Differential binding of antibodies in PANDAS patients to cholinergic interneurons in the striatum

Abstract

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus, or PANDAS, is a syndrome of acute childhood onset of obsessive-compulsive disorder and other neuropsychiatric symptoms in the aftermath of an infection with Group A beta-hemolytic Streptococcus (GABHS). Its pathophysiology remains unclear. PANDAS has been proposed to result from cross-reactivity of antibodies raised against GABHS with brain antigens, but the targets of these antibodies are unclear and may be heterogeneous. We developed an in vivo assay in mice to characterize the cellular targets of antibodies in serum from individuals with PANDAS. We focus on striatal interneurons, which have been implicated in the pathogenesis of tic disorders. Sera from children with well-characterized PANDAS (n = 5) from a previously described clinical trial (NCT01281969), and matched controls, were infused into the striatum of mice; antibody binding to interneurons was characterized using immunofluorescence and confocal microscopy. Antibodies from children with PANDAS bound to ∼80% of cholinergic interneurons, significantly higher than the <50% binding seen with matched healthy controls. There was no elevated binding to two different populations of GABAergic interneurons (PV and nNOS-positive), confirming the specificity of this phenomenon. Elevated binding to cholinergic interneurons resolved in parallel with symptom improvement after treatment with intravenous immunoglobulin. Antibody-mediated dysregulation of striatal cholinergic interneurons may be a locus of pathology in PANDAS. Future clarification of the functional consequences of this specific binding may identify new opportunities for intervention in children with this condition.

Autoantibody Biomarkers for Basal Ganglia Encephalitis in Sydenham Chorea and Pediatric Autoimmune Neuropsychiatric Disorder Associated With Streptococcal Infections

“…Elevation of CaMKII activity suggested that the autoantibodies have bioactivity, consistent with findings of autoimmunity and neuroinflammation in PANDAS and SC (27), including basal ganglia and/or dopamine receptor encephalitis (26,33). Additional studies are in progress to further investigate the validity of our conclusions, the presence of other neuronal autoantibodies (38), and better understand the pathogenetic mechanisms in disease.…”

“…Expression of the chorea-derived human monoclonal antibody (mAb) 24.3.1 in transgenic mice led to autoantibody targeting of dopaminergic neurons in basal ganglia as well as additional neurons in the cerebral cortex (26). Further, anti-neuronal autoantibodies in sera of PANDAS patients have been shown to target cholinergic interneurons in mouse striatum (38). These interneurons depolarize spontaneously in a manner similar to the cardiac sinoatrial node and help to auto-regulate the local neuronal circuitries (39).…”

Alterations in the Nervous System and Gut Microbiota after β-Hemolytic Streptococcus Group A Infection—Characteristics and Diagnostic Criteria of PANDAS Recognition

“…PANDAS patients exhibited significantly enlarged volumes of striatum in comparison to control groups, according to Giedd et al [62]. The binding of serum antibodies obtained from children diagnosed with PANDAS to cholinergic interneurons in the striatum of mice was significantly higher in comparison to control groups [64]. This finding may present one of the potential loci of the pathophysiology of PANDAS.…”

What does immunology have to do with brain development and neuropsychiatric disorders?

“…Antibodies from children with PANDAS bound to ∼80% of cholinergic interneurons, significantly higher than the <50% binding seen with matched healthy controls. Remarkably, after treatment with IVIG, symptom improvement resolved in parallel with a reversal of the elevated binding of antibodies to cholinergic interneurons 40 . Individuals with TS have fewer cholinergic interneurons in their striatum, based on the examination of postmortem brain tissue 41 .…”