Characterization of leptomeningeal inflammation in rodent experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.

BACKGROUND: Leptomeningeal inflammation, as evidenced by leptomeningeal contrast enhancement (LMCE), is associated to cortical pathology in multiple sclerosis. The temporal pattern of LMCE in experimental autoimmune encephalomyelitis (EAE) myelin oligodendrocyte glycoprotein (MOG) is unknown. OBJECTIVE: To investigate LMCE using serial MRI in the EAE model of MS, and its association with clinical disease progression. To characterize the relationship between LMCE and underlying histological correlates. DESIGN: Thirteen C57BL/6J mice, MOG-immunized (35-55 amino acid) and 8 saline injected animals were assessed at pre-induction and at 3, 6, 10, 20, 27, 32, 45 and 63 days post induction (dPI). LMCE scan was obtained using FLAIR-RARE sequence after post-contrast gadolinium administration on 9.4 T scanner. Brain cryo-sections were assessed for measuring cellular density of Iba1 positive macrophage/microglia at 10 dPI and 32 dPI, and for the presence of T, B and macrophage cells in the meningeal layer at 10 dPI and 63 dPI. RESULTS: All EAE-MOG animals showed presence of LMCE and none of the control mice. The peak signal intensity of LMCE was evidenced at 10dPI in the meninges and decreased through 10-63 dPI. The peak of LMCE was associated with a weight loss starting at 1 week PI and with clinical symptoms starting at 2 weeks PI. Histological analysis of the brain tissue showed a higher density of Iba1 positive microglial cells in the EAE-MOG animals, corresponding to the areas of LMCE. Meninges of EAE mice showed higher density of Iba1 stained macrophage cells relative to saline animals. EAE animals also showed the presence of T and B cells in the meninges which were absent in the saline animals. CONCLUSIONS: LMCE peak intensity in the meninges corresponds to the acute inflammatory phase of EAE-MOG disease progression, and is associated with clinical symptoms and higher inflammatory cell density.

ESC-derived thymic epithelial cells expressing MOG prevents EAE by central and peripheral tolerance mechanisms.

Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS), and is induced by immunization with disease-causative self-antigens such as myelin oligodendrocyte glycoprotein (MOG). We have previously reported that transplantation of MOG expressing thymic epithelial progenitors (TEPs) derived from 129S6SvEv Tac mouse embryonic stem cells (mESCs) prevented the development of EAE. In this study, we expand our previous studies to show that transplantation of MOG expressing mESC-TEPs derived from C57BL/6 mice also prevents EAE development. Furthermore, by using a MOG-specific T cell receptor (TCR) transgenic mouse model, we demonstrate that both central and peripheral tolerances are involved in the prevention of EAE induced by MOG expressing mESC-TEPs. Our results suggest that transplantation of human ESC-TEPs expressing MOG may provide an effective approach for the induction of MOG-specific immune tolerance, thereby the prevention and treatment of MS.

Correlation between antibodies to bisphenol A, its target enzyme protein disulfide isomerase and antibodies to neuron-specific antigens.

Evidence continues to increase linking autoimmunity and other complex diseases to the chemicals commonly found in our environment. Bisphenol A (BPA) is a synthetic monomer used widely in many forms, from food containers to toys, medical products and many others. The potential for BPA to participate as a triggering agent for autoimmune diseases is likely due to its known immunological influences. The goal of this research was to determine if immune reactivity to BPA has any correlation with neurological antibodies. BPA binds to a target enzyme called protein disulfide isomerase (PDI). Myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) are neuronal antigens that are target sites for neuroinflammation and neuroautoimmunity. We determined the co-occurrence of anti-MBP and anti-MOG antibodies with antibodies made against BPA bound to human serum albumin in 100 healthy human subjects. Correlation between BPA to PDI, BPA to MOG, BPA to MBP, PDI to MBP and PDI to MOG were all highly statistically significant (P < 0.0001). The outcome of our study suggests that immune reactivity to BPA-human serum albumin and PDI has a high degree of statistical significance with substantial correlation with both MBP and MOG antibody levels. This suggests that BPA may be a trigger for the production of antibodies against PDI, MBP and MOG. Immune reactivity to BPA bound to human tissue proteins may be a contributing factor to neurological autoimmune disorders. Further research is needed to determine the exact relationship of these antibodies with neuroautoimmunities. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd.

Administration of leukemia inhibitory factor increases Opalin and myelin oligodendrocyte glycoprotein expression in the cerebral cortex in a cuprizone-induced model of demyelination.

Multiple sclerosis (MS) lesions are characterized by inflammatory demyelination and reactive gliosis, and although remyelination occurs in some lesions it is limited and incomplete. Leukemia inhibitory factor (LIF) is an important cytokine that stimulates oligodendrocyte proliferation and survival in vitro. Opalin is a unique molecular marker for mature oligodendrocytes. The aim of this study was to demonstrate the role of LIF on Opalin and myelin oligodendrocyte glycoprotein (MOG) expression in the cerebral cortex of cuprizone-induced MS mice. The mice were treated with cuprizone for five weeks in order to induce MS. The mice were then divided into 3 groups. The first group was injected intraperitoneally (IP) with LIF for six weeks in the amount of 30 µg/kg bw per day. The second group (SHAM) was injected IP with normal saline and the third group was left without injection as a control. After six weeks the mice were killed, the cerebral cortex was harvested, and the expression of MOG and Opalin was studied. Using western blotting we found that LIF increases Opalin and MOG expression in the cerebral cortex extracts as compared to SHAM and control groups. However, no significant difference in the Opalin and MOG expression was seen between SHAM and control groups. It is concluded that LIF may have an important role in the process of remyelination by increasing Opalin expression and MOG expression.

Thymic gene transfer of myelin oligodendrocyte glycoprotein ameliorates the onset but not the progression of autoimmune demyelination.

Tolerance induction, and thus prevention of autoimmunity, is linked with the amount of self-antigen presented on thymic stroma. We describe that intrathymic (i.t.) delivery of the autoantigen, myelin oligodendrocyte glycoprotein (MOG), via a lentiviral vector (LV), led to tolerance induction and prevented mice from developing fulminant experimental autoimmune encephalomyelitis (EAE). This protective effect was associated with the long-term expression of antigen in transduced stromal cells, which resulted in the negative selection of MOG-specific T cells and the generation of regulatory T cells (Tregs). These selection events were effective at decreasing T-cell proliferative responses and reduced Th1 and Th17 cytokines. In vivo, this translated to a reduction in inflammation and demyelination with minimal, or no axonal loss in the spinal cords of treated animals. Significantly intrathymic delivery of MOG to mice during the priming phase of the disease failed to suppress clinical symptoms despite mice being previously treated with a clearing anti-CD4 antibody. These results indicate that targeting autoantigens to the thymic stroma might offer an alternative means to induce the de novo production of tolerant, antigen-specific T cells; however, methods that control the number and or the activation of residual autoreactive cells in the periphery are required to successfully treat autoimmune neuroinflammation.