Ann Hui Ching

In a study published last month, Yale researchers demonstrated how the eyes serve as an immunological barrier that protects the brain. 

Led by Eric Song, an associate research scientist and resident physician at the School of Medicine, the researchers found that injecting vaccines directly into the eyes of mice can activate an immune response, potentially protecting mice from brain infections caused by the herpes simplex virus. According to Song, their findings demonstrate that physicians could use the eye’s immune response to help fight bacteria and tumors. 

“We hear this phrase a lot: ‘the eye is like a window to the brain,’” Song told the News. “That’s kind of centered around this idea that the eye is central nervous system tissue, like the brain.” 

Song explained that when diseases affect the neurons, they are often observable in both the brain and the eye’s retina. His study demonstrated that immune reactions in the retina mirror those in the brain. His team discovered that stimulating the immune system in the retina can also protect the brain against diseases and tumors. 

“I think it’s important because this opens up a new anatomical avenue that hasn’t been described before,” Song said. “Our paper is the first to really show that there’s functional lymphatic vessels.” 

Song and his team primarily study “immune privilege,” a concept initially proposed in the 1940s which suggests that immune responses are significantly reduced in the brain and eyes. For a long time, the scientific community believed that these organs were immune-inactive, Song said. However, infections and autoimmune diseases still occur in these sites, which indicates that there is a present immune response distinct from other parts of the body. 

Song and his team previously discovered that the brain and eyes lack traditional lymphatic vessels, which help drain proteins and fluids. However, they identified that the membrane tissues surrounding these organs do contain lymphatic vessels, and physicians can manipulate these vessels to enhance immune responses.

The eye’s anterior and posterior compartments have different drainage systems to the lymph nodes, parts of the immune system that filter substances in the lymphatic fluid and contain white blood cells to help the body fight infections. 

In this study, Song and his team found that the posterior compartment drains through the optic nerve, which can be enhanced or inhibited to affect immune responses. Lymphatic vessels at the back of the eye and those surrounding the brain are interconnected and drain into the same lymph node, which facilitates a coordinated immune defense.  

They also discovered that blocking the lymphatic system’s communication in the optic nerve can reduce the immune system’s reaction to adeno-associated virus. This virus is often used in gene therapy, a technique that modifies a person’s gene to treat or cure a disease. 

They found that when the herpes vaccine is injected into the eye, it induces an immune response. By blocking this response, gene therapy could be more effective, as the vector viruses will not be attacked by the immune system, enabling the modification of genes. 

Ellen Foxman, a professor of immunobiology at the School of Medicine, noted that one of the initial FDA-approved gene therapies for a genetic eye disease had little effect because the body created an immune defense against the virus used to deliver the gene therapy. But now, Song and his team’s study offers a method to suppress this immune response, potentially enhancing gene therapy’s effectiveness. 

“It’s really exciting because there’s sort of a lore that the eye is an immunologically privileged site,” Foxman said. “It’s just that you don’t have any immune responses against things in the eye and the brain. But this challenges that dogma and says, ‘Well, let’s see, is that really true?’”

According to Akiko Iwasaki, Sterling Professor of Immunobiology at the School of Medicine, certain individuals have mutations or deficiencies in gene expression that lead to eye diseases. But gene therapy can compensate for these missing genes and introduce them to the body via viral vectors. While previously these vectors were quickly eliminated from the eye, Song’s findings suggest that scientists could obstruct this draining and prevent an immune response that would typically flush out this vector. 

“It’s significant because [the study] has many clinical implications,” Iwasaki said. “Now that we understand this new lymphatic drainage system, and [Song] manipulated it to enable gene therapy more efficiently. Other drugs can also benefit from this new knowledge and strategy of either blocking or enhancing the posterior eye drainage.”

Iwasaki also said that Song’s technique could be leveraged to use for gene therapy in the eye. 

The discovery opens up new avenues for treating a variety of eye-related diseases. Currently, Song and his team are investigating how their findings could be useful for treating other diseases that affect the eye, such as glaucoma and macular edema. He said that he will continue to look at other features of the nervous system and if there are other barriers to allowing effective immune responses.

“I think there’s still a lot of work to be done in order for anything to be translational,” Song said. “It should be our job and other labs to really focus down on specific diseases of the eye or the brain and see how this applies in those settings.”

Iwasaki also said scientists should conduct clinical trials to ensure the techniques are both effective and safe before applying their discoveries to human therapies. Nevertheless, Iwasaki said he is optimistic for its use in future clinical practice. 

“I suspect that translation of this finding is relatively straightforward,” Iwasaki said. 

The concept of gene therapy first arose in the 1960s.