To process the complex visual world, the eye connects to the brain through the optic nerve. Light enters the eye and quickly converts into electrical signals that flow along the optic nerve until they arrive at the occipital cortex. Scientists believed that this was the only direct connection between the eye and brain. Yet, when Eric Song, an immunologist and ophthalmology resident at Yale School of Medicine, and his colleagues began investigating where the drugs from eye injections end up, they found a previously hidden immunological nexus between the eye and the brain (1).
Song’s team showed that the optic nerve also serves as a lymphatic drainage system that leads to shared immune responses between the eye and brain. Specifically, a compartment at the back of the eye drains from the optic nerve into the same lymph nodes in the neck that collect cerebrospinal fluid. The finding unlocks new opportunities to explore therapeutic treatments for diseases of the eye and central nervous system.
“This really opens the door to stop thinking about the eye and the brain as a signaling privileged organ and isolated organ, but an organ system that really interacts with each other through an immunological pathway,” said Song.
This is really the beginning of trying to understand how the eye can be a sensor for things that are happening in the central nervous system beyond just light sensing.
– Eric Song, Yale School of Medicine
In the new work, Song’s team discovered that the lymphatic vessels that exist along the optic nerve sheath are conserved across diverse species in humans, primates, pigs, and even zebrafish. In mice, the researchers injected viral and bacterial intravitreal immunizations at the back of the eye and demonstrated that the immune responses were similar to those from local immunizations in the brain. They also showed that effective immune responses to brain tumors in mice could be generated via intravitreal immunizations.
“As you can imagine, we're not going to go around immunizing people into the eye just to have a protective immune response in the brain. So, we thought about in what kind of scenario … can we take advantage of this new finding?” said Song. They decided to test whether they could dampen immune responses that limit the effectiveness of retinal dystrophy gene therapy over time. By blocking the lymphatic signaling on the optic nerve in mice, they successfully reduced the immune response and improved the efficacy of gene therapy.
Now, Song’s team is studying how the optic nerve sheath lymphatic system influences diseases of the central nervous system and how they can manipulate it for therapeutic benefits. “The lymphatic system is an interesting system because there's actually no pharmacological agents or drugs that can stimulate lymphatics,” Song said.
The new results also invite investigations to probe whether the eye can alert the brain to incoming threats. “This is really the beginning of trying to understand how the eye can be a sensor for things that are happening in the central nervous system beyond just light sensing,” said Song. “It's really exciting to know that there's still a lot to be discovered … It's right under our noses.”
References
- Yin, X. et al. Compartmentalized ocular lymphatic system mediates eye–brain immunity. Nature 628, 204–211 (2024).
