Dopamine Receptor Autoantibodies Correlate with Symptoms in Sydenham's Chorea

Abstract

BackgroundSydenham chorea (SC), a neuropsychiatric sequela of group-A streptococcal infection, is associated with basal ganglia autoantibodies. Although autoantibodies have been proposed in neuropsychiatric disorders, little evidence has been shown to link autoimmunity and clinical symptoms. We hypothesized that dopamine receptor-autoantibody interactions may be the basis of neuropsychiatric symptoms in SC.MethodsSera from 22 children with SC (age 10.7±4.5 years) and 22 age-matched controls were studied. Clinical neuropsychiatric symptoms were measured in SC at sample collection using the UFMG-Sydenham's-Chorea-Rating-Scale (USCRS). Anti-dopamine D1 receptor (D1R) and anti-dopamine D2 receptor (D2R) autoantibodies were measured by the enzyme linked immunosorbent assay (ELISA) and were correlated with clinical symptoms.ResultsAnti-D1R and anti-D2R autoantibodies were significantly higher in SC compared to controls (n = 44; p = 0.010 and p = 0.017, respectively). We found that the ratio (anti-D2R/D1R) of the two anti-dopaminergic receptor antibodies correlated with neuropsychiatric symptoms as determined by USCRS measurements (n = 18; r = 0.53, p = 0.024). In addition, anti-D2R titers correlated with antistreptolysin-O titers (n = 43; r = 0.49, p = 0.0008).InterpretationOur report linked, for the first time, autoimmunity with neuropsychiatric symptoms. The significant correlation was found using ratios of autoantibodies against dopamine receptors (anti-D2R/D1R) rather than the absolute elevated individual anti-D1R or anti-D2R titers. We suggest that autoantibodies may lead to a receptor imbalance and induce greater sensitivity to dopamine signaling potentially leading to neuropsychiatric symptoms in SC. Our novel findings suggesting altered balance in the dopaminergic system may provide a new approach in understanding autoimmune neuropsychiatric disorders with possible implications for diagnosis and treatment.

Antibodies to Surface Dopamine-2 Receptor and N-Methyl-D-Aspartate Receptor in the First Episode of Acute Psychosis in Children

“…Extracellular N-terminus hemagglutinin (HA)-tagged human D2R (www.cdna.org) and the (untagged) human NR1 subunit of NMDAR (kind gift from Professor A. Vincent, FRCPath, Nuffield Department of Clinical Neurosciences, Oxford University, United Kingdom) were subcloned into the pIRES2-eGFP vector (Clontech, Mountain View, California) as previously described (19,25,26). The bicistronic pIRES2-eGFP vector enables co-expression of distinct green fluorescent protein and receptor molecules.…”

“…Data analysis was performed using FlowJo software (TreeStar, Ashland, Oregon) and Excel (Microsoft, Redmond, Washington) and antibody binding was expressed as mean fluorescence intensity (MFI) as previously described (19,27,28). Specific antibody binding to D2R or NR1 was measured as the difference between the binding to HEK293 D2R1 and HEK293 NR11 cells and the binding to HEK293 D2R2 and HEK293 NR12 cells and was labeled ΔMFI.…”

“…Indeed, recent reports suggest that antibodies against the NR1 subunit of the NMDAR (immunoglobulin [Ig]G isotype) are pathogenic in NMDAR encephalitis (14,15), a recently described disease that can present with psychosis, movement disorders, seizures, and autonomic dysfunction, and is most frequently seen in children and young women. Psychosis has also been described in encephalitis associated with antibodies to contactin-associated protein-like 2 (16), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (17), γ-aminobutyric acid type B receptor (18), and D2R (19)(20)(21). In these syndromes, autoantibodies bind to the antigen expressed on neuronal cell surface.…”

Antineuronal Antibodies in a Heterogeneous Group of Youth and Young Adults with Tics and Obsessive-Compulsive Disorder

“…with elevated antineuronal antibodies. Our previous work has supported this idea by demonstrating antistreptococcal/antineuronal antibody binding, including human monoclonal antibodies, to human neuronal cells and activation of CaMKII by sera IgG from SC and PANDAS patients (Kirvan et al 2003(Kirvan et al , 2006a(Kirvan et al ,b, 2007Brimberg et al 2012;Ben Pazi et al 2013;Cox et al 2013). We previously reported that antibody titers against neuronal antigens, lysoganglioside, and tubulin were significantly elevated in acute SC sera compared with convalescent sera.…”

The PANDAS Controversy: Why (and How) Is It Still Unsettled?

“…Immune abnormalities have been frequently observed in PANDAS patients [46][47][48], including findings analogous to those seen in SC, such as evidence of GAS-mediated anti-neuronal autoantibodies, dopamine receptor autoantibodies, and basal ganglia pathology [49,50]. Three putative antibodies that have been implicated in SC, including N-acetyl-beta-D-glucosamine (a streptococcal group-A carbohydrate antigen), tubulin, and dopamine 2 [46][47][48].…”