Both the initial insults and chronic exacerbations for many neuropsychiatric disorders with an autoimmune component, including the central nervous system (CNS) sequelae of S. pyogenes infections described in this proposal, remain unclear. Infections by Group A Streptococcus (GAS), which commonly lead to acute pharyngitis in children, are associated in a subset with a basal ganglia encephalitis that produces both motor (Sydenham?s chorea) and psychiatric [Pediatric Acute Neuropsychiatric Disorders Associated with Streptococcus (PANDAS)] deficits. The humoral adaptive immune response plays an important role in disease pathogenesis, both for patients and in rodent models. Autoantibodies against neuronal targets such as dopamine receptors (D1R/D2R) are found in sera from acutely ill children, and these autoantibodies elicit behavioral abnormalities when infused into rodent brains or administered intravenously into recipient rodents treated with agents that disrupt the blood-brain barrier (BBB). We have shown that an intranasal (i.n.) route of GAS infection leads to Th17 cell production, an essential component of the cell-mediated adaptive immune response, in nasal-associated lymphoid tissues of humans and mice. GAS-specific Th17 cells migrate from the nose into the olfactory bulb (OB), where they accumulate and disperse to other brain regions. Moreover, T cells present in the brain correlate with: 1) BBB breakdown, 2) extravasation and brain deposition of antibodies, 3) reduction in excitatory synaptic proteins, and 4) altered neuronal activity. We hypothesize that GAS-specific Th17 cells arising after multiple i.n. infections enter the brain via the olfactory nerve using specific chemokine cues, then induce BBB breakdown to thereby permit entry of autoantibodies into the brain. T cells and autoantibodies together then modulate synaptic communication and neural circuit function. The primary objective of the proposed study is to unravel the mechanisms by which GAS-specific Th17 cells enter the brain following multiple i.n. infections in mice. We will examine expression of several chemokines during infection and test the roles that chemokine ligand/receptor pairs play in this process after multiple i.n. GAS infections, using a genetic approach. We will analyze neurovascular damage, changes in excitatory synapses as well as neuronal activity in the OB and basal ganglia after multiple infections, in either chemokine receptor- or Th17-deficient strains. The second objective is to determine how brain-reactive autoantibodies, generated after i.n. GAS infections, cross the BBB. We will measure whether i.n. infections elicit antibodies against the CNS, and identify changes in BBB structural components (tight junctions or caveolae) in vitro after exposure of brain endothelial cells to sera from GAS-immunized mice. This project will reveal the autoimmune-mediated mechanisms underlying basal ganglia encephalitis that produce movement and psychiatric disorders, and aid in developing future therapeutics to treat these diseases.
The roles of cell-mediated and humoral mechanisms in the pathology of several autoimmune encephalitic syndromes, including motor and psychiatric basal ganglia encephalitis induced by Group A Streptococcus (GAS) infections, remain unclear. This project will explore the link between a causative agent (GAS) that produces an aberrant autoimmune response (Th17 cells and autoantibodies) in the host and induction of neuroinflammation, neurovascular pathology and neuronal circuit dysfunction. Because Th17 cells have been implicated in tissue damage in many autoimmune diseases, including multiple sclerosis, this proposal will consolidate the role of Th17 cells as key players in the pathogenesis of autoimmune encephalitis, which have been thought to be mediated primarily by circulating autoantibodies, and elucidate the mechanisms for autoantibodies gaining access to the brain. This represents a novel and exciting breakthrough in our understanding of how bacterial infections that produce an aberrant immune response can impair brain function and alter mental health, as well as aid in the development of therapeutics for these diseases.