IMMUNE MECHANISM MEDIATED GOA

 

Glaucoma is commonly associated with raised intraocular pressure (IOP). However, it is known that some patients develop/progress glaucomatous neurodegeneration in the absence of raised IOP. This has led to various non-pressure-mediated theories, such as vascular, biochemical, and inflammatory, responsible for glaucomatous optic atrophy (GOA).

Another possibility is that pathophysiological stress, such as that induced by elevated IOP, triggers secondary immune or autoimmune responses, leading to retinal ganglion cell (RGC) and axon damage even after the initial insult is gone.

The evidence for an autoimmune component in glaucomatous neurodegeneration includes the presence of a wide range of serum auto-antibodies particularly those against heat shock proteins (HSPs) and retinal deposits of immunoglobulins in glaucoma patients and animal models of glaucoma.

Experimental studies report inoculation of rats with human HSP27 and HSP60 induces an optic neuropathy that resembles glaucomatous neural damage, and elevated IOP has been reported to induce expression of HSPs in the retina, particularly RGCs.

 Therefore, there is a possibility of an association between IOP elevation, HSP upregulation, and induction of anti-HSP autoimmune responses in glaucoma.

It is also thought that the anti-HSP immune responses are induced originally by bacterial HSPs, and are reactivated by host HSPs during glaucoma. The facts that glaucoma patients exhibit increased titers of antibodies against Helicobacter pylori and that immunization with HSPs in rats induces glaucomatous neural damage are in line with this possibility.

In a study performed by Chen et al, microbeads (MB) were injected in the anterior chamber to increase IOP in one study population of mice. The control group was injected with saline.

The retina in the MB group showed infiltrating T-cells at 2 weeks after MB injection. The T-cells were scattered throughout the retina without apparent clustering or preference to any specific quadrant. The number of T cells then declined by 4 weeks.

During the infiltrative period, the glaucomatous retina also showed CD4+, but not CD8+, T cells in the ganglion cell layer (GCL), CD11b+ microglia, and macrophages.

The RGC and axon loss continued up to 8 weeks after MB injection, the longest time point that the mice were monitored. These results show that a transient elevation of IOP induces T cell infiltration into the retina and a prolonged period of retinal neurodegeneration, even after the IOP has returned to the normal level.

The study demonstrated that:

(1) a transient elevation of IOP is sufficient to induce CD4+ T-cell infiltration into the retina;

(2) T-cell responses are essential in the development of progressive GOA following IOP elevation;

(3) both bacterial and human HSPs are target antigens of these T cells; and 

(4) HSP-specific CD4+ T-cell responses and glaucomatous neurodegeneration are both abolished in mice raised in the absence of commensal microbial flora (germ-free (GF) mice), supporting a mechanism of bacteria-sensitized T-cell responses underlying the pathogenesis of glaucoma.

These observations identify a sequence of events that contribute to progressive GOA, implicating immune mechanisms, possibly in response to commensal flora.

REFERENCE:

Chen H, Cho KS, Vu THK, Shen CH, Kaur M, Chen G, Mathew R, McHam ML, Fazelat A, Lashkari K, Au NPB, Tse JKY, Li Y, Yu H, Yang L, Stein-Streilein J, Ma CHE, Woolf CJ, Whary MT, Jager MJ, Fox JG, Chen J, Chen DF. Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma. Nat Commun. 2018 Aug 10;9(1):3209. doi: 10.1038/s41467-018-05681-9.