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Brain Behav Immun. 2018 Mar;69:304-311. doi: 10.1016/j.bbi.2017.12.004. Epub 2017 Dec 9.

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

Author information

1
Department of Psychiatry, Yale University, United States.
2
Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, United States.
3
Department of Psychology, Yale University, United States; Child Study Center, Yale University, United States.
4
Department of Psychiatry, Yale University, United States; Child Study Center, Yale University, United States; Department of Psychiatry, Massachusetts General Hospital, and Harvard Medical School, United States. Electronic address: KWILLIAMS42@partners.org.
5
Department of Psychiatry, Yale University, United States; Department of Psychology, Yale University, United States; Child Study Center, Yale University, United States; Interdepartmental Neuroscience Program, Yale University, United States. Electronic address: christopher.pittenger@yale.edu.

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.

KEYWORDS:

Animal model; Antibody; Autoimmunity; Interneurons; Obsessive-compulsive disorder; PANDAS; Tics

PMID:
29233751
PMCID:
PMC5857467
DOI:
10.1016/j.bbi.2017.12.004
[Indexed for MEDLINE]
Free PMC Article

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