Inherited neurodegenerative diseases are characterised by progressive disappearance of neurons due to either intrinsic metabolic deficits or malfunctioning within neuronal networks. Our understanding of the mechanisms involved in hereditary degeneration relies substantially on studies using animal models, like the RCS rat strain, which have a mutation in the RPE cells affecting their phagocytic ability,4748 leading to insufficient clearance of photoreceptor outer segment debris produced during phototransduction. Degeneration of the photoreceptor outer segments, and later of the entire cells, commences at the end of the second week (period of eye opening), progressively resulting in a complete loss of the photoreceptor cell layer at the end of the third month of life.47 49
Long-term prelabelling of microglia (monitored for up to 12 months with 4Di-lOASP in vivo) helps the detection of intraretinal migration of microglia in RCS rats. RGC of the RCS rat strain are prelabelled by applying 4Di-l0ASP at the cross-sectional area of the cut optic nerve at postnatal day 50. This was done to determine if phagocytosing microglia either remain within the RGL as occurs in normal rats (albino Sprague-Dawley and pigmented rats) or move into the photoreceptor layer where degeneration is occurring. In RCS rats, fluorescent microglia translocate into the photoreceptor layer during the weeks after optic nerve transection and label microglia within the GCL and IPL. The results of this experiment confirm the predicted responsiveness of microglia to degeneration-derived stimuli,42 although they do not shed light on the nature of signals mediating microglial attraction. Nevertheless, the findings demonstrate double phagocytosis, since the same micro-glia that have ingested fluorescent RGC can respond to photoreceptor degeneration by migrating to the photoreceptor layer, where they accumulate and actively participate in the degradation of photoreceptors.15
A fundamental feature of axotomy-induced TCD within the retina consists of a series of changes in the morphology of the perikarya, finally resulting in the decay of neurons. TCD is not considered a physiological event within the mature retina unless an external insult like axotomy, or pathological conditions like stroke, ischaemia, infections, and toxic agents force the neurons to break down and die. Isolated mechanical axotomy, close to or distant from the cell body is a less dramatic intervention which leads to Wallerian degeneration, disconnecting the cell from its natural target and target-derived trophic factors. The optic nerve macrophages, as detected with EDl-positive immunostaining50 and electron microscopy,5152 are activated to remove the lesion-derived debris.
Vitreoretinopathic diseases are usually the result of perforating lesions and of manual or laser-assisted vitreoretinal surgery.53 Rhegmatogenous damage of the ILM
severs neuroglia and disrupts Müller cell end-feet, the integrity of adjacent astrocytes, and parts of the inner retinal vasculature. As a consequence, physiological wound healing processes are initiated which frequently develop into a proliferative retinopathy with the involvement of neuroglial epiretinal scars and activation of mononuclear cells.53 The origin of the phagocytic cells is not yet clear.54 The mechanisms leading to so-called idiopathic vitreoretinopathy are very similar because these diseases also develop as a result of retinal detachment, thus leading to the same effects on the cellular elements in the vitreoretinal interface. Retinal microglia identified by different staining methods seem to be involved in both types of vitre-oretinopathy.55 The prevalence is higher in idiopathic than in traumatic vitreoretin-opathy, and is insignificant in diabetic forms of the disease.56 The simultaneous activation of astrocytes and microglia indicates their interaction during the development of the disease. Microglia may activate astrocytes with mitogens,57 whereas astrocytes may reciprocally activate microglia with IL-3.58 In effect, treatment of the disease will not be different assuming a causal contribution of microglia in traumatic retinal degenerations and subsequent scarring.
Both microglia- and macrophage-associated diseases include the late stages of retinitis pigmentosa, macular degenerations, viral infections leading to chorioretin-itis, and multiple sclerosis frequently leading to optic nerve demyelination. Apart from neurological diseases involving the retina, age-related brain dystrophies like Parkinson's and AD59-61 have strong connections with microglial cells. We shall discuss one of the most prominent cases of retinal pathology, namely HIV-chorio-retinitis and the optic nerve neuritis in the frame of MS, whose pathogenesis and relation to the activation of microglia is still being debated.
HIV-I is known to replicate in the CNS of AIDS patients primarily in microglia. In 50 to 80% of patients, encephalitis, low myelopathy, and retinopathy occur, often resulting in dysfunction and tissue damage.62 On histological examination, a typical finding is microglial nodules in the neural tissue of AIDS patients, frequently seen in the white matter with immunostaining of the gp4l viral envelope antigen. Although the pathogenetic cascade is still obscure, the primarily affected microglia seem to play a key role.63 These cells may either encode for neurotoxic proteins,57 or alter the microenvironment, causing retinal damage by retina-derived neurotoxins, or modify the BBB and BRB to permit both the entrance of haematogenous cells and leakage of proteins.29 Most likely, a combination of these three mechanisms can be assumed, although isolated components like the envelope glycoprotein gp12O62 have been shown to cause neuronal cell death in culture. Besides the question as to how the virus exerts its pathology, the mechanism of infection remains unknown. The most likely pathway is through antibody-mediated uptake.63
Microglia are capable of antigen detection and specifically display Fc receptors.64 This demonstrates that transfection may occur via Fc receptors or via the CD4 antigen, which is a viral receptor expressed on microglial cells.42 Access to retinal and brain tissue may occur after breakdown of the BRB and BBB.63
MS is a multifocal disease frequently starting with ocular symptoms like diplopia when it becomes established in the brain stem, or a reduction of visual acuity, or disturbances in colour vision and pain when established as optic nerve neuritis. The typical plaques are initial sites of demyelination, whereas inflammatory elements including myelinophagic microglia appear at early stages of the disease.65 Due to the lack of myelination within the retina, the disease becomes established within the optic nerve. At early stages, leukocytes pass the permeated BBB, and astrocytes become reactive to later form typical gliotic scars. The appearance of microglia in and around the plaques indicates their involvement in the cascade of plaque formation. The favourable model of EAE, however, shows that inflammation and cytokine production accompany the disease. Although the exact cascade of inflammation and myelinolysis is not elucidated, microglial IL-6 seems to play a key role in stimulating lymphocytes.66 In particular, B-cell stimulation can result in autoantibody production, although it remains to be shown whether this production is involved in the pathogen-esis of the disease. The direct involvement of microglia in demyelination is experimentally induced in IL-3 transgenic mice.67 The patterns of demyelination produced in these mice are very reminiscent of both human MS and HIV encephalopathy.67
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