Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders

Abstract

Recent reports of autoantibodies that bind to neuronal surface receptors or synaptic proteins have defined treatable forms of autoimmune encephalitis. Despite these developments, many cases of encephalitis remain unexplained. We have previously described a basal ganglia encephalitis with dominant movement and psychiatric disease, and proposed an autoimmune aetiology. Given the role of dopamine and dopamine receptors in the control of movement and behaviour, we hypothesized that patients with basal ganglia encephalitis and other putative autoimmune basal ganglia disorders harboured serum autoantibodies against important dopamine surface proteins. Basal ganglia encephalitis sera immunolabelled live surface cultured neurons that have high expression of dopamine surface proteins. To detect autoantibodies, we performed flow cytometry cell-based assays using human embryonic kidney cells to express surface antigens. Twelve of 17 children (aged 0.4-15 years, nine males) with basal ganglia encephalitis had elevated immunoglobulin G to extracellular dopamine-2 receptor, compared with 0/67 controls. Immunofluorescence on wild-type mouse brain showed that basal ganglia encephalitis sera immunolabelled microtubule-associated protein 2-positive neurons in striatum and also in cultured striatal neurons, whereas the immunolabelling was significantly decreased in dopamine-2 receptor knock-out brains. Immunocytochemistry confirmed that immunoreactivity localized to the surface of dopamine-2 receptor-transfected cells. Immunoabsorption of basal ganglia encephalitis sera on dopamine-2 receptor-transfected human embryonic kidney cells decreased immunolabelling of dopamine-2 receptor-transfected human embryonic kidney cells, neurons and wild-type mouse brain. Using a similar flow cytometry cell-based assay, we found no elevated immunoglobulin G binding to dopamine 1, 3 or 5 receptor, dopamine transporter or N-methyl-d-aspartate receptor. The 12 dopamine-2 receptor antibody-positive patients with encephalitis had movement disorders characterized by parkinsonism, dystonia and chorea. In addition, the patients had psychiatric disturbance with emotional lability, attention deficit and psychosis. Brain magnetic resonance imaging showed lesions localized to the basal ganglia in 50% of the patients. Elevated dopamine-2 receptor immunoglobulin G was also found in 10/30 patients with Sydenham's chorea, 0/22 patients with paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and 4/44 patients with Tourette's syndrome. No dopamine-1 receptor immunoglobulin G was detected in any disease or control groups. We conclude that assessment of dopamine-2 receptor antibodies can help define autoimmune movement and psychiatric disorders.

Infectious and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome

“…27 Antibodies to D2R were found in only 4 patients with dystonia-Parkinsonism and basal ganglia lesions, representing a small subgroup (2%). 16 There were no patients with antibodies to glutamic acid decarboxylase and only 1 patient with glycine R antibody (who also had VGKC-complex antibodies and Mycoplasma), and reported pediatric cases with these antibodies are rare. Nine (20%) of the patients with unknown encephalitis did not have serum available for autoantibody testing, and comprehensive testing may help to ensure recognition of known autoantibodies and to define some of the "unknown" patients in the future.…”

“…16 Three patients had acute necrotizing encephalopathy with the typical radiologic features. 18,20 There were no other…”

Disciplined approach to drug discovery and early development

“…A genome-wide association study identified genetic variation in the DRD2 gene locus as being associated with schizophrenia risk (16). In patients with encephalitis and clinical symptoms related to psychosis, autoantibodies against DRD2 have been identified (17). Although these human experiments of nature were not used in the development of antipsychotic medications to treat schizophrenia, they do provide PoC that mechanistic data from human genetics and tissue-specific autoimmunity can, in retrospect, identify the in vivo targets of approved drugs.…”

Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis

“…We used fluorescence-activated cell sorting (FACS) analysis to detect antibody binding of patient serum IgG to surface MOG transduced in HEK293 cells as we have previously described (methodology presented in appendix e-2). 30,31 Samples were considered positive if they were above threshold on at least 2 of 3 repeated experiments, and the intraassay variation is summarized in appendix e-2. Classification of evidence.…”