Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells. J Exp Med

Department of Neuroimmunology, Max Planck Institute of Neurobiology, D-82152 Martinsried, Germany.
Journal of Experimental Medicine (Impact Factor: 12.52). 07/2009; 206(6):1303-16. DOI: 10.1084/jem.20090299
Source: PubMed


We describe new T cell receptor (TCR) transgenic mice (relapsing-remitting [RR] mice) carrying a TCR specific for myelin oligodendrocyte glycoprotein (MOG) peptide 92-106 in the context of I-A(s). Backcrossed to the SJL/J background, most RR mice spontaneously develop RR experimental autoimmune encephalomyelitis (EAE) with episodes often altering between different central nervous system tissues like the cerebellum, optic nerve, and spinal cord. Development of spontaneous EAE depends on the presence of an intact B cell compartment and on the expression of MOG autoantigen. There is no spontaneous EAE development in B cell-depleted mice or in transgenic mice lacking MOG. Transgenic T cells seem to expand MOG autoreactive B cells from the endogenous repertoire. The expanded autoreactive B cells produce autoantibodies binding to a conformational epitope on the native MOG protein while ignoring the T cell target peptide. The secreted autoantibodies are pathogenic, enhancing demyelinating EAE episodes. RR mice constitute the first spontaneous animal model for the most common form of multiple sclerosis (MS), RR MS.

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Available from: Helena Sofia Domingues, Feb 11, 2015
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    • "Lesion development in presymptomatic sRR-EAE In the sRR-EAE mice (TCR1640 transgenic) the disease develops spontaneously in the absence of immune boosters like the complete Freund's adjuvant and pertussin toxin. In addition, this mouse model closely recapitulates various features of MS, such as the relapsing– remitting pattern in females, the progressive course in males and the brain disease (Pollinger et al., 2009) as opposed to the spinal cord involvement seen in active EAE models. As these mice develop symptoms around day 65, we determined the kinetics of BBB changes during asymptomatic lesion development (days 30 to 55). "
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    ABSTRACT: Early changes in the normal appearing white matter of multiple sclerosis (MS) patients precede the appearance of gadolinium-enhancing lesions. Although these findings suggest blood-brain barrier (BBB) breakdown as an important feature in MS pathogenesis, limited information is available on the BBB alterations during lesion genesis. Here, we perform a longitudinal characterization of the vascular, neuropathological and immunological changes before lesion formation in mice developing spontaneous relapsing-remitting experimental autoimmune encephalomyelitis (sRR-EAE). We found a significant upregulation of Th1 and Th17 cytokines in the periphery of sRR-EAE mice before any evident neuropathology. In the CNS, BBB and astroglial activations were the first pathological changes occurring after 45days of age and were followed by immune cell infiltration by day 50. These pathological alterations subsequently led to perivascular demyelination and disease onset. In MS, (p)reactive lesions mirrored the changes seen in early sRR-EAE by displaying considerable BBB disruption, perivascular astrogliosis, redistribution of junctional proteins and increased expression of endothelial cell adhesion molecules. Our findings suggest that BBB breach occurs before significant immune cell infiltration and demyelination. In addition, peripheral immune activation during sRR-EAE precedes CNS pathology, suggesting that outside in signaling mechanisms play a role in the development of neuroinflammatory lesions. Copyright © 2014 Elsevier Inc. All rights reserved.
    Full-text · Article · Nov 2014 · Neurobiology of Disease
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    • "EAE is induced by active immunization with CNS antigens [6] that are typically derived from the myelin sheath, or by the passive transfer of autoreactive T cells [7]. In addition, spontaneous models exist that make use of genetically-modified mice, which harbor T cell receptor (TCR) transgenic T cells [8]–[13]. Studying a spontaneous model of EAE that involves MOG: 92–100 transgenic T cells, it has been shown that germ-free mice did not develop EAE compared to mice that were housed in a specific pathogen free (SPF) environment [2]. The authors suggested that autoreactive T cells were activated by commensal microbiota in the gut, where the cells expanded and subsequently triggered autoantibody production by B cells [2]. "
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    ABSTRACT: Background The etiology of multiple sclerosis (MS) has remained unclear, but a causative contribution of factors outside the central nervous system (CNS) is conceivable. It was recently suggested that gut bacteria trigger the activation of CNS-reactive T cells and the development of demyelinative disease. Methods C57BL/6 (B6) mice were kept either under specific pathogen free or conventional housing conditions, immunized with the myelin basic protein (MBP)–proteolipid protein (PLP) fusion protein MP4 and the development of EAE was clinically monitored. The germinal center size of the Peyer’s patches was determined by immunohistochemistry in addition to the level of total IgG secretion which was assessed by ELISPOT. ELISPOT assays were also used to measure MP4-specific T cell and B cell responses in the Peyer’s patches and the spleen. Ear swelling assays were performed to determine the extent of delayed-type hypersensitivity reactions in specific pathogen free and conventionally housed mice. Results In B6 mice that were actively immunized with MP4 and kept under conventional housing conditions clinical disease was significantly attenuated compared to specific pathogen free mice. Conventionally housed mice displayed increased levels of IgG secretion in the Peyer’s patches, while the germinal center formation in the gut and the MP4-specific TH17 response in the spleen were diminished after immunization. Accordingly, these mice displayed an attenuated delayed type hypersensitivity (DTH) reaction in ear swelling assays. Conclusions The data corroborate the notion that housing conditions play a substantial role in the induction of murine EAE and suggest that the presence of gut bacteria might be associated with a decreased immune response to antigens of lower affinity. This concept could be of importance for MS and calls for caution when considering the therapeutic approach to treat patients with antibiotics.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "A wild-type B10.S mice colony was established from a breeding pair obtained from the McLaughlin Research Institute (Montana, USA). TCR transgenic RR SJL/J mice [15] were backcrossed for more than 9 generations to B10.S mice. Mice were bred at the animal facility of the Max Planck Institute of Neurobiology (Martinsried, Germany). "
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    ABSTRACT: Myelin-specific, pro-inflammatory TH17 cells are widely regarded as the drivers of experimental autoimmune encephalomyelitis (EAE), an animal model for Multiple sclerosis (MS). The factors, responsible for the generation and maintenance of TH17 cells as well as their participation in the pathogenic cascade leading to the demyelinating disease, have been studied extensively. However, how these harmful autoreactive cells are controlled in vivo remains unclear. By comparing TCR transgenic mice on a disease susceptible and a disease resistant genetic background, we show here that pathogenic TH17 cells are sequestered within the intestine of spontaneous EAE resistant B10.S mice. Disease resistant B10.S mice harbored higher frequencies of TH17 cells in the intestine compared to EAE susceptible SJL/J mice. Moreover, transferred TH17 cells selectively migrated to intestinal lymphoid organs of B10.S mice. The sequestration of TH17 cells in the gut was partially dependent on the gut homing receptor α4β7-mediated adhesion to the intestine. Administration of α4β7 blocking-antibodies increased the peripheral availability of TH17 cells, resulting in increased EAE severity after immunization in B10.S mice. Together, these results support the concept that the intestine is a check-point for controlling pathogenic, organ-specific T cells.
    Full-text · Article · Feb 2014 · PLoS ONE
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