Antigen presentation, but not antibody secretion, by B cells drives CNS autoimmunity induced by immunization with human MOG.

Objective Clinical studies indicate that anti-CD20 B cell depletion may be an effective multiple sclerosis therapy. We investigated mechanisms of its immune modulation using two paradigms of experimental autoimmune encephalomyelitis (EAE). Methods Murine EAE was induced by either recombinant myelin oligodendrocyte glycoprotein (rMOG), a model in which B cells are considered to contribute pathogenically, or MOG peptide (p)35–55, a model that does not require B cells. Results In EAE induced by rMOG, B cells became activated and, when serving as antigen presenting cells (APC), promoted differentiation of proinflammatory MOG-specific Th1 and Th17 cells. B cell depletion prevented or reversed established rMOG-induced EAE, which was associated with less CNS inflammation, elimination of meningeal B cells, and reduction of MOG-specific Th1 and Th17 cells. In contrast, in EAE induced by MOG p35–55, B cells did not become activated or efficiently polarize proinflammatory MOG-specific T cells, similar to naïve B cells. In this EAE setting, anti-CD20 treatment exacerbated EAE, and did not impede development of Th1 or Th17 cells. Irrespective of the EAE model used, B cell depletion reduced the frequency of regulatory T cells, and increased the capacity of remaining APC to promote development of encephalitogenic T cells. Interpretation Our study highlights distinct roles for B cells in pathogenesis and regulation of CNS autoimmune disease. Clinical benefit from depletion of antigen-activated B cells may relate primarily to abrogation of proinflammatory B cell APC function. However, in certain clinical settings, elimination of unactivated B cells, which participate in regulation of T cells and other APC, may be undesirable.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by localized areas of demyelination. Although the etiology and pathogenesis of MS remain largely unknown, it is generally assumed that immune responses to myelin antigens contribute to the disease process. The exact sequence of events, as well as the molecular mediators that lead to myelin destruction, is yet to be defined. As a potent mediator of inflammation, the cytopathic cytokine, tumor necrosis factor (TNF) has been considered to be a strong candidate in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). However, its role in immune-mediated demyelination remains to be elucidated. To determine the contribution of TNF to the pathogenesis of the MS-like disease provoked by the myelin oligodendrocyte glycoprotein (MOG), we have tested mice with an homologous disruption of the gene encoding TNF. Here we report that upon immunization with MOG, mice lacking TNF develop severe neurological impairment with high mortality and extensive inflammation and demyelination. We show further that inactivation of the TNF gene converts MOG-resistant mice to a state of high susceptibility. Furthermore, treatment with TNF dramatically reduces disease severity in both TNF-/- mice and in other TNF+/+ mice highly susceptible to the MOG-induced disease. These findings indicate that TNF is not essential for the induction and expression of inflammatory and demyelinating lesions, and that it may limit the extent and duration of severe CNS pathology.

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.

While neuromyelitis optica (NMO) immunoglobulin (Ig) G is considered the hallmark serologic marker of NMO, its association is not absolute, as NMO IgG is not detected in approximately one-fourth of the patients diagnosed with NMO spectrum disorder (NMOSD). Thus, the recent discovery that antibodies to myelin oligodendrocyte glycoprotein (MOG) are detected in some NMO IgG-seronegative patients manifesting clinical and neuroimaging signs of NMO or NMOSD has created tremendous excitement. However, it may be premature to classify this subgroup as NMOSD. NMO is considered an autoimmune astrocytopathy, and aquaporin-4 (AQP4), expressed on astrocytes, is recognized as the target autoantigen of NMO IgG. As its name denotes, MOG is produced by oligodendrocytes, CNS myelin-producing cells, and MOG is well-recognized as one of the candidate autoantigens in multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM). Thus, is it possible that the clinical NMOSD-like phenotype associated with MOG-specific antibodies represents a variant of opticospinal MS or ADEM but not AQP4 autoimmunity or NMOSD? Whether this MOG-Ig positive AQP4-seronegative phenotype should be classified as NMOSD, opticospinal MS, or a unique entity is not simply a theoretical question but rather has practical implications for patients, their physicians, insurance carriers, and clinical investigators conducting NMO treatment trials.