An important BREAKTHROUGH finding has been revealed by Dr. Chandra Menendez, an emerging young scientist in immunopathology and neuroinflammation related to Group A Strep infections and associated autoimmunity, from the Cunningham Lab at the University of Oklahoma Health Sciences Center.
Dopamine Receptor Autoantibodies Target the Basal Ganglia
Everyone with a Group A Strep infection makes helpful antibodies that attack the bacteria. However, some of these antibodies become harmful by inadvertently attacking a brain region called the basal ganglia potentially resulting in symptoms of PANDAS/PANS and Sydenham chorea.
The term used to describe the production of these autoimmune-related antibodies, known as autoantibodies, is molecular mimicry. In this particular example, molecules expressed by Group A Strep ‘mimic’ dopamine receptors 1 and 2 resulting in the production of autoantibodies that stick to dopamine receptors. While there are ways your immune system discourages the production of these pathological autoantibodies some slip through the cracks and cause harmful autoimmune reactions.
It turns out that both dopamine receptors (D1R and D2R) are expressed in high abundance in the basal ganglia. Could this explain why PANDAS/PANS children show evidence of basal ganglia encephalitis?
Dopamine Receptor Autoantibodies Cause Receptor Activation (Not Inhibition)
The anti-D1R and anti-D2R autoantibodies stick to dopamine receptors 1 and 2 resulting in their overstimulation. Specifically, the overstimulation of D1R was associated with PANDAS/PANS children exhibiting tics and OCD while children with Sydenham chorea were found to have high levels of anti-D2R autoantibodies. The study also mapped exactly where these antibodies bind to the dopamine receptors and showed that they enhance normal dopamine signaling.
Study Details
Dr. Menendesz consistently detected these autoantibodies in both blood and cerebral spinal fluid from the following large groups of patients (cohorts) collected independently by medical professionals:
- Cohort 1 – 25 children with SC & PANDAS from the original NIMH PANDAS cohort compared to SC
- Cohort 2 – 35 children with PANDAS studied from the NIMH and Yale from the Intravenous
- Cohort 3 – 858 children with PANDAS or PANS from Univ of Oklahoma
- Cohort 4 – 14 children with acute SC from international regions with endemic Rheumatic Fever
The findings of the article are visually summarized here:
Significance
For the past 20 years, it has been difficult to identify and distinguish the pathological characteristics of PANDAS/PANS and Sydenham chorea. Now, through meticulous research and biomarker analysis, it has been shown that D1R autoantibody levels can effectively identify neuropsychiatric symptoms in PANDAS compared to healthy individuals. Additionally, D2R autoantibodies serve as a useful biomarker for movement-related symptoms, such as chorea, in both PANDAS and Sydenham Chorea.
An important key takeaway is that upper respiratory infections can activate immune cells in the nasal area, triggering cytokines that disrupt the blood-brain barrier (allowing the autoantibodies into the brain). This highlights the importance of accurate diagnostic tools that measure both dopamine autoantibodies and cytokine activity, as well as the need for immunomodulatory treatments. Therapies like IVIG, plasma exchange, and new targeted approaches have been shown to effectively reduce immune responses in both PANDAS and Sydenham Chorea
Diagnostics
This work supports the clinical significance of the Autoimmune Brain Panel from Moleculera in identifying patients with PANDAS/PANS and Sydenham chorea. We at the PANDAS Network will continue to advocate for the use of anti-D1R and anti-D2R and biomarkers for PANDAS/PANS and Sydenham chorea.
Let’s Keep The Ball Rolling!
This work was partly funded by generous donations from supporters of the PANDAS Network. We would like to stress just how important your donations are toward fueling progress in PANDAS/PANS biomedical research.
We won’t stop until PANDAS/PANS is unanimously understood, promptly diagnosed, and effectively treated with approaches covered by all health insurance companies. If you share the same vision please consider making a donation, big or small, to support PANDAS research.