Immune Mediated Degeneration and Possible Protection in Glaucoma

Teresa Tsai, Sabrina Reinehr, Ana M Maliha, Stephanie C Joachim, Teresa Tsai, Sabrina Reinehr, Ana M Maliha, Stephanie C Joachim

Abstract

The underlying pathomechanisms for glaucoma, one of the most common causes of blindness worldwide, are still not identified. In addition to increased intraocular pressure (IOP), oxidative stress, excitotoxicity, and immunological processes seem to play a role. Several pharmacological or molecular/genetic methods are currently investigated as treatment options for this disease. Altered autoantibody levels were detected in serum, aqueous humor, and tissue sections of glaucoma patients. To further analyze the role of the immune system, an IOP-independent, experimental autoimmune glaucoma (EAG) animal model was developed. In this model, immunization with ocular antigens leads to antibody depositions, misdirected T-cells, retinal ganglion cell death and degeneration of the optic nerve, similar to glaucomatous degeneration in patients. Moreover, an activation of the complement system and microglia alterations were identified in the EAG as well as in ocular hypertension models. The inhibition of these factors can alleviate degeneration in glaucoma models with and without high IOP. Currently, several neuroprotective approaches are tested in distinct models. It is necessary to have systems that cover underlying pathomechanisms, but also allow for the screening of new drugs. In vitro models are commonly used, including single cell lines, mixed-cultures, and even organoids. In ex vivo organ cultures, pathomechanisms as well as therapeutics can be investigated in the whole retina. Furthermore, animal models reveal insights in the in vivo situation. With all these models, several possible new drugs and therapy strategies were tested in the last years. For example, hypothermia treatment, neurotrophic factors or the blockage of excitotoxity. However, further studies are required to reveal the pressure independent pathomechanisms behind glaucoma. There is still an open issue whether immune mechanisms directly or indirectly trigger cell death pathways. Hence, it might be an imbalance between protective and destructive immune mechanisms. Moreover, identified therapy options have to be evaluated in more detail, since deeper insights could lead to better treatment options for glaucoma patients.

Keywords: autoantibody; complement system; glaucoma; neuroprotection; organ culture; porcine.

Figures

FIGURE 1
FIGURE 1
The complement system can be activated via three different pathways. The classical pathway is initiated by antibody complexes binding to C1q. The mannose binding lectin (MBL) and the mannose-associated-serine-proteases (MASPs) bind to specific carbohydrate structures leading to the activation via the lectin pathway. The alternative pathway is spontaneously activated through the cleavage of C3 to C3b. All three pathways lead to the generation of C3 convertases that cleaves the C3 protein into C3a and C3b. C3b acts in the opsonization of target cells and additionally form the C5 convertase, which cleaves C5 to C5a and C5b. C5a and C3a act as anaphylatoxins. At the end, the interaction of C5b with C6, C7, C8, and C9 lead to the formation of C5b-9, the membrane attack complex (MAC). MAC is the terminal pathway, which can cause lysis of the target cells due to a formation of a pore.
FIGURE 2
FIGURE 2
Various mechanisms can influence a loss of retinal ganglion cells. To identify novel neuroprotective treatments for glaucoma, different experimental setups are currently used. In vitro analyses reveal the function of new therapeutics on single cells, mixed cultures, or organoids. Ex vivo experiments can provide insights into the whole retina, e.g., in cultured porcine/bovine retina. In vivo investigations in animals have the advantage to provide a closer look at local and systemic mechanisms and possible side effects.
FIGURE 3
FIGURE 3
(A) Schematic illustration of the explantation process. Porcine eyes were obtained from the local slaughterhouse. Anterior parts of the eyeball were separated from the posterior, retina containing part of the eye. A dermal punch was used to punch out four retinal explants per eye and cultivated on an insert the ganglion cell layer facing up. (B) Retinal explants were cultivated in 6-well plates for up to eight days at 37°C and 5% CO2. There are two possibilities to induce different pathomechanisms in the retina, which lead to a degeneration of the inner layers. Either with 300 μM H2O2 for 3 h to induce oxidative stress on day one of cultivation or with 300 μM CoCl2 for 48 h, starting on day one, to induce hypoxic processes. The best point in time to start therapeutic treatment is at day one, simultaneously to the degeneration via H2O2 or CoCl2. The treatment-duration varies, depending on the substance. In the end of the cultivation, retinal explants can be prepared for e.g., immunohistological and qPCR-analyses.

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