Human anti-dopamine receptor 1 monoclonal autoantibody (mAb) identifies potential mechanisms of neuronal signaling in post-infectious autoimmune-mediated neuropsychiatric disease

Neuropsychiatric and movement disorders are associated with infections and anti-neuronal autoantibodies against dopamine receptors D1R and D2R. Most characterized of these disorders is Sydenham chorea (SC), an autoimmune neurologic manifestation of streptococcal-induced rheumatic fever where autoantibodies target the basal ganglia. Pediatric autoimmune neuropsychiatric disorder associated with streptococci (PANDAS) have similar autoantibodies that react with D1R and D2R. SC-derived human mAb 24.3.1 or SC derived IgG signal D2R in transfected cells by decreasing cyclic AMP-dependent kinase (cAMP) activity, reflective of an inhibitory receptor. Anti-D2R 24.3.1 increases dopamine release from human neuronal cells. However, signaling of D1R, an activating receptor, can have different biological effects. Our PANDAS-derived anti-D1R mAb, B4C, and PANDAS sera signaled D1R by activation of cAMP in transfected cells. IgG titers against D1R were significantly elevated in SC and PANDAS sera. To further show IgG recognized the D1R receptor, peptides of the extracellular loop of D1R were constructed and a defined sequence reacted significantly with human mAb B4C and PANDAS serum IgG. Human anti-D1R mAb B4C induced cAMP activity levels comparable to dopamine in a dose-dependent manner. Combined with dopamine, mAb B4C sensitized D1R to at least 50X more responsive to dopamine. In neuropsychiatric diseases where both anti-D1R and anti-D2R autoantibodies may be in combination, anti-D1R autoantibodies could sensitize D1R making it more sensitive to excess dopamine induced by anti-D2R autoantibodies; thus, contributing to dopamine signaling abnormalities and neuropsychiatric pathogenesis.