Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection.

Center for Infection and Immunity and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
Molecular Psychiatry (Impact Factor: 15.15). 09/2009; 15(7):712-26. DOI: 10.1038/mp.2009.77
Source: PubMed

ABSTRACT Streptococcal infections can induce obsessive-compulsive and tic disorders. In children, this syndrome, frequently associated with disturbances in attention, learning and mood, has been designated pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Autoantibodies recognizing central nervous system (CNS) epitopes are found in sera of most PANDAS subjects, but may not be unique to this neuropsychiatric subset. In support of a humoral immune mechanism, clinical improvement often follows plasmapheresis or intravenous immunoglobulin. We recently described a PANDAS mouse model wherein repetitive behaviors correlate with peripheral anti-CNS antibodies and immune deposits in brain following streptococcal immunization. These antibodies are directed against group A beta-hemolytic streptococcus matrix (M) protein and cross-react with molecular targets complement C4 protein and alpha-2-macroglobulin in brain. Here we show additional deficits in motor coordination, learning/memory and social interaction in PANDAS mice, replicating more complex aspects of human disease. Furthermore, we demonstrate for the first time that humoral immunity is necessary and sufficient to induce the syndrome through experiments wherein naive mice are transfused with immunoglobulin G (IgG) from PANDAS mice. Depletion of IgG from donor sera abrogates behavior changes. These functional disturbances link to the autoimmunity-related IgG1 subclass but are not attributable to differences in cytokine profiles. The mode of disrupting blood-brain barrier integrity differentially affects the ultimate CNS distribution of these antibodies and is shown to be an additional important determinant of neuropsychiatric outcomes. This work provides insights into PANDAS pathogenesis and may lead to new strategies for identification and treatment of children at risk for autoimmune brain disorders.

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    ABSTRACT: The acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) has been used to describe a syndrome characterized by various obsessions, compulsions, tics, hyperactivity, motor stereotypies, and paroxysmal movement disorders that are correlated with prior infection by group A beta-hemolytic Streptococcus pyogenes (GABHS) infections. Five clinical criteria can be used to diagnose PANDAS: (1) the presence of obsessive-compulsive disorder (OCD) and/or any other tic disorders; (2) prepuberal onset (between 3 years of age and the start of puberty); (3) abrupt onset and relapsing-remitting symptom course; (4) a distinct association with GABHS infection; and (5) association with neurological abnormalities during exacerbations (adventitious movements or motoric hyperactivity). The exact pathogenesis of PANDAS remains unclear, and several theories that focus on multiple etiologic or contributive factors have emerged. PANDAS appears to be a neurobiological disorder that potentially complicates GABHS infections in genetically susceptible individuals. The current standard of care for PANDAS patients remains symptomatic, and cognitive behavioral therapy, such as exposure and response prevention, combined with family counseling and psychoeducation, should be the first approach for treating PANDAS. This review examines current theories of PANDAS pathogenesis, identifies possible treatments for managing this complex condition, and highlights areas for future research. Moving forward, developing more standardized diagnostic criteria and identifying specific laboratory markers to facilitate PANDAS diagnoses are crucial.
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    ABSTRACT: BACKGROUND: Autoimmune-mediated basal ganglia dysfunction is implicated in the pathophysiology of neuropsychiatric disorders commonly manifesting with obsessive-compulsive features (e.g. Sydenham chorea). The relationship between autoimmunity and primary obsessive-compulsive disorder (OCD), however, is less clear. AIMS: To pool data on serum and cerebrospinal fluid (CSF) anti-basal ganglia antibody (ABGA) positivity in primary OCD (without neurological or autoimmune comorbidity) relative to controls or neuropsychiatric disorders previously associated with increased odds of ABGA positivity. METHOD: We performed electronic database and hand-searches for studies meeting pre-specified eligibility criteria from which we extracted data using a standardised form. We calculated pooled estimates of ABGA positivity using a random-effects model. RESULTS: Seven case-control studies totalling 844 participants met the eligibility criteria. Meta-analysis showed that a significantly greater proportion of those with primary OCD were ABGA seropositive compared with various controls (odds ratio (OR) = 4.97, 95% CI 2.88-8.55, P<0.00001). This effect was not associated with heterogeneity or publication bias, and remained significant after stratifying the analysis by age, gender, disease severity, illness duration, immunostaining methodology, study quality, publication type, kind of control group, and sample size. There were no significant differences in ABGA seropositivity for comparisons between primary OCD and Tourette syndrome, attention-deficit hyperactivity disorder or paediatric acute-onset neuropsychiatric syndrome. Results of one study testing CSF samples showed that a significantly greater proportion of participants with primary OCD were ABGA CSF-positive compared with healthy controls (OR = 5.60, 95% CI 1.04-30.20, P = 0.045). CONCLUSIONS: Odds of ABGA seropositivity are increased fivefold in primary OCD compared with controls, but are comparable to those associated with disorders previously associated with ABGA, providing circumstantial evidence of autoimmunity in a subset of those with primary OCD. Further experimental studies are needed to ascertain whether this relationship is causal. Royal College of Psychiatrists. PMID: 24986387 [PubMed - as supplied by publisher] PubMed MEDLINE British Journal of Psychiatry
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