ABOVE: By vaccinating mice through the vitreous portion of their eyes, researchers induced a protective immune response against pathogens and even cancer cells in the brain. © ISTOCK, unomat

As an extension of the central nervous system, the eyes share an anatomical connection with the brain that is key to an animal’s ability to see. Besides the visual connection, both the brain and the eye are considered immune-privileged sites, wherein the immune response to pathogens is highly controlled to preserve the organ’s functions and minimize potential damage to tissues that do not easily regenerate.1 Despite both organs bearing the immune-privileged tag, the brain has received far more attention than the eye, according to Eric Song, a physician scientist at Yale University. This prompted Song to take a closer look at eye immunity.

In a recent study, Song and his colleagues described how the lymphatic drainage system in the back of the eye communicates with the central nervous system to generate an immune response in the brains of mice.2 Their findings, published in Nature, revealed a previously unknown immunological link between these two organs.      

“We say that the eyes are the windows into the soul. This paper shows that they are also the windows into the immunology of the brain,” said Jonathan Kipnis, a neuroimmunologist at the Washington University in St. Louis, who was not involved in the research.

For their experiments, the researchers focused on the lymphatic drainage system, an essential component of the immune system. The lymphatic system helps remove byproducts and pathogens from tissues and allows the movement of immune cells to sites of infection throughout the body. To map the ocular drainage system, the scientists injected a fluorescently labeled molecule into the anterior and posterior chambers of mouse eyes. They found that these compartments drained into different lymph nodes, with the posterior chamber, or vitreous, draining into the same lymph nodes in the neck that receive drainage from the brain.3,4 

The image shows lymphatic vessels in green and magenta that are present in a thin membrane surrounding the optic nerve.
Researchers found that lymphatic vessels present in the optic nerve sheath mediate eye-brain immunity. They labelled the CD31 marker (red) to visualize endothelial cells, and stained LYVE1 (green) and VEGFR3 (magenta) to show the lymphatic vasculature.
Xiangyun Yin, Yale University

“That's when we realized we had something exciting, and that the two systems might actually share an immune response to the shared lymph nodes,” Song said. 

To explore this potential immunological link between the eye and the brain, the researchers immunized mice with an inactivated version of herpes simplex virus 2 (HSV-2) via the anterior or posterior chambers of the eye. One month later, they challenged the mice with a lethal dose of HSV-2 in the brain and found that immunization through the vitreous protected the mice from the viral infection, whereas immunization through the anterior chamber did not. 

Using a similar vaccination strategy, the team also showed that the vitreous-mediated brain protection extended to other infectious agents such as Streptococcus pneumoniae, the causative agent of bacterial meningitis, and HSV-1. Treating the mice with a cancer cell vaccine via this immunization route also prolonged their survival after tumor cell injection into their brains. 

In subsequent experiments, the team surgically damaged the lymphatic vessels that flow to the deep lymph nodes (dLN), structures in the neck into which the vitreous and brain drain their byproducts. They found that these lymphatic structures are necessary for eye-brain immunity since mice with dLN ligatures succumbed to HSV-2 challenge in the brain, as do nonimmunized animals.           

Next, the researchers investigated the organization of this lymphatic network, which was not well understood. By combining a spatial transcriptomic approach with immunolabeling of lymphatic vessel markers, the team identified a lymphatic vasculature in the optic nerve sheath, a very thin membrane that covers the optic nerve. Intravitreal administration of the lymphatic stimulator vascular endothelial growth factor C (VEGFC) increased the drainage of a fluorescent molecule to the dLN, indicating that this vasculature functionally supports the vitreous drainage to these lymph nodes.

“This paper showed that [drainage from the] anterior chamber of the eye may go into the spleen, but in the posterior chamber, which is closer to the brain, it all goes through the lymphatic vessels and into the deep cervical lymph nodes, which are shared with the brain,” Kipnis explained. “This is the first study to describe that communication.”

Despite the extensive anatomical and functional characterization of this lymphatic drainage system in the eye and its effects on brain immunity, Kipnis remains curious about how the immune cells that mediate the protective response in the brain get there. Song is excited to address this and other questions, hoping to further advance researchers’ understanding of this previously unknown eye-brain connection.  

“This gives us an idea of a new space to study things,” Song said. “Now we can think about ways to both monitor and understand immune responses in the brain, hopefully through the eye, which people have thought about in the past.”

References

  1. Streilein JW. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol. 2003;3(11):879-889. 
  2. Yin X, et al. Compartmentalized ocular lymphatic system mediates eye-brain immunity. Nature. 2024;628(8006):204-211.
  3. Louveau A, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337-341. 
  4. Aspelund A, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015;212(7):991-999.