Serum Autoantibodies to Optic Nerve Head Glycosaminoglycans in Patients With Glaucoma

Abstract

Background: Serum autoantibodies that cross-react with glycosaminoglycans have been proposed to play a significant role in specific tissue injury in patients with systemic autoimmune diseases. Objective: To investigate whether serum immunoreactivity to glycosaminoglycans is present in patients with glau-comawhohaveaberrantserumautoantibodiestoDNA,RNA, nuclear proteins, or retinal proteins, as proteoglycans and their glycosaminoglycan side chains are important components of the optic nerve head and its vasculature. Methods: We performed Western blotting using patient serum samples and human optic nerve head homogenates that were treated with or without specific glycosaminoglycan degrading enzymes. Monoclonal antibodies that recognize different determinants of glycosaminoglycans were used to identify specific substrate antigenicity. We compared the serum immunoreactivity to glycosaminoglycans in 60 age-matched patients with normal-pressure glaucoma, 36 patients with primary open-angle glaucoma, and 20 control subjects by enzyme-linked immunosorbent assay. In addition, immunohistochemistry was performed to compare the distribution patterns of glycosaminoglycans in the optic nerve head of postmortem eyes of agematched patients with normal-pressure glaucoma, primary open-angle glaucoma, and control subjects. Results: Western blotting demonstrated that serum samples from patients with glaucoma who have circulating autoantibodies can recognize optic nerve head proteoglycans, including chondroitin sulfate and heparan sulfate. The level of serum autoantibodies binding purified chondroitin sulfate and heparan sulfate glycosaminoglycans in an enzyme-linked immunosorbent assay was approximately 100% higher in patients with normal-pressure glaucoma than that in control subjects and approximately 50% higher than that in patients with primary open-angle glaucoma. We also observed increased immunostaining of glycosaminoglycans in the optic nerve head of eyes with glaucoma, particularly those with normal intraocular pressure, compared with control eyes. Conclusion: There are increased levels of autoantibodies recognizing glycosaminoglycans of the optic nerve head in the serum samples of some patients with glaucoma. Clinical Relevance: These autoantibodies may increase the susceptibility of the optic nerve head to damage in these patients by changing the functional properties of the lamina cribrosa, its vasculature, or both.

Prevalence of serum autoantibodies and paraproteins in patients with glaucoma

“…20 It has also been suggested that serum autoantibodies that crossreact with GAGs around the optic nerve may play a significant role in the development of NTG in some patients with systemic autoimmune diseases. 11 A recent study showed 21 that the immune system plays a key role in an animal's ability to resist the damaging consequences of an increase in IOP. Rats deprived of T cells were found to be more prone to IOP-induced retinal ganglion cell (RGC) loss than rats with normal T-cell populations.…”

“…2 This study found a statistically significant increase in autoantibodies to extractable nuclear antigens (ENA) and serum monoclonal proteins in NTG, but failed to show a statistically significant increase in antinuclear antibodies. Other workers have identified immunoglobulin deposition in the retina in NTG, 10 whereas numerous elevated serum autoantibody titres have also been demonstrated, for example, to optic nerve head glycosaminoglycans (GAGs), 11 to gammaenolase, 12 to retinal antigens (including rhodopsin 13 ), to heat-shock proteins, 14 and to glutathione S-transferase.…”

Proteomics in ocular fluids

“…These studies showed antibodies against, e.g., heat shock proteins [99], g-enolase [100], GST [101], glycosaminoglycans [102], and a-fodrin [80]. Studies of our group revealed significant differences in antibody patterns against ocular antigens in sera of glaucoma patients in comparison to healthy controls [80,[103][104][105][106].…”

Manipulating Glia to Protect Retinal Ganglion Cells in Glaucoma

“…Feedback loops regulated by astrocytes in microglia work in reverse too: Microglia can activate the Nrf2-ARE (anti-oxidant response element) in astrocytes and change the redox level there. An autoimmune component to glaucomatous optic neuropathy has emerged from observations of serum autoantibodies against proteoglycans in open-angle glaucoma patients (Tezel et al, 1999), and against heat shock proteins (hsp) hsp27 and hsp60 (Wax et al, 2008) in patients with normal tension glaucoma (NTG). Microglia have a complex, context-dependent role in autoimmunity.…”

“…As demonstrated in the retina (see Figure 1), glia overexpress proteoglycans during gliosis in glaucoma. Serum autoantibodies obtained from patients with normal tension glaucoma and those with increased IOP bind to chondroitin sulfate and heparan sulfate glycosaminoglycans, proteins upregulated in the optic nerve head of glaucoma patient tissue (Tezel et al, 1999). However, chondroitin sulfate proteoglycan 4 (CSPG4) and CSPG1 (aggrecan) mRNA stood out on one ONH astrocyte microarray for being downregulated 35-fold and 29-fold, respectively in glaucoma patients (Hernandez et al, 2002).…”