsensitized rat, 1-pm epoxy resin section. Detail from a transverse section of an S i dorsal root from an experimental allergic
neuritis (EAN)-afjacted rat. This corresponded to grades 4 (inflammation) and 3 (demyelination).Note the presence of some
polymorpbonuclear leukocytes and an axon undergoing demyelination (arrow}. (E) Pz and galactocerebroside (GC)-sensitized
rat, 1-pm epoxy resin section. Transverse section of sciatic nerve
from a rat with clinical EAN. Note the conjuent perivascular
cufs and scattered demyelinated fibers. This corresponded t o
graah 4 (inflammation) and 3 (&myelination). Note the perivascular cuf and some demyelinated axons (arrows). (F)Pz and
GA(b)-sensitized rat, 1-pm epoxy resin section. Transverse section of an S1 ventral root of a rat displaying EAN. This root
scored 3 for injammation and 4 for demyelination. Note the demyelinated axons (arrow) and an injammatory cell adhering t o
the endothelium of the vessel (center). (A, C-F, toluidine blue;
A, B, x 375; C-F, x 755.)
The present experimental protocol compared Lewis
rats sensitized against a known neuritogenic dose of P,
protein with animals given P, plus different doses of
GAS and, for comparative purposes, GC.A mixture of
GAS was used since it has been observed that the immune reaction to these compounds yields antibodies
reacting with the Gal(P 1-3)GalNAc epitope of GM,.
This is shared by other glycolipids and glycoproteins in
the myelin and ponmyelin fractions {22]. Furthermore,
when mixtures of total brain GAS are administered,
the predominant antibody response is against GM, and
asialo-GM1 1311.
In agreement with previous observations, the combination of P, with G C in the inoculum increased the
PNS lesion area but not its severity. While inflammation and demyelinarion in P, animals were limited to
spinal roots supplying the sciatic nerve, the inclusion
of GC into the protocol led to lesions in the distal
nerve as well. In contrast to GC, GAS did not enhance
lesion areas induced by P2.The data showed that when
used alone, GAS produced no pathological changes,
and when GASwere coupled with P, protein, signs that
occurred were less severe than those seen in animals
receiving P, alone (see Table 1).
In the present study, the clinical score was lower
when either GAS or G C were combined with P,, a
finding discordant with the observation that there was
essentially no difference in the degree of neuropathological involvement between the groups. The reduced
clinical score for the P, + G C group, in spite of the
increased pathology, might be related to the lesions
being less radicular and more distal, thus rendering the
effect less detectable clinically. A similar dissociation between clinical and structural changes has also been reported in previous studies of EAE and EAN C32, 331.
The lack of change in the humoral response to P,
protein after the addition of G C or GAS to the emulPonzin et al: Gangliosides and EAN
sion might be explained by the neuritogenic activity of
the CN-1 peptide of P, correlating better with a T-cell,
rather than a B-cell, response E343. Antibodies against
GAS were not detected in most animals. This supports
further the low immunogenicity of these glycolipids
c35, 361.
The failure of exogenous GAS to enhance the response to P, might relate to a number of phenomena,
particularly when one compares the effect with that of
GC. The neuritogenicity of P, appears to be conformation dependent [ 3 7 ) and interactions between P, and
GAS might lead to conformational changes that are
ineffective in augmenting neuritogenicity, in contrast
to the case with GC. Thus, it appears that GAS exert
no augmenting role in autoimmune demyelination and
it is possible that the presence of GASin the sensitizing
mixture may have interfered with interactions between
neuritogenic determinants and the immune system.
Interestingly, the administration of exogenous GAS
has been claimed to offer partial protection against
EAN induced in myelin-sensitized rats [38). Other
studies on EAE have documented a protective role for
GM, and GM4 [39J and a delayed hypersensitivity response to GAS that was not encephalitogenic c251.
Taken in concert, our observations have shown GAS
to be nonantigenic in the PNS and suggest that when
combined with P,, a strong neuritogen, exogenous
GAS might lead to a lessened pathological effect. The
possible immunological mechanisms underlying these
discrepanices are currently under investigation.
This study was supported in part by grants (to C.S.R.) from the
National Instirutes of Health (NS 08952 and NS 11920) and National Multiple Sclerosis Society (RG 1001-G-7).
The authors thank Drs Krzysztof W. Selma], Alessandro Bruni, Lanfranc0 Callegaro, Alberta Leon, and Gin0 Toffano for helpful discussion; Everett Swanson, Howard Finch, Miriam Pakingan, Marta Bassan, Paola Facco, and Anna Rosa Morandin for expert technical
assistance; Dr George Hashim for P, protein; and Michele Brigs
for careful preparation of the manuscript.
1. Rame CS, Traugotr U, Farooq M, et al. Augmentation of
immune-mediated demyelination by lipid haptens. Lab Invest
2. Brosnan CF, Traugoa U, Raine CS. Analysis of humoral and
cellular events and the role of lipid haptens during CNS demyelination. Acta Neuropathol (Berl) 1983;9(suppl):S59-S70
3. Hosein 22, Gilbert JJ, Strejan GH. The role of myelin lipids
in experimental allergic encephalomyelitis. J Neuroimmunol
4. Hughes RAC,Powell HC. Experimental allergic neuritis: demyelination induced by P2 alone and non-specific enhancement by
cerebroside. J Neuropathol Exp Neurol 1984;43:154-161
5 . Yu RK, Saito M. Structure and localization of gangliosides. In:
Margolis RU, Margolis F X , eds. Neurobiology of glycoconjugates. New York: Plenum Press, 1989:l-42
6. Fong JW,
Ledeen RW, Kundu SK, Brostoff SW. Gangliosides
of peripheral newe myelin. J Neurochem 1976;26:157-162
684 Annals of Neurology Vol 30 No 5
7. Ledeen RW, Cochran FB, Yu RK, et al. Gangliosidcs of the
CNS myelin membrane. Adv Exp Med Biol1980;125:167-176
8. Quarles RR, Ilyas AA, Willison HJ. Antibodies to glycolipids in
demyelinating diseases of the human peripheral nervous system.
Chem Phys Lipids 1986;42:235-248
9. Latov N, Hays AP, Sherman WH. Peripheral neuropathy and
anti-MAG antibodies. CRC Crit Rev Neurobiol 1988;3:
10. Ilyas AA, Wilhon HJ, Dalakas MO, et d. Identificacion and
characterization of gangliosides reacting with 1gM paraproceins
in three patients with neuropathy associated with biclonal gammopathy. J Neurochem 1988;5:85 1-858
11. Nardelli E, Steck AJ, Barkas T, et al. Motor neuron syndrome
and monoclonal IgM with antibody activity against gangliosides
GM1 and G D l b . Ann Neurol 1988;23:524-528
12. Larov N , Hays AP, Donofrio PD, et al. Monoclonal IgM with
unique specificity to gangliosides GM1 and G D l b and to lactoN-tetraose associated with human motor neuron disease. Neurology 1988;38:763-768
3. Ito H, Latov N. Monoclonal IgM in two patients with motor
neuron disease bind to the carbohydrate antigens Gal(B13)GalNAc and Gal(B1-3)GlcNAc. J Neuroimmunol 1988;19:
4. Marcus DM, Percy L, Gilbert S, et al. Human IgM monoclonal
proteins that bind 3-fucosyllactosamine, asialo GM1 and GM1.
J Immunol 1989;143:2929-2932
15. Endo T, Scott DD, Stewart SS, et al. Antibodies to glycosphingolipids in patients with mulciple sclerosis and SLE. J Immunol
16. Pestronk A, Chaundhry V, Feldman EL, ec al. Lower motor
neuron syndromes defined by parterns of weakness, nerve conduction abnormalities, and high titers of antiglycolipid antibodies. Ann Neurol 1990;27:316-326
17. Pestronk A, Adams RN, Clawson L,et al. Serum antibodies to
GM1 ganglioside in amyotrophic lateral sclerosis. Neurology
18. Ilyas AA, Willison HJ, Quarles RH, et al. Serum antibodies to
gangliosides in Guillain-Barri. syndrome. Ann Neurol 1988;
19. Pestronk A, Cornbluth DR, Ilyas AA, et al. A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Ann
Neurol 1988;24:73-78
20. Shy ME, Evans VA, Lublin FD, et al. Antibodies to GMI and
G D l b in patients with motor neuron disease without plasma
cell dyscrasia. Ann Neurol 1989;25:511-513
21. Svennerholm L, Fredman P. Antibody detection in GuillainBarrC syndrome. Ann Neurol 1990;27(suppl):S36-S40
22. Latov N. Neuropathy and anti-GM1 antibodies. Ann Neurol
23. Quarles RH, Ilyas AA, Willison HJ. Antibodies to gangliosides
and myelin proteins in Guillain-Barre syndrome. Ann Neurol
8-S 52
24. Brostoff SW, Sachs H, Dal Canto M, et al. The P2 protein of
bovine root myelin: isolation and some chemical and immunological properties. J Neurochem 1974;23:1037-1043
25. Offner H , Standage BA, Burger DR, Vandenbark AA.
Delayed-type hypersensitivity to gangliosides in the Lewis rat.
J Neuroimmunol 1985;9:147-157
26. Quarles RH. Human monoclonal antibodies associated with
neuropathy. Methods Enzymol 1989;179:291-299
27. Nakayasa H , Ota K, Tanaka H , er al. Suppression of actively
induced and passively transferred experimental allergic neuritis
hy cyclosporin A. J Neuroimmunol 1990;26:219-227
28. Kadlubowski M, Hughes RAC. Identification of the neuritogen
of experimental allergic neuritis. Nature (Lond) 1979;277:
29. Kadlubowski M, Hughes RAC, Gregson IVA. Experimental al-
November 1991
lergic neuritis in the Lewis rat: characterization of the activity of
peripheral myelin and its major basic protein, P,. Brain Res
Saida K, Sumner AJ, SaidaT, et al. Antiserum-mediated demyelinarion: relationship between remyelination and functional recovery. Ann Neurol 1980;8:12-24
Rapport MM, Graf L, Brunner W, Yu RK. Antibodies to total
brain gangliosides: titer and specificity of antisera. In: Svennerholm L, Mandel P, Dreyfus H, Urban P-F, eds. Advances of
experimental medicine and biology, vol 125. New York, Plenum Press, 1980:327-334
Raine CS, Snyder DH, Stone SH, Bornstein MB. Suppression of acute and chronic experimental allergic encephalomyelitis in strain 13 guinea pigs. J Neurol Sci 1977;31:355367
Rostami A, Brown MJ, ksak RP, et al. The role of myelin P,
protein in the production of experimental allergic neuritis. Ann
Neurol 1984;16:680-685
Milek DJ, Cunningham JM, Powers JM, Brostoff SW. Experi-
mental allergic neuritis: humoral and cellular response to the
cyanogen bromide peptides of the P, protein. J Neuroimmunol
Marcus DM. A review of the immunogenic and immunomodulatory properties of glycosphingolipids. Mol Immunol 1984;
Lvingston PO, Ritter G, Calves MJ. Antibody response after
immunization with the gangliosides GM,, GM?, GM,, GD, and
GD3 in the mouse. Cancer Immunol Immunother 1989;29:
Brostoff SW. Immunological responses to myelin and myelin
components. In: Morel1 P, ed. Myelin. New York, Plenum
Press, 1984:405-439
Ledeen RW, Oderfeld-Now& B, Brosnan CP, Cervone A. Gangliosides offer partial protection in experimental allergic neuritis.
Ann Neurol 14c)0;27(suppl):S6c)-S74
Mullin RB, Patrick DH, Poore CMB, et al. Prevention of experimental allergic encephalomyelitis by ganghoside GMS. A
follow-up study. J Neurol Sci 1986;73:55-60
Ponzin et al: Gangliosides and EAN
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expressions, effect, periphery, nervous, autoimmune, ganglioside, system, demyelination
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