Aspects of the Immunobiology of Myelin Oligodendrocyte Glycoprotein (MOG)-induced Experimental Autoimmune Encephalomyelitis (EAE)

This study investigated the immunobiology of MOG-induced EAE in the
DA rat, an animal model, which reproduces the immunopathology of
the type II MS lesion (Lucchinetti et al., 2000). A newly
established immunisation protocol results in a highly synchronised
biphasic form of EAE, which mimics the disease course of secondary
progressive MS, albeit in a strongly abbreviated time course
(Figure 3.1.1). This study demonstrates that MOG-specific
autoantibodies are responsible for initiating clinical relapse and
driving disease progression. On the background of mild,
sub-clinical inflammatory activity in the CNS, pathogenic
antibodies enter the CNS and mediate demyelination, a process that
in turn amplifies the local inflammatory response (Figure 3.1.14
A). It should however be noted that lethal clinical relapses may
also occur in the absence of a pathogenic antibody response if an
inflammatory lesion develops in a region of the CNS that is
particularly sensitive to damage, or where it may perturb vital
functions, such as the brain stem. Although antibodies have been
shown to amplify the severity of ongoing clinical EAE (Schluesener
et al., 1987; Linington et al., 1988; Lassmann et al., 1988), firm
evidence for a role in driving relapse and disease progression was
missing. This study has now established this principal, which in
all probability is relevant to our understanding of the
pathogenesis of severe, steroid non-responsive relapses in MS
patients. However, this model of EAE is an artificial system, in
which the role of antibody is only apparent because of the
different kinetics of MOG-specific T and B cell responses. In MS we
still have to answer two crucial questions, namely the identity of
the autoantigens targeted by the demyelinating antibody response,
and the factors that may trigger this response. MOG is the only
myelin protein known to initiate a demyelinating antibody response
in EAE, and MOG-induced EAE has provided a valuable tool to
identify the role of pathogenic autoantibodies in immune mediated
demyelination. However, there is a major discrepancy between the
proportion of MS patients with pathogenic MOG-specific antibodies
in their circulation (5%; Haase et al., 2000) and the frequency of
patients with pathological changes suggestive of antibody-mediated
pathomechanisms (>50%; Lucchinetti et al., 2000). This
discrepancy may in part be accounted for by the absorption of the
pathogenic antibodies into the CNS, which will lead to a dramatic
reduction of the antibody titre in the periphery, as demonstrated
in section 3.1.3.4 of this study. On the other hand, it is unlikely
that MOG is the only target autoantigen, which is exposed on the
myelin surface and can therefore initiate a demyelinating
autoantibody response. The identification of potential targets is a
prerequisite to develop diagnostic kits to identify those patients
with pathogenic autoantibody responses and then provide an
appropriate therapy such as plasma exchange, or immuno-absorption.
As demonstrated in this study, DNA vaccination using a plasmid
encoding a myelin antigen is one approach to generate high titre
autoantibody responses directed against the native protein. The
pathogenicity of this antibody response can then be assayed in the
same animal by inducing EAE. This method circumvents problems such
as purity, yield and denaturation, all of which complicate any
study using antigens isolated from the CNS or generated using
recombinant technologies. Coupling this approach to a proteomics
based analysis of the myelin membrane and reverse genomics to
identify candidate gene products provides the means to map out
those protein antigens that can be targeted by a demyelinating
autoantibody response. The feasibility of this concept is currently
being tested in the rat using PLP and MAG as myelin components that
may in certain circumstances provoke a pathogenic autoantibody
response. Such an analysis will, however, not detect pathogenic
antibody responses to glycolipid antigens, which are major target
autoantigens in a number of diseases affecting the peripheral
nervous system such as Guillain Barré syndrome (GBS). In GBS a
pathogenic antibody response to gangliosides appears to be
triggered by infections with particular serotypes of Campylobacter
jejuni (Fredman, 1998; Willison and O´Hanlon, 1999). In the
majority of patients these antibody responses are an acute
phenomenon and disappear as the patients recover (Hahn, 1998). It
is conceivable that a similar mechanism is responsible for the
initiation of severe relapses in some MS patients, if an infection
triggers a cross-reactive antibody response to a surface glycolipid
epitope. This would induce an episode of acute CNS demyelination
that would not be immediately responsive to immunosuppressive
therapy, as tissue damage and amplification of the local
inflammatory response would be driven by the pre- existing antibody
response. Analysis of the autoantibody responses in MS should
therefore be extended to examine lipid as well as protein
autoantigens. Such studies should also not be restricted to myelin,
but also address the question of responses to other structures such
as the axon and oligodendrocyte progenitor cells. Such autoantibody
responses are however only conditionally pathogenic, in other words
their pathogenic potential is only expressed if they can enter the
CNS across the blood brain barrier (BBB)(Litzenburger et al., 1998;
Bourquin et al., 2000). In EAE the inflammatory insult to the CNS
is responsible for the disruption of BBB function and the entry of
antibody into the nervous system. MS is characterised by repeated
episodes of CNS inflammation but what initiates and maintains this
response is unclear. The observation, that DA rats develop a
similar, although eventually self-limiting response in the CNS
after immunisation with MOG-peptide in CFA provides a model to
investigate the immuno-regulatory deficit(s) responsible for
chronic CNS inflammation. The disease model is very reproducible
with >90% of animals relapsing after peptide immunisation as
opposed to