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

Article (PDF Available)inMolecular Psychiatry 15(7):712-26 · September 2009with55 Reads
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.
    • "Obsessions and compulsions were observed in post-streptococcal infection and pediatric autoimmune neuropsychiatric disorders, then commonly referred to as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) [199][200][201]. An animal model was established to study if these antibodies cause neuropsychiatric symptoms [202]. Plasma exchange affects the disease and removal of the autoantibodies could cause improvement of symptoms in OCD and tic disorders in childhood [203]. "
    [Show abstract] [Hide abstract] ABSTRACT: Little is known about the etiology of neuropsychiatric disorders. The identification of autoantibodies targeting the N-methyl-d-aspartate receptor (NMDA-R), which causes neurological and psychiatric symptoms, has reinvigorated the hypothesis that other patient subgroups may also suffer from an underlying autoimmune condition. In recent years, a wide range of neuropsychiatric diseases and autoantibodies targeting ion-channels or neuronal receptors including NMDA-R, voltage gated potassium channel complex (VGKC complex), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R), γ-aminobutyric acid receptor (GABA-R) and dopamine receptor (DR) were studied and conflicting reports have been published regarding the seroprevalence of these autoantibodies. A clear causative role of autoantibodies on psychiatric symptoms has as yet only been shown for the NMDA-R. Several other autoantibodies have been related to the presence of certain symptoms and antibody effector mechanisms have been proposed. However, extensive clinical studies with large multicenter efforts to standardize diagnostic procedures for autoimmune etiology and animal studies are needed to confirm the pathogenicity of these autoantibodies. In this review, we discuss the current knowledge of neuronal autoantibodies in the major neuropsychiatric disorders: psychotic, major depression, autism spectrum, obsessive-compulsive and attention-deficit/hyperactivity disorders.
    Full-text · Article · Apr 2016
    • "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). "
    Full-text · Chapter · Feb 2016 · PLoS ONE
    • "These data differ from that in SC where an association has been identified between ASO titers and antibodies against the dopamine D1 and D2 receptor [16]. Animal models have also been used to support an association between streptococcal antibodies and disease symptoms [19, 20, 50]. To our knowledge, there has never been a study attempting to correlate streptococcal antibodies and anti-neuronal antibody titers or CaMKII activity in the PANDAS-choreiform cohort. "
    [Show abstract] [Hide abstract] ABSTRACT: Several autoantibodies (anti-dopamine 1 (D1R) and 2 (D2R) receptors, anti-tubulin, anti-lysoganglioside-GM1) and antibody-mediated activation of calcium calmodulin dependent protein kinase II (CaMKII) signaling activity are elevated in children with Sydenham's chorea (SC). Recognizing proposed clinical and autoimmune similarities between SC and PANDAS (pediatric autoimmune neuropsychiatric disorder associated with a streptococcal infection), we sought to identify serial biomarker changes in a slightly different population. Antineuronal antibodies were measured in eight children (mean 11.3 years) with chronic, dramatic, recurrent tics and obsessive-compulsive disorder (OCD) associated with a group A β-hemolytic streptococcal (GABHS) respiratory tract infection, but differing because they lacked choreiform movements. Longitudinal serum samples in most subjects included two pre-exacerbation samples, Exac), one midst Exac (abrupt recurrence of tic/OCD; temporally association with a GABHS infection in six of eight subjects), and two post-Exac. Controls included four groups of unaffected children (n = 70; mean 10.8 years) obtained at four different institutions and published controls. Clinical exacerbations were not associated with a significant rise in antineuronal antibody titers. CaMKII activation was increased at the GABHS exacerbation point in 5/6 subjects, exceeded combined and published control's 95th percentile at least once in 7/8 subjects, and median values were elevated at each time point. Anti-tubulin and anti-D2R titers did not differ from published or combined control group's 95th percentile or median values. Differences in anti-lysoganglioside-GM1 and anti-D1R titers were dependent on the selected control. Variances in antibody titers and CaMKII activation were identified among the institutional control groups. Based on comparisons to published studies, results identify two groups of PANDAS: 1) a cohort, represented by this study, which lacks choreiform movements and elevated antibodies against D2R; 2) the originally reported group with choreiform movements and elevated anti-D2R antibodies, similar to SC. Increased antibody mediated CaMKII activation was found in both groups and requires further study as a potential biomarker.
    Full-text · Article · Mar 2015
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