Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis
- 11 March 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (12), 6708-6716
- https://doi.org/10.1073/pnas.1911097117
Abstract
Antibodies against neuronal receptors and synaptic proteins are associated with a group of ill-defined central nervous system (CNS) autoimmune diseases termed autoimmune encephalitides (AE), which are characterized by abrupt onset of seizures and/or movement and psychiatric symptoms. Basal ganglia encephalitis (BGE), representing a subset of AE syndromes, is triggered in children by repeated group A Streptococcus (GAS) infections that lead to neuropsychiatric symptoms. We have previously shown that multiple GAS infections of mice induce migration of Th17 lymphocytes from the nose into the brain, causing blood–brain barrier (BBB) breakdown, extravasation of autoantibodies into the CNS, and loss of excitatory synapses within the olfactory bulb (OB). Whether these pathologies induce functional olfactory deficits, and the mechanistic role of Th17 lymphocytes, is unknown. Here, we demonstrate that, whereas loss of excitatory synapses in the OB is transient after multiple GAS infections, functional deficits in odor processing persist. Moreover, mice lacking Th17 lymphocytes have reduced BBB leakage, microglial activation, and antibody infiltration into the CNS, and have their olfactory function partially restored. Th17 lymphocytes are therefore critical for selective CNS entry of autoantibodies, microglial activation, and neural circuit impairment during postinfectious BGE.Funding Information
- HHS | NIH | National Institute of Mental Health (R01 MH112849)
- HHS | NIH | National Institute of Mental Health (R56 MH109987)
- HHS | NIH | National Institute on Deafness and Other Communication Disorders (DC015525)
- HHS | NIH | National Institute on Deafness and Other Communication Disorders (R01 DC016782)
- Fondation Leducq (15CDV-02)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (R01 NS107344)
This publication has 52 references indexed in Scilit:
- Brain-Reactive Antibodies and DiseaseAnnual Review of Immunology, 2013
- Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent MannerNeuron, 2012
- Mitral Cells in the Olfactory Bulb Are Mainly Excited through a Multistep Signaling PathJournal of Neuroscience, 2012
- Robust Antigen Specific Th17 T Cell Response to Group A Streptococcus Is Dependent on IL-6 and Intranasal Route of InfectionPLoS Pathogens, 2011
- Th1 versus Th17: Are T cell cytokines relevant in multiple sclerosis?Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2011
- Caveolae-mediated Internalization of Occludin and Claudin-5 during CCL2-induced Tight Junction Remodeling in Brain Endothelial CellsOnline Journal of Public Health Informatics, 2009
- The Biological Functions of T Helper 17 Cell Effector Cytokines in InflammationImmunity, 2008
- The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper CellsCell, 2006
- A Murine Model for Neuropsychiatric Disorders Associated with Group A β-Hemolytic Streptococcal InfectionJournal of Neuroscience, 2004
- Interferon-γ and Interleukin-10 Reciprocally Regulate Endothelial Junction Integrity and Barrier FunctionMicrovascular Research, 2001