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
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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"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). "
[Show abstract][Hide abstract]ABSTRACT: Tourette’s syndrome (TS) is a neurodevelopmental disorder characterized by fluctuating motor and vocal tics, usually preceded by sensory premonitions, called premonitory urges. Besides tics, the vast majority – up to 90% - of TS patients suffer from psychiatric comorbidities, mainly attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). The etiology of TS remains elusive. Genetics is believed to play an important role, but it is clear that other factors contribute to TS, possibly altering brain functioning and architecture during a sensitive phase of neural development. Clinical brain imaging and genetic studies have contributed in elucidating TS pathophysiology and disease mechanisms; however, TS disease etiology still is poorly understood. Findings from genetic studies led to the development of genetic animal models, but they poorly reflect the pathophysiology of TS. Addressing the role of neurotransmission, brain regions and brain circuits in TS disease pathomechanisms is another focus area for pre-clinical TS model development. We are now in an interesting moment in time when numerous innovative animal models are continuously brought to the attention of the public. Due to the diverse and largely unknown etiology of TS, there is no single pre-clinical model featuring all different aspects of TS symptomatology. TS has been dissected into its key symptoms that have been investigated separately, in line with the Research Domain Criteria concept. The different rationales used to develop the respective animal models are critically reviewed, to discuss the potential of the contribution of animal models to elucidate TS disease mechanisms.
Full-text · Article · Apr 2016 · Frontiers in Neuroscience
"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). "
"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). "
[Show abstract][Hide abstract]ABSTRACT: Abrupt, dramatic onset obsessive-compulsive disorder (OCD) and/or eating restriction with at least two coinciding symptoms (anxiety, mood dysregulation, irritability/aggression/oppositionality, behavioral regression, cognitive deterioration, sensory or motor abnormalities, or somatic symptoms) defines pediatric acute-onset neuropsychiatric syndrome (PANS). Descriptions of clinical data in such youth are limited.
We reviewed charts of 53 consecutive patients evaluated in our PANS Clinic; 47 met PANS symptom criteria but not all met the requirement for "acute onset." Patients meeting full criteria for PANS were compared with patients who had a subacute/insidious onset of symptoms.
Nineteen of 47 (40%) patients in the study had acute onset of symptoms. In these patients, autoimmune/inflammatory diseases and psychiatric disorders were common in first-degree family members (71% and 78%, respectively). Most acute-onset patients had a relapsing/remitting course (84%), prominent sleep disturbances (84%), urinary issues (58%), sensory amplification (66%), gastrointestinal symptoms (42%), and generalized pain (68%). Inflammatory back pain (21%) and other arthritis conditions (28%) were also common. Suicidal and homicidal thoughts and gestures were common (44% and 17%, respectively) as were violent outbursts (61%). Group A streptococcus (GAS) was the most commonly identified infection at onset (21%) and during flares (74%). Rates of the abovementioned characteristics did not differ between the acute-onset group and the subacute/insidious-onset groups. Low levels of immunoglobulins were more common in the subacute/insidious-onset group (75%) compared with the acute-onset group (22%), but this was not statistically significant (p=0.06).
In our PANS clinic, 40% of patients had acute onset of symptoms. However, those with and without acute onset of symptoms had similar symptom presentation, rates of inflammatory conditions, somatic symptoms, and violent thoughts and behaviors. GAS infections were the most commonly identified infection at onset and at symptom flares. Because of the wide variety of medical and psychiatric symptoms, youth with PANS may require a multidisciplinary team for adequate care management.
Full-text · Article · Feb 2015 · Journal of Child and Adolescent Psychopharmacology