Enhanced Insight into the Autoimmune Component of Glaucoma: IgG Autoantibody Accumulation and Pro-Inflammatory Conditions in Human Glaucomatous Retina

Abstract

BackgroundThere is accumulating evidence that autoimmune components, such as autoantibodies and autoantibody depositions, play a role in the pathogenesis of neurodegenerative diseases like Alzheimeŕs disease or Multiple Sclerosis. Due to alterations of autoantibody patterns in sera and aqueous humor, an autoimmune component is also assumed in the pathogenesis of glaucoma, a common reason for irreversible blindness worldwide. So far there has been no convincing evidence that autoantibodies are accumulated in the retina of glaucoma patients and that the local immune homeostasis might be affected.Methods and ResultsSix human glaucomatous donor eyes and nine samples from donors with no recorded ocular disease were included. Antibody microarrays were used to examine the patterns of pro-inflammatory proteins and complement proteins. Analysis of TNF-α and interleukin levels revealed a slight up-regulation exclusively in the glaucomatous group, while complement protein levels were not altered. IgG autoantibody accumulations and/or cellular components were determined by immunohistology (n = 4 per group). A significantly reduced number of retinal ganglion cells was found in the glaucomatous group (healthy: 104±7 nuclei/mm, glaucoma: 67±9 nuclei/mm; p = 0.0007). Cell loss was accompanied by strong retinal IgG autoantibody accumulations, which were at least twice as high as in healthy subjects (healthy: 5.0±0.5 IgG deposits/100 cells, glaucoma: 9.4±1.9 IgG deposits/100 cells; p = 0.004). CD27+ cells and CD27+/IgG+ plasma cells were observed in all glaucomatous subjects, but not in controls.ConclusionThis work provides serious evidence for the occurrence of IgG antibody deposition and plasma cells in human glaucomatous retina. Moreover, the results suggest that these IgG deposits occurred in a pro-inflammatory environment which seems to be maintained locally by immune-competent cells like microglia. Thereby, glaucoma features an immunological involvement comparable to other neurodegenerative diseases, but also shows a multifactorial pathomechanism, which diverges and might be linked to the specific nature of both eye and retina.

The Complex Role of Neuroinflammation in Glaucoma

“…4A) . No other type of immune cell (including B cells or T cells) was found in DBA/2J glaucomatous tissue, although one study has shown B cells in human glaucomatous retinas (Gramlich et al 2013). Monocyte infiltration was apparently blocked by DBA/2J mice treated with radiation ( Fig.…”

Macro- and microglial responses in the fellow eyes contralateral to glaucomatous eyes

“…In this context, greater prevalence of monoclonal gammapathy has been observed in glaucoma patients, together with higher autoantibody levels in the serum and in the aqueous humor, deposition of immunoglobulins and plasma cells in the retina (Gramlich et al, 2013;Hammam et al, 2008;PinazoDuran et al, 2013;Wax et al, 1998), and chronic activation of resident immunoregulatory glial cells and complement activation (Tezel and The Fourth ARVO/Pfizer Ophthalmics Research Institute Conference Working Group, 2009). Similar to other autoimmune disorders, a serum alteration of the populations of T-cell repertoires and of interleukin-2 receptors has been detected (Yang et al, 2001a).…”

Biochemische Grundlagenprozesse im Verlauf der Glaukomerkrankung

“…TNFα (Tumornekro sefaktorα) und Interleukin (IL)1β, IL6 und IL8 bzw. INFγ (Interferonγ) wa ren erhöht, was darauf hinweist, dass die IgGAntikörperablagerungen in der Reti na in einer proinflammatorischen Umge bung vorliegen [22]. Diese Ergebnisse ste hen so weit im Einklang mit anderen Stu dien zu Zytokinmessungen im Kammer wasser von Glaukompatienten, bei denen die Konzentrationen verschiedener Inter leukine wie CXCL8 ["chemokine (CXC motif) ligand 8" oder IL8], VEGF ("va scular endothelial growth factor"), IFNγ, IL12 und CXCL9 (Monokine indiziert von γInterferon, MIG) stark erhöht vor lagen [23].…”

“…Sie werden maßgeblich dar über moduliert und können andererseits beide Chemokine selbst sezernieren. Eine Aktivierung des Komplementsystems in glaukomatösen Retinae konnte bereits nachgewiesen werden [22]. Beim experi mentellen Glaukom im Tiermodell konn te gezeigt werden, dass der degenerative Verlust von retinalen Ganglienzellen mit einer verstärkten Expression von Kompo nenten (C1q und C3) der Komplement kaskade einhergeht und dass eine Inak tivierung dieser Kaskade den Ganglien zellverlust verlangsamen kann [29].…”

“…Bis her nicht geklärt werden konnte, ob pri mär die Komplementaktivierung oder die Autoantikörper pathogenetisch relevant sind oder sogar ein additiver Mechanis mus bei der glaukomatösen Neurodege neration vorliegt. Bei einigen Glaukom patienten konnten auch wir eine erhöh te Proteinkonzentration von Bestand teilen der Komplementkaskade (C3 und C6) feststellen [22] …”