Increasing evidence correlates the presence and levels of anti-MOG antibodies with demyelination in EAE. This was first suggested by the demonstration that the demyelinating activity of chronic EAE sera assayed in vivo by intrathecal injection of normal rats is proportional to the anti-MOG antibody titer of the serum.45 In guinea pigs with chronic EAE, antibodies against MOG are not always detected in sera but are always present in acid extract of CNS tissue, with levels correlating with severity of clinical signs and the intensity of demyelinating lesions; most importantly, in animals which did not develop chronic EAE, anti-MOG antibodies could not be detected and demyelination was absent.11 The relationship between anti-MOG antibodies and demyelination has been shown best in the marmoset model of EAE. In these non-human primates, immunization with CNS white matter homogenate produces a demyelinating form of EAE, while adoptive transfer of MBP-reactive T-cell clones or active immunization with MBP produces only modest inflammation unaccompanied by demyeli-nation,46 unless anti-MOG antibody is administered sytemically.47 Immunization of marmosets with MOG induces demyelinating EAE identical to that induced by immunization with CNS white matter homogenate,47 and which can be exacerbated if the production of the pathogenic anti-MOG antibodies is enhanced.48 Further convincing evidence linking demyelination with anti-MOG antibodies in marmoset EAE was obtained in marmosets immunized with MP4, a chimeric molecule composed of the human 21.5-kDa isoform of MBP and APLP4, a recombinant form of human PLP lacking the hydrophobic domains. Severe symptomatic EAE developed in these animals and histopathological analysis revealed that lesions induced by MP4 could be either demyelinating or purely inflammatory, and that, while all animals developed significant titers of anti-MBP antibodies, a determinant spreading of the humoral response to MOG had occurred in all animals which exhibited demyelinating lesions, while animals with non-demyelinating disease did not develop antibodies against MOG.49 That anti-MOG antibodies in MOG-induced EAE in marmosets are likely to be directly involved in myelin damage was recently suggested by in situ demonstration of MOG-specific auto-antibodies using gold-conjugated MOG peptides comprising epitopes located within amino acids 1-20, 21-40 and 61-80.50 It is interesting to note that in severe demyelinating EAE induced by MOG in rhesus monkeys, non-human primates closely related to humans immunologically, anti-MOG antibodies, which appear early after immunization, also recognize epitopes within these MOG regions.51 Altogether, these data strongly implicate a role for anti-MOG antibodies as mediators of demyelination in EAE. It should, however, be noted that antibody-independent mechanisms of autoimmune demyeli-nation exist, as demonstrated by recent studies with B-cell-deficient mice in which neither B-cells nor antibodies can be detected, and which developed EAE with primary demyelination upon immunization with the encephalitogenic MOG 35-55 peptide.52,53 Of interest, and not fully understood, was the finding in one of these studies that while B-cell-deficient mice are susceptible to EAE induced by
MOG 35-55, they neither develop clinical disease nor show significant CNS pathology when immunized with the 120-amino acid-long recombinant MOG.53
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