The long-term goal of this Project is to establish whether or not immunological alterations accompany an increase in clinical severity in patients with Tourette's syndrome (TS), obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD). It has been hypothesized that susceptible individuals develop symptoms of these disorders as a result of post-infectious autoimmune processes. Infections with group A beta-hemolytic streptococci are thought to initiate these processes. Two mechanisms have been proposed to explain the putative post-infectious autoimmunity: antigenic mimicry and superantigens (SAGs). We plan to explore each of these mechanisms by performing a prospective longitudinal study of children and adolescents at risk of symptom exacerbation. Based on pilot data reported in a Project, we plan to examine in an exploratory fashion the predictive value of rises in anticytoskeletal, antinuclear, and antineuronal antibodies for ensuing symptom exacerbations. Based on pilot data, we postulate that symptom exacerbations in susceptible individuals are associated with skewing of the T-cell receptor (TCR) V beta repertoire and changes in cytokine expression. In order to evaluate the SAG hypothesis, we will make repeated measures to determine the TCR V beta repertoire of CD4+ T cells and CD8+ T cells using flow cytometry. Patients with Sydenham's chorea are reported to have increased volumes of their basal ganglia. We propose to collect serial magnetic resonance imaging scans to monitor basal ganglia volumes over the course of symptom exacerbation. Patients with autoimmune disorders often share specific HLA alleles within the histocompatability complex. As in a Project, we propose to now test whether a similar sharing of alleles exists. The DR and DQ alleles for all patients will be determined. In contrast to a Project, the HLA genotypes can be examined in relation to clinical and immunological phenotypes defined over the period of the prospective longitudinal study. Phenotypic data will be obtained by direct structured psychiatric interviews of all pertinent family members with respect to the occurrence of symptom exacerbations using expert interviewers trained by the Clinical Core. If specific immunological alterations are consistently associated with acute clinical exacerbations, then the exact nature of these alterations should provide insight as to the immunologic mechanisms involved. Most importantly, this knowledge may provide a basis for the rational design of therapeutic and preventative interventions, primarily in the form of antimicrobial prophylaxis, but possibly including plasmapheresis, IVIG therapy, and future vaccination.
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