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Editors Selection IGR 8-2

Experimental Glaucoma: Pathophysiology of RGC loss

Comment by Martin Wax on:

51056 Retinal ganglion cell loss is accompanied by antibody depositions and increased levels of microglia after immunization with retinal antigens, Joachim SC; Gramlich OW; Laspas P et al., PLoS ONE, 2012; 7: e40616

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The interest in auto-antibodies and their potential roles in glaucoma began with studies that are now almost two decades old. Our laboratory identified an increased prevalence of paraproteinemias in some patients with glaucoma in 1994 (Am J Ophthalmol 1994; 117: 561-578). Over the next ten years, we proceeded to identify possible auto-antibodies directed against the retina or optic nerve in glaucoma patient sera by systematically performing Western blots to identity the most common of these auto-antibodies, many of which were found primarily in patients with normal pressure glaucoma. Among the earliest auto-antibodies identified were those to heat shock proteins, a common antigenic determinant on the surface of many bacteria, which gave rise to the hypothesis that in some patients, glaucoma might be an autoimmune neuropathy mediated by molecular mimicry; an aberrant response to a host protein in the retina/optic nerve could be triggered by an inappropriately 'mimicked' immune response to bacterial heat shock proteins (hsps)(Am J Ophthalmol 1998; 125: 145-157; Exp Eye Research 2011; 93: 187-190). Missing, however, were the answers to many key questions pertaining to the role of auto-antibodies in patients with glaucoma. Chief among these, and the two most interesting, were (1) whether the auto-antibody response was truly disease-causing or whether it merely comprised an accompanying epiphenomenon with no significant sequelae; and (2) what exactly is the identity of the retinal or optic nerve proteins in patients that were supposedly mimicked by the bacterial heat shock protein epitopes?

Although a key breakthrough occurred when we found that immunization by heat shock proteins in rats resulted in ganglion cell specific loss that was due in part to activated T cell-derived Fas ligand (J Neuroscience 2008; 28: 12085-12096), it remained unclear whether specific heat shock proteins were the only antigens capable of immunization and eliciting a RGC specific cell loss in the retina, or whether other areas, namely the brain, were uninvolved in the autoimmune response.

The recent work of Joachim et al. Answers these questions and more. Rather than focus on a specific antigenic trigger, they immunized rats with a ganglion cell layer homogenate, and noted not only a reduction in Brn 3+ RGCs at six weeks, but the accompanying development of autoreactive antibodies in the retina and optic nerve, IgG deposits in the RGC layer as well as two other key events that signal a compromise of the innate immune system; namely co-localization of microglial activation (Iba1+ staining) and GFAP staining. Equally important, however, was that no such activity or immunological disturbance was found in the brains of these animals. These results suggested that immunization to a broad array of likely RGC antigens is also capable of eliciting an RGC specific immune response much like that found previously to heat shock proteins alone.

Two aspects of the study are worth noting. Firstly, the investigators looked carefully at the immunized animal retinas but found no evidence of the presence of T cells in that tissue. At first this might be surprising. However, more than likely this is explained by the fact that by the time they looked at six weeks, and the T cell response may have been transient and already dissipated much like that which occurs in EAE studies in multiple sclerosis in which the presence of T cells disappears within two weeks of immunization.

The question still remains as to whether there is one or perhaps more than one single antigen that might truly be 'the' auto-antigen mimicked

Secondly, the question still remains as to whether there is one or perhaps more than one single antigen that might truly be 'the' auto-antigen mimicked by both heat shock proteins, or by a protein found in RGC homogenates, such that RGC loss occurs in experimental paradigms utilizing either hsps or RGC homogenates as immunogens. Perhaps future work which might feasibly utilize yeast two hybrid technology to yield the identity of a common epitope of an as yet unidentified associated protein which shares epitope homology to both bacterial hsps and a protein in RGC cells which it mimics. Such a 'genuine' auto-antigen might be responsible for the pathogenic autoimmune mechanism reproduced and validated here by Joachim et al., and which might occur in some patients with presumed autoimmune glaucoma.

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