Article

Yaddanapudi K, Hornig M, Serge R, De Miranda J, Baghban A, Villar G et al. Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Mol Psychiatry 15: 712-726

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: 14.5). 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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Available from: Mady Hornig, Apr 11, 2014
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    • "Passive exposure to immunomediators (Ponzio et al., 2007; Smith et al., 2007; Depino et al., 2011; Patel et al., 2012; Zalcman et al., 2012) or to immunogenic microbial components (Hoffman et al., 2004; De Miranda et al., 2010; Yaddanapudi et al., 2010; Brimberg et al., 2012; Kirsten et al., 2012; Malkova et al., 2012) led to increased stereotypies and locomotion. However, additional deficits in motor coordination, learning/memory and social interaction, and the presence of immune deposits in the brain severely hamper their face validity for TS (Yaddanapudi et al., 2010). Transplantation into naïve animals of antibodies derived from animals actively immunized with patients' sera (Taylor et al., 2002; Singer et al., 2005; Martin et al., 2008; Zhang et al., 2012) led to a similar phenotype and episodic vocalizations were reported (Hallett et al., 2000). "
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    • "Evidence in animal models and humans strongly suggest that antibodies mediate inflammatory consequences in SC, PANDAS, and PANS (Brimberg, et al., 2012; Lotan, et al., 2014a; Lotan, Cunningham, & Joel, 2014b). There may be other brain antigens targeted by autoantibodies in PANDAS/PANS and related autoimmune diseases that may affect memory and behavior (Hoffman, Hornig, Yaddanapudi, Jabado, & Lipkin, 2004; Yaddanapudi, et al., 2010; Huerta, Kowal, DeGiorgio, Volpe, & Diamond, 2006; Kowal, et al., 2004; DeGiorgio, et al., 2001). Finally, molecular mimicry between S. pyogenes and the brain is supported by evidence from studies of human mAbs and serum IgG antibodies from rheumatic fever (Kirvan, Swedo, Heuser, & Cunningham, 2003; Galvin, Hemric, Ward, & Cunningham, 2000). "
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    • "As GAS infections in youth are common and possibly coincidental in this population, it is also difficult to establish causality in those patients who test positive. However, there has been a substantial body of literature linking GAS infections with OCD, eating restriction, and movement disorders including chorea and tics (Husby et al. 1976; Swedo et al. 1989 Swedo et al. , 1993 Swedo et al. , 1998 Mercadante et al. 2000; Leonard and Swedo 2001; Kirvan et al. 2003; Hoffman et al. 2004; Singer et al. 2004; Kirvan et al. 2006 Kirvan et al. , 2007 Murphy et al. 2007; Yaddanapudi et al. 2010; Brimberg et al. 2012; Lotan et al. 2014; Toufexis et al. 2014; Williams and Swedo 2014). We are not fully able to interpret our mycoplasma data, because IgM serology has poor positive predictive value (52%) (Chang et al. 2014); we hope to further explore this possible infectious trigger with more specific testing in the future (mycoplasma PCR). "
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