Christopher Linington

Multiple Sclerosis and Chronic Autoimmune Encephalomyelitis : A Comparative Quantitative Study of Axonal Injury in Active, Inactive, and Remyelinated Lesions

Recent magnetic resonance (MR) studies of multiple sclerosis lesions indicate that axonal injury is a major correlate of permanent clinical deficit. In the present study we systematically quantified acute axonal injury, defined by immunoreactivity for beta-amyloid-precursor-protein in dystrophic neurites, in the central nervous system of 22 multiple sclerosis patients and 18 rats with myelin-oligodendrocyte glycoprotein (MOG)-induced chronic autoimmune encephalomyelitis (EAE). The highest incidence of acute axonal injury was found during active demyelination, which was associated with axonal damage in periplaque and in the normal appearing white matter of actively demyelinating cases. In addition, low but significant axonal injury was also observed in inactive demyelinated plaques. In contrast, no significant axonal damage was found in remyelinated shadow plaques. The patterns of axonal pathology in chronic active EAE were qualitatively and quantitatively similar to those found in multiple sclerosis. Our studies confirm previous observations of axonal destruction in multiple sclerosis lesions during active demyelination, but also indicate that ongoing axonal damage in inactive lesions may significantly contribute to the clinical progression of the disease. The results further emphasize that MOG-induced EAE may serve as a suitable model for testing axon-protective therapies in inflammatory demyelinating conditions.

Myelin Oligodendrocyte Glycoprotein–specific T Cell Receptor Transgenic Mice Develop Spontaneous Autoimmune Optic Neuritis

Multiple sclerosis (MS) is considered to be an autoimmune disease of the central nervous system (CNS) that in many patients first presents clinically as optic neuritis. The relationship of optic neuritis to MS is not well understood. We have generated novel T cell receptor (TCR) transgenic mice specific for myelin oligodendrocyte glycoprotein (MOG). MOG-specific transgenic T cells are not deleted nor tolerized and are functionally competent. A large proportion (>30%) of MOG-specific TCR transgenic mice spontaneously develop isolated optic neuritis without any clinical nor histological evidence of experimental autoimmune encephalomyelitis (EAE). Optic neuritis without EAE could also be induced in these mice by sensitization with suboptimal doses of MOG. The predilection of these mice to develop optic neuritis is associated with higher expression of MOG in the optic nerve than in the spinal cord. These results demonstrate that clinical manifestations of CNS autoimmune disease will vary depending on the identity of the target autoantigen and that MOG-specific T cell responses are involved in the genesis of isolated optic neuritis.

Autoimmunity to Myelin Oligodendrocyte Glycoprotein in Rats Mimics the Spectrum of Multiple Sclerosis Pathology

Multiple sclerosis is a chronic inflammatory disease characterized by perivenous inflammation and focal destruction of myelin. Many attempts have been undertaken previously to create animal models of chronic inflammatory demyelinating diseases through autoimmunity or virus infection. Recently, however, a new model of myelin oligodendrocyte glycoprotein (MOG) induced autoimmune encephalomyelitis became available, which, in a very standardized and predictable way, leads to chronic (relapsing or progressive) disease and widespread CNS demyelination.

Neurofascin as a novel target for autoantibody-mediated axonal injury

Axonal injury is considered the major cause of disability in patients with multiple sclerosis (MS), but the underlying effector mechanisms are poorly understood. Starting with a proteomics-based approach, we identified neurofascin-specific autoantibodies in patients with MS. These autoantibodies recognize the native form of the extracellular domains of both neurofascin 186 (NF186), a neuronal protein concentrated in myelinated fibers at nodes of Ranvier, and NF155, the oligodendrocyte-specific isoform of neurofascin. Our in vitro studies with hippocampal slice cultures indicate that neurofascin antibodies inhibit axonal conduction in a complement-dependent manner. To evaluate whether circulating antineurofascin antibodies mediate a pathogenic effect in vivo, we cotransferred these antibodies with myelin oligodendrocyte glycoprotein–specific encephalitogenic T cells to mimic the inflammatory pathology of MS and breach the blood–brain barrier. In this animal model, antibodies to neurofascin selectively targeted nodes of Ranvier, resulting in deposition of complement, axonal injury, and disease exacerbation. Collectively, these results identify a novel mechanism of immune-mediated axonal injury that can contribute to axonal pathology in MS.

Late complications of immune deviation therapy in a nonhuman primate.

The administration of antigens in soluble form can induce antigen-specific immune tolerance and suppress experimental autoimmune diseases. In a marmoset model of multiple sclerosis induced by myelin oligodendrocyte glycoprotein (MOG), marmosets tolerized to MOG were protected against acute disease, but after tolerization treatment a lethal demyelinating disorder emerged. In these animals, MOG-specific T cell proliferative responses were transiently suppressed, cytokine production was shifted from a T helper type 1 (TH1) to a TH2 pattern, and titers of autoantibodies to MOG were enhanced. Thus, immune deviation can increase concentrations of pathogenic autoantibodies and in some circumstances exacerbate autoimmune disease.

Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate.

In the human disease multiple sclerosis (MS), the immune mechanisms responsible for selective destruction of central nervous system myelin are unknown. In the common marmoset Callithrix jacchus, a unique demyelinating form of experimental allergic encephalomyelitis resembling MS can be induced by immunization with whole myelin. Here we show that the MS-like lesion can be reproduced by immunization against the extracellular domain of a single myelin protein, myelin/oligodendrocyte glycoprotein (MOG). By contrast, immunization against the quantitatively major myelin proteins myelin basic protein or proteolipid protein results in inflammation but little or no demyelination. Furthermore, in the presence of encephalitogenic (e.g., disease-inducing) T cells, the fully demyelinated lesion is reconstructed by systemic administration of IgG purified from whole myelin-, or MOG-immunized animals, and equally by a monoclonal antibody against MOG, but not by control IgG. Encephalitogenic T cells may contribute to the MS-like lesion through disruption of the blood-brain barrier that permits access of demyelinating antibody into the nervous system. The identification of MOG as a major target antigen for autoimmune demyelination in a nonhuman primate should facilitate development of specific immunotherapies for human MS.

Inhibition of autoimmune encephalomyelitis by a tetracycline

We have explored the use of minocycline, a tetracycline with antiinflammatory properties, to treat chronic relapsing‐remitting experimental allergic encephalomyelitis, an animal model of multiple sclerosis. Therapeutic treatment with minocycline dramatically suppresses ongoing disease activity and limits disease progression. Disease suppression is associated with immune deviation in the periphery and with suppression of the inflammatory cascade in the central nervous system. This association is demonstrated by inhibition of microglial activation and metalloproteinase‐2 expression, which results in a concomitant decrease in inflammation and demyelination. As an established antiinflammatory drug with neuroprotective properties, minocycline may provide a novel therapeutic agent for relapsing‐remitting multiple sclerosis.

MHC haplotype-dependent regulation of MOG-induced EAE in rats.

Experimental autoimmune encephalomyelitis (EAE) induced in the rat by active immunization with myelin-oligodendrocyte-glycoprotein (MOG) is mediated by synergy between MOG-specific T cells and demyelinating MOG-specific antibody responses. The resulting disease is chronic and displays demyelinating central nervous system (CNS) pathology that closely resembles multiple sclerosis. We analyzed major histocompatibility complex (MHC) haplotype influences on this disease. The MHC haplotype does not exert an all-or-none effect on disease susceptibility. Rather, it determines the degree of disease susceptibility, recruitment of MOG-specific immunocompetent cells, clinical course, and CNS pathology in a hierarchical and allele-specific manner. Major haplotype-specific effects on MOG-EAE map to the MHC class II gene region, but this effect is modified by other MHC genes. In addition, non-MHC genes directly influence both disease and T cell functions, such as the secretion of IFN-gamma. Thus, in MOG-EAE, allelic MHC class II effects are graded, strongly modified by other MHC genes, and overcome by effects of non-MHC genes and environment.

T‐ and B‐cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis

The identification of myelin oligodendrocyte glycoprotein (MOG) as a target for autoantibody‐mediated demyelination in experimental autoimmune encephalomyelitis (EAE) resulted in the re‐evaluation of the role of B cell responses to myelin autoantigens in the immunopathogenesis of multiple sclerosis. MOG is a central nervous system specific myelin glycoprotein that is expressed preferentially on the outermost surface of the myelin sheath. Although MOG is only a minor component of CNS myelin it is highly immunogenic, inducing severe EAE in both rodents and primates. In rat and marmoset models of MOG‐induced EAE demyelination is antibody‐dependent and reproduces the immunopathology seen in many cases of MS. In contrast, in mice inflammation in the CNS can result in demyelination in the absence of a MOG‐specific B cell response, although if present this will enhance disease severity and demyelination. Clinical studies indicate that autoimmune responses to MOG are enhanced in many CNS diseases and implicate MOG‐specific B cell responses in the immunopathogenesis of multiple sclerosis. This review provides a summary of our current understanding of MOG as a target autoantigen in EAE and MS, and addresses the crucial question as to how immune tolerance to MOG may be maintained in the healthy individual. GLIA 36:220–234, 2001.

The N-terminal domain of the myelin oligodendrocyte glycoprotein (MOG) induces acute demyelinating experimental autoimmune encephalomyelitis in the Lewis rat

Using a highly purified recombinant protein, mMOG, we demonstrated that autoimmune responses to the N-terminal domain (a.a 1-125) of the myelin oligodendrocyte glycoprotein (MOG) induce an acute demyelinating variant of experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. Immunisation with 100 micrograms of mMOG in adjuvant at the base of the tail induced mild clinical disease in 9 of 11 animals (mean clinical score 1.1). The disease was characterised histopathologically by the presence of inflammation and focal demyelinating lesions in the central nervous system (CNS). Adoptive transfer experiments suggest that this inflammatory demyelinating pathology is mediated by synergy between a weakly encephalitogenic, MOG-specific T cell response and a demyelinating, MOG-specific autoantibody response. Using in vitro selected mMOG-reactive T cell lines, the encephalitogenic T cell response to this domain of MOG was found to recognise two distinct epitopes, MOG1-20 and MOG35-55; whereas ELISA demonstrated that the immunodominant B cell epitope was located within the amino acid sequence MOG1-25. However although active immunisation with synthetic peptides corresponding to the T cell epitopes, MOG1-20 or MOG35-55, induced an inflammatory response in the CNS, this was not associated with demyelination indicating that the demyelinating antibody response recognises other, possibly conformation dependent epitopes. This study unequivocally demonstrates that MOG-specific autoimmune responses are alone sufficient to induce a demyelinating disease of the CNS and supports the proposal that MOG may play an important role in the immunopathogenesis of multiple sclerosis.