Induction of Subthalamic Dysfunction by Tourette Antibodies and Anti-Rheumatogenic-M-Protein Antibodies: Development of a Rodent Model of Neuronal Dysfunction

Grant Type
Grant Year
Institution Location
Institution Organization Name
Memorial Hospital of Rhode Island
Investigators Name
Harling-Berg, Christine, PhD

Can a streptococcal protein cause the generation of misguided antibodies which can bind to brain cells and affect their function? The immune system is designed to protect us from pathogens, such as bacteria and viruses. In response to an infection, antibodies (immune proteins) are normally generated within our bodies. Antibodies (generally referred to as immunoglobulins), protect by binding or sticking to these pathogens and promoting their elimination. The consequences of antibody binding can be powerful. Therefore, the immune system tries to discriminate, that is, to make antibodies which will specifically bind to foreign pathogenic “intruders,” but not the body’s own proteins and cells. Some children with Tourette Syndrome (TS), however, have antibodies in their blood which have been shown to bind to human nerve cells, probably a protein embedded on the surface (or membrane) of the nerve cell. In other words, despite the immune system’s protective intentions, antibodies have been produced that do bind to the body’s own cells. There are two important questions relevant to these “anti-neuronal antibodies.” First, what causes the body to generate anti-neuronal antibodies? Second, do they bind to nerve cells within the brain and change the way nerve cells function, ultimately changing behavior? With respect to the first question, we suspect that one cause could be infection with a rheumatogenic (causing rheumatic fever) bacteria known as group A beta-hemolytic streptococci, type 5 (GABHS-5). Portions of this bacteria’s molecular structure are similar to portions of the molecular structure of proteins normally found within the human brain. Therefore, antibodies made to protect against GABHS-5 infection are cross-reactive, and will bind to both GABHS-5 and, unintentionally, nerve cells. Addressing the second question, we have used an animal model to show that TS antibodies have the ability to bind to rat brain cells and disrupt behavior. Immunoglobulins from TS blood samples (containing all types of antibodies) were introduced into the rat striatum—a region of the brain associated with regulating behavior. Vocal and motor activity were altered in these rats, and TS immunoglobulins were found bound to rat nerve cells in the striatum. Considering this evidence, the main goal of our proposal is to determine whether the TS antibodies which bind to nerve cells and disrupt behavior in rats consist of antibodies made against GABHS-5 (antiGABHS-5 antibodies). TS immunoglobulins will be infused into an area of the rat brain which is associated with behavior and disruption in motor activity and will be measured over 4 days. The experiment will then be repeated in a second group of rats (group 2). However, this time the antiGABHS-5 antibodies will be removed from the TS immunoglobulins. We predict that in the first group, motor function will be affected and TS immunoglobulins will be bound to rat brain cells, but in group 2, these events will not occur. To understand more precisely the role of antiGABHS-5 antibodies in brain function, we have begun parallel studies in a rat model. Here rats are immunized with a protein from a GABHS-5. It is our hope that a strong understanding of antibody-mediated neuronal dysfunction will help in the development of more effective treatments for people with TS. Christine J. Harling-Berg, Ph.D. Memorial Hospital of Rhode Island, Pawtucket, RI Award: $40,000 Tourette Association of America Inc. – Research Grant Award 2000-2001