Interleukin-17A (IL-17A), a molecule that mediates immune and inflammatory responses, likely promotes inflammation and tissue damage in relapsing-remitting multiple sclerosis (RRMS) and should be considered a potential target for treating the disease, a study reports.
The findings of the study, “IL-17A is associated with the breakdown of the blood-brain barrier in relapsing-remitting multiple sclerosis,” were published in the Journal of Neuroimmunology.
Previous studies have shown that IL-17 is produced by certain immune cells and nerve cells at active brain lesions in the central nervous system (CNS; composed of the brain and spinal cord), where its effects, combined with those of other pro-inflammatory molecules, cause inflammation and tissue damage.
It is also known that IL-17 can disrupt the integrity of the blood-brain barrier (BBB), a highly selective and semipermeable barrier that protects the brain from possible insults (like viruses) carried in the blood. It does so by interfering with cells that line the walls of small blood vessels (endothelial cells) and which are a point of contact between the brain and the body.
Studies in mouse models have also shown that lowering brain levels of IL-17A, through specific drugs or genetic manipulation, may slow the deterioration of the BBB and some symptoms of experimental autoimmune encephalomyelitis (EAE) in animal models of multiple sclerosis. EAE mimics key features of MS in humans.
Now, researchers from Genentech, a subsidiary of Roche, in collaboration with investigators from the Weill Institute for Neurosciences, set out to explore the mechanisms by which IL-17 compromises BBB integrity, and leads to the development of EAE in mice.
First, researchers showed that treating animals with an anti-IL-17A antibody reduced disease activity in mice with EAE. However, treatment with an anti-IL-17F antibody that targeted IL-17F, another member of the IL-17 family that shares many similarities with IL-17A, did not have any effect.
Then, the team analyzed cerebrospinal fluid (CSF) samples from 50 RRMS patients, and found their levels of IL-17A abnormally high compared to healthy individuals serving as controls. Of note, CSF is the liquid that circulates in the brain and spinal cord.
Researchers also found that the unusually high IL-17A levels in patients’ CSF correlated with the CSF/serum albumin ratio (Qalb), a measure of BBB dysfunction. This was true for the first group of 50 RRMS patients analyzed, and for a second group of 69 RRMS patients at an early stage of the disease.
Finally, the investigators found that when they treated brain endothelial cells cultured in a lab dish with IL-17A and IL-6 (which has been linked to MS development and BBB breakdown), the expression levels of genes encoding proteins necessary to maintain BBB integrity, such as OCLN, TJP1, CDH5, and PECAM1, were low, resulting in abnormally high cellular permeability of the BBB.
But unlike IL-17A, levels of IL-6 in the CSF of RRMS patients did not correlate with Qalb.
“Taken together, our findings reaffirm the importance of IL-17A, likely acting as an amplifier of inflammatory cytokine signaling, as a mediator of tissue damage in RRMS and should be considered as a therapeutic target to preserve BBB integrity in these patients, potentially in combination with other inflammatory [molecules] such as IL-6,” the researchers wrote.
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