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

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 b-hemolytic streptococcus matrix (M) protein and cross-react with molecular targets complement C4 protein and a-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.

Behavioral, Pharmacological, and Immunological Abnormalities after Streptococcal Exposure: A Novel Rat Model of Sydenham Chorea and Related Neuropsychiatric Disorders

“…A subset of these mice developed motoric and behavioral disturbances that were correlated with immunoreactivity to the deep cerebellar nuclei (Hoffman et al, 2004). In a subsequent study, passive transfer of antistreptococcal sera from immunized mice to naive mice (concomitant with lipopolysaccharides (LPS) to break the blood brain barrier) resulted in antibody deposition in the hippocampus and in the development of motoric and behavioral disturbances similar to those seen in immunized mice (Yaddanapudi et al, 2009). Both studies (Hoffman et al, 2004;Yaddanapudi et al, 2009) support a role for antibodies in the induction of behavioral alterations.…”

“…In a subsequent study, passive transfer of antistreptococcal sera from immunized mice to naive mice (concomitant with lipopolysaccharides (LPS) to break the blood brain barrier) resulted in antibody deposition in the hippocampus and in the development of motoric and behavioral disturbances similar to those seen in immunized mice (Yaddanapudi et al, 2009). Both studies (Hoffman et al, 2004;Yaddanapudi et al, 2009) support a role for antibodies in the induction of behavioral alterations. Although the mouse model was successful in showing behavioral changes in streptococcal-immunized mice and was related to passively transferred antibody, it did not investigate specific neural and immune characteristics reported previously in SC and PANDAS (Husby et al, 1976;Kirvan et al, 2003Kirvan et al, , 2006a).…”

The Immunobiology of Tourette's Disorder, Pediatric Autoimmune Neuropsychiatric Disorders Associated withStreptococcus, and Related Disorders: A Way Forward

“…More recently, the same group extended this model by examining whether peripheral anti-CNS antibodies are sufficient to reproduce the syndrome, and whether or not the effect is eliminated by depleting IgG before transfer into naive mice (Yaddanapudi et al 2009). Their results demonstrated that the immunized animals showed stereotypic behaviors as well as deficits in motor coordination, learning/memory, and social interaction.…”

Multidisciplinary Clinic Dedicated to Treating Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome: Presenting Characteristics of the First 47 Consecutive Patients

“…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 1989Swedo et al , 1993Swedo et al , 1998Mercadante et al 2000;Leonard and Swedo 2001;Kirvan et al 2003;Hoffman et al 2004;Singer et al 2004;Kirvan et al 2006Kirvan et al , 2007Murphy et al 2007;Yaddanapudi et al 2010;Brimberg et al 2012;Lotan et al 2014;Toufexis et al 2014;Williams and Swedo 2014). …”