How does COVID-19-Active Immune Response Damage the Brain?
Understanding how SARS-CoV-2 can cause brain damage could help inform the development of therapies for COVID-19 patients with persistent neurological symptoms.
“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process remains unknown,” said Avindra Nath, MD, clinical director at NINDS and senior author of the study. clearly understand. “Earlier, we had shown vascular damage and inflammation in the patient’s brain at autopsy, but we didn’t understand the cause of the damage. I think in this paper we had gain important insight into the sequence of events.”
Dr. Nath and his team found that antibodies produced in response to COVID-19 could mistakenly target cells important for the blood-brain barrier. The tightly packed endothelial cells help form the blood-brain barrier, which blocks harmful substances from reaching the brain while allowing essential substances to pass through. Damage to endothelial cells in blood vessels in the brain can lead to leakage of proteins from the blood. This causes bleeding and clotting in some COVID-19 patients and may increase the risk of stroke.
For the first time, the researchers observed the deposition of immune complexes – molecules formed when antibodies bind to antigens (foreign substances) – on the surface of endothelial cells during brains of COVID-19 patients. Such immune complexes can damage tissue by triggering inflammation.
The study builds on their previous research, which found evidence of brain damage from thin and leaky blood vessels. They suspect that the damage may be due to the body’s natural inflammatory response to the virus.
To further explore this immune response, Dr. Nath and his team examined brain tissue from a group of patients in the previous study. Nine people, aged 24 to 73, were selected because they had signs of damage to blood vessels in the brain based on scans of brain structures. Samples were compared with samples from 10 controls. The team looked at neuroinflammation and immune responses with immunohistochemistry, a technique that uses antibodies to identify specific marker proteins in tissues.
As in their previous study, the researchers found signs of leaky blood vessels, based on the presence of proteins in the blood that don’t normally cross the blood-brain barrier. This suggests that the tight junctions between endothelial cells in the blood-brain barrier are damaged.
Dr. Nath and his colleagues found evidence that endothelial cell damage could be due to an immune response – the detection of deposition of immune complexes on the surface of cells.
COVID-19 as a brain autoimmunity activator
These observations suggest an antibody-mediated attack that activates endothelial cells. When endothelial cells are activated, they express proteins called adhesion molecules that cause platelets to stick together. High levels of adhesion molecules were found in endothelial cells in brain tissue samples.
Dr. Nath explains: “Activation of the endothelial cells that carry platelets adheres to the blood vessel wall, causing clot formation and leakage. At the same time, tight junctions between the endothelial cells occur. tissue breaks down causing them to leak,” explains Dr. “Once the leak occurs, immune cells like macrophages can come in to repair the damage, causing inflammation. This causes damage to the nerve cells.”
The researchers found that in areas of endothelial cell damage, more than 300 genes had decreased expression, while 6 genes were increased. These genes are implicated in oxidative stress, DNA damage, and metabolic dysregulation. This may provide clues to the molecular basis of the neurological symptoms associated with COVID-19 and offer potential therapeutic targets.
Taken together, these findings provide insight into the damaging immune response to the brain following COVID-19 infection. But it remains unclear which antigen the immune response is targeting, as the virus itself has not been detected in the brain. It is possible that antibodies against the SARS-CoV-2 spike protein could bind to the ACE2 receptor used by the virus to enter cells. More research is needed to explore this hypothesis.
The research could also have implications for understanding and treating long-term neurological symptoms after COVID-19, including headaches, fatigue, loss of taste and smell, sleep problems, and “fog.” brain blindness”. If the patients in the study survived, the researchers believe they may have developed long-term COVID.
“It is very likely that this same immune response persists in persistent COVID patients leading to neuronal damage,” said Dr. “There may be a small continuing sluggish immune response, meaning that immunomodulatory therapies could help these patients. So these findings have very important therapeutic implications. important.”