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

Abstract

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.

Oligodendrocyte‐specific protein is encephalitogenic in rhesus macaques and induces specific demyelination of the optic nerve

“…OSP mRNA and protein expression profiles demonstrate that OSP is present in Sertoli cells in the testis and in interlamellar strands of myelin sheaths throughout the CNS in mice [16,18,19,29], and OSP -/-mice are characterized by impaired CNS nerve conduction and not by optical problems [30]. In addition, optic neuritis has been reported to occur spontaneously in MOG-specific T cell receptor transgenic mice [31] and can be induced by immunization with MOG [32]. The notion that MOG-specific T cells can lead to spontaneous optic neuritis, without infiltrating the CNS where their target is also expressed, suggests that the optic nerve is vulnerable to T cell infiltration.…”

An MHC anchor‐substituted analog of myelin oligodendrocyte glycoprotein 35–55 induces IFN‐γ and autoantibodies in the absence of experimental autoimmune encephalomyelitis and optic neuritis

“…In this study, we show that immunization with 45D results in the generation of T cells that are hypo-proliferative in response to antigen and do not induce EAE or optic neuritis, a potentially more sensitive indicator of the activation of autoreactive T cells [11]. However, these cells are able to secrete IFN-+ upon MOG 35-55 stimulation.…”

“…We observed no symptoms of clinical EAE in the 45D-immunized mice ( [22], Fig. 1A), even up to 180 days post-immunization (data not shown Based on evidence that optic neuritis is an early and more easily induced symptom of the activation of MOG 35-55-specific T cells [11], we used the development of optic neuritis as a potentially more sensitive indicator of the activation of MOG 35-55-specific responses and the ability of 45D-primed T cells to mediate pathology. Our data indicate that C57BL/6 mice immunized with MOG 35-55 develop optic neuritis (Fig.…”

“…The optic nerve may also express increased levels of MOG relative to the spinal cord, suggesting that the increased amount of antigen may facilitate the early activation of self-reactive T cells. In support of this possibility, Bettelli et al found that immunization of B6 mice with a suboptimal dose of MOG 35-55 resulted in optic neuritis alone, while the full immunization regimen resulted in optic neuritis in addition to fulminant EAE [11].…”

“…Optic nerve lesions have also been reported in EAE [8][9][10], and may represent an early event in the progression of anti-myelin immune responses [11]. The optic nerve may also express increased levels of MOG relative to the spinal cord, suggesting that the increased amount of antigen may facilitate the early activation of self-reactive T cells.…”