Immunoregulation of retinal ganglion cell fate in glaucoma

doi:10.1016/j.exer.2009.02.005

Experimental Eye Research

Volume 88, Issue 4, 30 April 2009, Pages 825-830

https://doi.org/10.1016/j.exer.2009.02.005 Get rights and content

Abstract

Glaucomatous neurodegeneration has been associated with the activation of multiple pathogenic mechanisms that can result in RGC death and axonal degeneration. Growing evidence obtained from clinical and experimental studies over the last decade also strongly suggests the involvement of the immune system in the neurodegenerative process of glaucoma. The roles of the immune system in glaucoma have been described as either neuroprotective or neurodestructive. It has been proposed that a critical balance between beneficial protective immunity and harmful sequelae of autoimmune neurodegenerative injury determines the ultimate fate of RGCs in response to various stressors in patients with glaucoma. Here, we review the key role for immunoregulation in cell fate decisions regarding RGC survival in response to glaucomatous tissue stress. Furthermore, we review the mechanisms by which autoimmunity to specific antigens such as heat shock proteins may result in RGC demise in some patients with glaucoma. In these patients, we hypothesized that one form of glaucoma may be an autoimmune optic neuropathy in which an individual's immune system facilitates a somatic or axonal degeneration of RGCs by the very system which normally serves to protect it against stress.

Section snippets

Immunoregulation governs RGC death in glaucoma

It is likely that all experienced glaucoma specialists have treated patients that cause them to question some commonly accepted paradigms of our profession. Consider, for example, the glaucoma patient whose intraocular pressure (IOP) appears to be perfectly controlled at each office visit. Perhaps it is as low as 10 mmHg or is even in single digits, yet continues to manifest progressive nerve loss and visual field deterioration despite having such low pressures. On the other hand, there is the

Retinal ganglion cell fate decisions in glaucoma

An impressive to summarize RGC fate decisions that has been linked to some of the presumptive causative factors of glaucomatous neurodegeneration was depicted by Tatton et al. (2003) as seen in modified form in Fig. 1. As summarized in this figure, cysteine aspartic acid proteases, also known as caspases, are the “executioners” of RGC death, and the key thermostat that regulates caspase activation may be depicted as the relative ratio of two proto-oncogenes known as Bax (which promotes cell

RGC death signaling after axonal injury

Elevated IOP-induced mechanical and/or ischemic injury to RGC axons at the optic nerve head is commonly believed to be the initial injury triggering a sequence of events leading to glaucomatous neurodegeneration at different sub-cellular compartments of RGCs from the retina to the brain. Such an initial injury to RGC axons may result in the blockage of axoplasmic neurotrophin transport to RGC bodies (Anderson and Hendrickson, 1974, Minckler et al., 1976, Quigley and Addicks, 1980, Pease et al.,

Pro-inflammatory cytokines in RGC death

Tumor necrosis factor-alpha (TNF-α) is an inducer of apoptotic cell death through TNF receptor-1 binding. Based on our initial observations that the expression of TNF-α and its death receptor is increased in the glaucomatous retina (Tezel et al., 2001) and optic nerve head (Yan et al., 2000), and that TNF-α exposure results in the apoptotic death of cultured RGCs (Tezel and Wax, 2000a), we have proposed that this pro-inflammatory cytokine may be a mediator of glaucomatous neurodegeneration. In

Is TNF-α involved in neurocytotoxicity of immunesystem cells?

Glial cells, including both macroglial cells (mainly astrocytes) and microglia in the retina and optic nerve head, are the main source of increased TNF-α in glaucomatous eyes (Yan et al., 2000, Tezel et al., 2001). Besides these resident immunoregulatory cells, TNF-α is the most abundantly produced cytokine that is generated by reactive T cells during glia-T cell interactions (Sun et al., 1996, Sun et al., 1997). In addition, another member of the same death receptor family, FasL, have recently

Aberrant immune activity in glaucoma patients

The immune system functions for day-to-day maintenance of the central nervous system functional integrity by providing tissue cleaning and limiting the neurodegenerative consequences of stressful conditions. However, a failure in the regulation of immunity and an immune insufficiency resulting from increased levels of stressful risk factors may turn the protective immunity into an autoimmune neurodegenerative process (Schwartz, 2003, Schwartz and Ziv, 2008). There is now considerable evidence

Heat shock proteins and immune activity

A widespread and chronic tissue stress is evident in the retina and optic nerve head of glaucomatous eyes by a prominent up-regulation of stress proteins, also called HSPs (Tezel et al., 2000). HSPs are among the most highly conserved and abundant proteins in nature and play an important role in cell survival under many environmental stresses as well as under normal conditions. Increased expression of HSPs, particularly including HSP70 and HSP27, is notable in the brain, since both proteins are

Oxidative stress and immune activity

Glial cells exhibit activation in their immunogenic function and antigen presenting ability in glaucoma (Yang et al., 2001b, Tezel et al., 2003). Besides HSPs serving as an early stress response, other constituents of the tissue stress or injury likely act as signals and potential activators of the immune response. For example, reactive oxygen species (ROS) can function as second messengers and modulators of the immune activity (Rutault et al., 1999). ROS and protein oxidation products have

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ReviewImmunoregulation of retinal ganglion cell fate in glaucoma

Abstract

Section snippets

Immunoregulation governs RGC death in glaucoma

Retinal ganglion cell fate decisions in glaucoma

RGC death signaling after axonal injury

Pro-inflammatory cytokines in RGC death

Is TNF-α involved in neurocytotoxicity of immunesystem cells?

Aberrant immune activity in glaucoma patients

Heat shock proteins and immune activity

Oxidative stress and immune activity

Free Radic. Biol. Med.

Ophthalmology

Exp. Eye Res.

Jpn. J. Ophthalmol.

Am. J. Ophthalmol.

Free Radic. Biol. Med.

Trends Immunol.

Cell

J. Neuroimmunol.

Prog. Retin. Eye Res.

Brain Res. Bull.

Exp. Eye Res.

Brain Res.

Free Radic. Biol. Med.

Surv. Ophthalmol.

Am. J. Ophthalmol.

Ophthalmology

Am. J. Ophthalmol.

Am. J. Ophthalmol.

Curr. Opin. Immunol.

Cell

Effect of intraocular pressure on rapid axoplasmic transport in monkey optic nerve

Invest. Ophthalmol.

T-cell-based vaccination for morphological and functional neuroprotection in a rat model of chronically elevated intraocular pressure

J. Mol. Med.

Immune-related disease and normal-tension glaucoma. A case-control study

Arch. Ophthalmol.

Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma

Arch. Ophthalmol.

The role of heat shock proteins Hsp70 and Hsp27 in cellular protection of the central nervous system

Int. J. Hyperthermia.

Hsp27 phosphorylation in experimental glaucoma

Invest. Ophthalmol. Vis. Sci.

Antibodies to alpha B-crystallin, vimentin, and heat shock protein 70 in aqueous humor of patients with normal tension glaucoma and IgG antibody patterns against retinal antigen in aqueous humor

Curr. Eye Res.

Autoantibodies in patients with glaucoma: a comparison of IgG serum antibodies against retinal, optic nerve, and optic nerve head antigens

Graefes Arch. Clin. Exp. Ophthalmol.

IgG antibody patterns in aqueous humor of patients with primary open angle glaucoma and pseudoexfoliation glaucoma

Mol. Vis.

Antiphosphatidylserine antibodies are elevated in normal tension glaucoma

Clin. Exp. Immunol.

Complement activation during glaucomatous neurodegeneration

Invest. Ophthalmol. Vis. Sci.

Retinal ganglion cells recognized by serum autoantibody against gamma-enolase found in glaucoma patients

Invest. Ophthalmol. Vis. Sci.

Generation and function of reactive oxygen species in dendritic cells during antigen presentation

J. Immunol.

Review
Immunoregulation of retinal ganglion cell fate in glaucoma