Demyelinating Myelin Oligodendrocyte Glycoprotein-Specific Autoantibody Response Is Focused on One Dominant Conformational Epitope Region in Rodents

Abstract

Conformational epitopes of myelin oligodendrocyte glycoprotein (MOG) provide a major target for demyelinating autoantibodies in experimental autoimmune encephalomyelitis and recent studies indicate that a similar situation may exist in multiple sclerosis. We recently solved the crystal structure of the extracellular domain of MOG (MOGex) in complex with a Fab derived from the demyelinating mAb 8-18C5 and identified the conformational 8-18C5 epitope on MOG that is dominated by the surface exposed FG loop of MOG. To determine the importance of this epitope with regard to the polyclonal Ab response to MOGex we investigated the effects of mutating His103 and Ser104, the two central amino acids of the FG loop, on Ab binding. Mutation of these two residues reduced binding of a panel of eight demyelinating conformation-dependent mAbs to <20% compared with binding to wild-type MOGex, whereas substitution of amino acids that do not contribute to the 8-18C5 epitope had only a minor effect on Ab binding. The same restriction was observed for the polyclonal MOG-specific Ab response of MOG DNA-vaccinated BALB/c and SJL/J mice. Our data demonstrate that the pathogenic anti-MOG Ab response primarily targets one immunodominant region centered at the FG loop of MOG. Comparison of the structure of MOGex with the structures of related IgV-like domains yields a possible explanation for the focused Ab response.

Experimental Autoimmune Encephalomyelitis

“…Crystallographic studies have indicated that the region MOG 91-108 is accessible to antibodies (Breithaupt et al, 2008). In addition, we demonstrated by spectroscopic TCR analysis that depending on the expressed RT1 haplotype, the predominance of certain TCRBV chains was the same in rat strains with different non-MHC genomes underscoring the strong influence of the MHC II haplotype on TCRBV usage in the MOG model (de Graaf et al, 2008).…”

The Encephalitogenic, Human Myelin Oligodendrocyte Glycoprotein–Induced Antibody Repertoire Is Directed toward Multiple Epitopes in C57BL/6-Immunized Mice

“…Abs recognizing myelin oligodendrocyte glycoprotein (MOG) are of particular relevance because the extracellular Ig V-like domain of MOG is exposed on the outer lamellae of the myelin sheath (5,6), providing an appropriate target for Ab-mediated attack. Anti-MOG humoral responses in MS patients, nonhuman primates (marmosets), and rodent models of MS have therefore been extensively studied (3,4,(7)(8)(9)(10)(11)(12)(13)(14). However, the analysis of anti-MOG responses in humans has led to inconsistent results (3,4,(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

“…By contrast with BALB/c or SJL/J mice (7,(17)(18)(19), immunization of C57BL/6 mice with rat MOG (rMOG), which shares 95% homology with mouse MOG (mMOG), induces EAE that is B cell independent and does not involve a demyelinating Ab response (24)(25)(26). Interestingly, in human MOG (hMOG)-immunized C57BL/6 mice, EAE is dependent on B cells (24,27,28).…”

“…MOG-specific Abs that are elicited following immunization of BALB/c or SJL/J mice with rodent (mouse/rat) MOG or brain extract can have demyelinating activity (7,(17)(18)(19). For example, Abs such as the extensively characterized mouse monoclonal, 8-18C5, exacerbate experimental autoimmune encephalomyelitis (EAE) when transferred into autoantigen-immunized rats or mice (20,21).…”

“…For example, Abs such as the extensively characterized mouse monoclonal, 8-18C5, exacerbate experimental autoimmune encephalomyelitis (EAE) when transferred into autoantigen-immunized rats or mice (20,21). A feature of pathogenic, demyelinating Abs in both rodents and nonhuman primates (marmosets) is that they recognize native, but not denatured, MOG (7,11,18,22,23). Significantly, MOG recognition by demyelinating Abs induced by immunization of mice with MOG (rat, mouse, or bovine) has been reported to be critically dependent on residues in an exposed loop (the FG loop in the Ig V-like domain) of this autoantigen, leading to the conclusion that in rodents the pathogenic humoral response to MOG is centered on one immunodominant region (7).…”