Dopamine receptor autoantibody signaling in infectious sequelae differentiates movement versus neuropsychiatric disorders.

Despite growing recognition, neuropsychiatric diseases associated with infections are a major unsolved problem worldwide. Group A streptococcal (GAS) infections can cause autoimmune sequelae characterized by movement disorders, such as Sydenham chorea (SC), and neuropsychiatric disorders. The molecular mechanisms underlying these diseases are not fully understood. Our previous work demonstrates that autoantibodies (AAbs) can target dopaminergic neurons and increase dopamine receptor D2 (D2R) signaling. However, AAb influence on dopamine receptor D1 (D1R) activity is underexplored. We found evidence that suggests GAS-induced cross-reactive AAbs promote autoimmune encephalitis of the basal ganglia (BGE), a region of high dopamine receptor density. Here, we report a new mechanism whereby neuropsychiatric syndromes are distinguished from movement disorders by differences in D1R and D2R AAb titers, signaling, receiver operating characteristic (ROC) curves, and immunoreactivity with D1R and D2R autoreactive epitopes. D1R AAb signaling was observed through patient serum AAbs and novel patient-derived mAbs, which induced both D1R G protein- and -arrestin transduced signals. Furthermore, patient AAbs and mAbs enhanced D1R signaling mechanisms mediated by the neurotransmitter dopamine. Our findings suggest that AAb-mediated D1R signaling may contribute to the pathogenesis of neuropsychiatric sequelae and inform new options for diagnosis and treatment of GAS sequelae and related disorders. .