Abstract
BackgroundThe 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.MethodsC57BL/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.ResultsIn 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.ConclusionsThe 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.
Highlights
Multiple sclerosis (MS) is considered to be an autoimmune disorder of the central nervous system (CNS) and the most common cause of irreversible disability in young adults [1]
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]
In order to investigate the contribution of commensal gut bacteria to the development of EAE, we induced active EAE in two groups of B6 mice kept under different housing conditions
Summary
Multiple sclerosis (MS) is considered to be an autoimmune disorder of the central nervous system (CNS) and the most common cause of irreversible disability in young adults [1]. It has been shown that molecular mimicry between known autoimmune immunogens such as myelin basic protein (MBP) or oligodendrocyte glycoprotein (MOG) and nonpathogenic gut bacteria frequently occurs [5] and could explain the autoimmune activity in MS patients. Among these potential bacteria resembling CNS antigens are E. coli, Lactobacillus spp., Enterobacter and Streptococcus spp. 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] This concept is clinically highly relevant since non-invasive therapeutic strategies such as the administration of antibiotics to MS patients represent a reasonable option with low risks for adverse side effects. It was recently suggested that gut bacteria trigger the activation of CNSreactive T cells and the development of demyelinative disease
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