(December 14, 2015 online) Journal of Clinical Investigation publishes a SIGNIFICANT STEP IN UNDERSTANDING THE MECHANISMS of PANDAS. Scientists investigated how Group A Strep Causes Autoimmune Reactivity, Breaks Down the Blood Brain Barrier (BBB), and then allows Autoantibodies Specific to Strep to Enter the BBB. The immune cell found (TH17) and its sometimes concomitant inflammatory processes is often found in the blood system of people diagnosed with autoimmune illnesses such as rheumatoid arthritis or multiple-sclerosis. These TH17 cells were also found in a sampling of tonsils from PANDAS subjects investigated in the study. This research is VERY EXCITING because it shows how infectious agents play a role in PANDAS and potentially other CNS (central nervous system) autoimmune diseases.
Group A Streptococcal (S. pyogenes) infections, the primary cause of acute pharyngitis in children, are associated with several autoimmune diseases including those of the central nervous system (CNS), Sydenham’s chorea and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS). Sydenham’s chorea is characterized by uncoordinated motor involvement, and is reported to occur in 20-30% of children with acute rheumatic fever.
As an increasingly recognized neuropsychiatric risk, PANDAS represents a subset of individuals with abrupt onset of obsessive-compulsive behavior (OCD), anorexia nervosa, separation anxiety and other abnormal behaviors. Autoantibodies generated against S. pyogenes that recognize various neuronal targets are found in sera from acutely ill children. However, the mechanisms that allow autoantibodies to cross the blood-brain barrier (BBB) and induce immunopathology remained unresolved. S. pyogenes is known to induce a robust Th17 cell response in the nasal-associated lymphoid tissue (NALT), a tissue that is equivalent to the human tonsils, in mice that are infected intranasally with live bacteria. Yet it was unclear if these Th17 cells travelled to the brain and induce neuropathology.
In the latest issue of the Journal or Clinical Investigation that was published online on December 14th, 2015, Dr. Dritan Agalliu’s laboratory in the Department of Neurology, Stroke division at Columbia University, in collaboration with the laboratory of Dr. Patrick Cleary in the Department of Microbiology at the University of Minnesota, have identified that Streptococcal A-specific Th17 cells (a type of immune cell in the body) are found in the naturally-exposed human tonsils, prompting to explore whether bacterial-specific immune cells home to mouse brains following intranasal infection.
The scientists found that repeated intranasal infections with Strep A promoted 1. bacterial-specific Th17 cell movement from the NALT (nasal tissue) into the brain, 2. blood-brain barrier breakdown, 3. serum IgG deposition, 4. neuroinflammation and 5. loss of excitatory synaptic proteins, under conditions where no viable bacteria were detected in the brain.
T cells were located predominantly in the olfactory bulb suggesting that these cells had migrated from the nose into the brain along the olfactory sensory axons that send information about the sense of smell to the brain.
Once in the brain, the Th17 cells release proteins (cytokines) that are known to break down the blood-brain barrier, allowing circulating autoantibodies to cross the leaky blood-brain barrier, enter the brain and recognize neuronal targets. These findings provide new insights into the immunopathology of PANDAS and suggest a general mechanism by which infectious agents could exacerbate symptoms associated with other CNS autoimmune disorders.
Below is a list of future PANDAS/PANS research projects. If interested in funding these exciting projects, please contact us for information on how you can help.
George Lynn Cross Research Professor
Presbyterian Health Foundation Presidential Professor
Department of Microbiology and Immunology
University of Oklahoma Health Sciences Center
Dr. Cunningham’s Current Research:
Investigation of anti-neuronal autoantibodies and their mechanisms of action in movement and behavioral disorders including PANDAS and PANS.
Correlation of autoantibodies and immune responses with disease onset and symptoms in defining movement and behavioral disorders including PANDAS and PANS.
Tanya Murphy, MD, MS
Maurice A. and Thelma P. Rothman Chair of Developmental Pediatrics
Professor, University of South Florida
Departments of Pediatrics and Psychiatry
Dr. Murphy’s Future Projects:
Microbiome Analysis in Children with PANS/PANDAS.
Examination of Macrophage Function in Children with PANS/PANDAS.
Healthy control Biorepository for PANS/PANDAS research.
Michael Cooperstock, MD, MPH
Chief, Division of Infectious Diseases
Department of Child Health
University of Missouri Health Care
Dr. Cooperstock’s Future Projects:
Pupillary light reflexes: A rapid, simple, highly accurate biomarker to aid diagnosis, quantitate neural dysfunction, examine pathogenic mechanisms, and study the effects of environmental stresses and therapeutic trials on neuronal function while following the course and outcome of PANS and PANDAS.
A prospective investigation of the factors affecting the often very high levels of “normal” neural autoantibodies in a general pediatric population, and an examination of the neurobehavioral correlates of these “normal” antibodies.
Application of a newly available extended panel of Streptococcal antibodies: (1) Greatly improved accuracy in serodiagnosis of group A Streptococcal colonization and infection. (2) Determine relationships between multiple Streptococcal antibodies and various neural autoantibodies in healthy children and children with PANDAS.
Dritan Agalliu, Ph.D.
Departments of Neurology, Pathology and Cell Biology, Pharmacology
Columbia University Medical Center
Dr. Agalliu’s Current Research at the Agalliu Lab:
Agalliu laboratory is investigating several fundamental issues in the biology of the mammalian blood-brain barrier (BBB):
The mechanisms that govern the development and maintenance of the BBB.
How structural components of the BBB are affected in diseases of the brain and spinal cord where barrier function is impaired including stroke, MS and PANDAS.
The role of Wnt signaling in repairing the damaged BBB in CNS diseases.
PANDAS is being investigated and research is forthcoming in 2016 on the role of Th17 cells that trigger inflammation and destruction of the BBB.