February 2019


Research highlight
Autoimmune component of glaucoma pathogenesis discovered

by Liz Hillman EyeWorld Senior Staff Writer

Epifluorescence photomicrograph showing an image taken from a flat-mounted retina of a glaucomatous mouse that was double immunolabeled for T cells (green) and retinal neurons (red) while all cell nuclei were also counter-stained by a nuclei marker (blue). Note T cells infiltrated the retina and localized close to the vicinity of retinal neurons and the nerve fibers (red).
Source: Dong Feng Chen, MD, PhD

Paradigm-shifting research finds that autoimmune response might lead to glaucomatous disease state

There are a number of risk factors that could increase one’s odds of developing glaucoma, but just what causes glaucoma remains poorly understood. A paper published in Nature Communications1 presents research that could represent a paradigm shift as to the root cause of this vision-threatening condition.
Through a series of experiments, the research from MIT and Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School suggests that glaucoma might be an autoimmune disorder.
“The finding is a surprise, largely because the eye is considered an immune-privileged site. Thus, the treatment of glaucoma has been focused solely on the intraocular pressure for decades,” said Dong Feng Chen, MD, PhD, associate professor of ophthalmology, Harvard Medical School, Boston. “However, the idea is emerging in recent years, in part because even perfect control of IOP does not seem to halt the disease progression in many patients, and also because many patients with glaucoma do not have elevated IOP; this is especially prevalent in Asian [patients] and can reach as high as 90%. For example, 90% of Japanese patients with glaucoma show normal IOP. What led to our team’s effort in autoimmune mechanisms [was] that when we developed this method of inducing glaucoma in mice, we noticed that mice also exhibited what ophthalmologists found in human patients: The neural damage in glaucomatous mice continued to occur even after IOP was returned to normal. It suggests that elevation of IOP may be a triggering factor that turns on a chronic mechanism to cause neuron loss, and immune or autoimmune responses usually are the consequences.”
Dr. Chen’s laboratory was among the first 7 years ago to develop a convenient method to induce glaucoma in mice, allowing her and other investigators to explore the roles immune players, such as T and B cells, might play in glaucomatous neural damage. The involvement of commensal microflora, specific to this recent study, began about 4 years ago, Dr. Chen said.
In short—and at a basic level— the research by Dr. Chen and fellow investigators found that the body’s immune reaction to bacteria can generate a response toward both bacterial and host heat shock proteins that trigger a T cell response. These T cells are then able to enter the retina and cause damage. So how are these potential disease-causing T cells able to enter the retina, an area from which they would otherwise be restricted? Dr. Chen speculated they could be entering under high IOP conditions or other injury of the eye.
“It is thought that elevated IOP compromised retina-blood barrier, thus opening the door to allow T cells coming in,” she said.
According to the study authors, this is the first report, to their knowledge, that shows an “unexpected link and the sequential roles of elevated IOP, intact commensal microflora, and activation of T cell responses in the pathogenesis of glaucoma.” The research shows that in the mouse model, elevated IOP results in an acute and prolonged phase of retinal neuron degeneration, the latter of which continues after IOP has returned to normal and, according to the study, is mediated by T cells. The researchers also observed certain mice with a lack of heat shock protein-specific T cell response and subsequent lack of neural damage, which provides evidence that IOP elevation does not, in and of itself, necessarily contribute to progressive retinal damage.
“It is the subsequent event, involving T cell responses, which have been pre-sensitized by commensal microflora, that mediates progressive glaucomatous neurodegeneration,” Chen et al. wrote.
Regarding commensal microflora, the researchers showed less damage to retinal ganglion cells and axons in mice with only eight defined bacteria, which they think indicates a T cell response by heat shock proteins “requires a diverse flora rather than a specific bacterium.”
Though most of the research involved glaucoma in induced and genetic mouse models, it showed that a heat shock protein specific T cell response occurred in human patients as well.
“These findings show that IOP elevation triggers secondary anti-HSP CD4+ T cell responses that mediate a prolonged retinal neurodegeneration, providing an explanation for continued neurodegeneration in patients with normal or perfectly controlled IOP,” according to Chen at al.
More specifically, human patients with glaucoma had T cells specific to heat shock proteins that were five times higher than normal.
Ultimately, Dr. Chen said this research could yield a new biomarker for early glaucoma detection as well as new treatment targets.
“Glaucoma can be a systemic disease,” Dr. Chen said. “The overall health, infection, autoimmune disorders, and other ocular injury or diseases of patients can have significant impact on glaucoma progression.”
This is not the first time glaucoma has been proposed as having systemic origins. Research by Astafurov et al. published in 2014, for example, identified an oral microbiome link to the neurodegeneration in glaucoma.2


1. Chen H, et al. Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma. Nat Commun. 2018;9:3209.
2. Astafurov K, et al. Oral microbiome link to neurodegeneration in glaucoma. PloS One. 2014;9:e104416.

Editors’ note: Dr. Chen has no financial interests related to her comments.

Contact information

Chen: Dongfeng_Chen@MEEI.HARVARD.EDU

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