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Immune-mediated demyelination.

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NEUROLOGICAL PROGRESS
Immune-Mediated Demyelination
Hans-Peter Hartung, MD
The Guillain-Bard syndrome (GBS) and multiple sclerosis (MS) are thought to result from aberrant immune responses
to myelin antigens. Recent evidence to implicate the cytokine tumor necrosis factor-a (TNF-a) and the intercellular
adhesion molecule-1 (ICAM-1) in the pathogenesis of these disorders is reviewed. In GBS, elevated serum concentrations of TNF-a are detectable in 20 to 50% of patients. TNF-a released from autoreactive T cells, macrophages, or
microglia may contribute to inflammatory demyelinative processes by upregulating the expression of recognition
molecules on antigen-presenting cells; by cytotoxic damage to endothelium; by stimulating the secretion of inflammatory mediators; by directly injuring the myelin sheath; or by interfering with impulse propagation. Its pathogenic
potential in GBS is underscored by findings in experimental autoimmune neuritis. Soluble ICAM-1, originating from
T cells, macrophages, endothelium, or glial cells, circulates at increased concentrations in serum and cerebrospinal
fluid of patients with active MS. ICAM-1 may be crucially involved in the migration of autoreactive T lymphocytes
from blood to brain. Whether ICAM-1 can serve as a marker of acute inflammatory events in MS associated with
clinical relapses warrants further investigation. TNF-a and ICAM-1 could be targets for antigen nonspecific treatment
approaches to the inflammatory demyelinating diseases GBS and MS.
Hartung H-P. Immune-mediated demyelination. Ann Neurol 1993;33:563-567
The Guillain-Barre syndrome (GBS) and multiple sclerosis (MS) are thought to result from aberrant immune
responses to myelin antigens. Perivascular infiltration
by T lymphocytes and macrophage-mediated demyelination are pathological hallmarks of both disorders
11-51, In this issue of the Annals, Sharief and colleagues [GI and Tsukada and co-workers C71 report on
immune system abnormalities detectable in peripheral
blood of patients with GBS and MS.
Immune responses are coordinated by cytokines.
Evidence is available to implicate these signaling molecules in the pathogenesis of acute inflammatory demyelinating polyradiculoneuropathy 1-31. Tumor necrosis factor-a (TNF-a), produced by macrophages and T
lymphocytes, is a pleiotropic inflammatory mediator
[S, 91 and has been reported to change ionic channel
expression and membrane potential of oligodendrocytes in vitro; to disrupt myelin; to cause necrosis of
oligodendrocytes in organotypic culture; and to induce gliotic proliferation 110- 12). These properties
prompted attempts to elucidate the role of this cytokine in immune-mediated nerve damage.
Sharief and colleagues [GI examined serum levels of
TNF-a in patients with GBS. Raised concentrations
were detected in 55% of their patients but also in 26%
of unrelated neuropathies and with similar frequency
in other neurological disorders. Sequential determinations showed high TNF-a levels decline as patients
recovered from the disease. A striking correlation be-
tween serum TNF-a levels and severity of the neuropathy was noted. GBS is preceded by an acute infectious
illness in up to 70% of cases C11, and it has been argued
that cytokine changes observed in these patients
merely reflect this statistic. However, Sharief and colleagues did not find a difference in TNF-a levels of
patients with or without antecedent infections.
This report by Sharief and co-workers underscores
previous observations indicating activation of macrophages and T cells in peripheral blood of GBS patients
[4, 5 , 13, 14). The temporal association with disease
severity points toward a role of TNF-a in the pathogenesis of GBS. This is corroborated by experimental
data. Intraneural injection of TNF-a produces predominantly axonal damage of sciatic nerve in mice
[l5]. An immunocytochemical study in experimental
autoimmune neuritis (EAN), an animal model of GBS,
showed TNF-(Y positive macrophages appearing in
nerve around the time of first clinical signs. As animals
recovered, TNF-a immunoreactivity was no longer detectable 1161. Macrophages invading peripheral nerve
during Wallerian degeneration, by contrast, were
mostly TNF-a negative. When animals with EAN received a neutralizing monoclonal antibody to TNF-a,
inflammatory demyelination was greatly diminished.
TNF-a may act at several stages in the development
of inflammatory demyelination. It is released by activated T cells and can synergize with interferon-y (IFNy) to upregulate the expression of recognition mole-
From the Clinical Research Group for Multiple Sclerosis and Department of Neurology, Julius-Maximilians-UniversirarWiirzburg,
Germany.
Address correspondence ro Dr Hartung, Department of Neurology,
University of Wiirzburg, Josef-Schneider-Srrane 11, D-8700 Wiirzburg, Germany.
Received Mar 12, 1993. Accepted for publication Mar 16, 1993.
Copyright 0 1993 by the American Neurological Association 563
cules (major histocompatibility complex [MHCl class
I1 gene products, adhesion molecules) on macrophages
or other accessory cells [8, 91. Thereby it facilitates
initiation of a local immune response in peripheral
nerve. TNF-a can also stimulate macrophages to elaborate potentially injurious inflammatory mediators such
as reactive oxygen species and proteases and exerts
cytotoxic effects on vascular endothelium 19, 171.
Based on its myelinotoxic properties, TNF-a may represent a major noxious molecule by which macrophages, the chief effector cells of the immune response
in GBS, damage peripheral nerve. Finally, TNF-a
could, short of inciting tissue destruction, cause functional changes by interfering with impulse propagation
1181. It would of course be interesting to examine
TNF-a production at the cellular level, both in peripheral blood of GBS patients and by in situ hybridization
techniques in nerve biopsies.
The findings of Sharief and colleagues are in accord
with an earlier study by Tsukada and associates 1191
who determined high serum levels of TNF-a in 5 of 8
GBS patients. The situation is different in MS. Although Sharief and colleagues found raised serum concentrations of TNF-a only occasionally in active
chronic progressive MS, Tsukada and associates noted
increased TNF-a levels in more than half of their patients with active disease C7, 197. These reports add to
a conflicting literature. Several groups demonstrated
increased cerebrospinal Auid (CSF) concentrations of
TNF-a in MS patients, whereas other groups did not
120-241. Failure to pick up measurable concentrations
of cytokines in serum or CSF of course does not preclude local production of cytokines. It may in this instance be more meaningful to examine cytokine gene
message and the capacity of T cells or macrophages to
generate TNF-a upon appropriate stimulation. T-cell
clones derived from CSF of MS patients secrete large
amounts of TNF-a 1251. Likewise, monocytes or macrophages from blood or CSF showed enhanced inducible TNF-a synthesis 1261. Another group 1271, by
contrast, found monocytes from MS patients in an
active stage of their disease to generate diminished
amounts of TNF-a. Still other investigators C28, 291
documented a rise of stimulated whole blood TNF-a
production that was temporally related to acute exacerbations.
These discrepancies are not easily explained. Different methodology, time of sampling, the definition
of active versus stable disease (whether on clinical
grounds or documented by magnetic resonance imaging) may be invoked. Nevertheless, increased TNF-a
production in MS may be pathogenetically important
in view of a number of observations in animal models
of the disease and made on pathological examination
of MS brains [171. TNF-a was immunocytochemically
recognized in lesions of chronic experimental allergic
564 Annals of Neurology Vol 3 3 No 6 June 1993
encephalomyelitis (EAE) [30}. In myelin basic proteinspecific T cell line-mediated EAE, encephalitogenicity
correlated with TNF-a production by these autoreactive clones [3 11. Antibodies against TNF-a abrogated
T cell transfer EAE in mice C32, 331 whereas recombinant TNF-a augmented disease in Lewis rats E34). Finally, TNF-a could be localized by immunocytochemistry in active MS plaques C35, 361.
Cells engaged in immunoinflammatory responses
may communicate not only by means of cytokines.
Crosstalk is also possible through a receptor-ligand
type interaction of adhesion molecules expressed on
leukocytes and target cells. The article by Tsukada and
colleagues [7] in this issue may contribute to a better
appreciation of the role of adhesion-related events in
the pathogenesis of inflammatory demyelination.
Tsukada and colleagues report on serum levels of
the soluble intercellular adhesion molecule- 1 (ICAM1) in MS and patients with human T-lymphotrophic
virus type I-associated (HTLV-I-associated) myelopathy (HAM). ICAM-1 (CD54) is a 90 kd glycoprotein
belonging to the immunoglobulin superfamily that under the influence of cytokines is expressed on a variety
of hematopoietic and nonhematopoietic cells including
brain endothelial cells, astrocytes, oligodendrocytes,
and microglia 137-431. ICAM-1 functions as a natural
receptor for the integrins LFA-1 and Mac-1 [37}. A
soluble form of this adhesion molecule was recently
detected in serum 144-461.
Tsukada and colleagues assayed serum from 31 MS
patients for soluble ICAM-1 (SICAM-1). Samples collected during exacerbation of the disease contained
levels that were significantly increased over those from
patients with stable disease. Remission following highdose corticosteroid therapy was associated with a reduction in serum concentrations of SICAM-1. Similarly
high levels were measured in patients with HTLV-Iassociated myelopathy. sICAM- 1 may originate from
T cells, macrophages, endothelial cells, or glia. Furthermore, Tsukada and colleagues noted a positive correlation between SICAM-1 and TNF-a in patients with
active MS (see above).
We measured SICAM-1 concentrations in sera from
147 MS patients and determined similarly elevated levels in patients with active lesions identified by gadolinium enhancement on magnetic resonance imaging
147). Jander and co-workers 1481 have also looked at
SICAM-1 concentrations in serum of MS patients. Using a different commercially available enzyme-linked
immunosorbent assay they measured much higher levels in neurological controls (305 5 140 ng/mL) which
were not different from those detectable in MS patients. However, they found increased levels in CSF.
Again, these apparently divergent results may be due
to differences in methodology and time of sampling in
relation to' disease activity, and hence warrant further
investigation. These observations point out a potentially important role for ICAM in the pathogenesis of
MS.
In MS myelin-antigen specific T cells circulate in
peripheral blood. Autoreactive T cells, however, can
also be retrieved from the blood of normal individuals.
The pathogenicity of T cells from MS patients directed
to the same putative myelin autoantigen(s>may reside
in their preferential recognition of certain epitopes of
the antigen, their biased usage of T cell receptor genes,
and their predilective elaboration of inflammatory cytokines [4, 5 , 143. Additional factors must operate that
focus this systemic immune response into the brain
parenchyma, rendering autoreactive T lymphocytes
autoaggressive. Resting T cells apparently are unable
to access the central nervous system. How T lymphocytes are activated and by what mechanisms they
invade the central nervous system through the bloodbrain barrier is an area of extensive current investigation {49, 50). A first step in the cellular traffic from
blood to brain is adhesion of inflammatory cells to endothelium. After transendothelial migration, activated
T cells encounter resident accessory cells (pericytes,
microglia, brain macrophages, astrocytes). As briefly
mentioned before, the trimolecular interaction of T
cell receptors, MHC class I1 gene products, and suitably processed autoantigenic epitopes on antigenpresenting cells then starts a local immune response
with subsequent clonal proliferation of autoantigenspecific T lymphocytes.
ICAM-1 is involved in these processes. ICAM-1,
through binding to its ligand LFA- 1, facilitates contact
between T cells and antigen-presenting cells and also
provides a costimulatory signal for T cell activation [5 1,
521. ICAM-1 promotes homing of T cells to endothelid cells 1531. Resident accessory cells in brain can be
induced to enhanced ICAM-1 expression by T cellderived cytokines (IFN-7 and TNF-a) [38-431.
ICAM-1 has been localized to vessels, brain macrophages and astrocytes in EAE lesions, and active MS
plaques [38, 54-56}. In chronic EAE of SJL mice, influx of T cells during relapses was associated with temporary upregulation of ICAM- 1. Adhesion molecules
were coexpressed along with cytokines including
TNF-a 1543. Finally, administration of a monoclonal
antibody to ICAM- 1 attenuates myelin-induced and
myelin basic protein-T cell line-mediated EAE in the
Lewis rat [573. Similar findings have recently been
made in EAN [58, 591. These observations emphasize
a decisive role of ICAM-1 in the focal accumulation
and activation of autoreactive T cells in inflammatory
demyelinating diseases of the central nervous system
and peripheral nervous system. Whether increased serum levels of SICAM-1 may serve as a marker of acute
inflammatory events in MS and HAM associated with
clinical relapses needs to be assessed in longitudinal
studies. A number of other adhesion molecules may
have similar impact on CNS or PNS inflammation
C563.
SICAM-1 retains its capacity to engage in ligand interactions with LFA-1 and hence may exert immunomodulating effects 1441. For example, SICAM-1 shed
from human melanoma cell lines blocks non-MHCrestricted cytotoxicity of killer cells [GO]. It is therefore
an intriguing question whether SICAM-1 can inhibit
inflammatory responses in neural tissue.
Its possible pathogenic role and yet to be proven
utility as a marker of acute disease aside, ICAM-1 may
be a target for future immunointerventional strategies.
Phase 2 trials are underway in patients with rheumatoid
arthritis using antibodies to ICAM-1.
Taken together these reports, while awaiting confirmation, provide additional evidence for systemic T
cell and macrophage activation in GBS and MS, emphasize common features of these two disorders, and
point out possible avenues for future therapy. In our
current state of ignorance or uncertainty about the relevant autoantigens in GBS and MS, antigen nonspecific
treatment approaches may be useful and involve modulation of cytokine activity by monoclonal antibodies,
soluble receptors or receptor antagonists, interference
with the activation of autoreactive T lymphocytes, or
blockade of their immigration into the target tissue.
Addendum
Sharief and co-workers 1611 have recently also reported increased levels of SICAM-1 in serum and cerebrospinal fluid of patients with active MS.
This work was supported by BMIT OlKDg001/8.
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Neurological Progress: Hartung: Immune-Mediated Demyelination
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