by Chris Pittenger, MD, PhD

This work was funded in part by a 2015 IOCDF Research Grant to Luciana Frick with significant contributions from Kyle Williams. 

This article was initially published in the Summer 2018 edition of the OCD Newsletter. 

For most people with obsessive compulsive disorder (OCD), symptoms appear gradually over time. However, some children experience a sudden, almost overnight, onset of OCD symptoms. Researchers have observed that in some of these children, OCD symptoms appear alongside an infectious illness, such as the one caused by the Streptococcus bacterium (“Strep”). This combination of signs and symptoms is called “Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus”, or PANDAS. Though PANDAS was first recognized in the late 1990s, there is still much that we don’t know about the disorder; there is no definitive diagnostic test, and we are still not entirely sure what it is about a Strep infection that might be causing some children to quickly develop OCD. Our research sought to better understand how the body’s immune system may be playing a role.

“Cross-Reactivity” Hypothesis
Researchers have long speculated that PANDAS may be caused by the body’s immune system responding to a Strep infection in a way that also affects the brain. In order to understand how this might be the case, it’s important to consider how the body’s immune system works to fight infection. When the body senses the presence of an illness-causing bacteria or virus (a pathogen), it generates proteins called antibodies. Antibodies enter the bloodstream and travel throughout the body. They attack and neutralize the pathogens, helping our bodies heal from infection. Most of the time, our antibodies are “smart” enough to avoid attacking healthy cells and tissue. Sometimes, in a phenomenon called “cross-reactivity”, antibodies attack our own cells. Cross-reactivity is the cause of some autoimmune disorders, and we think that it plays a role in PANDAS as well.

We hypothesize that in children with PANDAS, the antibodies raised by their immune systems to fight Strep bacteria are also targeting healthy cells in the brain, and that this cross reaction is what causes OCD symptoms. Some of the available medical treatments for PANDAS, which include antibiotic therapy and intravenous infusion of immunoglobulin (IVIG), are based on this hypothesis. While there is some research that has looked at which molecules the antibodies in PANDAS patients may be targeting, much remains unclear.

Study Details
If PANDAS works through cross-reactivity of antibodies with targets in the brain, it should be possible for us to identify the cells in the brain that the antibodies are binding to. Our research study sought to do just that. We took serum (the part of human blood that contains antibodies) from seven children who are diagnosed with PANDAS, and who recently took part in an IVIG treatment trial at the National Institute for Mental Health. We introduced this serum into the brains of laboratory mice. We also took serum from healthy children who do not have PANDAS, and introduced it into the brains of a different group of mice, for comparison. We then examined the brains of the mice to see what cells the antibodies were sticking to. We repeated this experiment using serum taken after the children with PANDAS had undergone IVIG treatment. In that way, we hoped to see if IVIG treatment was changing the way that antibodies interacted with the brain.

Results
We focused on a part of the brain called the basal ganglia, which we know to be affected in OCD. Within the basal ganglia, antibodies from children with PANDAS bound specifically to a particular type of neuron, termed the cholinergic interneurons, much more than antibodies from healthy control children. There were not differences in the binding of PANDAS antibodies to other neuron types – the effect seems to be specific to these cholinergic interneurons. When we performed the experiment with serum from the same children with PANDAS drawn after they had undergone IVIG treatment, antibody binding to the cholinergic interneurons was reduced.

Significance
These cholinergic interneurons have been linked by previous research to Tourette’s syndrome. The brains of people with severe Tourette’s, studied post-mortem, have a reduced number of cholinergic interneurons, when compared to the brains of people without Tourette’s. Other research from our lab has found that disrupting the cholinergic interneurons in mice causes repetitive, tic-like behavior – that is, damage to these neurons can cause behaviors that may recapitulate aspects of Tourette’s, which often occurs together with OCD (and PANDAS). This previous research, combined with what we have discovered through this project, suggests that PANDAS may be caused by antibodies that target the cholinergic interneurons in the brains of affected children.
There are limitations to our study. The most important is that the approach we used is extremely laborious, and as a consequence we studied a very small number of children with PANDAS. It will be important to try our approach in a larger number of subjects, so that we can be sure that what we observed is not specific to the seven children that were part of our study, and is applicable to the wider population of children with PANDAS. Looking at a larger number of children will also allow us to better understand whether there are correlations between the types of cross-reactions that we see, and the symptoms and other characteristics of individual children.

Despite these limitations, this investigation may provide an important new insight into the causes of PANDAS. By clarifying how antibodies affect the brains of children with PANDAS, this research helps to confirm the reality of the diagnosis, and may open new avenues for diagnostic tests and treatment. Establishing standard diagnostic testing for PANDAS, rather than relying on clinical diagnosis, would allow more children to receive proper diagnosis and effective treatment, sooner.

Notes

  • Researchers have long thought that PANDAS may be the result of the body’s immune system targeting cells in the brain.
  • New research shows antibodies from PANDAS patients attach more frequently to certain cells in the brains of mice—the same cells that are implicated in Tourette’s.
  • Antibodies attached themselves to these brain cells less frequently after patients had undergone IVIG, a therapy for PANDAS.