Molecular Mimicry, Autoimmunity and Infection: Sydenham Chorea and Related Disorders

Sydenham chorea is an autoimmune sequelae which follows group A streptococcal infection and is the major neurologic manifestation of acute rheumatic fever. Neurologic symptoms may result from crossreactive autoimmune responses against brain and group A streptococcal antigens. Human monoclonal antibodies (mAb) derived from Sydenham chorea crossreacted with group A streptococcal antigen and caudate putamen tissue as well as brain antigens lysoganglioside and tubulin. mAb and acute Sydenham chorea sera or CSF targeted human neuronal cells leading to activation of calcium-calmodulin dependent protein (CaM) kinase II and dopamine release. Sera from other streptococcal diseases did not demonstrate such increased antibody reactivity with brain or activation of CaM kinase II. Primary neuronal cells from striatal tissue demonstrated increased CaM kinase II activity when reacted with acute Sydenham chorea sera or CSF. Our recent evidence suggests that dopamine D2 receptors are targeted by the chorea-derived anti-brain mAbs and sera. Serum antibodies from Pediatric Autoimmune Neurologic Disorder Associated with Streptococci (PANDAS) with obsessive compulsive behaviors, vocal tics or tic-like movements demonstrated activation of CaM kinase II at an intermediate level and reactivity with lysoganglioside and dopamine D2 receptor. Comparison of matched acute and convalescent PANDAS sera taken before and during exacerbations demonstrated an elevation in CaM kinase II activity associated with disease. Study of an animal model revealed that immunization with group A streptococcal antigen led to behavioral changes which correlated with antibody deposition in the striatum as well as reactivity of serum IgG with dopamine receptors and the induction of CaM kinase II activity. Our data are consistent with the hypothesis that PANDAS, Sydenham chorea, and some cases of TS may be due to immunologically mediated increases in central dopamine levels and selective activation of central dopamine D2 receptors which combine to produce the neuropsychiatric symptoms seen in these disorders.