Post-streptococcal autoimmune neuropsychiatric disease : clinical spectrum and identification of brain auto-antigens
Group A beta haemolytic Streptococcus (GAS) is a bacteria that causes a range of invasive and autoimmune complications in humans. It is also the commonest single cause of tonsillitis in children. Occasionally, in predisposed individuals, GAS can induce an immune mediated brain syndrome with particular vulnerability of the basal ganglia. This results in extrapyramidal movement disorders (classically chorea) and psychiatric disease. Recently the clinical spectrum of disease associated with GAS has been expanded to include motor tics. The clinical aim of this thesis was to define the clinical spectrum of CNS disease associated with GAS in a tertiary referral sample. I found that a broader range of extrapyramidal movements (chorea, tics, dystonia and Parkinsonism) and psychiatric disease (obsessive-compulsive disorder, anxiety, depression and attention deficit hyperactivity disorder) occurred in patients with post streptococcal autoimmune neuropsychiatric disease. The proposed mechanism of brain injury is cross-reactivity of the immune response between GAS and brain antigens (molecular mimicry). A number of investigators have previously demonstrated auto-antibodies that bind to brain auto-antigens in the serum of post-streptococcal neuropsychiatric patients. Using protein purification strategies (2-dimensional electrophoresis, ion exchange and hydrophobic interaction chromatography followed by mass spectrometry), I identified the brain antigens as neuronal isoforms of the glycolytic enzymes enolase, pyruvate kinase and aldolase. These findings were confirmed with commercial antigens, recombinant human antigens and commercial antibodies. These enzymes arc present in the neuronal cytoplasm, but also on the membrane surface where they have a number of functions. Collaborative investigation into the effects of anti-neuronal glycolytic enzyme antibodies on neurones in vitro demonstrated increased neuronal apoptosis compared to controls. In addition, the enzymes are present on the membrane surface of GAS, therefore representing a potential example of molecular mimicry.