Did you know that the brains of children with PANDAS and PANS can become inflamed due to peripheral infection? In this blog post, we will share the latest research findings on the diagnosis and treatment of these diseases, made possible by generous donations from PANDAS Network families. This science shows the importance of early diagnosis and appropriate treatment to prevent progressive brain damage in this complex patient population.

Font: Looking at the Brain of PANDAS and PANS Childon

What are PANDAS and PANS?

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS) are a group of autoimmune diseases or autoinflammatory disorders that affect the central nervous system (CNS).. These disorders are triggered by infections, whether bacterial, viral, or fungal, which occur when the body's immune system inappropriately attacks healthy brain tissue, causing neurological and/or psychiatric symptoms. Post-infectious responses in PANDAS and PANS primarily affect the region of the brain known as the basal ganglia, which are a group of interconnected structures within the brain that are associated with regulatory functions such as motor, cognitive, and emotional movement and the procedural learning. Due, PANDAS and PANS are mainly characterized by a sudden onset of abnormal movements and/or psychiatric symptoms..

How do peripheral bacterial or viral infections cause brain inflammation?

Peripheral bacteria or viruses can cause brain inflammation in a number of ways. One of them is through the production of toxins or antigens that can cross the blood-brain barrier (BBB), which is a protective layer that separates the brain from the bloodstream. Another way is by activating immune cells called T lymphocytes, which can recognize antigens as foreign and produce antibodies to fight them. However, in some cases, these antibodies can mistake healthy brain tissue for the antigen and attack it, causing damage and inflammation. This phenomenon is known as molecular mimicry or cross reaction. Besides, activation of T lymphocytes can release chemicals called cytokines, which can disrupt the normal functioning of brain cells and lead to changes in behavior and mood.

How do peripheral bacteria or viruses work?

Infections cause brain swelling. Repeated exposure to an infectious agent, such as Group A Streptococcus or Group A Streptococcus, or a virus such as COVID-19, causes the body to mount an immune response against the infectious agent.. The body produces antibodies to fight the invading infection. However, in certain patients, this immune response leads to the production of abnormal antibodies, known as autoantibodies, which attack the host's own healthy brain cells. How these autoantibodies enter the brain is not well understood. Recent research on mice and children with PANDAS may provide an answer.

What are Th17 and Th1 lymphocytes?

The Th17 and Th1 lymphocytes are proinflammatory immune cells that are generated to fight bacterial infection. However, in many autoimmune diseases, these cells can cause a misdirected immune response that targets the host's own healthy cells. Research studies in mice suggest that Th17 lymphocytes can travel along the nerves that detect odor, called olfactory nerves, from the nose to the brain. Once in the brain, Th17 cells release inflammatory cytokines that are important for immune cell communication. These cytokines also stimulate specialized immune cells in the CNS called microglia, which release their own inflammatory cytokines. In addition to microglial activation, Th17 lymphocytes release two proinflammatory cytokines called IL-17A and GM-CSF.

What causes damage to the blood-brain barrier?

These inflammatory cytokines cause the BBB or blood-brain barrier to break down in two ways. First, they damage the tight junction, or TJ, proteins of endothelial cells.. TJ proteins bind BBB endothelial cells to each other and prevent the transport of molecules from the blood to the brain. The second way that cytokines disrupt the BBB is by increasing transcytosis, or the transport of molecules within endothelial cells and into the brain..

The BBB is a limit highly selective semipermeable specialized cells known as endothelial cells that line the blood vessels of the brain and prevent molecules circulating in the blood from entering the brain indiscriminately.

How is this relevant to PANDAS and PANS?

Damage to tight junctions and increased endothelial transcytosis allow potential autoantibodies circulating in the blood to enter the brain, where they can cause further damage.

Recent work at Yale University with children with PANDAS and PANS has shown that once these autoantibodies crossed the BBB, they attack a group of neurons in the basal ganglia called cholinergic interneurons, which are important for movement and mood. In addition, work from the University of Oklahoma has suggested that these antibodies interact with dopamine receptors in the basal ganglia, causing their abnormal activation and causing mood and movement disorders. Recent studies in the mouse model have further shown that blocking IL-17A function does not prevent Th17 lymphocytes from entering the brain. However, this treatment is very effective in blocking microglial activation and preventing damage to the blood-brain barrier, thereby improving disease outcomes. Therefore, therapies that target IL-17A may prove beneficial in children suffering from PANDAS and PANS.

Human studies have identified that a set of proinflammatory cytokines are highly elevated in children with PANDAS and PANS in the acute phase of the disease. Furthermore, these pro-inflammatory cytokines are capable of breaking down the BBB in research experiments. This implies that they can potentially trigger BBB rupture in patients.

This is the first study that have identified lymphocytes Th17 and to the cytokines IL-17A and GM-CSF as important players in causing the rupture of the BBB after repeated group A streptococcal infections in mice. Additional studies are currently underway to examine the role of cells Th17 or other immune cells in humans suffering from PANDAS and PANS. To improve the diagnosis of these CNS disorders, it is imperative to develop biomarkers that can be used to test for disease. These tests can range from blood tests, cerebrospinal fluid inflammatory cytokine tests, and dynamic contrast-enhanced imaging tools to MRI to detect BBB rupture during disease flares. Existing therapies that target IL-17A have already been developed and are being used to treat certain autoimmune diseases. These therapies may prove beneficial in children suffering from PANDAS and PANS.

Results from studies of the mouth indicate that there is a previously undiscovered communication between the CNS and adaptive cellular immunity to infections. this may help understand how other CNS autoimmune disorders develop, such as Sydenham's chorea, a PANDAS and PANS-related disease, multiple sclerosis, NMDAR encephalitis, and long-term COVID. Additionally, these findings support the need for early identification of PANDAS and PANS cases and the critical role of immunity.

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