Lymphatic vessels, the “roads” that work to clear waste material from the brain, can also carry messages that direct immune system attacks against myelin, promoting the onset of multiple sclerosis (MS), new study shows.
While the identity of these messages remains unknown, the findings suggest that blocking these signals could help to ease or even prevent MS progression.
“Our data suggests that there is a signal coming from the brain to the lymph nodes that tells immune cells to get back into the brain, causing the [multiple sclerosis] pathology,” Antoine Louveau, PhD, the study’s lead author with the University of Virginia (UVA), Department of Neuroscience and its Center for Brain Immunology and Glia (BIG), said in a press release.
“This is an important proof of principle that exploring the role of these vessels in different neurological disorders, including multiple sclerosis, is worth it,” Louveau added.
The study, “CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature,” was published in the journal Nature Neuroscience.
Previously, scientists thought the brain lacked a lymphatic draining system, but experimental data from the research team at UVA and follow-up work by colleagues has identified lymphatic vessels surrounding the brain.
This led the researchers to ask whether autoreactive T-cells, which are involved in MS development, could gain access to the brain via lymphatic vessels located at the meninges. Meninges (derived from the Greek word for membrane) are three membranes that enclose the central nervous system (meaning the brain and spinal cord).
The UVA researchers injected a fluorescent tracer into the cerebrospinal fluid (CSF) of mice. Within one hour, they were able to detect the tracer in meningeal lymphatic vessels, showing that the molecules can enter draining lymph nodes of the brain. The same was observed when they injected antibodies into the CSF.
Importantly, T-cells labeled with the marker and injected into the CSF also accumulated in meningeal lymphatics vessels.
Since the meninges surrounding the brain are rich in several types of immune cell, including T-cells, researchers hypothesized that these cells could use the lymphatic vessels to penetrate lymph nodes located at the neck, called cervical lymph nodes.
Again using a fluorescent marker to track cells, they found that T-cells localized in the meningeal and CSF spaces were able to find their way into cervical lymph nodes.
Additional experiments identified the receptor protein called CCR7 (short for C-C chemokine receptor type 7) as the protein that mediates the trafficking of T-cells into these lymph nodes. CCR7 is actually a main regulator of T-cells and other immune cells moving through the lymphatic system.
“Meningeal lymphatic vessels are quite small compared to other lymphatics in the body, and we and others wondered if this might limit the amount and size of cargo they can pass through,” said Jasmin Herz, a study author. “During inflammation, they did not change in size or complexity much, but what was really exciting to discover [was that] they allowed whole immune cells to traffic through them, and we found the molecular cues for that.”
Researchers next assessed the role of these meningeal lymphatics vessels in a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE) model.
Using a laser, they cut the vessels and saw this delayed EAE development in mice and led to a milder disease, accompanied by fewer inflammatory T-cells infiltrating the spinal cord.
“The idea was to prevent more widespread damage to the nervous system,” Herz said. “If communication of brain inflammation through lymphatic vessels is the root cause of multiple sclerosis, therapies targeting these vessels could be clinically important.”
Overall, the findings suggest that the content of the CSF carries important “messages” that travel through the meningeal lymphatic system, and are important in turning T-cells into autoreactive, MS-triggering cells. However, their content remains unclear.
“I think the next step in this specific research is to identify what that signal is. Is it a cellular signal, is it a molecular signal?” Louveau said. “And then to try to target that signal specifically.”
Since removing lymphatic vessels in the meninges of mice only eased the MS phenotype, other mechanisms might be involved in disease development, the team suggested.
Of note, while cutting the vessels helped ease MS severity, enhancing their function proved vital to halt the cognitive decline seen with aging, including in Alzheimer’s disease and other neurodegenerative diseases.
“These findings on the role of brain-draining lymphatic vessels in MS, together with our recent work on their role in Alzheimer’s disease, demonstrate that the brain and the immune system are closely interacting. When these interactions go out of control, pathologies emerge,” said Jonathan Kipnis, chairman of UVA’s neuroscience department and director of the BIG Center.
The UVA team recently entered into an agreement with PureTech Health, a biopharmaceutical company, to explore possible clinical applications of these discoveries.