Autoimmunity in Neuropsychiatric Disorders

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of California
Investigators Name
Hoffman, Kurt, PhD

Tourette syndrome (TS), tic disorders, and obsessive-compulsive disorder (OCD) have overlapping symptoms such as tics, obsessive and intrusive thoughts, attentional deficits, and compulsive and repetitive behaviors. These conditions have a strong genetic basis for vulnerability, most often begin in childhood, and are linked to dysfunction in a group of brain structures called the basal ganglia. Many interacting genetic, environmental, and developmental factors could contribute to basal ganglia dysfunction and result in the symptoms of TS and OCD. During childhood, developing and maturing neural circuitry of the basal ganglia may be particularly vulnerable to environmental insults, including infection or abnormal immune responses to infectious agents. Such insults may perturb normal brain development or function, and thus result in neuropsychiatric symptoms. Abnormal immune function associated with group A b-hemolytic streptococcal (“strep throat”) infection has been proposed to be a factor in the pathogenesis of a subset of TS, chorea, tic disorders, and OCD. Dr. Susan Swedo and colleagues at the National Institutes of Health defined a subgroup of childhood-onset OCD that has an episodic course, sudden exacerbation of symptoms associated with streptococcal infection, and neuropsychiatric abnormalities, including hyperactivity and tics. This diagnostic subtype is designated by the acronym PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections). PANDAS is believed to be caused by an abnormal immune response to the streptococcal infection that targets the basal ganglia and interrupts their function. I am testing the hypothesis that basal ganglia autoimmunity is responsible for the tics and obsessive-compulsive symptoms seen in PANDAS. One prediction of the autoimmune hypothesis is that self-reactive antibodies (called “autoantibodies”) directed against the basal ganglia may be present in the serum of individuals with PANDAS. Using control and PANDAS serum samples provided to us by Dr. Swedo, we will test for the presence of antibodies that react with brain tissue. Preliminary data show a difference in serum antibody reactivity between control and PANDAS subjects. These results may provide greater insight into how an abnormal immune response to this common childhood infection could cause psychiatric illness and movement disorders. A second prediction of this hypothesis is that experimentally-induced autoimmunity targeting the basal ganglia in an animal model system may result in behavioral abnormalities analogous to those seen in PANDAS. In mice, as in humans, the basal ganglia are responsible for the control of movement, and moreover, behavioral symptoms of basal ganglia dysfunction in mice are similar to those in humans. Experiments are ongoing in which mice are immunized during early development with streptococcal or basal ganglia homogenates. Preliminary results show that some of these mice produced autoantibodies that bound to the basal ganglia, and other specific regions of the brain. This suggests that brain autoimmunity had been induced. Future studies will further characterize experimentally-induced brain autoimmunity, and determine its effect on basal ganglia-mediated behaviors. In addition to testing the autoimmune hypothesis of PANDAS, these experiments should define periods of developmental vulnerability of basal ganglia circuits to autoimmune or infectious insults. A long-term goal of this work is to establish mouse model systems in which to study the role of central nervous and immune system interactions in the development of neuropsychiatric symptoms. These studies may provide insight into the mechanisms of immune system dysfunction in TS and OCD, and suggest new strategies for prevention and treatment of these disorders. Kurt L. Hoffman, Ph.D. University of California, Irvine CA Award: $43,366 Tourette Association of America Inc. – Research Grant Award 2001-2002