Human monoclonal autoantibodies in autoimmune basal ganglia encephalitis target dopamine receptors and act as drug agonists

Abstract

Abstract Neuropsychiatric diseases in autoimmune basal ganglia encephalitis (BGE) are associated with anti-neuronal autoantibodies which target the basal ganglia. BGE includes the group A streptococcal sequelae Sydenham chorea (SC) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). In SC, autoantibodies against dopamine receptors 1 and 2 (D1R and D2R) are elevated, and IgG in SC sera and cerebrospinal fluid (CSF) induce excessive dopaminergic D2R signaling and dopamine release. D1R autoantibody reactivity targeting the basal ganglia is not defined. Here we demonstrate specific IgG targeting of D1R in multiple neuropsychiatric PANDAS cohorts by serum, CSF, and human-derived mAbs. Anti-D1R human mAbs and serum autoantibodies induced D1R second messenger signaling in a dose-dependent manner. The results suggest that D1R autoantibodies enhanced antibody-mediated IgG signaling activity in the presence of the neurotransmitter dopamine. D1R autoantibodies sensitized D1R and exacerbated endogenous dopamine signaling in disease. Agonistic D1R signaling was inhibited by synthetic D1R peptide epitopes derived from human D1R extracellular loops which identified the immunodominant epitopes and antibody specificity. Taken together, D2R autoantibodies in BGE lead to excessive dopamine release and chorea, while D1R autoantibodies act like dopamine on receptors leading to allosteric enhancement and neuropsychiatric disease. Collectively, our novel findings suggest dopamine receptor autoantibodies in basal ganglia disorders act like drugs and mediate hyperactive dopaminergic receptor signaling.