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


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.

Download full-text


Available from: Mady Hornig, Apr 11, 2014
39 Reads
  • Source
    • "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 , 1993 , 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 , 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"
    [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.
    Journal of Child and Adolescent Psychopharmacology 02/2015; 25(1):38-47. DOI:10.1089/cap.2014.0081 · 2.93 Impact Factor
  • Source
    • "Obsessive-compulsive disorder (OCD), tic disorders, a subgroup of childhood-onset OCDs called Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal (PANDAS) are pre-pubertal onset autoimmune neuropsychiatric disorders associated with the basal ganglia abnormalities in which antibodies produced against Group A Beta Hemolytic Streptococcus (GABHS) infections cross react with neuron epitopes.[1] Therefore, these disorders are referred as post-streptococcal movement disorders.[2–7] OCD and tic disorders may be triggered by stress, anxiety, and illnesses (for example; GABHS infections).[8] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is a newly defined disease in neuropsychiatry and occurs with an autoimmune mechanism after Group A Beta Hemolytic Streptococcus (GABHS) infection. Tumor necrosis factor (TNF), encoded by TNF-α gene has an important role in the apoptotic mechanisms of autoimmune diseases. Recently, TNF-α polymorphisms and autoimmune/psychiatric disorders have been reported to be related. In this regard, we focused on to investigate a possible relation between the TNF-α gene promoter region-308 G/A and - 850 C/T polymorphisms and PANDAS. In this study, ages of PANDAS patient and control groups were ranging from 4 years to 12-year-old. Patient group includes childhood onset PANDAS patients (n = 42) and control group includes healthy children (n = 58). Diagnoses have been carried out according to Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) criteria with Affective Disorders and Schizophrenia-Present and Lifetime (KSAD-S-PL) and Children Yale-Brown Obsessive Compulsive Scale Moreover, PANDAS criteria established by the American National Psychiatry Institute have been employed for diagnoses. For identifying polymorphisms; Polymerase Chain Reaction, Restriction Fragment Length Polymorphism and Polyacrylamid Gel Electrophoresis were used. For -308 polymorphism, 37 of 42 PANDAS patients' results and for -850 C/T polymorphism, 38 of 42 PANDAS patients' results were obtained. According to our statistical analysis there is a positive relationship between PANDAS patients for -308 G/A polymorphism but not for -850 C/T polymorphism. There is no positive relationship between -308 G/A polymorphism and antistrep-tolysin O (ASO) titers and no relationship between -850 C/T polymorphism and ASO titers. We found, however, positive relationship between genders of patients (boys) and the disease. According to our results, we propose that the AA polymorphism of -308 G/A polymorphism can be used as a molecular indicator for PANDAS.
    Indian Journal of Human Genetics 04/2013; 19(2):196-201. DOI:10.4103/0971-6866.116116
  • Source
    • "Circumstantial evidence for autoimmunity includes environmental triggers of relapses, familial risk, and response to immune modulating therapies (Murphy, Sajid, & Goodman, 2006). Recreating the illness either by animal models via recreation of autoimmune pathology or by passive transfer of antibodies has been mixed (Loiselle, Lee, Moran, & Singer, 2004; Yaddanapudi, et al., 2009). In addition, poor standardization in the field for phenotype characterization and assay methodology has hampered progress thus far. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A commonality across a number of pediatric neuropsychiatric disorders is a higher than typical rate of familial - and especially maternal - autoimmune disease. Of recent interest, a subtype of obsessive-compulsive disorder (OCD) and tic disorders known collectively as Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) is believed to be secondary to central nervous system (CNS) autoimmunity that occurs in relation to group A streptococcal infection. Thus, we hypothesized that a sample of children with OCD and/or tics would have an increased maternal risk for an autoimmune response relative to population norms. We also expected maternal prevalence of various autoimmune diseases to be higher among those participants that met the putative criteria for PANDAS. We examined, via structured interview, the medical history of the biological mothers of 107 children with OCD and/or tics. Autoimmune disorders were reported in 17.8% of study mothers, which is significantly greater than the general prevalence among women in the United States (approximately 5%). Further, study mothers were more likely to report having an autoimmune disease if their children were considered "likely PANDAS" cases versus "unlikely PANDAS" cases. The results offer preliminary support for hypothesized links between maternal autoimmune disease and both OCD/tics and PANDAS in youth. Further research is necessary to clarify these general associations; links to specific autoimmune disease; and relevance of autoimmune disease in other family members (e.g., fathers).
    Journal of neuroimmunology 12/2010; 229(1-2):243-7. DOI:10.1016/j.jneuroim.2010.08.017 · 2.47 Impact Factor
Show more