Anti-myelin oligodendrocyte glycoprotein antibodies in multiple sclerosis.

Can serum antibodies to myelin oligodendrocyte glycoprotein (MOG) be used as a marker of multiple sclerosis (MS) or to predict the course of MS? Recent articles present conflicting data in response to these questions. Berger et al.1 tested for presence of serum antibodies to MOG in patients experiencing a first clinically isolated syndrome suggestive of MS. Those who progressed almost invariably had anti-MOG antibodies. Conversely, Lampasona et al.2 in this issue of Neurology report only low levels of anti-MOG antibodies in patients with MS and control subjects. Autoantibodies to many myelin constituents are present in patients with MS. These antibodies may be an autoimmune reaction to an “MS antigen” or simply part of a generalized “nonsense” antibody response. In either case, the antibodies may affect the pathology of MS. Potential myelin autoantigens include myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), 2',3'cyclic nucleotide 3'-phosphodiesterase, and MOG. Because MBP accounts for ~30% of central myelin protein, it has traditionally been viewed as the major target for immune responses in MS and experimental allergic encephalomyelitis (EAE). However, MBP and PLP are in compact myelin and not easily accessible to the immune system. Although MOG is only a minor constituent of myelin proteins (at most 0.05%), this 218-amino acid glycoprotein may be an important immune target in MS. MOG is unique to the brain; it is located on the outer lamellae of oligodendroglial membranes and myelin; it is highly immunogenic; and MOG immunization induces severe relapsing EAE in rodents and marmosets.3 The extracellular portion of MOG protein is the dominant target in EAE induced by brain homogenates. It is recognized by encephalitogenic T cells and antibodies, with these two arms of immunity synergizing to cause CNS destruction. IV anti-MOG antibodies convert EAE from a nondemyelinating, moderately inflammatory disease to a severe inflammatory disease with extensive demyelination.3 T cells proliferate to MOG more than to other myelin antigens in patients with MS.4 Anti-MOG antibodies fix complement and are bound to disintegrating myelin in acute MS lesions.5 Anti-MOG antibodies are present in serum and CSF of one-third of patients at the time of their first attack of MS.6 The antibodies persist at a stable titer (usually 1:1000 to 1:2000) and are present at the same frequency in all stages of MS. More than two-thirds of patients with MS have T cells in the blood that proliferate when exposed to purified human MOG; in the CSF, T cells from 12 of 14 patients were responsive.7 There are also immunoglobulin (Ig) G anti-MOG responses in viral and bacterial meningitis. However, these antibodies disappear as the meningitis resolves, but the CSF anti-MOG index is persistently higher in MS. Why do these results seem to conflict with those of Lampasona et al.?2 A difference in patient populations is unlikely because the MOG response seems to be present in all forms and all stages of MS in multiple studies. Technical differences are more likely and suggest important immune principles in MS. Berger et al.1 used the first 102 N-terminal amino acids of recombinant human MOG, expressed in Escherichia coli, as the antigen in their Western blot analyses and previous ELISAs.6 Sugar groups are missing from the recombinant molecule, yet MOG is a brain glycoprotein. When antigens are directly isolated or expressed in mammalian cells,2 they are glycosylated; when they are expressed in bacteria, as in the report of Berger et al.,1 sugar moieties are lost. Glycosylated proteins conserve their tertiary structure better, and tertiary structure is necessary for antibody binding. Sugars can also protect some otherwise hidden antibody-binding sites. Therefore, glycosylated and unglycosylated proteins may have different antibody-binding patterns. Smaller unglycosylated MOG peptides have varying antigenicity. Sera from patients with MS bind to several members of a panel of overlapping 25 amino acid peptides; however, the same sera do not bind to native MOG on the oligodendrocyte surface.8 Antibodies induced by vaccination with DNA encoding