Findings: New Look at Eye’s Immune Status
“I love to challenge dogma,” says A. Sue Menko, PhD, who has a knack for doing so.
Knowing how crucial the lens of the eye is to vision, she recently overturned the long-standing assumption that this tissue is immune-privileged. “It just didn’t make sense that in evolution there wouldn’t be ways for the lens to protect and repair itself,” says Menko, a professor of Pathology, Anatomy and Cell Biology at Thomas Jefferson University.
Menko’s interest in the eye’s immune status was spurred by a 2013 conversation with her longtime collaborator, Mary Ann Stepp, PhD, a corneal wound researcher at George Washington University. “From the moment we started talking about how this dogma doesn’t make sense, we thought we would be able to find a way to prove it,” Menko recalls.
“Previously, people assumed that the anterior segment of the eye, including the lens, was immune privileged just because it is avascular,” says Menko, noting that her refutation of this accepted wisdom was “definitive” in her Nature Scientific Reports paper, “Induction of Immune Surveillance of the Dysmorphogenic Lens” (epublished in November 2017).
Working with first author Caitlin M. Logan, PhD, a third-year medical student at Jefferson, and second author Caitlin J. Bowen, MS, Menko used a knockout mouse model with a lens malformation (caused by deletion of N-cadherin in the lens) to assess the eye’s immune surveillance system. “Dysgenic tissues are where immune cells react, so we thought this is the easiest way to prove our point that immune cells can get to the lens,” says Menko. “Our remarkable results show a large immune surveillance in the eye and a coordinated protective response throughout the visual system of the cornea, vitreous humor, and retina to defects in lens tissue.”
Recent discoveries that the brain is immune-quiescent, not immune-privileged—and that lymphatic vessels extend immune response to the brain—informed Menko’s experimental methods. Her lab asked if lymph vasculature also extended to the lens via the most likely path: the ciliary zonules, the fibrillar ligaments that suspend the lens in the eye and link to the vascular-rich ciliary body. They labeled the eyes for both MAGP1, a component of the zonules, and LYVE-1, a protein expressed on vascular cells and the surface of immune cells. While the results were positive for LYVE-1, no vascular cells could be detected. “This finding showed that lots of immune cells had traversed along the ligaments to the lens and left behind their footprints,” says Menko. These are virtual footprints—leftover, cleaved-off LYVE-1 proteins from immune cells. The data suggest that the ciliary zonulas serve as a vasculature-free molecular highway that’s a conduit for immune response.
Caitlin J. Bowen, MS (right), of Jefferson’s College of Health Professionals, conducts research while working toward certification to become a high school science teacher. Sue Menko, PhD (left), says of Bowen, “She has developed some amazing data on immune surveillance of the lens in response to corneal wounding, and is the best teacher in the world. I will miss her terribly when she gets her next job.”
“We additionally showed that the immune cells can become fibrotic disease-causing myofibroblasts,” says Menko. “This could totally change the way we think about cataract-causing diseases and ways we could possibly
prevent cataracts and posterior capsular opacification
(a fibrosis-related complication in 20 to 40 percent of cataract surgeries). You’re talking about potential causes of cataract and are there new ways we could now prevent that from happening, and new ways to improve treatment of eye wounding.”
“We’re interested in all aspects of understanding how the eye protects itself, and specifically the role of immune cells and their connection to fibrosis, which is a problem in almost every tissue in the eye,” says Menko, who chairs Jefferson’s Committee on Research and leads Jefferson’s Programmatic Initiative on Fibrosis. “This aligns with the big passion and focus of my research, which is how to prevent cells that are involved in repair from tipping the balance to fibrosis.”
Menko’s experimental methods for the Scientific Reports paper were developed in tandem with her ongoing collaboration with Stepp, whom she has known since their postdoctoral years; this spring they’re preparing to submit a paper for publication that further applies these methods with important results on immune surveillance of the lens in response to corneal wounding.
The culture of Menko’s seven-member research group is informed by her 2013 fellowship in Executive Leadership in Academic Medicine for women faculty (the ELAM© program at Drexel University). “I learned a huge amount from that about what becoming a leader means,” Menko says, noting that the program taught her to build on her strengths in caring about all the people with whom she interacts, especially those she relies on to help achieve her scientific goals. “I tell people in this lab, ‘You are all my colleagues. You may have better ideas than me. I am not the dictator of ideas, and we need to think together.’
“I owe a lot to the people with whom I interact on a regular basis for being willing to not only share ideas, but also challenge what I’m thinking,” Menko adds. “I’ve been really lucky to be able to interact with brilliant colleagues, who are happy to think outside the box.
By Jessica Stein Diamond