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Autoimmune mechanisms in peripheral neuropathies.

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Autoimmune Mechanisms
in Peripheral Neuropatlues
Robert K. Yu, PhD, Med ScD, Toshio Ariga, PhD, Med ScD, Tatsuo Kohriyama, MD, PhD,”
Susumu Kusunoki, MD, PhD,? Yasuhiro Maeda, MD, and Nobuyuki Miyatani, MD, PhD
In certain patients with demyelinating neuropathy and plasma cell dyscrasia, there are IgM monoclonal antibodies
that recognize a carbohydrate epitope shared by myelin-associated glycoprotein (MAG) and at least two acidic glycolipids in the peripheral nervous system (PNS). The structures of the two acidic lipids have been elucidated as a new
class of glycosphingolipids, termed sulfoglucuronyl glycolipids (SGGLs). SGGLs have been demonstrated to be present
in myelin, axolemma, and other glia-related membranes in PNS of several animal species, as well as in human dorsal
root ganglia and sympathetic ganglia. In rabbits sensitized with sulfoglucuronyl paragloboside (SGPG), a major SGGL
in PNS, antibodies developed with reactivities toward SGPG and MAG. The animals also showed moderate weakness,
a slowed nerve conduction velocity, and evidence of conduction block. Recently we also found SGPG in rat brain
microvessels. This finding supports our hypothesis that autoantibodies may first interact with endothelial cell-bound
antigens and that this might change the permeability of the blood-brain or blood-nerve barrier to permit the entry of
these autoantibodies into the nervous system. Our data are consistent with the concept that an autoimmune response
against the sulfoglucuronyl residue may participate in the pathogenesis of immune-mediated neuropathy.
Yu RK, Ariga T, Kohriyama T, Kusunoki S, Maeda Y,Miyatani N. Autoimmune mechanisms
in peripheral neuropathies. Ann Neurol 1990;27(suppl):S30-S35
Guillain-Barre syndrome (GBS) is considered to be an
acquired inflammatory demyelinating peripheral neuropathy. Although it has been proposed that humoral
or cell-mediated immune factors contribute to the
pathogenesis of the demyelination in peripheral nervous system (PNS), the target antigens in PNS have
not been well defined. We have been interested in the
potential immunological role of glycolipid antigens in
the pathogenesis of neuropathies. We have focused on
certain patients with demyelinating neuropathy and
plasma cell dyscrasia, in whom IgM monoclonal antibodies (M-proteins) develop that react with peripheral
nerve components 111. Approximately 60% of these
patients have been found to have M-proteins that recognize myelin-associated glycoprotein (MAG) E2-6).
Some patients with neuropathy have monoclonal IgMs
that do not react with MAG but with various gangliosides C7-12). Recent studies indicate that the antiMAG M-protein binds to a carbohydrate determinant
shared by MAG, several low-molecular-weight glycoproteins in PNS C13, 141, and at least two acidic glycolipids in PNS C12, IS]. Therefore, we have focused
on the glycolipids that can be recognized by patients’
anti-MAG M-proteins.
Sulfoglucuronyl Glycolipids as Target
Antigens of M-Proteins
The structures of the glycolipids that are recognized by
patients’ M-proteins have been elucidated by our
group 116) and others C171 as a new class of acidic
glycosphingolipids, termed stllfoglucuronyl glycolipids
(SGGLs). The carbohydrate sequences of two of these
SGGLs are sulfoglucuronyl paragloboside (SGPG) (sulfate-3GlcUAPl-3 GalP1-4GlcNAcPl-3GalPl-4GlcPl-1’
ceramide) and sulfoglucuronyl lactosaminyl paragloboside (SGLPG) (sulfate-3GlcUAP 1-3Galpl-4GlcNAcP 1-3GalP 1-4GlcNAcP 1-3GalP 1-4GlcP 1-1’ ceramide) (Fig 1).
To determine the antigenic determinants for Mproteins, the carbohydrate structure of SGPG was
chemically modified. Mild acid methanolysis removed
the sulfate moiety, producing desulfated SGPG methyl
ester, and the subsequent mild alkaline hydrolysis of
this compound produced desulfated SGPG. None of
the M-proteins reacted with desulfated SGPG methyl
ester; however, some patients’ M-proteins revealed
partial reactivity with desulfated SGPG in addition to
the intact glycolipid [lS, 191. These data indicate that
patients’ M-proteins can be divided into at least two
From the Department of Biochemistry and Molecular Biophysics,
Medical College of Virginia, Virginia Commonwealth University,
Richmond, VA.
tPresent address: Department of Neurology, Institute of Brain Research, University of Tokyo, Bunkyo-ku, Tokyo 113, Japan.
*Present address: Third Department of Internal Medicine, Hiroshima University School of Medicine, Minami-ku, Hiroshima 734,
Address reprint requests to Dr Yu, Department of Biochemistry
and Molecular Biophysics, Medical College of Virginia, 1101 E Marshall St, Richmond, VA 23298-0614.
Fig I . Structures of sulfoglucuronylparagloboside (1) and sulfoglucutvnyl kzctosaminylparagloboside (2).
groups according to their antigenic specificities: one in
which the carboxyl group on the sulfoglucuronyl residue is essential for the binding, and the other in which
both the sulfate and carboxyl moieties are essential for
the binding. M-proteins of the former group frequently recognize a third minor glycolipid (glycolipid
X) in PNS 118, 191. Although the structure of this
lipid has not been determined, these data suggest that
glycolipid X has the glucuronyl residue without the
sulfate moiety. This observation raises the intriguing
possibility that heterogeneity in antigenic specificities
of patients’ M-proteins may underlie the varieties in
clinical manifestations 1201, although this hypothesis
needs substantiation.
Localization of SGGLs
SGGLs have been detected in PNS of various animal
species, including human beings 118, 2 11. Their concentration in animals varies from species to species,
and is the highest in human and bovine cauda equina.
The amount of SGGLs in rat and chicken sciatic nerve
is one-tenth-in rabbit nerve, one one-hundredth-of
that in human or bovine cauda equina (Table 1). Subcellular localization studies of bovine spinal accessory
nerve have demonstrated that SGGL levels are high in
an axolemma-enriched fraction and are also present in
myelin and other &a-related membranes in lower concentrations (Table 2) 121). In addition, we 121) have
found SGGLs in transformed rat Schwann cells.
SGGLs have also been detected in human dorsal root
ganglia, sciatic nerve, and cauda equina 1221, but not in
adult rodent brain 1231 or adult human brain regions
such as the frontal cortex, frontal white matter, caudate, thalamus, dentate, and cerebellar cortex (unpub-
lished data). Although SGGLs are expressed in the rat
embryonic forebrain, they disappear during the postnatal period 1231. Shashoua and colleagues [241 have
reported in adult fish brain the presence of SGGLs that
may have the ability to reinitiate neuronal cell proliferation. Recently, Chou and Jungalwala 1251 demonstrated the presence the SGGLs in murine cerebellum;
here, SGGLs were reported to be localized in Purkinje
cells and their arbors. In autonomic nervous system,
SGGLs have been detected in human sympathetic
ganglia 1221. In addition, we have detected SGPG in
bovine dura mater 1211. This finding prompted us to
examine the presence of SGGLs in other mesodermal
tissues. Our recent studies have indicated that SGPG is
indeed present in rat brain microvessels and cultured
endothelial cells of human umbilical veins 1261.
Common Antigenic Epitope i n Nervous Tissues,
Lymphocytes, and Mesodermul Cells
As noted earlier, glucuronyl-3-sulfate is the epitope
recognized by all anti-SGGL antibodies. This epitope
is known to be present not only in MAG and SGGLs,
but also in several other glycoproteins. In the central
nervous system, (CNS), neural cell adhesion molecule
(N-CAM), J1, and L1 glycoproteins are known to express this epitope 127-29]. These glycoproteins are
presumably involved in neuron-neuron, neuronastrocyte, or asuocyte-astrocyte interactions. Margolis
and co-workers 1301 have also reported the appearance
of this epitope in sulfated glycoproteins of PC12 pheochromocytoma cells and chromaffin granule membranes. Furthermore, glycoconjugates in small cell
lung cancer 1311 and melanoma cells 1321, carcinomas
of neuroectodermal origin, have been reported to
Yu et al: Autoimmune Mechanisms in Neuropathy S31
Table I . Concentration of Sulfoglucuronyl Glycolipids in Various Tissues
Cauda equina
Dorsal root ganglia
Sympathetic ganglia
Sciatic nerve
Cerebral cortex
Cerebral white matter
Cerebellar cortex
Cultured endothelial
cells of umbilical
Cauda equina
Spinal cord
Dura mater
Sciatic nerve
Brain microvessels
Cerebral myelin
Schwann cells
Sciatic nerve
Sciatic nerve
1.34 r 0.56
1.02 t 0.21
0.04 r 0.02
0.85 t 0.14
0.051 f 0.034
0.29 2 0.13
0.18 t 0.03
0.22 t 0.02
0.77 2 0.26
0.11 t 0.01
0.09 t 0.04
0.10 t 0.02
0.27 &
0.05 2
0.02 2
0.02 t
0.10 t 0.02
0.02 t 0.007
"Measured in micrograms per milligram of protein.
ND = not detected; UD = Unpublished data of Ariga and colleagues. SGPG = sulfoglucuronyl paragloboside; SGLPG = sulfoglucuronyl
lactosaminyl paragloboside.
Table 2. Distribution of Sulfoglucuronyl Glycolipids
in Subcellular Fractions Obtained from Bovine
Spinal Accessory Nerve"
Nerve Tissue
Light myelin
Medium myelin
Heavy myelin and
glial membrane
1.63 & 0.42
1.34 f 0.37
1.46 f 0.25
0.56 ? 0.08
0.50 & 0.10
0.40 f 0.02
0.84 t 0.02
"Data reproduced from Kohriyama and colleagues [2 11.
bMeasured in micrograms per milligram of protein.
SGPG = sulfoglucuronylparagloboside; SGLPG
lactosaminyl paragloboside.
share the same antigenic determinant. Thus, this
epitope may be involved in regulating cellular adhesion and proliferation of neural and cancer cells.
The glucuronyl-3-sulfate epitope is also recognized
by the mouse monoclonal antibody HNK-1, which
recognizes a subset of human lymphocytes, including
natural killer cells (Leu-7) r33-361. Although a decrease in the number of Leu 7 cells has been reported
in some patients with neuropathy and anti-MAG IgM
1371, this has not been confirmed E387. In addition to
dura mater and brain endothelial cells, Margolis and
associates 130) reported the presence of the glucuronyl-3-sulfate epitope in chondroitin sulfate proteoglycans of cartilages and chondrosarcoma, tissues of
mesodermal origin.
SGPG-Induced Experimental Neuropathy
To study the antigenicity of SGGLs, we immunized 3
New Zealand white rabbits with SGPG emulsified in
complete Freund's adjuvant and keyhole limpet hemocyanin [19]. The immunogen, SGPG, was purified
from bovine cauda equina with the peptidic contamination carefully removed. All 3 rabbits showed weight loss,
sluggishness in righting response from the outstretched
position, and a slight to mild weakness predominantly in their hind feet 2 to 5 weeks postinoculation. Although they recovered 2 to 4 weeks after the
initial symptoms, 2 rabbits showed a relapse with
weight loss and neurological signs three and eight
months post inoculation, respectively (Fig 2). N o incontinence of feces or urine was noted. Electrophysiological studies revealed slightly diminished conduction
velocity and conduction block in the sciatic nerves of
the SGPG-injected animals (Fig 3). Anti-SGPG antibodies were detected at dilutions of 1: 1,000 to
S32 Annals of Neurology Supplement to Volume 27, 1990
2 m s
Fig 3. Typical electrophysiologicalfinding recordedfrom Rabbit
2 inoculated with sulfoglucuronylparagloboside (SGPG). The
proximal (upper tracing) to distal (lower tracing) ratio ofthe
compound muscle action potential amplitude was 0.40 (controls,
0.85 2 0.4). The nerve conduction velocity in the sciatic nerve
of the rabbits inoculated with SGPG was 40.0 2.3 mls (controls, 58 i. 5.2 mls). Data reproducedfrom Kohriyama et al
post-inoculation days
F i g 2. Immunization program, clinical course, and anti-sulfoglucuronyl paragloboside (SGPG)antibody titers. (A)Rabbit 1
was immunized intrademzalh (id.) and intravenously (i.v.)at
the date indicated. (B) Anti-SGPG antibody titers in the IgG
class are represented as absorbance values at a dilution of
1 :1,000. (C)The onset of the clinical manifestations in the
acute phase appeared to cowelate with the elevation of antiSGPG antibody titers of the IgG class. The clinical manifestation in the chronicphase did not appear to cowelate with
the antibody titers. (Data reproducedfrom Kohriyama et a1
1:2,500 by an enzyme-linked immunosorbent assay
and a high-performance thin-layer chromatography immunostaining method. As was the case with human
patient sera, the rabbit antibodies showed a fine
heterogeneity in antigenic specificity. In addition, all
rabbit sera reacted with human and bovine MAG and
PNS low-molecular-weight glycoproteins (Fig 4).
Thus, we have demonstrated that the rabbit antisera
generated against SGPG have the same or similar antigenic specificity as those of the anti-MAG M-proteins
from patients with neuropathy.
We 1391 recently carried out similar experiments in
Lewis rats and confirmed these findings. Pathological
changes associated with the experimental animals were
generally minor, consisting of axonal shrinkage and
loss. However, intraneural injection of the rat antiSGPG antisera with guinea pig complement into the
sciatic nerve of Lewis rats revealed extensive demyelination and axonal degeneration (unpublished data).
These observations support the concept that SGGLs
may be important target antigens in this type of neuropathy.
SGPG and Blood-Brain and
Blood-Nerve Barriers
There is considerable evidence suggesting the presence of humoral demyelinating factors in sera of patients with GBS. It has been reported that passive
transfer of the GBS serum by direct injection into rat
sciatic nerve produces perivenular demyelination associated with lymphocyte and macrophage infiltration
140, 4 11. However, the circulating humoral demyelinating factors need to gain access to PNS through
the blood-nerve barrier. In experimental allergic neuritis (EAN) produced by immunization with peripheral
nerve homogenate, one of the animal models of GBS,
an alteration in blood-nerve barrier permeability has
been reported 142). Intraneural injection of anti-MAG
antiserum into cat sciatic nerves also produces demyelination {43, 44}. Our finding that brain microvessels
contain SGPG supports our earlier hypothesis that
autoantibodies recognize endothelial cell-bound autoantigens and that this might change the permeability of
the blood-brain barrier or the blood-nerve barrier.
This possibility is substantiated by our most recent
work showing damages of endothelial cells in the
spinal cord of Lewis rats sensitized with SGPG, in
which high titers of anti-SGPG antibodies developed
(unpublished data).
Yu et al: Autoimmune Mechanisms in Neuropathy
1 2 - 3 4
Fig 4. Immunostaining of central nervous system and peripheral
nervous system myelin proteins. (A, B) Blots immunostained
with serum from a patient with anti-myelin-associated glycoprotein (MAG)IgM M-proteins, and antiserumfrom a rabbit inoculated with sulfoglucuronyl paragloboside, respectively. Column
1 contains myelin from human brain; column 2, myelin from
human caudz equina; column 3, myelin from bovine brain; and
column 4, myelin from bovine cauda equina. (Data reproduced
from Kohriyama et a1 119}.)
As an experimental model of GBS, EAN induced
by P2 protein has been well characterized. A cellmediated immune mechanism has been suggested by
the finding that EAN can be transferred with a P2reactive T-cell line [45]. On the contrary, intraneural
injections of antigalactocerebroside (GC) antiserum or
repeated systemic injections of GC into rabbits can
also produce EAN, in which the involvement of humoral immunity has been suggested [46,47). The relevance of the latter studies to EAN is not entirely clear,
as GC is also present in CNS-myelin; hence, the involvement of the CNS is expected. In contrast, the
occurrence of SGGLs is restricted to the PNS tissues,
immune cells, and endothelial cells, and they may thus
be important in relation to peripheral neuropathies.
Further studies are needed to clarify the role of these
compounds in the pathogenesis of autoimmunemediated experimental neuropathy.
This work was supported by U.S. Public Health Service grants NS11853 and NS-26994.
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