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* Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; and
Department of Clinical Neurosciences and
Department of Physiology and Biophysics, Institute of Infection, Immunity and Inflammation and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
The rising incidence of autoimmune diseases such as multiple sclerosis (MS) in developed countries might be due to a more hygienic environment, particularly during early life. To investigate this concept, we developed a model of neonatal exposure to a common pathogen-associated molecular pattern, LPS, and determined its impact on experimental autoimmune encephalomyelitis (EAE). Mice exposed to LPS at 2 wk of age showed a delayed onset and diminished severity of myelin oligodendrocyte glycoprotein (MOG)-induced EAE, induced at 12 wk, compared with vehicle-exposed animals. Spinal cord transcript levels of CD3
and F4/80 were lower in LPS- compared with PBS-exposed EAE animals with increased IL-10 levels in the LPS-exposed group. Splenic CD11c+ cells from LPS-exposed animals exhibited reduced MHC class II and CD83 expression but increased levels of CD80 and CD86 both before and during EAE. MOG-treated APC from LPS-exposed animals stimulated less T lymphocyte proliferation but increased expansion of CD4+FoxP3+ T cells compared with APC from PBS-exposed animals. Neuropathological studies disclosed reduced myelin and axonal loss in spinal cords from LPS-exposed compared with PBS-exposed animals with EAE, and this neuroprotective effect was associated with an increased number of CD3+FoxP3+ immunoreactive cells. Analyses of human brain tissue revealed that FoxP3 expression was detected in lymphocytes, albeit reduced in MS compared with non-MS patients’ brains. These findings support the concept of early-life microbial exposure influencing the generation of neuroprotective regulatory T cells and may provide insights into new immunotherapeutic strategies for MS.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 These studies were supported by the Multiple Sclerosis Society of Canada and the NeuroScience Canada Foundation. S.T. is a Multiple Sclerosis Society of Canada Fellow. F.N. is an Alberta Heritage Foundation for Medical Research Fellow. V.W.Y. is an Alberta Heritage Foundation for Medical Research Medical Scientist and holds a Canada Research Chair in Neuroimmunology. Q.J.P. is an Alberta Heritage Foundation for Medical Research Medical Scientist. C.P. is an Alberta Heritage Foundation for Medical Research Senior Scholar and holds a Canada Research Chair in Neurological Infection and Immunity.
2 K.K.E. and S.T. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Christopher Power, Division of Neurology, HMRC 6-11, University of Alberta, Edmonton, Alberta, Canada. E-mail address: chris.power{at}ualberta.ca
4 Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; Treg, regulatory T; Teff, effector T; DC, dendritic cell; MOG, myelin oligodendrocyte glycoprotein; MHC II, MHC class II; LFB, Luxol fast blue; poly(I:C), polyinosinic-polycytidylic acid.
5 The online version of this article contains supplemental material.
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