Native Myelin Oligodendrocyte Glycoprotein Research Articles

The crystal structure of myelin oligodendrocyte glycoprotein, a key autoantigen in multiple sclerosis.

Myelin oligodendrocyte glycoprotein (MOG) is a key CNS-specific autoantigen for primary demyelination in multiple sclerosis. Although the disease-inducing role of MOG has been established, its precise function in the CNS remains obscure. To gain new insights into the physiological and immunopathological role of MOG, we determined the 1.8-A crystal structure of the MOG extracellular domain (MOGED). MOGED adopts a classical Ig (Ig variable domain) fold that was observed to form an antiparallel head-to-tail dimer. A dimeric form of native MOG was observed, and MOGED was also shown to dimerize in solution, consistent with the view of MOG acting as a homophilic adhesion receptor. The MOG35-55 peptide, a major encephalitogenic determinant recognized by both T cells and demyelinating autoantibodies, is partly occluded within the dimer interface. The structure of this key autoantigen suggests a relationship between the dimeric form of MOG within the myelin sheath and a breakdown of immunological tolerance to MOG that is observed in multiple sclerosis.

Requirement for endocytic antigen processing and influence of invariant chain and H-2M deficiencies in CNS autoimmunity.

The role of processing in antigen (Ag) presentation and T cell activation in experimental allergic encephalomyelitis (EAE) was evaluated in wild-type mice, mice that selectively express either Ii p31 or p41, and mice completely deficient in Ii or H-2M. We demonstrate that processing of myelin oligodendrocyte glycoprotein (MOG) is required for presentation of the dominant encephalitogenic MOG epitope, p35-55. Ii p31- and p41-expressing mice developed EAE with similar incidence to wild-type mice, although p41 mice had a more severe course. Ag-presenting cells (APCs) from Ii- or H-2M-deficient mice could present p35-55, but not MOG, demonstrating that these APCs could not process native MOG. Ii- and H-2M-deficient mice were not susceptible to EAE by immunization with p35-55 or MOG or by adoptive transfer of encephalitogenic T cells. However, CD4+ T cells from p35-55-immunized H-2M-deficient mice proliferated, secreted IFN-gamma, and transferred EAE to wild-type, but not H-2M-deficient, mice. Thus, EAE resistance in H-2M-deficient mice is not due to an inability of APCs to present p35-55, or an intrinsic defect in the encephalitogenic T cell repertoire, but reflects a defect in APC function. Our results indicate that processing is required for initial Ag presentation and CNS T cell activation and suggest that autopathogenic peptides of CNS autoantigen may not be readily available for presentation without processing.

Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: reactivity to the extracellular domain of MOG is directed against three main regions.

Our previous analysis of the T cell reactivity to myelin antigens in a group of 24 patients with multiple sclerosis (MS) and 16 control individuals revealed that the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) predominates in MS over that to myelin basic protein (MBP), proteolipid protein or myelin-associated glycoprotein, suggesting a prevalent role for the autoimmune response to MOG in the pathogenesis of MS. Using a recombinant human MOG (rhMOG) preparation corresponding to the extracellular immunoglobulin-like domain of the MOG molecule, we have now analyzed another group of 52 MS patients and 49 control individuals for reactivity of their peripheral blood lymphocytes (PBL) to rhMOG and to MBP concomitantly. Of the 52 MS patients tested 24 responded to MOG and 10 out of 49 responded to MBP, whereas only 5 MOG-reactive and 4 MBP-reactive control individuals were detected out of the 49 tested. These results are therefore highly confirmatory of the predominant reactivity to MOG in MS. The analysis of the primary proliferative response to 11 synthetic overlapping peptides (phMOG) spanning the extracellular domain of human MOG by PBL from 9 MS patients and 15 control individuals (9 healthy controls and 6 patients with neurological diseases other than MS) further supports a prevalent role for the autoimmune response to MOG in MS, as only 1 of the 15 controls tested showed reactivity to any of the phMOG, whilst 5 out of the 9 patients studied reacted to at least 1 of the phMOG. PBL from 10 MS patients, and from 4 controls, were selected in vitro with each of the phMOG. Of the 10 patients studied 7 reacted to at least 1 phMOG upon secondary stimulation and the reactivity was mostly directed to epitopes localized within three main regions (amino acids 1-22, 34-56 and 64-96), as was observed for the primary response of PBL. The predominant response to MOG of PBL from MS patients as demonstrated in two separate studies using native MOG and rhMOG as antigens, and the high incidence of reactivity of these PBL compared to the lack of response to phMOG by control PBL, emphasize the relevance of MOG in MS pathogenesis and support a primary role for the autoimmune T cell response to MOG in disease development.

Myelin oligodendrocyte glycoprotein: a novel candidate autoantigen in multiple sclerosis.

Myelin oligodendrocyte glycoprotein (MOG) is a member of the immunoglobulin superfamily expressed exclusively in central nervous system (CNS) myelin. While the function of MOG is unknown, a number of studies have shown that immune responses to MOG contribute to the autoimmune-mediated demyelination seen in animals immunized with whole CNS tissue. This paper summarizes our recent studies, which unequivocally demonstrate that MOG by itself is able to generate both an encephalitogenic T cell response and an autoantibody response in Lewis rats and in several strains of mice. In Lewis rats the injection of both native MOG and MOG35-55 peptide produces a paralytic relapsing-remitting neurological disease with extensive plaque-like demyelination. The antibody response to MOG35-55 was highly restricted, as no reactivity to either other MOG peptides or myelin proteins could be detected. Fine epitope mapping showed that antibody from serum and cerebrospinal fluid of injected rats reacted strongly to MOG37-46, which is contiguous to the dominant T cell epitope contained within MOG44-55. NOD/Lt and C57BL/6 mice were also susceptible to severe neurological disease following injection with recombinant MOG or MOG35-55 peptide, indicating that this specific CNS autoantigen, or some of its determinants, can induce a pathogenic response across animal species. Severe paralysis and extensive demyelination were seen in both strains, but NOD/Lt mice experienced a chronic relapsing disease whereas C57BL/6 mice had a chronic non-remitting disease. Moreover, transfer of MOG35-55 T cells into naive NOD/Lt mice also produced severe neurological impairment as well as histological lesions. These results emphasize that a synergism between a T cell-response and anti-MOG antibodies may be important for the development of severe demyelinating disease. This, together with our demonstration that there is a predominant T cell response to MOG in patients with multiple sclerosis, clearly indicates that MOG is probably an important target autoantigen in this disease.

Analysis of the fine B cell specificity during the chronic/relapsing course of a multiple sclerosis-like disease in Lewis rats injected with the encephalitogenic myelin oligodendrocyte glycoprotein peptide 35-55.

We have recently shown that a single injection of myelin oligodendrocyte glycoprotein (MOG), or the MOG35-55 peptide, produces a relapsing-remitting neurologic disease with extensive plaque-like demyelination. Given the features that this new autoimmune demyelinating model has in common with the clinicopathologic manifestations of multiple sclerosis, we have examined the Ab reactivity to native MOG and MOG35-55 peptide during the course of the disease in Lewis rats. Following immunization with MOG35-55, varied clinical symptoms were observed; these included hind and foreleg paralysis and various degrees of balance impairment. Disease progression also varied: 3 out of 21 animals had a single mild disease episode; 4 out of 21 had a mild relapsing-remitting disease; and 14 out of 21 had severe relapsing-remitting disease. Ab reactivity to MOG35-55 and native MOG was first detected in all rats 4 wk postimmunization and persisted throughout the 12 wk of observation. The Ab response was highly restricted with no reactivity to other peptides encompassing different extracellular segments of MOG. Fine epitope mapping showed that Ab from serum and cerebrospinal fluid of injected rats reacted strongly to MOG37-46 and to a lesser extent to MOG43-50. Although significant levels of anti-MOG Abs appeared necessary for the development of demyelinating lesions, their presence in blood and cerebrospinal fluid alone was not sufficient to produce severe clinical symptoms. These results demonstrate that the MOG35-55 peptide is highly encephalitogenic and can induce strong T and B cell responses. It is probably the complex interaction between these T and B cells that determines the severity of disease in individual rats.

Antibody response in Lewis rats injected with myelin oligodendrocyte glycoprotein derived peptides.

Previous studies from our laboratory have demonstrated a predominant response to myelin oligodendrocyte glycoprotein (MOG) in patients with multiple sclerosis (MS) and showed that this molecule is able to induce in Lewis rats a chronic relapsing MS-like disease with extensive demyelination. To further study the possibility that MOG is a primary target antigen in MS, we have begun to investigate the encephalitogenicity and antibody response of different sequences of the extracellular domains of MOG in Lewis rats. We report that none of the synthetic peptides encompassing the MOG amino acid sequences 1-21, 67-87, 104-117 and 202-218 were encephalitogenic. In contrast, a single injection of MOG35-55 was able to induce severe neurological signs associated with inflammation and demyelination. All rats injected with MOG peptides 1-21, 35-55, 67-87 and 202-218 developed a high level of antibodies to their respective immunizing peptides as detected by ELISA and immunoblotting. Although all MOG peptide antisera reacted with immunoblots of native MOG separated under reducing conditions, only anti-MOG35-55 and anti-MOG202-218 antibodies reacted to native MOG, when tested under nonreducing conditions. These results indicate that the MOG35-55 peptide, which is found in the extracellular Ig V-like domain of MOG, is not only an encephalitogenic epitope but could also be an important determinant for initiating antibody-mediated demyelination. As indicated by the absence of reactivity to the other MOG peptides tested, as well as other central nervous system myelin proteins including myelin basic protein and proteolipid protein, the antibody response produced by MOG peptides is highly restricted.