Myelin/oligodendrocyte glycoprotein–deficient (MOG-deficient) mice reveal lack of immune tolerance to MOG in wild-type mice

Abstract

We studied the immunological basis for the very potent encephalitogenicity of myelin/oligodendrocyte glycoprotein (MOG), a minor component of myelin in the CNS that is widely used to induce experimental autoimmune encephalomyelitis (EAE). For this purpose, we generated a mutant mouse lacking a functional mog gene. This MOG-deficient mouse presents no clinical or histological abnormalities, permitting us to directly assess the role of MOG as a target autoantigen in EAE. In contrast to WT mice, which developed severe EAE following immunization with whole myelin, MOG-deficient mice had a mild phenotype, demonstrating that the anti-MOG response is a major pathogenic component of the autoimmune response directed against myelin. Moreover, while MOG transcripts are expressed in lymphoid organs in minute amounts, both MOG-deficient and WT mice show similar T and B cell responses against the extracellular domain of MOG, including the immunodominant MOG 35-55 T cell epitope. Furthermore, no differences in the fine specificity of the T cell responses to overlapping peptides covering the complete mouse MOG sequence were observed between MOG +/+ and MOG -/-mice. In addition, upon adoptive transfer, MOG-specific T cells from WT mice and those from MOG-deficient mice are equally pathogenic. This total lack of immune tolerance to MOG in WT C57BL/6 mice may be responsible for the high pathogenicity of the anti-MOG immune response as well as the high susceptibility of most animal strains to MOG-induced EAE.

Anatomy of T cell autoimmunity to myelin oligodendrocyte glycoprotein (MOG): Prime role of MOG44F in selection and control of MOG‐reactive T cells in H‐2b mice

“…Hence, the relatively diverse TCR repertoire associated with MOG-induced EAE could well result from escape of reactive T cells from negative thymic selection due to sequestration of MOG in the CNS as an immunoprivileged site [46] and to the relatively late expression of MOG during ontogeny. This possibility finds support in the demonstration that H-2 b MOG-knockout mice and wild-type mice immunized with MOG respond to MOG equally well and to the same immunodominant epitope [47]. In contrast, shiverer mice (MBP-deficient) on a BALB/c or C3H background responded well to MBP, while the wild-type mice were non-responsive [48,49].…”

Antibody Cross-Reactivity between Myelin Oligodendrocyte Glycoprotein and the Milk Protein Butyrophilin in Multiple Sclerosis

“…The expression of MOG protein outside the immunologically privileged environment of the CNS is controversial (37,38). However, if MOG is expressed in immune organs, recent studies using genetically manipulated MOG-deficient mice demonstrate that MOG itself is unable to induce immunological selftolerance (39). As a consequence, potentially pathogenic MOGreactive lymphocytes are retained within the healthy immune repertoire and may be activated due to mimicry with epitopes derived from environmental agents (8,19,40).…”

T Cell Repertoire Diversity Is Required for Relapses in Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

“…The MOG 113-127 (LKVE DPFYWVSPGVL), MOG 120 -134 (YWVSPGVLTLIALVP), MOG 183-197 (FVIVPVLGPLVALII) have been described as potential SD peptides of MOG (6). All peptides were produced by NEOSYSTEM.…”

“…TdT ϩ/ϩ , TdT ϩ/Ϫ , and TdT Ϫ/Ϫ littermates were immunized subcutaneously with 200 g of rMOG 1-118 or 100 g of murine MOG 35-55 in CFA containing 600 g of Mycobacterium tuberculosis H37RA (Difco Laboratories) according to a previously described protocol (6). For EAE induction, animals received additional i.v.…”

“…11, 12, and 13 were isolated, labeled with CFSE, and recalled in vitro with the ID peptides of MOG, MBP, PLP, and three different potential SD peptides of MOG (6). Splenocytes from EAE-suffering mice responded strongly to MOG 35-55 only (Fig.…”