Glaucoma affects 70 million people worldwide and is the most common cause of irreversible blindness. While the primary risk factor for glaucoma is high intraocular pressure (IOP), the mechanisms that underpin the disease aren’t fully understood. Studies in mice by a team at the Massachusetts Eye and Ear Hospital, and the Massachusetts Institute of Technology (MIT) now suggest that glaucoma could be an autoimmune disease. Their findings indicate that the high IOP triggers an autoimmune response by T cells that are primed to attack nerve cells in the eye because of previous contact with the many different types of bacteria that naturally live in the body.
The researchers hope that the discovery could lead to new glaucoma treatments that target this autoimmune reaction. “Our work shows that there is hope for finding a cure for glaucoma, or even preventing its development entirely, if we can find a way to target this pathway,” comments co-senior author Dong Feng Chen, M.D., Ph.D., a vision scientist at Massachusetts Eye and Ear, and associate professor of ophthalmology at Harvard Medical School. “Current glaucoma therapies are designed solely to lower eye pressure; however, we've known that, even when patients with glaucoma are treated and their eye pressure returns to normal, they can still go on to have vision loss. Now, we know that stress from high eye pressure can initiate an immune response that triggers T cells to attack neurons in the eye.”
The researchers reported their findings today, in a paper in Nature Communications, titled, “Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma.”
Glaucoma is caused by gradual degeneration of retinal ganglion cells (RGCs) and nerve axons. However, while high IOP is the most important risk factor, and is believed to cause some direct damage to neurons and the optic nerve, it’s not the complete answer. Glaucomatous nerve cell damage can also occur in patients with normal IOP, while the progressive loss of neurons and vision may continue in patients whose IOP is controlled by drug therapy, the authors point out. In these cases, mechanisms other than pressure-mediated damage may be involved.
One possibility is that a stress mechanism, such as high IOP, may trigger secondary immune or autoimmune responses. It’s a hypothesis that is supported by multiple previous studies in human patients and animal models of glaucoma, which have discovered serum antibodies against heat shock proteins (HSPs) and retinal deposits of immunoglobulins. HSPs are a family of proteins that are produced in response to stress, and which vary very little between different types of organism and species. Other studies have shown that injecting HSPs into the eyes of rats induces nerve cell damage that is similar to that caused by glaucoma, and that high IOP induces the expression of HSPs in the retina. “Thus, a link among IOP elevation, HSP upregulation, and induction of anti-HSP autoimmune responses in glaucoma has been suggested,” the authors write. “… however, the roles of these events in the disease pathogenesis remain unknown.”
A potential immune system connection to glaucoma raises another “a critical question,” because the eye is an immune privileged site, so how could an autoimmune response, such as that against HSPs in the eye, be induced in glaucoma? The authors suggest that because HSPs are among the most highly conserved proteins between species, it is feasible that immune responses and memory induced originally to HSPs produced by bacteria that live naturally in the body, might be reactivated by the host’s own HSPs, which are produced in response to high IOP.
The authors set out to investigate this further, initially mouse models of induced and spontaneous high IOP. Their results showed that high IOP somehow allowed T cells to penetrate the blood-retinal barrier into the retina, and that this T cell infiltration was associated with RGC and axonal loss. Interestingly, neurodegeneration continued even after IOP was returned to normal in the induced model.
In contrast, inducing high IOP in mice that lacked B and T cells led to a small amount of retinal damage, but there was no progression of damage after IOP was returned to normal. Their initial studies and experiments in the B cell- and T cell-deficient animals hinted that neurodegeneration in glaucoma might be a two-stage process, which is initially triggered by high IOP. “… the acute phase correlates with the IOP elevation, likely mediated by physical stress; the prolonged retinal degeneration, which continues even after IOP has returned to normal, is mediated by T cells,” they write. “Neither T- nor B-cell deficiency attenuates the initial phase of neural damage, but T cells are an essential player in the prolonged phase of glaucomatous RGC and axon degeneration.… Supporting this notion, mice deficient in T cells, but not B cells, displayed a dramatically attenuated RGC and axon damage.”
The next stage was to look for which autoantigens might be responsible for stimulating the mobilization of T cells in glaucoma. HSPs seemed a logical starting point, given that prior research had identified autoantibodies to HSPs in both human glaucoma patients and animal models of the disease. Using their mouse models, the team found that while levels of HSPs were low in the retinas of animals with normal IOP, inducing high IOP led to a three-fourfold increase in HSP levels, and this high IOP then triggered the activation of CD4+ T cell responses targeting the HSPs. More detailed analyses confirmed that the T cells infiltrated the retina, and were responsible for the prolonged phase of RGC and axon degeneration characteristic of glaucoma.
Using their mouse models, the researchers then investigated how T cell responses to high IOP might are induced, especially given that the retina is an immune-privileged site. “We hypothesized that mice harbor memory T cells to bacterial HSPs that can be activated by host HSPs through molecular mimicry when the blood-retinal barrier is compromised by elevated IOP, ” the team noted. With this hypothesis in mind, they reasoned that mice raised in a completely germ-free environment wouldn’t exhibit the HSP-specific T cell responses or retinal neurodegeneration in response to IOP elevation.
In fact, this is exactly what they found. Increasing IOP in the germ-free mice prompted the production of elevated levels of HSPs, but there was no resulting T cell infiltration or T cell activation. Nor did the germ-free animals develop the characteristic glaucomatous RGC or axon damage. Results from the experiments also showed that the induction of a complete repertoire of HSP-specific T cell responses and retinal neurodegeneration required pre-exposure to a wide range of microbial flora, not just one or a few different species. IOP-induced retinal damage was reduced in a mouse model that only carried a few commensal bacterial species.
The team’s findings in mice were supported by the results of blood tests in human patients with primary open angle glaucoma (POAG), the most common form of glaucoma, which showed that human glaucoma patients exhibited more than fivefold higher levels of HSP-responsive T cells than healthy individuals.
“This is the first report that, to our knowledge, describes 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 authors state. “… these findings are compelling as they suggest the essential involvement of a T-cell-mediated mechanism in the pathogenesis of glaucoma.” The team concluded that their findings may “lead to a paradigm shift for the diagnosis, prevention, and treatment of glaucoma.”