Reimagining immunity in the eye
Immune cells could be doing much more than we think in protecting our
eyes

Date:
December 8, 2021
Source:
Thomas Jefferson University
Summary:
Immune cells could be doing much more than we think in protecting
our eyes -- researchers uncover new details.



FULL STORY ========================================================================== There's a lot that our eyes have to protect themselves from -- dust and
debris; viruses and bacteria; chemicals from things we use every day
like soaps and lotions; ultraviolet radiation from the sun; and hours
of looking at computer screens or devices. It might be surprising then
to learn that parts of the eye that are central to vision -- the lens,
cornea and retina -- are immune privileged, meaning they lack immune
cells and the protection they offer. But then how do these critical
tissues protect themselves?

==========================================================================
A few years ago, Sue Menko, PhD, professor of Pathology, Anatomy and
Cell Biology at Thomas Jefferson University and researchers in her lab
were studying a mouse that was engineered to lack a key protein required
for the perfectly clear structure of the lens. As they expected, without
this protein, the lens was malformed. But to their surprise, they also
observed immune cells in the lens trying to fix the damage. This was the
first time immune cells had been found to be recruited to the lens, and it challenged decades of scientific dogma. Building on their evidence, last
year the Menko lab, in a collaboration with Mary Ann Stepp's lab at George Washington University, found that when the cornea was wounded, immune
cells travelled to the surface of the lens to protect from further damage.

Now in a new study published in The FASEB Journal on Dec 7th, the
researchers show that immune cells respond to the lens, not just following
an acute injury in the eye, but also to long-lasting inflammation. In collaboration with Dr.

Rachel Caspi's lab at the National Eye Institute and the Stepp lab, they studied a mouse model of uveitis, a form of eye inflammation triggered by infection or injury, and is considered to be an autoimmune disease like diabetes. Left untreated, uveitis can lead to a number of complications, including retinal scarring, glaucoma and cataracts of the lens. However, because the lens was thought for so long to have immune privilege,
the role of immune cells in cataracts associated with uveitis has never
been explored.

Dr. Menko and her lab used high-resolution microscopy to look at the whole
eye and the surface of the lens. The first thing the researchers wanted
to know was, do immune cells interact with the lens in this experimental
model of uveitis? They were shocked at what they saw.

"In our previous study in which the cornea was wounded, we saw a small
number of immune cells on the surface of the lens, acting almost like sentinels," says Dr. Menko. "In this case, it was like a battering
ram. There were dozens of immune cells, and different types of them,
including T-cells and macrophages.

It's clearly a robust immune response and could reflect in part
that inflammation in uveitis is so severe." The researchers then
monitored this immune response to the lens over the course of 26 days,
as inflammation sets in at day 14, reaches its peak at day 19 and begins
to resolve by day 26.



========================================================================== Using their high-powered microscopes, they observed different regions
of the lens' surface. On either side of the lens are two fluid-filled
chambers -- the aqueous humor at the front of the eye between the lens
and the cornea, and the vitreous humor at the back of the eye, separating
the lens and the retina. In uveitis, one or both chambers become filled
with immune cells. However, it's been thought that the lens is protected
from these immune cells by the thick protein-rich layer that surrounds
it, called the lens capsule.

JodiRae DeDreu, a PhD student in Dr. Menko's lab at Jefferson and first
author of the study, stained the lens with fluorescent markers to label
a protein that makes up the capsule in red, immune cells in green and
their nuclei in blue.

She then captured high resolution images and used imaging software
to create 3D renderings of the capsule to detect changes in its
structure. The software allowed her to look at all three colors at the
same time, remove one or two, or make one of the colors transparent.

"When we look at the colors together, we see these blue dots, which are
the nuclei of the immune cells, sticking out of the red surface of the
lens capsule," explains DeDreu. "When you take away the blue nuclei, we
see these deep pits or divots along the capsule. This is evidence that
the immune cells are actually integrating into the lens capsule, which
had never been shown before." Not only do the number of divots increase
over time from day 14 to day 19, but also become deeper, indicative of increasing invasion into the lens capsule as the disease progresses.

Their collaborators in Dr. Stepp's lab confirmed this by using a scanning electron microscope, which can capture detailed changes on the surface of
the lens capsule. They found many bumps, indicating regions where immune
cells had become integrated within the lens capsule. This correlated
with the fluorescent labeling results from the Menko lab.

Immune cells are well-equipped to get to places where there might be
damage or infection, secreting enzymes that break down tissues that are
in the way. But are they able to get past the thick lens capsule? In a surprising finding, the researchers found that some immune cells were
able to do so and actually infiltrate into the lens tissue.

"Till now, the mechanisms for damage that happen in this region of the
eye after uveitis have been poorly understood," says Dr. Menko. "For
the first time, we've been able to provide evidence that immune cells
could be driving this damage, particularly to the lens." It also opens
up possibilities of understanding lens pathology in other eye diseases
like glaucoma.

Interestingly, they also found that even after uveitis begins to resolve
at day 26 and the majority of immune cells were gone, there were still
some that remained integrated on the surface of the lens capsule and infiltrated into the lens tissue itself.

"Why are these cells sticking around? Are they providing some
continued surveillance, or could they predispose the eye to future inflammation?" asks Dr. Menko. "And what is the ultimate fate of these
cells?" These questions form the foundation of future studies for the
Menko lab, and the answers to them could reveal important new roles of
immune cells in the eye. Importantly, their work thus far underscores
that the presence of immune cells in the eye is much more complex than previously thought.

========================================================================== Story Source: Materials provided by Thomas_Jefferson_University. Original written by Karuna Meda. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. JodiRae DeDreu, Sonali Pal‐Ghosh, Mary J. Mattapallil,
Rachel R.

Caspi, Mary Ann Stepp, A. Sue Menko. Uveitis‐mediated
immune cell invasion through the extracellular matrix of the lens
capsule. The FASEB Journal, 2021; 36 (1) DOI: 10.1096/fj.202101098R ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211208110301.htm

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