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Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination

Abstract

Active multiple sclerosis lesions show inflammatory changes suggestive of a combined attack by autoreactive T and B lymphocytes against brain white matter1. These pathogenic immune cells derive from progenitors that are normal, innocuous components of the healthy immune repertoire but become autoaggressive upon pathological activation. The stimuli triggering this autoimmune conversion have been commonly attributed to environmental factors, in particular microbial infection2. However, using the relapsing–remitting mouse model of spontaneously developing experimental autoimmune encephalomyelitis3, here we show that the commensal gut flora—in the absence of pathogenic agents—is essential in triggering immune processes, leading to a relapsing–remitting autoimmune disease driven by myelin-specific CD4+ T cells. We show further that recruitment and activation of autoantibody-producing B cells from the endogenous immune repertoire depends on availability of the target autoantigen, myelin oligodendrocyte glycoprotein (MOG), and commensal microbiota. Our observations identify a sequence of events triggering organ-specific autoimmune disease and these processes may offer novel therapeutic targets.

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Figure 1: Commensal microbiota are required for the development of spontaneous EAE.
Figure 2: Effect of microbiota on T-cell activation and their cytokine profiles in the GALT.
Figure 3: B-cell recruitment is impaired in germ-free RR mice.
Figure 4: MOG-specific B cells home to the germinal centre of brain draining cervical lymph nodes.

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Acknowledgements

We thank I. Arnold-Ammer, N. Reißer and L. Penner for technical assistance, and M. Pfunder, U. Stauffer, C. Hornung and N. Joswig for maintaining our germ-free colony and technical support. We are much obliged to R. Kemler for his support. This work was funded by SFB 571 (Project B6), the German Competence Network on Multiple Sclerosis (KKNMS), ARSEP (France), and by the Max Planck Society. K.B. is supported by a fellowship from ARSEP. Z.A.R. is supported by a PhD fellowship from the Emirates Foundation. M.B. receives a fellowship from the Hellenic Neurological Society.

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K.B., H.W. and G.K. designed experiments and wrote the manuscript with input from co-authors. K.B. performed most of the experiments. M.M., M.K. and M.B. performed flow cytometry experiments or assisted in experiments. Z.A.R. performed flow cytometry and immunofluorescence staining for brain infiltrates. C.J. supervised the maintenance of germ-free mouse colony and colonization experiments.

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Correspondence to Hartmut Wekerle or Gurumoorthy Krishnamoorthy.

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The authors declare no competing financial interests.

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Berer, K., Mues, M., Koutrolos, M. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011). https://doi.org/10.1038/nature10554

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