Antibodies against neuronal receptors and synaptic proteins are associated with encephalitic syndromes that produce either movement or psychiatric disorders. While the identification of autoantibodies has facilitated diagnosis and treatments for some of these disorders, the mechanisms by which autoantibodies enter the brain and cause neurovascular pathology remain unclear. Group A Streptococcus (GAS) infections in children are associated with basal ganglia encephalitis (BGE) that produces both motor [Sydenham?s chorea (SC)] and psychiatric [Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections (PANDAS)] symptoms. The humoral adaptive immune response plays an important role in disease pathogenesis. Autoantibodies that recognize dopamine receptors (D1R/D2R) are found in sera from acutely ill children with SC/PANDAS. These autoantibodies elicit behavioral abnormalities when infused into rodent brains or administered intravenously (i.v.) into naive recipient rodents in conjunction with agents that break down the blood-brain barrier (BBB). We have previously shown that an intranasal (i.n.) route of GAS infection leads to production of Th17 cells, which are an essential component of the cell-mediated adaptive immune response, in the nasal-associated lymphoid tissue of mice and humans. GAS-specific Th17 cells migrate from the nose into the brain via an olfactory route and their presence correlates with BBB breakdown, extravasation and brain deposition of antibodies. We hypothesize that GAS-specific Th17 cells arising after multiple i.n. infections enter the brain via the olfactory nerve using specific chemokine cues, to induce BBB breakdown thus enabling entry of autoantibodies into the brain, and modulate the function of specific neural circuits together with autoantibodies. The primary objective of the study is to examine the mechanisms by which GAS-specific Th17 cells enter the CNS in mice. The second objective is to determine the specific roles that Th17 cells or autoantibodies play in brain vasculature pathology (BBB damage), neuroinflammation and dysfunction of olfactory and dopaminergic neural circuits. We will first examine whether GAS-specific T cells enter the CNS via the i.n. or i.v. route by passively transferring them into nave mice and examining their distribution into the brain. We will then inhibit migration of T cells into the CNS using pharmacological inhibitors for immune cell trafficking after multiple GAS infections. We will analyze the consequences of i.n. GAS infections for the function of olfactory circuits and odor perception as well as basal ganglia circuitry and motor behaviors. Finally, we will determine the relative contribution that cell-mediated (Th17 cells) versus humoral (autoantibodies) immune mechanisms play in neurovascular and dopamine circuitry deficits in brains of GAS-infected mice using both genetic loss-of-function studies and adoptive transfer experiments. This project will shed light in autoimmune-mediated mechanisms of encephalitic syndromes associated with movement or psychiatric disorders and aid in developing future therapeutics to treat these diseases.

Public Health Relevance

The role of cell-mediated and humoral mechanisms in the pathology of various autoimmune encephalitic syndromes, including motor and psychiatric basal ganglia encephalitis (BGE) induced by Group A Streptococci (GAS) infections, remain unclear. This project will explore the link between a causative infectious agent (GAS) that produces an aberrant autoimmune response in the host (Th17 cells and autoantibodies) with induction of neuroinflammation, neurovascular pathology and neuronal circuitry dysfunction. Since Th17 cells have been implicated in tissue damage in several autoimmune diseases including multiple sclerosis, this proposal will consolidate the role of Th17 cells as key players in the pathogenesis of autoimmune encephalitic syndromes, that were primarily thought to be mediated by circulating autoantibodies and elucidate the mechanisms of how autoantibodies gain access to the brain. This proposal represents a novel and exciting breakthrough in our understanding of how bacterial infections that produce an aberrant immune response can impair brain function and mental health and aid in development of potential therapeutics to treat GAS-induced BGEs.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Tonelli, Leonardo H
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Lutz, Sarah E; Smith, Julian R; Kim, Dae Hwan et al. (2017) Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation. Cell Rep 21:2104-2117
Mazzoni, Jenna; Smith, Julian R; Shahriar, Sanjid et al. (2017) The Wnt Inhibitor Apcdd1 Coordinates Vascular Remodeling and Barrier Maturation of Retinal Blood Vessels. Neuron 96:1055-1069.e6