IMMUNOLOGICAL BASIS OF GLAUCOMA

 

Experimental and clinical studies suggest a role of auto-immunity in the pathogenesis of glaucoma. A wide range of serum auto-antibodies especially against heat shock proteins (HSPs) and deposits of immunoglobins have been detected in glaucoma patients, as well as, animal models of glaucoma, pointing to an immunological mechanism for the causation of glaucoma.

It has been found that even transient intraocular pressure (IOP) elevation is sufficient to induce T-cell infiltration into the retina. This T-cell infiltration leads to a prolonged phase of retinal ganglion cell (RGC) degeneration that persists after IOP returns to a normal level.

A study found that inoculation of rats with human HSP27 and HSP60 induced an optic neuropathy that resembles glaucomatous neural damage, and elevated IOP has been reported to induce expression of HSPs in the retina, particularly in the RGCs. [1]

Therefore, an association of elevated IOP, HSP upregulation, and induction of anti-HSP autoimmune responses in glaucoma has been suggested.

A critical question is how autoimmune responses, such as those against HSPs, are induced in glaucoma? As HSPs are among the most highly conserved proteins from bacteria to mice to humans (up to 60% identity), a possibility is that the anti-HSP immune responses are induced originally by commensal bacterial HSPs, and are reactivated by host HSPs during glaucoma.

The fact 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. 

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Both bacterial and human HSPs are target antigens of T cells; retina-infiltrating T cells cross-react with human and bacterial HSPs. 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 commensal microflora sensitized T-cell responses underlying the pathogenesis of glaucoma.

Chen et al, have 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. Their study indicates a need for prior exposure to commensal microbial flora in the induction of both HSP-specific T-cell responses as well as RGC and axon loss following IOP elevation. [1]

HSP-specific T-cell responses probably contribute to normal-tension glaucoma (NTG) as HSP immunization elicits glaucomatous RGC loss in rats. Elevation of IOP upregulates membrane-bound and extracellular HSPs in the ganglion cell layer of the retina, subsequently leading to immune-mediated neural damage through activating HSP-specific CD4+ T cells, which are originally induced by microbial HSPs.

REFERENCE:

[1] 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. Erratum in: Nat Commun. 2018 Sep 20;9(1):3914. PMID: 30097565; PMCID: PMC6086830.