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Review
, 216 (1), 90-100

Autoimmunity Against Dopamine Receptors in Neuropsychiatric and Movement Disorders: A Review of Sydenham Chorea and Beyond

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Review

Autoimmunity Against Dopamine Receptors in Neuropsychiatric and Movement Disorders: A Review of Sydenham Chorea and Beyond

M W Cunningham et al. Acta Physiol (Oxf).

Abstract

Antineuronal autoantibodies are associated with the involuntary movement disorder Sydenham chorea (SC) and paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) which are characterized by the acute onset of tics and/or obsessive compulsive disorder (OCD). In SC and PANDAS, autoantibodies signal human neuronal cells and activate calcium calmodulin-dependent protein kinase II (CaMKII). Animal models immunized with group A streptococcal antigens demonstrate autoantibodies against dopamine receptors and concomitantly altered behaviours. Human monoclonal antibodies (mAbs) derived from SC target and signal the dopamine D2L (long) receptor (D2R). Antibodies against D2R were elevated over normal levels in SC and acute-onset PANDAS with small choreiform movements, but were not elevated over normal levels in PANDAS-like chronic tics and OCD. The expression of human SC-derived anti-D2R autoantibody V gene in B cells and serum of transgenic mice demonstrated that the human autoantibody targets dopaminergic neurones in the basal ganglia and other types of neurones in the cortex. Here, we review current evidence supporting the hypothesis that antineuronal antibodies, specifically against dopamine receptors, follow streptococcal exposures and may target dopamine receptors and alter central dopamine pathways leading to movement and neuropsychiatric disorders.

Keywords: autoimmunity; chorea; dopamine; dopamine receptor; streptococci.

Conflict of interest statement

Conflict of interest

Madeleine Cunningham is the chief scientific officer and co-founder with financial interest in Moleculera Labs, a commercial laboratory for diagnostic testing of antineuronal antibodies. Carol J. Cox declares financial interest in Moleculera Labs.

Figures

Figure 1
Figure 1
Human Sydenham chorea 24.3.1 V gene expressed as human V gene-mouse. IgG1a constant region in transgenic (Tg) mice targets dopaminergic neurons. Chimeric Tg24.3.1 VH IgG1a Ab expressed in Tg mouse sera penetrated dopaminergic neurons in Tg mouse brain in vivo. Colocalization of Tg 24.3.1 IgG1a (anti-IgG1a Ab, green, left panel) and tyrosine hydroxylase antibody (anti-TH Ab, yellow, middle panel). TH is a marker for dopaminergic neurons. Left panel shows IgG1a (FITClabelled), centre panel shows TH Ab (TRITC-labelled), and right panel is merged image (FITC-TRITC). Brain sections (basal ganglia) of VH24.3.1 Tg mouse (original magnification 320), showing FITC-labeled anti-mouse IgG1a (a), TRITC-labelled anti-TH Ab (b) and merged image (c). Colocalization by double immunostaining used Abs conjugated to FITC and TRITC. For localization of chimeric Tg24.3.1 VH IgG1a, primary Ab was biotin-conjugated mouse anti-mouse IgG1a (BD Pharmingen) which was used in combination with FITC-conjugated streptavidin (Invitrogen). For immunostaining of dopaminergic neurons, rabbit polyclonal Ab (Abcam) was used as primary Ab with TRITC-conjugated sheep anti-rabbit Ab as the secondary Ab (Sigma). Conjugate controls, secondary Ab controls (secondary Ab, no primary Ab) shown: FITC-conjugated streptavidin (1 : 20) (left panel) and TRITC-conjugated sheep anti-rabbit Ab (1 : 100) (middle panel); right panel is merged image (FITC-TRITC) (Cox et al. 2013).
Figure 2
Figure 2
Protein sequence similarities between dopamine D1 and D2 receptors and serotonin receptors. Protein sequence alignments were performed between 5HT-2A and 2C serotonin receptors and dopamine receptors D1 and D2. (a) is a diagram of protein regions analyzed, including three extracellular regions (extracellular loop 1, extracellular loop 2, extracellular loop 3) of D2R. (b) shows residues analysed in each extracellular loop (1, 2 and 3). Identical residues are indicated in bold and highlighted (grey). Protein sequence alignments were performed using the basic local alignment search tool analysis program (BLAST) (National Center for Biotechnology Information) and WUR MUSCLE multiple alignment analysis program (www.bioinformatics.nl/tools/muscle.html).
Figure 3
Figure 3
Summary of evidence for the role of streptococcal infections in the induction of antibodies that may lead to movement or neuropsychiatric disorders. The pathogenesis of Sydenham chorea and PANDAS begins with an infection with group A streptococci in the throat or soft tissues or skin. The susceptible host may produce antibodies which react with brain tissues and in particular the dopamine receptors or neural antigens such as tubulin or lysoganglioside (Kirvan et al. 2003, 2006a,b, 2007, Ben-Pazi et al. 2013, Cox et al. 2013). Antibodies target primarily the basal ganglia, in particular the ventral tegumental area or the substantia nigra which project to the striatum. The mechanism of the antibodies as shown would signal the neuronal cell through activation of CaMKII and lead to excess dopamine release. Binding of high-avidity cross-reactive antistreptococcal/antineuronal antibodies to lysoganglioside or dopamine receptors on the surface of neurons may lead to alterations in dopamine transmission.

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