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Review  |   March 2013
The Pathogenesis of Glaucoma in the Interplay with the Immune System
Author Notes
  • From the Institut für Zoologie, Johannes Gutenberg-Universität Mainz, Mainz, Germany. 
  • Corresponding author: Jochen Rieck, Institut für Zoologie, Johannes Gutenberg-Universität Mainz, Johannes von Müller-Weg 6, 55099 Mainz, Germany; rieck@uni-mainz.de
Investigative Ophthalmology & Visual Science March 2013, Vol.54, 2393-2409. doi:10.1167/iovs.12-9781
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      Jochen Rieck; The Pathogenesis of Glaucoma in the Interplay with the Immune System. Invest. Ophthalmol. Vis. Sci. 2013;54(3):2393-2409. doi: 10.1167/iovs.12-9781.

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Abstract

Glaucoma was previously thought to be caused only through an elevated intraocular pressure as a sole trigger. Emerging evidence indicates that the pathogenesis of glaucoma depends on several interacting pathogenetic mechanisms, which include mechanical effects by an increased IOP, decreased neutrophine-supply, hypoxia, excitotoxicity, oxidative stress and the involvement of autoimmune processes. These autoimmune processes within the central nervous system are a highly organized response of the innate immunity. Through the recognition of neuronal epitopes, the long-term induction of the innate immune response and its transition to an adaptive form might be central to the pathophysiology of the glaucoma disease. Regardless of the pathogenic mechanism, the consequences are always the establishment of extensive degenerative processes in the optic nerve head, the retinal ganglion cells and the axons of the optic nerve, which will lead in the irreversible destruction of these neurons. This review article summarizes the current knowledge concerning the pathogenesis of glaucoma, with special focus on its interplay with the immune system.

Introduction
Glaucoma, behind cataracts, is the second leading cause of blindness worldwide. For the year 2020 it is expected that approximately 80 million people will suffer from glaucoma, which is anticipated to result in 11.2 million cases of bilateral blindness. 1  
Nowadays glaucoma is a collective term for a group of neurodegenerative processes affecting the entire visual pathway, characterized by progressive, irreversible destruction and death of retinal ganglion cells. 215 These neurodegenerative processes are associated with a progressive visual field loss, which typically begins with an arcuate Bjerrum scotoma in the central visual field and ends with the total blindness of the eye. 13,1623  
Well-marked symptoms are known only in acute angle-closure glaucoma; all other forms of chronic glaucoma are largely asymptomatic. This is the main reason the disease accomplishes its destruction to a far extent unnoticed. As many as 50% of all affected patients live without diagnosis until advanced illness. 13 A simplified diagnostic procedure, ideally a rapid glaucoma test that could be carried out by an optician, would be an effective tool to gain time through early diagnosis and treatment. However, to date the pathogenesis of glaucoma is understood only in part; as a result, useful mass screening for glaucoma is lacking with respect to reliable yet affordable and expeditious diagnosis. 24  
Undisputedly, a permanent raised individual ocular pressure above 21 mm Hg is an important pathogenic factor in the disease risk. 9,10,2527 Individual ocular pressure constitutes a person-specific variation and follows a circadian rhythm. 28 Following this rhythm, the IOP oscillates between 10 and 21 mm Hg in healthy adults. Newborns have an IOP between 6 and 8 mm Hg, which rises approximately 1 mm Hg every 2 years. 25,26,2934  
In addition, there are healthy people who have an IOP significantly elevated above normal without ever developing glaucoma. This condition is known as ocular hypertension (OHT). In direct contrast, many patients with an IOP ≤ 21 mm Hg progress to glaucoma. Accordingly, this form of glaucoma is called normal-tension glaucoma (NTG). Important for the pathogenesis of glaucoma therefore seems to be the individual, relative value of IOP. 
Available Treatment Options for Glaucoma
The treatment of glaucoma is almost always aimed at reducing the IOP, which leads, surprisingly, even in patients with NTG, to an alleviation of the disease process. 4,13,15,3539 The reduction of IOP is obtained by eye drops or systemic application of glaucoma medications. These include carbonic anhydrase inhibitors, beta-blockers, cholinergic agonists, α2-adrenoceptor agonists and prostaglandins. 25,27,37,4043 Laser therapy or surgical procedures for ensuring an adequate aqueous humor outflow are seen as a last resort to use. 44  
Pathogenesis and Progression of Glaucoma
For decades, a permanent raised IOP over 21 mm Hg was considered the sole trigger for the onset of glaucoma. In fact, in the most common glaucoma type, primary open-angle glaucoma (POAG), the majority of those affected exhibit a raised IOP. Therefore this glaucoma subtype belongs to the group of high-tension glaucomas (HTG). However, approximately one-third of all POAG patients had at no time a pathologically elevated IOP (NTG patients); this raises the question what, if not the IOP, is responsible for the destruction of retinal ganglion cells. 25,27,4547 It is worth mentioning that therapeutic lowering of the IOP leads to a slowing of disease progression in a subgroup of NTG patients. 43,4850  
The substantial demise of retinal ganglion cells (RGCs) is accompanied by morphologic changes of the retina, of which the cupping of the optic nerve head (ONH) is the most prominent. Thereby glaucomatous damage is not confined just to the RGCs and their axons, somata, and dendrites. Rather the entire visual pathway from the retina to the visual cortex in the brain is affected. 14,26,5154 However, it is not clear whether the remodeling of the ONH leads to the destruction of RGCs, or conversely, whether the RGC loss in glaucoma is causative for the characteristic cupping of the ONH. 8,9,15,30,50,55,56 Beyond controversy, apoptosis is accepted as an important component of glaucomatous neurodegeneration. 6,10,12,13,17,19,20,31,36,50,5764  
The involvement of apoptotic processes, as well as the correlation between IOP and glaucomatous damage, is rather obvious in pathologic conditions with rapidly raised IOP, as it can be monitored in acute angle-closure glaucomas and acute secondary glaucomas. 12,15,20,6567 As demonstrated in animal models, severe pressure insults may cause axonal degeneration and apoptosis within hours. 15,31,33,68  
However, in open-angle glaucomas and mild forms of secondary glaucomas, the correlation between IOP and neuronal degeneration is not so apparent. OHT patients with slightly elevated IOP between 21 and 30 mm Hg, without detectable signs of disc cupping and/or visual field defects, do not necessarily progress to glaucoma. 69 The Ocular Hypertension Treatment Study demonstrated that over 90% of the untreated control group did not develop any form of glaucoma within the 5-year study period. 25,27,70  
The Lamina Cribrosa as the Most Vulnerable Part of the Retinal Ganglion Cell
As mentioned above, an elevated IOP is one of the main risk factors for glaucoma, which may be associated with a deficiency in the cellular nutritional state of the RGCs. This presumption is suggested by an animal model in which an elevated IOP causes the failure of the neurotrophin supply due to the collapse of axonal transport. 71,72  
RGCs respond to a variety of neurotrophins, but mainly to brain-derived neurotrophic factor (BDNF), ciliary nerve trophic factor (CNTF), glial cell–derived neurotrophic factor (GDNF), and nerve growth factor. 7377 In animal models, as well as in cell culture, the neuroprotective effects of these trophic factors are documented. 78,79 Like other neurotrophins, nerve growth factor (NGF) and BDNF are taken up into the target cell through receptor-mediated endocytosis. Binding partners are the high-affinity receptors TrkA (for NGF) and TrkB (for BDNF), and a low-affinity receptor, p75NTR, to which all other neurotrophins can bind. The internalization of the receptor–ligand complex followed by the retrograde transport to the soma of the neuron is coordinated by the G-proteins Rabenosyn 1 and 5 (Rab1 and Rab5). 8085 Immunohistochemical studies demonstrate that impairing neurotrophin transport from the visual thalamus to the soma of RCGs results in their destruction by apoptosis. 20,65,72 Similar effects are observed in the optic nerve crush model. 19,86  
Here the lamina cribrosa sclerae, through which the optic nerve and the central retinal artery and vein enter the bulbus oculi, appears to play a key role, since it is the weakest portion of the sclera. A raised IOP may cause an excavation at the position where the optic nerve (papilla nervi optici) enters the retina. 55 By dyeing RGC axons of freshly explanted eyes, Morgan et al. were able to document the path of individual axons through the lamina cribrosa: Most axons take a direct path toward the ONH, while others, approximately 8% to 12%, squeeze through collagenous plates. An increased IOP leads directly to a contusion of these nerve fibers. 87 Experiments with primates show that the retrograde and anterograde neuronal transport in glaucomatous eyes is disturbed or even interrupted at just this point. 65,71,72,8891 Additionally, the cerebrospinal fluid pressure influences the degree of mechanical stress, due to a pressure gradient across the tissue of the ONH. 92  
The Demise of Retinal Ganglion Cells as a Central Hallmark of Glaucoma Pathogenesis
In glaucoma, it seems that the nature and position of the injurious trigger determine which path is taken into neurodegeneration. Already documented is the initiation of programmed cell death of RGCs via tumor suppressor protein p53, but also through the direct activation of the “death receptor” CD95 in autoreactive conditions. 58,63,9395  
In general, the RGC's fate depends on multiple trophic as well as degenerative signaling pathways within the soma and/or signaling from the environment, which has the potential to disrupt neuronal homeostasis. One example is the cytotoxic effect of β-amyloid protein, which causes apoptosis by binding to neurotrophin receptor p75NTR or through the accumulation of protein aggregates, as in Alzheimer's disease. 96,97 p75NTR, another known cause, is involved in light-induced photoreceptor apoptosis. 98,99  
Furthermore, neurotransmitters such as dopamine, serotonin, and glutamate have the potential to drive RGCs into programmed cell death. As a cause for the triggering of apoptosis, excitatory mechanisms are suggested. 36,43,50,100110 Regarding the potential excitotoxicity of glutamate, it is noteworthy that glutamate transporters like GLAST and EEAC1, as well as glutamate receptors, are downregulated in glaucomatous eyes following astrocyte activation. 102,111,112 As a consequence, deficient glutamate removal from the extracellular space might represent an interaction by which astrocyte or glial activation can result in RGC death. 102,112  
Considering the complexity of RGCs, Whitmore et al. postulate the model of “compartmentalized self-destruction” in neurons, suggesting that depending on the nature and location of the initial insult, somal death can be preceded by a number of degenerative processes infesting the axons, dentrites, and synapses of the neuron. 15 These degenerative processes are phylogenetically highly conserved and known to be involved in a whole range of destructive processes within the vertebral central nervous system (CNS), as well as in axons of Drosophila. 10,79,113125 Since such widespread processes of neuronal degeneration may affect the entire CNS, one can assume that insights into neurons outside the eye are also applicable on RGCs. Current findings support the assumption that self-destruct processes, especially axonal degeneration as seen in non-RGC neurons, also take place during glaucoma. 10,124,126 One of these self-destruct processes, which is documented across species boundaries, is known as Wallerian degeneration (WD), a common phenomenon in cases of severe axonal damage such as transection or experimental nerve crush (i.e., nerve crush model). WD represents valid evidence that axonal degeneration is a soma-independently organized process that can be studied in mice carrying the Wallerian Degeneration Slow (WldS) gene. 15,61,127131  
This mutation results in a resistance to axonal degeneration while having no direct effect on somal apoptosis. During WD, the axonal section, which is detached from the soma by the injury, degenerates in a characteristic and autonomous manner, beginning at the point of transection and extending almost synchronously throughout the axon within days. 124,132,133  
A second frequently observed pathomechanism, so-called dying back (DB), seems to be a variation of WD and follows generalized neuronal stress without acute neuronal trauma. Differing from WD, DB is initiated by a withdrawal of the synapses, followed by an asynchronous progression of the destruction process toward the cell soma. 
In cases of DB, the neuron seems to have a distinct chance to regenerate if the neuronal stress decreases, whereas in WD, somal apoptosis appears to be unavoidable. 15,134,135 The review article by Whitmore et al. 15 provides detailed information concerning compartmentalized degeneration. 
The following sections provide an overview of how, on the one hand, the immune system eliminates pathogens and cell debris to maintain the homeostasis of the CNS and, on the other hand, observations of well-studied diseases such as Alzheimer's or multiple sclerosis (MS). The latter show what terrible damage the immune system is able to provoke in situations of cellular stress and unphysiological conditions. Many of the well-known neurodegenerative incidents that are caused by misdirected immune processes within the CNS (e.g., reactive astrogliosis) are also detectable in glaucoma. 136 This illustrates how homeostasis and survival of the RGC depend on a well-balanced function of the immune system. 
Autoimmune Mechanisms in the Onset of Glaucoma
The first hint for an involvement of the immune system in glaucoma was delivered by Wax in 1998 with the detection of antibodies against endogenous antigens such as heat shock protein 60 (HSP60) in the serum of NTG patients. 137 Heat shock proteins (HSPs) are components of cellular defense mechanisms and are upregulated under pathophysiological conditions. 138 According to their molecular weight, HSPs are divided into two main families: the major HSPs (HSP90, HSP70, and HSP60) and the small HSPs, including HSP27. HSP60 and HSP90 are constitutively expressed in the CNS, whereas HSP27 and HSP70 are highly inducible in the retinal glia, the Müller cells, and neurons by stressors such as ischemia and hyperthermia. 139142 However, HSP27 expression in the intact, undamaged retina has been found to be limited. 143 In states of cellular stress, HSP27 and HSP70 act in an antiapoptotic manner, whereas HSP60 promotes the induction of apoptosis. 144,145 Direct evidence for the involvement of HSP27 in glaucomatous processes comes from the detection of this protein in RGC axons and ONH of affected human donor eyes, considering that the axons and ONH are mainly battered under glaucoma. 146  
In an animal model, HSP27 develops its neuroprotective effects after axotomy and ischemia, possibly through the inhibition of caspase-3. 147149 Furthermore, HSP70 also shows neuroprotective effects after ischemic conditions. 141,150  
Since it has been documented that antibodies are able to enter the cytoplasm of intact cells, the effect of autoreactive immunoglobulins, in particular on cellular processes, is taken into account. 151,152 Rats immunized with HSP27 show an elevated rate of apoptosis in the RGC, where the loss is focused near the area centralis. NTG patients display the worst damage in the same retinal area. 153,154  
In the case of HSP27, either α-HSP27 autoantibodies could protect HSP27 from premature degradation by matrix metalloproteinases (MMPs), considering that neuroprotective HSP27 is among the MMP substrates, or this antibody may inhibit the neuroprotective activity of HSP27 and thus lead directly to increased apoptosis rates of RGC in glaucoma. 142,155,156 Significantly increased levels of MMPs in glaucomatous retinae support a hypothetical protective role of α-HSP27 autoantibodies. 157  
On the other hand, the accumulation of MMPs correlates with the release of TNF-α particularly in patients with NTG, in which MMPs are involved in the processing of the membrane-bound TNF-α precursor. 158  
But it's not just about antibodies against HSPs: Documented peculiarities in the antibody repertoire of glaucoma patients have been reported by Maruyama et al. These authors illustrated that the sera of approximately 20% of all glaucoma patients contain antibodies against neuron-specific γ-enolase, a key enzyme for glycolysis. In the healthy control group, only 10% of those examined showed these antibodies. However, in glaucoma patients with increased γ-enolase antibody titers, none of the elevated autoantibody titers against rhodopsin, α-crystallin, and HSP60 otherwise commonly detected in glaucoma patients could be demonstrated. 8,146,153,159,160 Further studies, published by Grus et al. and Joachim et al., also revealed significant differences in the antibody profiles of glaucoma patients. 161163  
Furthermore, a significantly increased antibody reactivity against ONH glycosaminoglycans (GAGs), glutathione S-transferase, alpha-fodrin, and neurofilament protein has been found in the sera of patients with glaucoma. 163166 In the case of anti-GAG antibodies, a direct physiological impact is postulated due to the change of organization and physical characteristics of GAGs located in the ONH. This may increase the susceptibility of the ONH and the lamina cribrosa to tissue damage and subsequently additional insult to the remaining axons. 164 However, in most studies, antibody titers in NTG patients are elevated, although some patients with elevated IOP show decreased autoantibody reactivity as well. 161  
An explanation for these measurable deviations in the antibody repertoire of patients with glaucoma could be found in our own evolutionary history: Some proteins, such as histones or HSP, are strongly enough conserved phylogenetically that molecular similarities between host and pathogenic germs occasionally result in cross-reactivity. 137,167169  
Additionally or independently thereof, epitope spreading could be another source of autoantibodies in glaucoma: Typically, a humoral response begins with the attack on the epitope that elicited the initial immune response, spreading to other epitopes on the same antigen (intramolecular epitope spread) or to similar epitopes on other antigens (intermolecular epitope spread). Autoimmunity may arise from epitope spreading on inflammation-induced posttranslational modified self-antigens or from self-antigens that result from immune-mediated apoptosis. 170172  
In many cases, the autoantigen that triggered the initial immune response has been identified and in fact shares sequence homology with a disease-causing antigenic pathogen component. In this context, the application of epitope mapping has allowed detailed characterization of those epitopes whose autoantibodies bind in diseases such as systemic lupus erythematosus (SLE) (antispliceosome antibodies), Devic's syndrome (anti-aquaporin-4 antibodies), and NTG (antirhodopsin antibodies). 173175 Intriguingly, antirhodopsin antibodies found in sera of NTG patients also bind to viral and bacterial epitopes. 174  
Regarding these facts, we have to keep in mind that autoreactive antibodies can be not only destructive but also protective. Recent findings support the hypothesis that these antibodies contribute to the clearance of cellular damage and promote repair. So, the humoral immune system can be seen as a double-edged sword, with the potential both to destroy and to heal. A repertoire of low-affine, so called natural autoantibodies is present in every healthy human and seems to be of great significance during tissue injury when these autoantibodies contribute to the removal of cellular debris and support tissue healing. 176,177 Furthermore, humoral autoimmunity seems to have a protective role. Under discussion, among other functions, are the masking of self-recognition against pathogenic autoantibodies, the neutralization of inflammatory cytokines like TNF-α through anticytokine antibodies, and an immune-regulatory function. 178181 A decreased reactivity of naturally occurring and perhaps protective autoantibodies may therefore lead to a loss of immune protection and consequently an increased risk of developing glaucoma. 182  
Microglia Coordinate the Immune System of the Central Nervous System
Today, three retinal glial cell types are known: The microglia, subdivided into star-shaped astrocytes and specialized retinal Müller cells, face the macroglia. In the retina, astrocytes are localized in the ganglion cell layer, whereas Müller cells span the entire retina. Microglia, ovoid or amoeboid shaped, can be found in the ganglion cell and inner plexiform layer. The macroglia provide the supply of the ganglion cells with neurotrophins, regulate extracellular ion concentration, and support neuronal metabolism. 183186 In contrast, microglia act as phagocytes that eliminate apoptotic neurons, cell debris, and pathogens. 187 Microglia recognize these via Toll-like receptors (TLR) and react by releasing proinflammatory cytokines such as TNF-α and nitric oxide synthase-2 (NOS-2). Apoptotic cells release anti-inflammatory mediators such as TGF-β prior to phagocytosis by microglia. 188 Microglia represent the first line of immune defense and are therefore equipped with a finely structured arsenal of defense mechanisms and a high degree of flexibility to act at the appropriate place. They destroy microbes by releasing cytotoxic substances, remove cell debris by phagocytosis, and act as antigen-presenting cells. 189  
Apart from the normal motility behavior under physiological conditions, in the event of activation the cells migrate collectively to the site of injury. Chipped neurons usually set free nucleotides such as adenosine triphosphate (ATP), which may activate microglia. 190,191 After a few days, this event is followed by glial proliferation that can end up in a reactive gliosis. 192 The involvement of a gliosis in neurodegenerative processes has been demonstrated in an animal model for Alzheimer's disease as well as in glaucoma. 68,105,136,193195  
An indication of the positive chemotactic motility of microglia is provided by experiments with CXCR3 knockout mice. The chemokine CXCL10 expressed under degenerative conditions by neurons cannot bind the microglial CXCR3 receptor. This results in an accumulation of damaged and dead cells that would have been gone after a few days under normal circumstances. 196 In an animal model of amyotrophic lateral sclerosis (ALS) and Parkinson's disease, another chemokine, CX3CL1, has been identified that is released from damaged neurons as a chemoattractant for glial cells. CX3CR1−/− mice whose microglia possess no functional chemokine receptor exhibit increased neuronal apoptosis, which indicates the neuroprotective role of microglia. 197,198 Apart from the supportive and protective function of the glia, an injury caused by degenerative processes or glial activation in glaucomatous eyes does damage. 32,187,199 At least in the eye, the activation correlates with the accumulation of mitogen-activated protein kinase within the glial cells. 200 Such activation occurs in the CNS as a general response to any form of injury or illness and is considered a cellular attempt to maintain the impaired mechanisms. 
The Role of Innate Immunity in the Manifestation of Central Nervous System Autoimmune Diseases
The activation of microglia, an unmistakable sign of inflammatory processes within the CNS, is documented in patients with Alzheimer's disease, Parkinson's disease, Huntington's disease, MS, and ALS. 201203 Found in serum and cerebrospinal fluid of these patients are elevated titers of IL-6, IL-1, and TNF-α, chemokines of innate immunity that are potent initiators of the extrinsic apoptosis of neurons. 201203 Especially for IL-1 and TNF-α, the activation of caspases has been shown, whereupon TNF-α increases apoptosis of neurons via the inhibition of insulin-like growth factor-1 (IGF-1). 204,205 In addition to the secretion of chemokines, activated microglial cells set free toxins such as nitric oxide (NO) and prostaglandins, which in turn initiate neurodegenerative processes. 203,206 As professional antigen-presenting cells, activated microglia control the transition from innate immunity to an adaptive immune response in the CNS. 206208  
However, in glaucoma, TNF-α is of special interest: TNF-α and its receptors TNFR1a and TNFR1b have been shown to be upregulated in the retinae of glaucoma patients, in whom increased expression of TNF receptors is predominant in the ONH. 158,209,210 In severely damaged ONHs, the axons of the RGCs express TNFR1 and may be the direct target for TNF-α–mediated neurodegeneration. 210 Thereby the increased TNF-α expression seems to be specifically controlled. TrkC.T1, a truncated neurotrophin receptor isoform lacking the kinase domain, has been shown to be rapidly upregulated in glaucomatous retinae. On closer examination, TrkC.T1 seems to be part of a fatal loop: Elevated IOP upregulates glial TrkC.T1 expression in glia; TrkC.T1 controls glial TNF-α production; and TNF-α causes RGC death. 211  
Another interesting aspect in this context is the occurrence of single-nucleotide polymorphisms of the TNF-α gene, found to be significantly higher in high-tension glaucoma patients. 212 Ambiguous so far are the effects of those polymorphisms on the pathogenesis of glaucoma. While studies from Pakistan and Iran have shown a strong connection of POAG and pseudoexfoliative glaucoma with TNF-α polymorphisms, others could not confirm this correlation. 213216  
So far, there are a number of findings of elevated cytokine titers and activated glial cells within the CNS, but it is not clear what is causative and what is classified as an epiphenomenon for the manifestation of an autoimmune disease. What seems to be clear is that cellular stressors such as oxidative stress, mitochondrial dysfunction, or excitotoxicity by glutamate are not sufficient as singular stressors to trigger the demise of neurons. Animal models for ALS, Alzheimer's disease, Parkinson's, and Huntington prove this assumption. 203,217,218  
Similarly, the presence of antibodies directed against neuronal antigens affects the cellular function of the epitope, but these are not able to trigger a neurodegenerative autoimmune disease. Tezel et al. succeeded in inducing apoptosis of neurons and cells of the retinal vascular system in a retinal cell culture by the application of antibodies against α-A- and α-B-crystallin, as well as against HSP27. 153 This, however, is not directly comparable with the induction of a complex autoimmune disease in vivo. 
In the case of paraneoplastic neurologic disease (PND), which can occur as a secondary symptom of a tumor disease, epitopes generated by tumor cells in the body correspond to those of neurons in the CNS. This leads to the establishment of a neurodegenerative process within the CNS. The therapeutic reduction of autoantibody titer by plasmapheresis provides no persistent relief of the clinical course. 219 Conversely, it is not possible to induce a PND in animal models by injecting antibodies from infected individuals. Autoantibodies alone are therefore not sufficient to initiate a neurodegenerative disease. 219,220 However, it is conceivable that autoantibodies directed against ocular structures have the potential to activate the complement system via binding C1q of the classical pathway. 165,221223  
The discovery of activated T cells and macrophages in the brain parenchyma of neurodegenerative disease patients confirms the participation of the cellular immune response directed against the body's own neural tissue within the CNS. 224232 The cause of inflammatory processes in the CNS may therefore be T cells and autoantibodies from the periphery that find access to the CNS, where they are again reactivated by local antigen-presenting cells (APC) or the microglia, or, in the case of antibodies, bind directly to their neuronal epitopes. The reactivation of T cells triggers the release of inflammatory cytokines and thereby the maintenance of the immune response. Phagocytes float to the site of inflammation, take up cell debris by endocytosis, present fragments thereof in peptide size on the major histocompatibility complex (MHC)-II on their surface, and thus again activate the adaptive immune response. The adaptive immunity leads to antigen-specific CD4+ T-helper cell activation and differentiation of naive B cells into antibody-producing plasma cells in the periphery. These antibodies cross the blood–brain barrier, particularly under pathologic circumstances, but even at elevated IOP. 233,234 These immunoglobulins not only bind to epitopes on the surface but also enter the cell by receptor-mediated endocytosis, as in the case of α-HSP27 antibody. In the cytoplasm of neurons, these immunoglobulins may cause apoptosis. 142,151 The resulting cellular debris is taken up by the phagocytes of the CNS, the microglia as antigen, and also peripheral T cells. This process is hosting an adaptive immune response to neural targets in the CNS. 
Through recurring cytokine release and antigen presentation, a self-perpetuating cycle is under way. The result is apoptosis of neurons, increased permeability of the blood–brain barrier, and upregulation of neuronal MHC-I, causing a chronic activation of innate immunity and establishment of an adaptive autoimmune response in the CNS. The induction of intercellular adhesion molecule 1 (ICAM 1) and vascular endothelial growth factor (VEGF) by proinflammatory cytokines of innate and adaptive immunity leads to further impairment of the barrier function of the blood–brain barrier, since they allow the passage of activated T lymphocytes 235,236 (Fig. 1). 
Figure 1
 
Hypothetical mechanism of neurodegeneration in the CNS involving innate and adaptive immunity. Damage of peripheral organs leads to the activation of immunological processes involving antigen-presenting cells (APC). The APC float to local lymph nodes where activation of the adaptive immune response takes place. (3, 4) The following clonal expansion of B cells leads to the production of antigen-specific antibodies. (5) These antibodies pass through the permeable blood–brain barrier. (6) In the CNS, the antibodies bind to neuronal antigens, interfering with their function, and cause cellular stress and finally apoptosis of the neuron. (7) The apoptosis of neurons leads to activation of microglia. (8) Activated microglia phagocytose the apoptotic cells and present their antigens on their surface. (9) Microglia secrete proinflammatory cytokines. Increased titers of vascular endothelial growth factor (VEGF) and the intercellular adhesion molecule 1 (ICAM 1) lead to increased permeability of the blood–brain barrier. (11) This leads to further influx of T lymphocytes. (12, 13) T cells and neuronal antigens activate microglia, which also leads to the destruction of neurons. (14) Alternatively, cellular damage or pathogens can cause chronic immune responses of the nonadaptive immune defense. Reprinted with permission from Nguyen MD, Julien JP, Rivest S. Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci. 2002;3:216–227. Copyright 2002 Macmillan Publishers Ltd: Nature Reviews Neuroscience.
Figure 1
 
Hypothetical mechanism of neurodegeneration in the CNS involving innate and adaptive immunity. Damage of peripheral organs leads to the activation of immunological processes involving antigen-presenting cells (APC). The APC float to local lymph nodes where activation of the adaptive immune response takes place. (3, 4) The following clonal expansion of B cells leads to the production of antigen-specific antibodies. (5) These antibodies pass through the permeable blood–brain barrier. (6) In the CNS, the antibodies bind to neuronal antigens, interfering with their function, and cause cellular stress and finally apoptosis of the neuron. (7) The apoptosis of neurons leads to activation of microglia. (8) Activated microglia phagocytose the apoptotic cells and present their antigens on their surface. (9) Microglia secrete proinflammatory cytokines. Increased titers of vascular endothelial growth factor (VEGF) and the intercellular adhesion molecule 1 (ICAM 1) lead to increased permeability of the blood–brain barrier. (11) This leads to further influx of T lymphocytes. (12, 13) T cells and neuronal antigens activate microglia, which also leads to the destruction of neurons. (14) Alternatively, cellular damage or pathogens can cause chronic immune responses of the nonadaptive immune defense. Reprinted with permission from Nguyen MD, Julien JP, Rivest S. Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci. 2002;3:216–227. Copyright 2002 Macmillan Publishers Ltd: Nature Reviews Neuroscience.
Even in the absence of inflammatory events in the CNS, the transfer of T cells in the subarachnoid space (SAS) between blood and cerebrospinal fluid is feasible. 237 Undoubtedly the permeability of the blood–brain barrier could play a major role in the pathogenesis of neurodegenerative processes in the CNS such as Alzheimer's disease, MS, and human immunodeficiency virus (HIV)-associated encephalitis. 202,238 Recently, Howell et al. documented the leukocyte transendothelial migration pathway as activated in the DBA/2J glaucoma model. This results in the inflow of proinflammatory monocytes (and/or monocyte-derived cells) into the optic nerve prior to detectable neuronal damage. 239  
Induction of Innate Immunity as a Pathogenic Factor in the CNS
Today, we know that innate immune responses are responsible for many chronic neurodegenerative processes within the CNS. 236 The retina in this case has its own immune system, including immune cells: microglia, dendritic cells, and even their own perivascular macrophages, all components of the innate immunity. 240 An essential component of innate immunity is receptor-mediated pathogen recognition by the Toll-like receptor family (TLR) and triggering receptor expressed on myeloid cells (TREM). These two classes of receptors are found on the microglia, neutrophils, dendritic cells, and macrophages in the CNS and the periphery. 241246 Since TREM was identified only in 2000, it is still not really clear what their ligands are. Nevertheless it seems that TREM modulates the activity of TLR; that is, TREM-1 has an activating and TREM-2 an inhibitory influence on TLR. 247,248  
In the case of pathogen recognition, TLR will induce the coordinated activation of transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B-cells), together with the increased expression of cytokines IL-1b and IL-6, chemokine IL-8, and the costimulatory proteins CD80 and CD86 (also known as B7.1 and B7.2) for targeted regulation of innate immunity. 225,249 In general, TLR are dimer-organized, mostly outward-directed receptors, activated by pathogen-associated molecular patterns (PAMPs). The PAMPS include substances such as lipopolysaccharide or bacterial CpG DNA, which is characteristic for Gram-negative bacteria. 249251 Of the total of 12 isotypes so far identified, TLR 3, 7, 8, and 9 monitor the internal cellular compartments. 242,252254  
In animal models, experimental elevation of IOP leads to increased expression of TLR 2, 3, and 4 and of HSP27, HSP60, and HSP72, as well as the characteristic TLR signaling cascade adapter proteins and kinases. These findings were confirmed by proteomic analysis of glaucomatous donor eyes. This supports the hypothesis that TLR contribute to the activation of the innate immune system in glaucoma. The increased HSP expression seems to stimulate the immune system even further. 255  
The latter may be due to the cross-reactivity between HSP and TLR, but it can also be explained by the ability of HSPs to present antigens. 256,257 Thus, TLR 4 reacts on HSP27 and HSP60, and TLR 2 recognizes glutathione S-transferase as PAMP. 258260 HSP72 interacts with TLR 2 and TLR 4. 261 This capability of HSPs to cause cross-reactivity can be explained by their distinctive antigenicity. Because HSPs are among the most highly conserved and abundant proteins in nature, as a logical consequence they are also among the major antigenic proteins for pathogens like bacteria, mycobacteria, and parasites, which share HSP epitopes with human HSPs. 169,262,263 Via the stimulation of innate immunity by a cross-reaction, which is not in these cases caused by molecular mimicry, autoreactive mechanisms are set in place. 264266 Molecular mimicry with a pathogen initially includes “appearance” to the surface properties of host cells to evade the surveillance of the immune defense. 267,268 Whether this is caused by cross-reactivity observed in phylogenetic conservation or molecular mimicry is obviously dependent on the relevant antigen. 
Either way, the consequences are the same. As seen in the cross-reactivity caused by conserved amino acid sequences, mimicry may also establish autoreactive processes. 269271 The correlation between the initiation of aberrant immune responses due to molecular mimicry between pathogen and host tissue has been unveiled in the development of numerous autoimmune diseases. The simultaneous occurrence of enteric bacteria or virus infection and the onset of autoimmune processes speaks for itself. 272,273 For glaucoma, an infection with Helicobacter pylori is discussed as a disease-causing trigger. 269,270,274  
Where Do the Neuronal Antigens in the Periphery Originate?
Besides the already mentioned cross-reactions, other theories could help to explain the existence of CNS-specific antigens and autoantibodies in the periphery. Proteins, fragmented or oxidatively modified by reactive oxygen species (ROS) or metalloproteinases (MMPs), could serve as autoantigens. 155,156,275,276 Examples include HSP27, HSP70, and HSP90, which are known to be substrates for MMP-9. 
Autoantibodies directed against these HSPs exhibit increased reactivity in glaucoma and other neurodegenerative diseases such as MS or Guillain-Barré syndrome. 153,155,277,278  
The Janus-Headed Complement System
In addition to the cellular components of immunological surveillance, the complement system represents the main component of the innate immune response that can be activated by the so-called classical path, the lectin pathway, and the alternative pathway. 
C1q represents the first component of the classical pathway, which can lead, either via antibody mediation or via direct binding, to complement activation. 
In the case of C1q binding to an apoptotic cell, a pathogen, or cell debris, the activation of a protease cascade directs the synthesis of complement component C3 (opsonization). 279 Opsonization with C3 fragments C3b and iCb heads the elimination of debris by direct activation of C3 receptors on macrophages and microglial phagocytosis. Activated C3 has the ability to activate the terminal components of the complement system. 
This allows the formation of membrane attack complex (MAC), the direct elimination of the target cell by a lytic process. These are the well-known facts about the function of the complement system. But how can one interpret recent findings regarding increased transcription rates and accumulation of complement protein C1q and downstream complement protein C3 within the adult glaucomatous retina? 280,281  
As described above, the production of autoantibodies is a hallmark of many autoimmune diseases, as well as in autoimmune glaucoma. 7,8,47,161163,165,172,179,282292 These autoantibodies may bind antigens on cell surfaces or form immune complexes after catching circulating antigens, which may, if not rendered harmless in time, accumulate in lymph nodes and diverse organs such as the kidney glomeruli. These immune complexes have the potential to activate the complement cascade via the classical pathway. 171,292,293  
However, in the OHT animal model (DBA/2 mice) and donor eyes of OHT patients, transcription rates of C1q and C3 are significantly increased. Twenty-eight days after experimental OHT induction, an accumulation of C1q and C3 transcripts is detected in the RGC layer and the ONH 29 (Fig. 2). 
Figure 2
 
Distribution of C1q transcripts in the retina. Compared to the control (A) strong signals for C1q can be detected in OHT patients in the ganglion cell layer (B) and the optic nerve head (ONH, [C]) strong signals for C1q (arrow). Reprinted with permission from Kuehn MH, Kim CY, Ostojic J, et al. Retinal synthesis and deposition of complement components induced by ocular hypertension. Exp Eye Res. 2006;83:620–628. Copyright 2006 Elsevier.
Figure 2
 
Distribution of C1q transcripts in the retina. Compared to the control (A) strong signals for C1q can be detected in OHT patients in the ganglion cell layer (B) and the optic nerve head (ONH, [C]) strong signals for C1q (arrow). Reprinted with permission from Kuehn MH, Kim CY, Ostojic J, et al. Retinal synthesis and deposition of complement components induced by ocular hypertension. Exp Eye Res. 2006;83:620–628. Copyright 2006 Elsevier.
This expression of C1q and C3 correlates with the activation of glial cells by the complement system. The activated glia hereupon responds with the secretion of NO, TNF-α, superoxide (O2–), and other effector substances. This involves glia in the reorganization of the ONH and the destruction of RGCs. 56,294297 Additionally, the classical complement cascade contributes to development and function refinement of the CNS and visual system via pruning of inappropriate synapses. 281,298300 This process of coordinated synapse elimination may be facilitated through the ability of developing CNS neurons to bind C1q directly. This allows activation of the classical complement cascade independently of antibodies. 301 However, the involvement of the complement system in synapse elimination is strictly limited to the development phase of the CNS and visual system under normal conditions, but seems to be reactivated in glaucoma. Recent studies point in the direction that components of the adaptive immune system also participate in the developmental synaptic refinement. In particular, class I major histocompatibily complex (MHC-I), which is not expressed by neurons under physiological conditions, is detectable on developing neurons and on neurons under inflammatory conditions. 302,303 It is intriguing to speculate that components of the complement pathway may be interacting with MHC-I, mediating synapse elimination. To date, such an interaction is elusive. However, the expression of the MHC-I complex on neuronal surfaces makes axons vulnerable to attacks of CD8+ T cells by perforin-mediated cytotoxicity and the release of granzyme 227 (Fig. 3). 
Figure 3
 
Cytotoxic T cells use three different routes to destroy their target. Initially the CD8+ T cell recognizes the target via the interaction of its T-cell receptor (TCR) with the target cell's MHC-I complex, including presented peptide (square). The destruction of the target cell is performed by either (i) release of cytotoxic granules and the resulting perforation of the cell membrane, (ii) activation of the target cell's Fas/CD95 receptor by Fas ligand/CD95 ligand, or (iii) the release of cytokines such as TNF-α. Reprinted with permission from Neumann H, Medana IM, Bauer J, Lassmann H. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci. 2002;25:313–319. Copyright 2002 Elsevier.
Figure 3
 
Cytotoxic T cells use three different routes to destroy their target. Initially the CD8+ T cell recognizes the target via the interaction of its T-cell receptor (TCR) with the target cell's MHC-I complex, including presented peptide (square). The destruction of the target cell is performed by either (i) release of cytotoxic granules and the resulting perforation of the cell membrane, (ii) activation of the target cell's Fas/CD95 receptor by Fas ligand/CD95 ligand, or (iii) the release of cytokines such as TNF-α. Reprinted with permission from Neumann H, Medana IM, Bauer J, Lassmann H. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci. 2002;25:313–319. Copyright 2002 Elsevier.
Reactive gliosis, release of inflammatory cytokines, and upregulation of the complement cascade as hallmarks of developmental synapse elimination in early stages of glaucoma reoccur in many disease models, as well as in eyes of human donors. 29,280,281,304 Recent work investigating the first steps of glaucoma genesis in the DBA/2J mouse points to the activation of astrocytes as one of the earliest events in glaucoma pathogenesis. This awakening of the innate immunity seems to be triggered by a contusion of RGC axons traversing the sclera through the lamina cribrosa. 10,126,305 Since the lamina is the weakest part of the sclera, elevated IOP inevitably leads to mechanical stress on RGC axons at this point. 2,87,305,306 In the course of glaucoma progression, microglial proliferation and activation are accompanied by the secretion of TNF-α and IL-1β. 57,210,295,307309 As a consequence, this release of inflammatory cytokines have the potential to impair the integrity of the blood–brain barrier. 209,233,234,310,311 The reactivation of the complement cascade is noticeable by an increased transcription rate of C1q, C3, and C4 and the subsequent accumulation of these proteins within the inner plexiform layer (IPL). 29,280,281,304,312 Synapses, “tagged” with C1q and/or C3b, are phagocytized by microglia; downstream formation of the MAC results in synapse loss without participation of glial cells. Apart from the neurotoxic effects of a misdirected complement cascade, the decease of RGCs is thought to be caused by proapoptotic TNF-α and the excitotoxic effect of glutamate, which is supported through the downregulation of glutamate transporters during reactive gliosis. What's left of the RGCs after their demise is thought to be opsonized and removed by the complement system. 299 The ongoing elimination of apoptotic bodies, cells, and debris has a high priority, because in the case of aggregation they endanger the metabolism and offer an autologous immune epitope. 313  
Where the C1q-controlled neutralization of endogenous antigens is defective, a misallocation of the immune system may result in the establishment of autoimmune processes such as SLE or glomerulonephritis. 314  
Generally, it appears that a deviation of the complement system is responsible for a number of neurodegenerative processes, such as ischemic conditions within the CNS, MS, Alzheimer's, and Parkinson's disease. 315318 Whereas C1q has a role as an eliminator of superfluous synaptic connections during a short phase of embryonic and postnatal maturation of the CNS, its expression in the adult CNS is suppressed under physiological conditions. However, the expression of C1q by neurons and microglia under ischemic, traumatic, and other pathogenic influences is raised very quickly. Apart from glaucoma, the massive upregulation of C1q expression is also detectable in Alzheimer's disease and ALS. 32,304,312,319323  
The key to understanding these degenerative events is to be found in the extensive cross talk between complement and TLR signaling pathways. This complement–TLR interplay, based on synergistic or antagonistic interactions, reinforces innate immunity or regulates excessive inflammation. The interaction of complement on TLR signaling is primarily executed via the C5a receptor (C5aR), and to a much lesser extent via the C3a receptor (C3aR). This cross talk appears to involve the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK1/2), and the c-Jun N-terminal kinase (JNK). 324 While the mutual reinforcement of complement cascade and TLR with its increased TNF-α, IL-1β, and IL-6 responses might be useful for rapid infection fighting, such an enhanced inflammatory response can slip out of control. Several membrane-associated proteins should help to control complement action to prevent the host from unintended injury. These proteins are decay-accelerating factor (DAF), membrane cofactor protein (MCP), complement receptor type 1 (CR1), and CD59. Although the complement cascade is accepted as participating in autoimmunity, little is known concerning the degree to which membrane complement regulatory proteins are capable of modulating complement action. In any case, knockout mice lacking these regulatory proteins display a higher susceptibility to autoimmune injury than wild-type mice. 325  
Increasingly, the complement system, traditionally known as a peripheral complemental function, migrates to the center of the immune system as a global mediator of immune surveillance, cell homeostasis, and tissue development and repair. The review article by Ricklin et al. 293 offers additional insights into recent findings concerning the complement system. 
Clinical Diagnosis of Autoimmune Glaucoma
To diagnose glaucoma caused by autoimmunity, the attending physician has no choice but first to exclude all other causes of glaucoma. These include elevated IOP in high-pressure glaucoma. In the case of NTG, pathogenic factors like ischemia, migraine, systemic nocturnal hypotension, or sleep apnea must be excluded as a cause for glaucoma. In summary, it can be said that the diagnosis of autoimmune glaucoma is a diagnosis of exclusion. 326  
Based on the available data on autoreactivities, one can presume a tissue specificity of the immune response in glaucoma. This specificity derives from the autoantigen that has been initially recognized. 327,328 A complicating factor is that any given autoimmune disease is heterologous, varying from patient to patient with regard to the course of disease, the severity, and the underlying dysfunction of the immune system. 
To minimize these uncertainties, the creation of a personalized “autoantibody signature” is proposed by some authors. Using the antigen microarray technique, this tool would provide insight into the course of disease, particularly with reference to the patient's response to a therapeutic agent. 172 A recent study, performed with patients suffering from rheumatoid arthritis (RA), investigated the antibody profile in response to the anti-TNF therapeutic agent etanercept. In summary, a panel of proteomic markers was shown to be able to distinguish responders from nonresponders. 291 Suggesting that TNF-α may also be an important factor in the neurodegenerative process of glaucoma, a OHT mouse model was used to investigate the effect of etanercept on glaucoma. In fact, the therapeutic anti-TNF-α antibody etanercept is effective in rescuing RGCs from OHT-induced death. 329 An investigation of the neuroprotective effect of etanercept could enable the discovery of proteomic factors that are involved in the pathogenesis of glaucoma. A panel of proteomic markers that allows the distinction of healthy from those suffering from glaucoma is an enticing perspective. 
While the investigation of autoantibody profiles as a methodical approach might help to increase understanding of the mechanisms of aberrant immunity in glaucoma, the identification of diagnostic biomarkers would be a great benefit. Proteomic biomarkers are established tools in early diagnosis and are well suited to monitoring the course of numerous diseases. As an example, superoxide dismutase is used in prenatal diagnostics as a biomarker for Down syndrome because of the excessive expression of genes encoded on chromosome 21. 330,331  
In glaucoma, distinct immunglobulins, such as autoantibodies to alpha-fodrin 163 or glutathione S-transferase, 165 may serve as biomarkers as well as proteins that are significantly linked to cytotoxic conditions in glaucoma. Actually, transthyretin has been identified as a biomarker for glaucoma in aqueous humor of patients with POAG. 332 Another biomarker for POAG, brain-derived neurotrophic factor (BDNF), could be detected in the sera of glaucoma patients. 333  
Markers that correspond with oxidative stress are superoxide dismutase, 334339 glutathione peroxidase, 334,337,340 ascorbic acid, 334,335,340 α-tocopherol, 340,341 retinol, 228,335 nitric oxide, 43,57,157,210,221,295,296,337,342346 8-hydroxy-20-deoxyguanosine, 347 and malondialdehyde. 337,348 Detailed information concerning all glaucoma biomarkers identified to date is provided in the review article of Pinazo-Duran et al. 349  
However, as of now, no neuroprotective treatments that directly target pathogenic mechanisms in the retina or optic nerve and no laboratory diagnostics are approved for clinical use against glaucoma. But the progress that glaucoma research has made in recent years gives reason to hope that this will change soon. 
Summary
According to current knowledge, a sole trigger for glaucoma can be excluded. Apparently the lamina cribrosa as the most vulnerable site of the RGCs is of special interest. This may be the position at which impact-induced stress triggers the activation of one or more self-destruct programs, depending on the severity of the impact, WD, DB, or the initiation of a gliosis—or none of these. While it is now understood that many cell types and mechanisms respond to cellular stress, it is not clear where the earliest pathologic events take place and where the key trigger comes from. In this context, the CNS-specific immune system is of particular importance. Under physiological conditions, this ensures a perfect homeostasis. However, this state can be destroyed in the next moment under conditions of cellular stress. As a trigger for cellular stress, a variety of possible factors are under consideration. Among these factors are reactive oxygen species (ROS), protein aggregation, ischemia, vasospasm, deficient neurotrophin supply, and even light. However, the early events in glial activation seem to be crucial for the manifestation of glaucoma. These events need further investigation, because they may be a key to an effective therapy. 
Acknowledgments
The author thanks Barbara Pullmann, Annette Weber, and Ulrich Hoeger for valuable support. The author thanks Paul L. Kaufman for detailed and helpful comments. 
References
Quigley HA Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol . 2006; 90: 262–267. [CrossRef] [PubMed]
Burgoyne CF. A biomechanical paradigm for axonal insult within the optic nerve head in aging and glaucoma. Exp Eye Res . 2010; 93: 120–132. [CrossRef] [PubMed]
Fechtner RD Weinreb RN. Mechanisms of optic nerve damage in primary open angle glaucoma. Surv Ophthalmol . 1994; 39: 23–42. [CrossRef] [PubMed]
Ferrer E. Trabecular meshwork as a new target for the treatment of glaucoma. Drug News Perspect . 2006; 19: 151–158. [CrossRef] [PubMed]
Henderson PA Medeiros FA Zangwill LM Weinreb RN. Relationship between central corneal thickness and retinal nerve fiber layer thickness in ocular hypertensive patients. Ophthalmology . 2005; 112: 251–256. [CrossRef] [PubMed]
Kerr JF Wyllie AH Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer . 1972; 26: 239–257. [CrossRef] [PubMed]
Maruyama I Ikeda Y Nakazawa M Ohguro H. Clinical roles of serum autoantibody against neuron-specific enolase in glaucoma patients. Tohoku J Exp Med . 2002; 197: 125–132. [CrossRef] [PubMed]
Maruyama I Ohguro H Ikeda Y. Retinal ganglion cells recognized by serum autoantibody against gamma-enolase found in glaucoma patients. Invest Ophthalmol Vis Sci . 2000; 41: 1657–1665. [PubMed]
Neufeld AH Sawada A Becker B. Inhibition of nitric-oxide synthase 2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma. Proc Natl Acad Sci U S A . 1999; 96: 9944–9948. [CrossRef] [PubMed]
Nickells RW Howell GR Soto I John SW. Under pressure: cellular and molecular responses during glaucoma, a common neurodegeneration with axonopathy. Annu Rev Neurosci . 2012; 35: 153–179. [CrossRef] [PubMed]
Quigley HA. Ganglion cell death in glaucoma: pathology recapitulates ontogeny. Aust N Z J Ophthalmol . 1995; 23: 85–91. [CrossRef] [PubMed]
Quigley HA. Neuronal death in glaucoma. Prog Retin Eye Res . 1999; 18: 39–57. [CrossRef] [PubMed]
Quigley HA. Glaucoma. Lancet . 2011; 377: 1367–1377. [CrossRef] [PubMed]
Weinreb RN Khaw PT. Primary open-angle glaucoma. Lancet . 2004; 363: 1711–1720. [CrossRef] [PubMed]
Whitmore AV Libby RT John SWM. Glaucoma: thinking in new ways--a rôle for autonomous axonal self-destruction and other compartmentalised processes? Prog Retin Eye Res . 2005; 24: 639–662. [CrossRef] [PubMed]
Harrington DO. The Bjerrum scotoma. Trans Am Ophthalmol Soc . 1964; 62: 324–348. [PubMed]
Garcia-Valenzuela E Shareef S Walsh J Sharma SC. Programmed cell death of retinal ganglion cells during experimental glaucoma. Exp Eye Res . 1995; 61: 33–44. [CrossRef] [PubMed]
Glovinsky Y Quigley HA Dunkelberger GR. Retinal ganglion cell loss is size dependent in experimental glaucoma. Invest Ophthalmol Vis Sci . 1991; 32: 484–491. [PubMed]
Nickells RW. Retinal ganglion cell death in glaucoma: the how, the why, and the maybe. J Glaucoma . 1996; 5: 345–356. [CrossRef] [PubMed]
Quigley HA Nickells RW Kerrigan LA Pease ME Thibault DJ Zack DJ. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci . 1995; 36: 774–786. [PubMed]
Bjerrum J. Om en tilføjelse til den sædvanlige synsfelt – undersögelse samt om synsfeltet ved glaukom. Nord ophthal Tidsskrift . 1889; 2: 141–185.
Jay JL Murray SB. Early trabeculectomy versus conventional management in primary open angle glaucoma. Br J Ophthalmol . 1988; 72: 881–889. [CrossRef] [PubMed]
Zur D Ullman S. Filling-in of retinal scotomas. Vis Res . 2003; 43: 971–982. [CrossRef] [PubMed]
Gloor BP Sarra GM. Visusverlust und Sehstörung (2. Teil). Schweiz Med Forum . 2004; 4: 308–312.
Kass MA Heuer DK Higginbotham EJ The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol . 2002; 120: 701–713. [CrossRef] [PubMed]
Weber AJ Chen H Hubbard WC Kaufman PL. Experimental glaucoma and cell size, density, and number in the primate lateral geniculate nucleus. Invest Ophthalmol Vis Sci . 2000; 41: 1370–1379. [PubMed]
Gordon MO Beiser JA Brandt JD The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol . 2002; 120: 714–720. [CrossRef] [PubMed]
Loewen NA Liu JH Weinreb RN. Increased 24-hour variation of human intraocular pressure with short axial length. Invest Ophthalmol Vis Sci . 2010; 51: 933–937. [CrossRef] [PubMed]
Kuehn MH Kim CY Ostojic J Retinal synthesis and deposition of complement components induced by ocular hypertension. Exp Eye Res . 2006; 83: 620–628. [CrossRef] [PubMed]
Naskar R Wissing M Thanos S. Detection of early neuron degeneration and accompanying microglial responses in the retina of a rat model of glaucoma. Invest Ophthalmol Vis Sci . 2002; 43: 2962–2968. [PubMed]
Guo L Moss SE Alexander RA Ali RR Fitzke FW Cordeiro MF. Retinal ganglion cell apoptosis in glaucoma is related to intraocular pressure and IOP-induced effects on extracellular matrix. Invest Ophthalmol Vis Sci . 2005; 46: 175–182. [CrossRef] [PubMed]
Steele MR Inman DM Calkins DJ Horner PJ Vetter ML. Microarray analysis of retinal gene expression in the DBA/2J model of glaucoma. Invest Ophthalmol Vis Sci . 2006; 47: 977–985. [CrossRef] [PubMed]
Johnson EC Deppmeier LM Wentien SK Hsu I Morrison JC. Chronology of optic nerve head and retinal responses to elevated intraocular pressure. Invest Ophthalmol Vis Sci . 2000; 41: 431–442. [PubMed]
Grehn F Hollo G Lachkar Y Migdal C Thygesen J. Terminology and Guidelines for Glaucoma . Vol. 2. Savona, Italy: European Glaucoma Society; 2003.
Weinreb RN Levin LA. Is neuroprotection a viable therapy for glaucoma? Arch Ophthalmol . 1999; 117: 1540–1544. [CrossRef] [PubMed]
Nickells RW. From ocular hypertension to ganglion cell death: a theoretical sequence of events leading to glaucoma. Can J Ophthalmol . 2007; 42: 278–287. [CrossRef] [PubMed]
Coleman AL. Glaucoma. Lancet . 1999; 354: 1803–1810. [CrossRef] [PubMed]
Mackenzie P Cioffi G. How does lowering of intraocular pressure protect the optic nerve? Surv Ophthalmol . 2008; 53 (suppl 1): S39–S43. [CrossRef] [PubMed]
Mozaffarieh M Flammer J. Is there more to glaucoma treatment than lowering IOP? Surv Ophthalmol . 2007; 52 (suppl 1): S174–S179. [CrossRef] [PubMed]
Enyedi LB Freedman SF. Safety and efficacy of brimonidine in children with glaucoma. J Pediatr Ophthalmol Strabismus . 2001; 5: 281–284. [CrossRef]
Schuettauf F Quinto K Naskar R Zurakowski D. Effects of anti-glaucoma medications on ganglion cell survival: the DBA/2J mouse model. Vis Res . 2002; 42: 2333–2337. [CrossRef] [PubMed]
Pfeiffer N Grierson I Goldsmith H Hochgesand D Winkgen-Bohres A Appleton P. Histological effects in the iris after 3 months of latanoprost therapy: the Mainz 1 Study. Arch Ophthalmol . 2001; 119: 191–196. [PubMed]
Chidlow G Wood JP Casson RJ. Pharmacological neuroprotection for glaucoma. Drugs . 2007; 67: 725–759. [CrossRef] [PubMed]
Pfeiffer N. Glaukom und okuläre Hypertension - Grundlagen, Diagnostik, Therapie . Vol. 1. Stuttgart, Germany: Thieme-Verlag; 2001.
Aung T Ocaka L Ebenezer ND A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene. Hum Genet . 2002; 110: 52–56. [CrossRef] [PubMed]
Bonomi L Marchini G Marraffa M Prevalence of glaucoma and intraocular pressure distribution in a defined population: the Egna-Neumarkt study. Ophthalmology . 1998; 105: 209–215. [CrossRef] [PubMed]
Grus FH Joachim SC Pfeiffer N. Analysis of complex autoantibody repertoires by surface-enhanced laser desorption/ionization-time of flight mass spectrometry. Proteomics . 2003; 3: 957–961. [CrossRef] [PubMed]
CNTGSG. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol . 1998; 126: 487–497. [CrossRef] [PubMed]
CNTGSG. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol . 1998; 126: 498–505. [CrossRef] [PubMed]
Kuehn MH Fingert JH Kwon YH. Retinal ganglion cell death in glaucoma: mechanisms and neuroprotective strategies. Ophthalmol Clin North Am . 2005; 18: 383–395, vi. [CrossRef] [PubMed]
Crawford ML Harwerth RS Smith ELIII, Mills S Ewing B. Experimental glaucoma in primates: changes in cytochrome oxidase blobs in V1 cortex. Invest Ophthalmol Vis Sci . 2001; 42: 358–364. [PubMed]
Yücel YH Zhang Q Gupta N Kaufman PL Weinreb RN. Loss of neurons in magnocellular and parvocellular layers of the lateral geniculate nucleus in glaucoma. Arch Ophthalmol . 2000; 118: 378–384. [CrossRef] [PubMed]
Yücel YH Zhang Q Weinreb RN Kaufman PL Gupta N. Atrophy of relay neurons in magno- and parvocellular layers in the lateral geniculate nucleus in experimental glaucoma. Invest Ophthalmol Vis Sci . 2001; 42: 3216–3222. [PubMed]
Yücel YH Zhang Q Weinreb RN Kaufman PL Gupta N. Effects of retinal ganglion cell loss on magno-, parvo-, koniocellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma. Prog Retin Eye Res . 2003; 22: 465–481. [CrossRef] [PubMed]
Fukuchi T Ueda J Hanyu T Abe H Sawaguchi S. Distribution and expression of transforming growth factor-beta and platelet-derived growth factor in the normal and glaucomatous monkey optic nerve heads. Jpn J Ophthalmol . 2001; 45: 592–599. [CrossRef] [PubMed]
Hernandez MR. The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog Retin Eye Res . 2000; 19: 297–321. [CrossRef] [PubMed]
Zhong YS Leung CK Pang CP. Glial cells and glaucomatous neuropathy. Chin Med J (Engl) . 2007; 120: 326–335. [PubMed]
Nickells RW. Apoptosis of retinal ganglion cells in glaucoma: an update of the molecular pathways involved in cell death. Surv Ophthalmol . 1999; 43 (suppl 1): S151–S161. [CrossRef] [PubMed]
Calandrella N Scarsella G Pescosolido N Risuleo G. Degenerative and apoptotic events at retinal and optic nerve level after experimental induction of ocular hypertension. Mol Cell Biochem . 2007; 301: 155–163. [CrossRef] [PubMed]
Levkovitch-Verbin H Dardik R Vander S Melamed S. Mechanism of retinal ganglion cells death in secondary degeneration of the optic nerve. Exp Eye Res . 2010; 91: 127–134. [CrossRef] [PubMed]
Libby RT Li T Savinova OV Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage. PLoS Genet . 2005; 1: 17–26. [CrossRef] [PubMed]
Murakami A Okisaka S. Neuronal cell death mechanism in glaucomatous optic neuropathy. Nippon Ganka Gakkai Zasshi . 1998; 102: 645–653. [PubMed]
Nickells RW. The molecular biology of retinal ganglion cell death: caveats and controversies. Brain Res Bull . 2004; 62: 439–446. [CrossRef] [PubMed]
Tatton WG Olanow CW. Apoptosis in neurodegenerative diseases: the role of mitochondria. Biochim Biophys Acta . 1999; 1410: 195–213. [CrossRef] [PubMed]
Pease ME McKinnon SJ Quigley HA Kerrigan-Baumrind LA Zack DJ. Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma. Invest Ophthalmol Vis Sci . 2000; 41: 764–774. [PubMed]
Agar A Li S Agarwal N Coroneo MT Hill MA. Retinal ganglion cell line apoptosis induced by hydrostatic pressure. Brain Res . 2006; 1086: 191–200. [CrossRef] [PubMed]
Agar A Yip SS Hill MA Coroneo MT. Pressure related apoptosis in neuronal cell lines. J Neurosci Res . 2000; 60: 495–503. [CrossRef] [PubMed]
Schlamp CL Li Y Dietz JA Janssen KT Nickells RW. Progressive ganglion cell loss and optic nerve degeneration in DBA/2J mice is variable and asymmetric. BMC Neurosci . 2006; 7: 66. [CrossRef] [PubMed]
Leske MC. The epidemiology of open angle glaucoma: a review. Am J Epidemiol . 1983; 118: 166–191. [PubMed]
Pfeiffer N. Results of the “Ocular Hypertension treatment study.” Ophthalmologe . 2005; 102: 230–234. [CrossRef] [PubMed]
Minckler DS Bunt AH Johanson GW. Orthograde and retrograde axoplasmic transport during acute ocular hypertension in the monkey. Invest Ophthalmol Vis Sci . 1977; 16: 426–441. [PubMed]
Quigley HA McKinnon SJ Zack DJ Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats. Invest Ophthalmol Vis Sci . 2000; 41: 3460–3466. [PubMed]
Mansour-Robaey S. Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. Proc Natl Acad Sci U S A . 1994; 91: 1632–1636. [CrossRef] [PubMed]
Sawai H Clarke DB Kittlerova P Bray GM Aguayo AJ. Brain-derived neurotrophic factor and neurotrophin-4/5 stimulate growth of axonal branches from regenerating retinal ganglion cells. J Neurosci . 1996; 16: 3887–3894. [PubMed]
Klöcker N Bräunling F Isenmann S Bähr M. In vivo neurotrophic effects of GDNF on axotomized retinal ganglion cells. Neuroreport . 1997; 8: 3439–3442. [CrossRef] [PubMed]
Ji JZ Elyaman W Yip HK CNTF promotes survival of retinal ganglion cells after induction of ocular hypertension in rats: the possible involvement of STAT3 pathway. Eur J Neurosci . 2004; 19: 265–272. [CrossRef] [PubMed]
Zweifel LS Kuruvilla R Ginty DD. Functions and mechanisms of retrograde neurotrophin signalling. Nat Rev Neurosci . 2005; 6: 615–625. [CrossRef] [PubMed]
Meyer-Franke A Kaplan MR Pfrieger FW Barres BA. Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron . 1995; 15: 805–819. [CrossRef] [PubMed]
Weibel D Kreutzberg GW Schwab ME. Brain-derived neurotrophic factor (BDNF) prevents lesion-induced axonal die-back in young rat optic nerve. Brain Res . 1995; 679: 249–254. [CrossRef] [PubMed]
Eathiraj S Pan X Ritacco C Lambright DG. Structural basis of family-wide Rab GTPase recognition by rabenosyn-5. Nature . 2005; 436: 415–419. [CrossRef] [PubMed]
Nielsen E Christoforidis S Uttenweiler-Joseph S Rabenosyn-5, a novel Rab5 effector, is complexed with Hvps45 and recruited to endosomes through a Fyve finger domain. J Cell Biol . 2000; 151: 601–612. [CrossRef] [PubMed]
Nielsen E Severin F Backer JM Hyman AA Zerial M. Rab5 regulates motility of early endosomes on microtubules. Nat Cell Biol . 1999; 1: 376–382. [CrossRef] [PubMed]
Schnatwinkel C Christoforidis S Lindsay MR The Rab5 effector rabankyrin-5 regulates and coordinates different endocytic mechanisms. PLoS Biol . 2004; 2: e261. [CrossRef] [PubMed]
Shin H-W Hayashi M Christoforidis S An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway. J Cell Biol . 2005; 170: 607–618. [CrossRef] [PubMed]
Valdez G Philippidou P Rosenbaum J Akmentin W Shao Y Halegoua S. Trk-signaling endosomes are generated by Rac-dependent macroendocytosis. Proc Natl Acad Sci U S A . 2007; 104: 12270–12275. [CrossRef] [PubMed]
Allcutt D Berry M Sievers J. A quantitative comparison of the reactions of retinal ganglion cells to optic nerve crush in neonatal and adult mice. Brain Res . 1984; 16: 219–230. [CrossRef]
Morgan JE Jeffery G Foss AJE. Axon deviation in the human lamina cribrosa. Br J Ophthalmol . 1998; 82: 680–683. [CrossRef] [PubMed]
Radius RL Anderson DR. Rapid axonal transport in primate optic nerve. Distribution of pressure-induced interruption. Arch Ophthalmol . 1981; 99: 650–654. [CrossRef] [PubMed]
Dandona L Hendrickson A Quigley HA. Selective effects of experimental glaucoma on axonal transport by retinal ganglion cells to the dorsal lateral geniculate nucleus. Invest Ophthalmol Vis Sci . 1991; 32: 1593–1599. [PubMed]
Bellezza AJ Rintalan CJ Thompson HW Downs JC Hart RT Burgoyne CF. Deformation of the lamina cribrosa and anterior scleral canal wall in early experimental glaucoma. Invest Ophthalmol Vis Sci . 2003; 44: 623–637. [CrossRef] [PubMed]
Pena JD Agapova O Gabelt BT Increased elastin expression in astrocytes of the lamina cribrosa in response to elevated intraocular pressure. Invest Ophthalmol Vis Sci . 2001; 42: 2303–2314. [PubMed]
Jonas JB. Role of cerebrospinal fluid pressure in the pathogenesis of glaucoma. Acta Ophthalmol . 2011; 89: 505–514. [CrossRef] [PubMed]
Li Y Schlamp CL Poulsen GL Jackson MW Griep AE Nickells RW. p53 regulates apoptotic retinal ganglion cell death induced by N-methyl-D-aspartate. Mol Vis . 2002; 8: 341–350. [PubMed]
Li Y Schlamp CL Poulsen KP Nickells RW. Bax-dependent and independent pathways of retinal ganglion cell death induced by different damaging stimuli. Exp Eye Res . 2000; 71: 209–213. [CrossRef] [PubMed]
Wax MB Tezel G Yang J Induced autoimmunity to heat shock proteins elicits glaucomatous loss of retinal ganglion cell neurons via activated T-cell-derived Fas-ligand. J Neurosci . 2008; 28: 12085–12096. [CrossRef] [PubMed]
McKinnon SJ. The cell and molecular biology of glaucoma: common neurodegenerative pathways and relevance to glaucoma. Invest Ophthalmol Vis Sci . 2012; 53: 2485–2487. [CrossRef] [PubMed]
Yaar M Pilch PF Doyle SM Eisnehauer PB Fine RE Gilchrest GA. Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer's disease. J Clin Invest . 1997; 100: 2333–2340. [CrossRef] [PubMed]
Hafezi F Marti A Munz K Remé CE. Light-induced apoptosis: differential timing in the retina and pigment epithelium. Exp Eye Res . 1997; 64: 963–970. [CrossRef] [PubMed]
Harada T Harada C Nakayama N Modification of glial neuronal cell interactions prevents photoreceptor apoptosis during light-induced retinal degeneration. Neuron . 2000; 26: 533–541. [CrossRef] [PubMed]
Lipton SA. Possible role for memantine in protecting retinal ganglion cells from glaucomatous damage. Surv Ophthalmol . 2003; 48 (suppl 1): S38–S46. [CrossRef] [PubMed]
Schori H Kipnis J Yoles E Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implications for glaucoma. Proc Natl Acad Sci U S A . 2001; 98: 3398–3403. [CrossRef] [PubMed]
Vorwerk CK Naskar R Schuettauf F Depression of retinal glutamate transporter function leads to elevated intravitreal glutamate levels and ganglion cell death. Invest Ophthalmol Vis Sci . 2000; 41: 3615–3621. [PubMed]
Honkanen RA Baruah S Zimmerman MB Vitreous amino acid concentrations in patients with glaucoma undergoing vitrectomy. Arch Ophthalmol . 2003; 121: 183–188. [CrossRef] [PubMed]
Ullian EM Barkis WB Chen S Diamond JS Barres BA. Invulnerability of retinal ganglion cells to NMDA excitotoxicity. Mol Cell Neurosci . 2004; 26: 544–557. [CrossRef] [PubMed]
Bringmann A Reichenbach A. Role of Muller cells in retinal degenerations. Front Biosci . 2001; 6: E72–E92. [CrossRef] [PubMed]
Russo R Rotiroti D Tassorelli C Identification of novel pharmacological targets to minimize excitotoxic retinal damage. Int Rev Neurobiol . 2009; 85: 407–423. [PubMed]
Inoue-Matsuhisa E Sogo S Mizota A Taniai M Takenaka H Mano T. Effect of MCI-9042, a 5-HT2 receptor antagonist, on retinal ganglion cell death and retinal ischemia. Exp Eye Res . 2003; 76: 445–452. [CrossRef] [PubMed]
Bucolo C Leggio GM Maltese A Castorina A D'Agata V Drago F. Dopamine-3 receptor modulates intraocular pressure: implications for glaucoma. Biochem Pharmacol . 2011; 83: 680–686. [CrossRef] [PubMed]
Lingor P Koeberle P Kügler S Bähr M. Down-regulation of apoptosis mediators by RNAi inhibits axotomy-induced retinal ganglion cell death in vivo. Brain . 2005; 128: 550–558. [CrossRef] [PubMed]
Osborne NN Lascaratos G Bron AJ Chidlow G Wood JP. A hypothesis to suggest that light is a risk factor in glaucoma and the mitochondrial optic neuropathies. Br J Ophthalmol . 2006; 90: 237–241. [CrossRef] [PubMed]
Aronica E Gorter JA Ijlst-Keizers H Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur J Neurosci . 2003; 17: 2106–2118. [CrossRef] [PubMed]
Naskar R Vorwerk CK Dreyer EB. Concurrent downregulation of a glutamate transporter and receptor in glaucoma. Invest Ophthalmol Vis Sci . 2000; 41: 1940–1944. [PubMed]
Bovolenta P Wandosell F Nieto-Sampedro M. CNS glial scar tissue: a source of molecules which inhibit central neurite outgrowth. Prog Brain Res . 1992; 94: 367–379. [PubMed]
Campenot RB. Local control of neurite development by nerve growth factor. Proc Natl Acad U S A . 1977; 74: 4516–4519. [CrossRef]
Campenot RB. Local control of neurite sprouting in cultured sympathetic neurons by nerve growth factor. Dev Brain Res . 1987; 37: 293–301. [CrossRef]
Castaño A Bell MD Perry VH. Unusual aspects of inflammation in the nervous system: Wallerian degeneration. Neurobiol Aging . 1996; 17: 745–751. [CrossRef] [PubMed]
Fu QL Li X Shi J Synaptic degeneration of retinal ganglion cells in a rat ocular hypertension glaucoma model. Cell Mol Neurobiol . 2009; 29: 575–581. [CrossRef] [PubMed]
Gillingwater TH Ribchester RR. The relationship of neuromuscular synapse elimination to synaptic degeneration and pathology: insights from WldS and other mutant mice. J Neurocytol . 2003; 32: 863–881. [CrossRef] [PubMed]
Hilliard MA. Axonal degeneration and regeneration: a mechanistic tug-of-war. J Neurochem . 2009; 108: 23–32. [CrossRef] [PubMed]
Jellinger K. Recent advances in our understanding of neurodegeneration. J Neural Transm . 2009; 116: 1111–1162. [CrossRef] [PubMed]
Linker RA Sendtner M Gold R. Mechanisms of axonal degeneration in EAE--lessons from CNTF and MHC I knockout mice. J Neurol Sci . 2005; 233: 167–172. [CrossRef] [PubMed]
Profyris C Cheema SS Zang D Azari MF Boyle K Petratos S. Degenerative and regenerative mechanisms governing spinal cord injury. Neurobiol Dis . 2004; 15: 415–436. [CrossRef] [PubMed]
Yoles E Schwartz M. Degeneration of spared axons following partial white matter lesion: implications for optic nerve neuropathies. Exp Neurol . 1998; 153: 1–7. [CrossRef] [PubMed]
Coleman MP Freeman MR. Wallerian degeneration, WldS, and Nmnat. Annu Rev Neurosci . 2010; 33: 245–267. [CrossRef] [PubMed]
Kisiswa L Dervan AG Albon J Morgan JE Wride MA. Retinal ganglion cell death postponed: giving apoptosis a break? Ophthalmic Res . 2010; 43: 61–78. [CrossRef] [PubMed]
Howell GR Soto I Libby RT John SW. Intrinsic axonal degeneration pathways are critical for glaucomatous damage [published online ahead of print January 18, 2012]. Exp Neurol . doi:10.1016/j.expneurol.2012.01.014 .
Li Y Semaan SJ Schlamp CL Nickells RW. Dominant inheritance of retinal ganglion cell resistance to optic nerve crush in mice. BMC Neurosci . 2007; 8: 19. [CrossRef] [PubMed]
Schwartz M. Vaccination for glaucoma: dream or reality? Brain Res Bull . 2004; 62: 481–484. [CrossRef] [PubMed]
Ohlsson M Bellander BM Langmoen IA Svensson M. Complement activation following optic nerve crush in the adult rat. J Neurotrauma . 2003; 20: 895–904. [CrossRef] [PubMed]
Tezel G Yang X Yang J Wax MB. Role of tumor necrosis factor receptor-1 in the death of retinal ganglion cells following optic nerve crush injury in mice. Brain Res . 2004; 996: 202–212. [CrossRef] [PubMed]
Waller A. Experiments on the section of the glossopharyngeal and hypoglossal nerves of the frog, and observations of the alterations produced thereby in the structure of their primitive fibres. Philos Trans R Soc Lond . 1850; 140: 423–429. [CrossRef]
Tse MT. Axon degeneration: a new pathway emerges. Nat Rev Neurosci . 2012; 13: 516. [PubMed]
Beirowski B Adalbert R Wagner D The progressive nature of Wallerian degeneration in wild-type and slow Wallerian degeneration (WldS) nerves. BMC Neurosis . 2005; 6: 6.
de Lima S Koriyama Y Kurimoto T Full-length axon regeneration in the adult mouse optic nerve and partial recovery of simple visual behaviors. Proc Natl Acad Sci U S A . 2012; 109: 9149–9154. [CrossRef] [PubMed]
Vidal-Sanz M Aviles-Trigueros M Whiteley SJ Sauve Y Lund RD. Reinnervation of the pretectum in adult rats by regenerated retinal ganglion cell axons: anatomical and functional studies. Prog Brain Res . 2002; 137: 443–452. [PubMed]
Sofroniew M Vinters H. Astrocytes: biology and pathology. Acta Neuropathol . 2010; 119: 7–35. [CrossRef] [PubMed]
Wax MB Tezel G Saito I Anti-Ro/SS-a positivity and heat shock protein antibodies in patients with normal-pressure glaucoma. Am J Ophthalmol . 1998; 125: 145–157. [CrossRef] [PubMed]
Feder ME Hofmann GE. Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology. Annu Rev Physiol . 1999; 61: 243–282. [CrossRef] [PubMed]
Currie RW Ellison JA White RF Feuerstein GZ Wang X Barone FC. Benign focal ischemic preconditioning induces neuronal Hsp70 and prolonged astrogliosis with expression of Hsp27. Brain Res . 2000; 863: 169–181. [CrossRef] [PubMed]
Manzerra P Rush SJ Brown IR. Temporal and spatial distribution of heat shock mRNA and protein (hsp70) in the rabbit cerebellum in response to hyperthermia. J Neurosci Res . 1993; 36: 480–490. [CrossRef] [PubMed]
Franklin TB Krueger-Naug AM Clarke DB Arrigo AP Currie RW. The role of heat shock proteins Hsp70 and Hsp27 in cellular protection of the central nervous system. Int J Hyperthermia . 2005; 21: 379–392. [CrossRef] [PubMed]
Tezel G Wax MB. The mechanisms of hsp27 antibody-mediated apoptosis in retinal neuronal cells. J Neurosci . 2000; 20: 3552–3562. [PubMed]
Krueger-Naug AM Emsley JG Myers TL Currie RW Clarke DB. Injury to retinal ganglion cells induces expression of the small heat shock protein Hsp27 in the rat visual system. Neuroscience . 2002; 110: 653–665. [CrossRef] [PubMed]
Garrido C Bruey JM Fromentin A Hammann A Arrigo AP Solary E. HSP27 inhibits cytochrome c-dependent activation of procaspase-9. FASEB J . 1999; 13: 2061–2070. [PubMed]
Garrido C Gurbuxani S Ravagnan L Kroemer G. Heat shock proteins: endogenous modulators of apoptotic cell death. Biochem Biophys Res Commun . 2001; 286: 433–442. [CrossRef] [PubMed]
Tezel G Hernandez MR Wax MB. Immunostaining of heat shock proteins in the retina and optic nerve head of normal and glaucomatous eyes. Arch Ophthalmol . 2000; 118: 511–518. [CrossRef] [PubMed]
Kretz A Schmeer C Tausch S Isenmann S. Simvastatin promotes heat shock protein 27 expression and Akt activation in the rat retina and protects axotomized retinal ganglion cells in vivo. Neurobiol Dis . 2006; 21: 421–430. [CrossRef] [PubMed]
Whitlock NA Agarwal N Ma JX Crosson CE. Hsp27 upregulation by HIF-1 signaling offers protection against retinal ischemia in rats. Invest Ophthalmol Vis Sci . 2005; 46: 1092–1098. [CrossRef] [PubMed]
Whitlock NA Lindsey K Agarwal N Crosson CE Ma JX. Heat shock protein 27 delays Ca2+-induced cell death in a caspase-dependent and -independent manner in rat retinal ganglion cells. Invest Ophthalmol Vis Sci . 2005; 46: 1085–1091. [CrossRef] [PubMed]
Wagstaff MJ Collaço-Moraes Y Smith J de Belleroche JS Coffin RS Latchman DS. Protection of neuronal cells from apoptosis by Hsp27 delivered with a herpes simplex virus-based vector. J Biol Chem . 1999; 274: 5061–5069. [CrossRef] [PubMed]
Yanase K Smith RM Puccetti A Jarett L Madaio MP. Receptor-mediated cellular entry of nuclear localizing anti-DNA antibodies via myosin 1. J Clin Invest . 1997; 100: 25–31. [CrossRef] [PubMed]
Sisto M Lisi S D'Amore S D'Amore M. Autoantibodies, human Fcγ receptors, and autoimmunity. J Receptor Ligand Channel Res . 2009; 2: 45–57.
Tezel G Seigel GM Wax MB. Autoantibodies to small heat shock proteins in glaucoma. Invest Ophthalmol Vis Sci . 1998; 39: 2277–2287. [PubMed]
Wax MB Yang J Tezel G Peng G Patil RV Calkins DJ. A model of experimental autoimmune glaucoma in rats elicited by immunization with heat shock protein27 [E-abstract 2884]. Invest Ophthalmol Vis Sci . 2002; 43.
Cauwe B Martens E Proost P Opdenakker G. Multidimensional degradomics identifies systemic autoantigens and intracellular matrix proteins as novel gelatinase B/MMP-9 substrates. Integr Biol . 2009; 1: 404–426. [CrossRef]
Ram M Sherer Y Shoenfeld Y. Matrix metalloproteinase-9 and autoimmune diseases. J Clin Immunol . 2006; 26: 299–307. [CrossRef] [PubMed]
Yuan L Neufeld AH. Activated microglia in the human glaucomatous optic nerve head. J Neurosci Res . 2001; 64: 523–532. [CrossRef] [PubMed]
Yan X Tezel G Wax MB Edward DP. Matrix metalloproteinases and tumor necrosis factor alpha in glaucomatous optic nerve head. Arch Ophthalmol . 2000; 118: 666–673. [CrossRef] [PubMed]
Meyerhof O Lohmann K. Über die enzymatische Gleichgewichtsreaktion zwischen Hexosediphosphorsäure und Dioxyacetonphosphorsäure. Naturwissenschaften . 1934; 22: 220. [CrossRef]
Romano C Barrett DA Li Z Pestronk A Wax MB. Anti-rhodopsin antibodies in sera from patients with normal-pressure glaucoma. Invest Ophthalmol Vis Sci . 1995; 36: 1968–1675. [PubMed]
Joachim SC Pfeiffer N Grus FH. Autoantibodies in patients with glaucoma: a comparison of IgG serum antibodies against retinal, optic nerve, and optic nerve head antigens. Graefes Arch Clin Exp Ophthalmol . 2005; 243: 817–823. [CrossRef] [PubMed]
Grus FH Joachim SC Hoffmann EM Pfeiffer N. Complex autoantibody repertoires in patients with glaucoma. Mol Vis . 2004; 10: 132–137. [PubMed]
Grus FH Joachim SC Bruns K Lackner KJ Pfeiffer N Wax MB. Serum autoantibodies to alpha-fodrin are present in glaucoma patients from Germany and the United States. Invest Ophthalmol Vis Sci . 2006; 47: 968–976. [CrossRef] [PubMed]
Tezel G Edward DP Wax MB. Serum autoantibodies to optic nerve head glycosaminoglycans in patients with glaucoma. Arch Ophthalmol . 1999; 917–924.
Yang J Tezel G Patil RV Romano C Wax MB. Serum autoantibody against glutathione S-transferase in patients with glaucoma. Invest Ophthalmol Vis Sci . 2001; 42: 1273–1276. [PubMed]
Yano T Yamada K Kimura A Autoimmunity against neurofilament protein and its possible association with HLA-DRB1*1502 allele in glaucoma. Immunol Lett . 2005; 100: 164–169. [CrossRef] [PubMed]
Thatcher TH Gorovsky MA. Phylogenetic analysis of the core histones H2A, H2B, H3, and H4. Nucleic Acids Res . 1994; 22: 174–149. [CrossRef] [PubMed]
Garsia RJ Hellqvist L Booth RJ Homology of the 70-kilodalton antigens from Mycobacterium leprae and Mycobacterium bovis with the Mycobacterium tuberculosis 71-kilodalton antigen and with the conserved heat shock protein 70 of eucaryotes. Infect Immun . 1989; 57: 204–212. [PubMed]
Schlesinger MJ. How the cell copes with stress and the function of heat shock proteins. Pediatr Res . 1994; 36 (1, pt 1): 1–6. [CrossRef] [PubMed]
Rosen A Casciola-Rosen L Ahearn J. Novel packages of viral and self-antigens are generated during apoptosis. J Exp Med . 1995; 181: 1557–1561.
Klareskog L Rönnelid J Lundberg K Padyukov L Alfredsson L. Immunity to citrullinated proteins in rheumatoid arthritis. Annu Rev Immunol . 2008; 26: 651–675. [CrossRef] [PubMed]
Sokolove J Lindstrom TM Robinson WH. Development and deployment of antigen arrays for investigation of B-cell fine specificity in autoimmune disease. Front Biosci (Elite Ed) . 2012; 4: 320–330. [CrossRef] [PubMed]
Arbuckle MR Schilling AR Harley JB James JA. A limited lupus anti-spliceosomal response targets a cross-reactive, proline-rich motif. J Autoimmun . 1998; 11: 431–438. [CrossRef] [PubMed]
Romano C Li Z Arendt A Hargrave PA Wax MB. Epitope mapping of anti-rhodopsin antibodies from patients with normal pressure glaucoma. Invest Ophthalmol Vis Sci . 1999; 40: 1275–1280. [PubMed]
Kampylafka EI Routsias JG Alexopoulos H Dalakas MC Moutsopoulos HM Tzioufas AG. Fine specificity of antibodies against AQP4: epitope mapping reveals intracellular epitopes. J Autoimmun . 2011; 36: 221–227. [CrossRef] [PubMed]
Vyshkina T Kalman B. Autoantibodies and neurodegeneration in multiple sclerosis. Lab Invest . 2008; 88: 796–807. [CrossRef] [PubMed]
Wright B Warrington AE Edberg DE Rodriguez M. Cellular mechanisms of central nervous system repair by natural autoreactive monoclonal antibodies. Arch Neurol . 2009; 66: 1456–1459. [PubMed]
Shoenfeld Y Toubi E. Protective autoantibodies: role in homeostasis, clinical importance, and therapeutic potential. Arthritis Rheum . 2005; 52: 2599–2606. [CrossRef] [PubMed]
Grus F Sun D. Immunological mechanisms in glaucoma. Semin Immunopathol . 2008; 30: 121–126. [CrossRef] [PubMed]
Poletaev AB Stepanyuk VL Gershwin ME. Integrating immunity: the immunculus and self-reactivity. J Autoimmun . 2008; 30: 68–73. [CrossRef] [PubMed]
Wax MB Tezel G. Immunoregulation of retinal ganglion cell fate in glaucoma. Exp Eye Res . 2009; 88: 825–830. [CrossRef] [PubMed]
Grus FH Joachim SC Wuenschig D Rieck J Pfeiffer N. Autoimmunity and glaucoma. J Glaucoma . 2008; 17: 79–84. [CrossRef] [PubMed]
Newman E Reichenbach A. The Müller cell: a functional element of the retina. Trends Neurosci . 1996; 19: 307–312. [CrossRef] [PubMed]
Newman EA Zahs KR. Modulation of neuronal activity by glial cells in the retina. J Neurosci . 1998; 18: 4022–4028. [PubMed]
Ramírez JM Triviño A Ramírez AI Salazar JJ García-Sánchez J. Structural specializations of human retinal glial cells. Vis Res . 1996; 36: 2029–2036. [CrossRef] [PubMed]
Tsacopoulos M Poitry-Yamate CL Poitry S Perrotet P Veuthey AL. The nutritive function of glia is regulated by signals released by neurons. Glia . 1997; 21: 84–91. [CrossRef] [PubMed]
Wang X Tay SS Ng YK. An immunohistochemical study of neuronal and glial cell reactions in retinae of rats with experimental glaucoma. Exp Brain Res . 2000; 132: 476–484. [CrossRef] [PubMed]
Napoli I Neumann H. Microglial clearance function in health and disease. Neuroscience . 2009; 158: 1030–1038. [CrossRef] [PubMed]
Hung J Chansard M Ousman SS Nguyen MD Colicos MA. Activation of microglia by neuronal activity: results from a new in vitro paradigm based on neuronal-silicon interfacing technology. Brain Behav Immun . 2010; 24: 31–40. [CrossRef] [PubMed]
Davalos D Grutzendler J Yang G ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci . 2005; 8: 752–758. [CrossRef] [PubMed]
Haynes SE Hollopeter G Yang G The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci . 2006; 9: 1512–1519. [CrossRef] [PubMed]
Ladeby R Wirenfeldt M Dalmau I Proliferating resident microglia express the stem cell antigen CD34 in response to acute neural injury. Glia . 2005; 50: 121–131. [CrossRef] [PubMed]
Meyer-Luehmann M Spires-Jones TL Prada C Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature . 2008; 451: 720–724. [CrossRef] [PubMed]
Inman DM Horner PJ. Reactive nonproliferative gliosis predominates in a chronic mouse model of glaucoma. Glia . 2007; 55: 942–953. [CrossRef] [PubMed]
Prasanna G Krishnamoorthy R Yorio T. Endothelin, astrocytes and glaucoma. Exp Eye Res . 2011; 93: 170–177. [CrossRef] [PubMed]
Rappert A Bechmann I Pivneva T CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion. J Neurosci . 2004; 24: 8500–8509. [CrossRef] [PubMed]
Cardona AE Pioro EP Sasse ME Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci . 2006; 9: 917–924. [CrossRef] [PubMed]
Biber K Neumann H Inoue K Boddeke HW. Neuronal On and Off signals control microglia. Trends Neurosci . 2007; 30: 596–602. [CrossRef] [PubMed]
Tezel GMD Wax MB. Glial modulation of retinal ganglion dell death in glaucoma. J Glaucoma . 2003; 12: 63–68. [CrossRef] [PubMed]
Tezel G Chauhan BC LeBlanc RP Wax MB. Immunohistochemical assessment of the glial mitogen-activated protein kinase activation in glaucoma. Invest Ophthalmol Vis Sci . 2003; 44: 3025–3033. [CrossRef] [PubMed]
Pasinetti GM. Cyclooxygenase and inflammation in Alzheimer's disease: experimental approaches and clinical interventions. J Neurosci Res . 1998; 54: 1–6. [CrossRef] [PubMed]
Gonzalez-Scarano F Baltuch G. Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci . 1999; 22: 219–240. [CrossRef] [PubMed]
Julien J-P. Amyotrophic lateral sclerosis: unfolding the toxicity of the misfolded. Cell . 2001; 104: 581–591. [CrossRef] [PubMed]
Venters HD Tang Q Liu Q VanHoy RW Dantzer R Kelley KW. A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc Natl Acad Sci U S A . 1999; 96: 9879–9884. [CrossRef] [PubMed]
Friedlander RM. Role of caspase 1 in neurologic disease. Arch Neurol . 2000; 57: 1273–1276. [PubMed]
González-Scarano F Baltuch G. Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci . 1999; 22: 219–240. [CrossRef] [PubMed]
Hickey WF Kimura H. Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science . 1988; 239: 290–292. [CrossRef] [PubMed]
Weiner H. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J Neurol . 2008; 255: 3–11. [CrossRef] [PubMed]
Tezel G. TNF-alpha signaling in glaucomatous neurodegeneration. Prog Brain Res . 2008; 173: 409–421. [PubMed]
Yuan L Neufeld AH. Tumor necrosis factor-α: a potentially neurodestructive cytokine produced by glia in the human glaucomatous optic nerve head. Glia . 2000; 32: 42–50. [CrossRef] [PubMed]
Bai Y Shi Z Zhuo Y In glaucoma the upregulated truncated TrkC.T1 receptor isoform in glia causes increased TNF-alpha production, leading to retinal ganglion cell death. Invest Ophthalmol Vis Sci . 2010; 51: 6639–6651. [CrossRef] [PubMed]
Fan BJ Liu K Wang DY Association of polymorphisms of tumor necrosis factor and tumor protein p53 with primary open-angle glaucoma. Invest Ophthalmol Vis Sci . 2010; 51: 4110–4116. [CrossRef] [PubMed]
Khan MI Micheal S Rana N Association of tumor necrosis factor alpha gene polymorphism G-308A with pseudoexfoliative glaucoma in the Pakistani population. Mol Vis . 2009; 15: 2861–2867. [PubMed]
Razeghinejad MR Rahat F Kamali-Sarvestani E. Association of TNFA −308 G/A and TNFRI +36 A/G gene polymorphisms with glaucoma. Ophthalmic Res . 2009; 42: 118–124. [CrossRef] [PubMed]
Mossböck G Renner W El-Shabrawi Y TNF-alpha −308 G>A and −238 G>A polymorphisms are not major risk factors in Caucasian patients with exfoliation glaucoma. Mol Vis . 2009; 15: 518–522. [PubMed]
Tekeli O Turacli ME Egin Y Akar N Elhan AH. Tumor necrosis factor alpha-308 gene polymorphism and pseudoexfoliation glaucoma. Mol Vis . 2008; 14: 1815–1818. [PubMed]
Mattson MP Pederson WA Duan W Culmsee C Camandola S. Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer's and Parkinson's diseases. Ann N Y Acad Sci . 1999; 893: 154–175. [CrossRef] [PubMed]
Lin MT Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature . 2006; 443: 787–795. [CrossRef] [PubMed]
Musunuru K Darnell RB. Paraneoplastic neurologic disease antigens: RNA-binding proteins and signaling proteins in neuronal degeneration. Annu Rev Neurosci . 2001; 24: 239–262. [CrossRef] [PubMed]
Solimena M De Camilli P. Synaptic autoimmunity and the Salk factor. Neuron . 2000; 28: 309–316. [CrossRef] [PubMed]
Maruyama I Nakazawa M Ohguro H. Autoimmune mechanisms in molecular pathology of glaucomatous optic neuropathy [in Japanese]. Nippon Ganka Gakkai Zasshi . 2001; 105: 205–212. [PubMed]
Schori H Yoles E Wheeler LA Raveh T Kimchi A Schwartz M. Immune-related mechanisms participating in resistance and susceptibility to glutamate toxicity. Eur J Neurosci . 2002; 16: 557–564. [CrossRef] [PubMed]
Wax MB Yang J Tezel G. Serum autoantibodies in patients with glaucoma. J Glaucoma . 2001; 10 (5)(suppl 1): S22–S24. [CrossRef] [PubMed]
Albert M Austin L Darnell RB. Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration. Ann Neurol . 2000; 47: 9–17. [CrossRef] [PubMed]
Fearon DT Locksley RM. The instructive role of innate immunity in the acquired immune response. Science . 1996; 272: 50–53. [CrossRef] [PubMed]
Li Y Ucccelli A Laxer KD Local-clonal expansion of infiltrating T lymphocytes in chronic encephalitis of Rasmussen. J Immunol . 1997; 158: 1428–1437. [PubMed]
Neumann H Medana IM Bauer J Lassmann H. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci . 2002; 25: 313–319. [CrossRef] [PubMed]
Caspi R. Autoimmunity in the immune privileged eye: pathogenic and regulatory T cells. Immunol Res . 2008; 42: 41–50. [CrossRef] [PubMed]
Nielsen HH Ladeby R Fenger C Enhanced microglial clearance of myelin debris in T cell-infiltrated central nervous system. J Neuropathol Exp Neurol . 2009; 68: 845–856. [CrossRef] [PubMed]
Streilein JW. Unraveling immune privilege. Science . 1995; 270: 1158–1159. [CrossRef] [PubMed]
Albert ML Darnell JC Bender A Francisco LM Bhardwaj N Darnell RB. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med . 1998; 4: 1321–1324. [CrossRef] [PubMed]
Whitney KD Andrews PI McNamara JO. Immunoglobulin G and complement immunoreactivity in the cerebral cortex of patients with Rasmussen's encephalitis. Neurology . 1999; 53: 699–708. [CrossRef] [PubMed]
Abbott N. Astrocyte-endothelial interactions and blood-brain barrier permeability. J Anat . 2002; 200: 527. [CrossRef]
Grieshaber MC Flammer J. Does the blood-brain barrier play a role in glaucoma? Surv Ophthalmol . 2007; 52 (6)(suppl 1): S115–S121. [CrossRef] [PubMed]
Goverman J. Autoimmune T cell responses in the central nervous system. Nat Rev Immunol . 2009; 9: 393–407. [CrossRef] [PubMed]
Nguyen MD Julien JP Rivest S. Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci . 2002; 3: 216–227. [CrossRef] [PubMed]
Ransohoff RM Kivisakk P Kidd G. Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol . 2003; 3: 569–581. [CrossRef] [PubMed]
Huber JD Egleton RD Davis TP. Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci . 2001; 24: 719–725. [CrossRef] [PubMed]
Howell GR Soto I Zhu X Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma. J Clin Invest . 2012; 122: 1246–1261. [CrossRef] [PubMed]
Xu H Dawson R Forrester JV Liversidge J. Identification of novel dendritic cell populations in normal mouse retina. Invest Ophthalmol Vis Sci . 2007; 48: 1701–1710. [CrossRef] [PubMed]
Colonna M. TREMs in the immune system and beyond. Nat Rev Immunol . 2003; 3: 445–453. [CrossRef] [PubMed]
Olson JK Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol . 2004; 173: 3916–3924. [CrossRef] [PubMed]
Lehnardt S. Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia . 2009; 58: 253–263.
Akira S Yamamoto M Takeda K. Role of adapters in Toll-like receptor signalling. Biochem Soc Trans . 2003; 31 (pt 3): 637–642. [PubMed]
Ford JW McVicar DW. TREM and TREM-like receptors in inflammation and disease. Curr Opin Immunol . 2009; 21: 38–46. [CrossRef] [PubMed]
Bouchon A Dietrich J Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol . 2000; 164: 4991–4995. [CrossRef] [PubMed]
Sharif O Knapp S. From expression to signaling: roles of TREM-1 and TREM-2 in innate immunity and bacterial infection. Immunobiology . 2008; 213: 701–713. [CrossRef] [PubMed]
Ito H Hamerman JA. TREM-2, triggering receptor expressed on myeloid cell-2, negatively regulates TLR responses in dendritic cells. Eur J Immunol . 2012; 42: 176–185. [CrossRef] [PubMed]
Janeway CA Medzhitov R. Innate immune recognition. Annu Rev Immunol . 2002; 20: 197–216. [CrossRef] [PubMed]
Choe J Kelker MS Wilson IA. Crystal structure of human Toll-like receptor 3 (TLR3) ectodomain. Science . 2005; 309: 581–585. [CrossRef] [PubMed]
Hajishengallis G Lambris JD. Crosstalk pathways between Toll-like receptors and the complement system. Trends Immunol . 2010; 31: 154–163. [CrossRef] [PubMed]
Beutler B. Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases. Immunol Rev . 2009; 227: 248–263. [CrossRef] [PubMed]
Butchi N Du MB Peterson KE. Interactions between TLR7 and TLR9 agonists and receptors regulate innate immune responses by astrocytes and microglia. Glia . 2009; 58: 650–664.
Heil F Hemmi H Hochrein H Species-specific recognition of single-stranded RNA via Toll-like receptors 7 and 8. Science . 2004; 303: 1526–1529. [CrossRef] [PubMed]
Luo C Yang X Powell DW Klein JB Tezel G. Stress proteins and immunostimulatory signaling through toll-like receptors in glaucoma [E-abstract 4048]. Invest Ophthalmol Vis Sci . 2009; 50.
Tsan MF Gao B. Heat shock proteins and immune system. J Leukoc Biol . 2009; 85: 905–910. [CrossRef] [PubMed]
Wallin RP Lundqvist A Moré SH von Bonin A Kiessling R Ljunggren HG. Heat-shock proteins as activators of the innate immune system. Trends Immunol . 2002; 23: 130–135. [CrossRef] [PubMed]
Roelofs MF Boelens WC Joosten LA Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis. J Immunol . 2006; 176: 7021–7027. [CrossRef] [PubMed]
Tükel Ç. CsgA is a pathogen-associated molecular pattern of Salmonella enterica serotype Typhimurium that is recognized by Toll-like receptor 2. Mol Microbiol . 2005; 58: 289–304. [CrossRef] [PubMed]
Ohashi K Burkart V Flohé S Kolb H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the Toll-like receptor-4 complex. J Immunol . 2000; 164: 558–561. [CrossRef] [PubMed]
Johnson JD Fleshner M. Releasing signals, secretory pathways, and immune function of endogenous extracellular heat shock protein 72. J Leukoc Biol . 2006; 79: 425–434. [CrossRef] [PubMed]
Young DB. Heat-shock proteins: immunity and autoimmunity. Curr Opin Immunol . 1992; 4: 396–400. [CrossRef] [PubMed]
Young RA Elliott TJ. Stress proteins, infection, and immune surveillance. Cell . 1989; 59: 5–8. [CrossRef] [PubMed]
Kol A Lichtman AH Finberg RW Libby P Kurt-Jones EA. Cutting edge: heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells. J Immunol . 2000; 164: 13–17. [CrossRef] [PubMed]
Liu D Yumoto D Hirota K Histone-like DNA binding protein of Streptococcus intermedius induces the expression of pro-inflammatory cytokines in human monocytes via activation of ERK1/2 and JNK pathways. Cell Microbiol . 2008; 10: 262–276. [PubMed]
Rajaiah R Moudgil KD. Heat-shock proteins can promote as well as regulate autoimmunity. Autoimmun Rev . 2009; 8: 388–393. [CrossRef] [PubMed]
Damian RT. Molecular mimicry in biological adaptation. Science . 1965; 147: 824. [CrossRef] [PubMed]
Damian RT. Molecular mimicry: antigen sharing by parasite and host and its consequences. Am Naturalist . 1964; 98: 129–149. [CrossRef]
Galloway PH Warner SJ Morshed MG Mikelberg FS. Helicobacter pylori infection and the risk for open-angle glaucoma. Ophthalmology . 2003; 110: 922–925. [CrossRef] [PubMed]
Kountouras J Zavos C Chatzopoulos D. Induction of apoptosis as a proposed pathophysiological link between glaucoma and Helicobacter pylori infection. Med Hypoth . 2004; 62: 378–381. [CrossRef]
Kountouras J Mylopoulos N Konstas AG Zavos C Chatzopoulos D Boukla A. Increased levels of Helicobacter pylori IgG antibodies in aqueous humor of patients with primary open-angle and exfoliation glaucoma. Graefes Arch Clin Exp Ophthalmol . 2003; 241: 884–890. [CrossRef] [PubMed]
Cohen IR. Antigenic mimicry, clonal selection and autoimmunity. J Autoimmun . 2001; 16: 337–340. [CrossRef] [PubMed]
Oldstone MB. Molecular mimicry, microbial infection, and autoimmune disease: evolution of the concept. Curr Top Microbiol Immunol . 2005; 296: 1–17. [PubMed]
Kim JM Kim SH Park KH Han SY Shim HS. Investigation of the association between Helicobacter pylori infection and normal tension glaucoma. Invest Ophthalmol Vis Sci . 2011; 52: 665–668.
Rodriguez D Morrison CJ Overall CM. Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics. Biochim Biophys Acta . 2010; 1803: 39–54. [CrossRef] [PubMed]
Kurien BT Scofield RH. Autoimmunity and oxidatively modified autoantigens. Autoimmun Rev . 2008; 7: 567–573. [CrossRef] [PubMed]
Chiba S Yokota S Yonekura K . Autoantibodies against HSP70 family proteins were detected in the cerebrospinal fluid from patients with multiple sclerosis. J Neurol Sci . 2006; 241: 39–43. [CrossRef] [PubMed]
Yonekura K Yokota S Tanaka S Prevalence of anti-heat shock protein antibodies in cerebrospinal fluids of patients with Guillain-Barre syndrome. J Neuroimmunol . 2004; 156: 204–209. [CrossRef] [PubMed]
Gasque P. Complement: a unique innate immune sensor for danger signals. Mol Immunol . 2004; 41: 1089–1098. [CrossRef] [PubMed]
Howell GR. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J Clin Invest . 2011; 121: 1429–1444. [CrossRef] [PubMed]
Stevens B Allen NJ Vazquez LE The classical complement cascade mediates CNS synapse elimination. Cell . 2007; 131: 1164–1178. [CrossRef] [PubMed]
Ikeda Y Maruyama I Nakazawa M Ohguro H. Clinical significance of serum antibody against neuron-specific enolase in glaucoma patients. Jpn J Ophthalmol . 2002; 46: 13–17. [CrossRef] [PubMed]
Buckley C Vincent A. Autoimmune channelopathies. Nat Clin Pract Neurol . 2005; 1: 22–33. [CrossRef] [PubMed]
Scofield RH. Autoantibodies as predictors of disease. Lancet . 2004; 363: 1544–1546. [CrossRef] [PubMed]
Arbuckle MR McClain MT Rubertone MV Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med . 2003; 349: 1526–1533. [CrossRef] [PubMed]
Quintana FJ Cohen IR. The natural autoantibody repertoire and autoimmune disease. Biomed Pharmacother . 2004; 58: 276–281. [CrossRef] [PubMed]
Lennon VA Wingerchuk DM Kryzer TJ A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet . 2004; 364: 2106–2112. [CrossRef] [PubMed]
Dziewas R Kis B Grus FH Zimmermann CW. Antibody pattern analysis in the Guillain-Barré syndrome and pathologic controls. J Neuroimmunol . 2001; 119: 287–296. [CrossRef] [PubMed]
Baroni SS, Santillo M, Bevilacqua F, . Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med . 2006; 354: 2667–2676. [CrossRef] [PubMed]
Kubo T Uchida Y Watanabe Y Augmented TLR9-induced Btk activation in PIR-B-deficient B-1 cells provokes excessive autoantibody production and autoimmunity. J Exp Med . 2009; 206: 1971–1982. [CrossRef] [PubMed]
Hueber W Tomooka BH Batliwalla F Blood autoantibody and cytokine profiles predict response to anti-tumor necrosis factor therapy in rheumatoid arthritis. Arthritis Res Ther . 2009; 11: R76. [CrossRef] [PubMed]
Walport MJ. Complement. N Engl J Med . 2001; 344: 1058–1066. [CrossRef] [PubMed]
Ricklin D Hajishengallis G Yang K Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol . 2010; 11: 785–797. [CrossRef] [PubMed]
Kulkarni AP Kellaway LA Lahiri DK Kotwal GL. Neuroprotection from complement-mediated inflammatory damage. Ann N Y Acad Sci . 2004; 1035: 147–164. [CrossRef] [PubMed]
Neufeld AH Liu B. Glaucomatous optic neuropathy: when glia misbehave. Neuroscientist . 2003; 9: 485–495. [CrossRef] [PubMed]
Tezel G Wax MB. Increased production of tumor necrosis factor-alpha by glial cells exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells. J Neurosci . 2000; 20: 8693–8700. [PubMed]
Tezel G Wax MB. Hypoxia-inducible factor 1alpha in the glaucomatous retina and optic nerve head. Arch Ophthalmol . 2004; 122: 1348–1356. [CrossRef] [PubMed]
Boulanger LM. Immune proteins in brain development and synaptic plasticity. Neuron . 2009; 64: 93–109. [CrossRef] [PubMed]
Rosen AM Stevens B. The role of the classical complement cascade in synapse loss during development and glaucoma. In: Cohen IR Lajtha A Lambris JD Paoletti R eds. Inflammation and Retinal Disease: Complement Biology and Pathology . Vol. 73. Berlin: Springer; 2010: 75–93.
Katz LC Shatz CJ. Synaptic activity and the construction of cortical circuits. Science . 1996; 274: 1133–1138. [CrossRef] [PubMed]
Singhrao SK Neal JW Rushmere NK Morgan BP Gasque P. Spontaneous classical pathway activation and deficiency of membrane regulators render human neurons susceptible to complement lysis. Am J Pathol . 2000; 157: 905–918. [CrossRef] [PubMed]
Huh GS Boulanger LM Du H Riquelme PA Brotz TM Shatz CJ. Functional requirement for class I MHC in CNS development and plasticity. Science . 2000; 290: 2155–2159. [CrossRef] [PubMed]
Neumann H Cavalié A Jenne DE Wekerle H. Induction of MHC class I genes in neurons. Science . 1995; 269: 549–552. [CrossRef] [PubMed]
Stasi K Nagel D Yang X Complement component 1Q (C1Q) upregulation in retina of murine, primate, and human glaucomatous eyes. Invest Ophthalmol Vis Sci . 2006; 47: 1024–1029. [CrossRef] [PubMed]
Howell GR Libby RT Jakobs TC Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J Cell Biol . 2007; 179: 1523–1537. [CrossRef] [PubMed]
Sigal IA Ethier CR. Biomechanics of the optic nerve head. Exp Eye Res . 2009; 88: 799–807. [CrossRef] [PubMed]
Ambrosini E Aloisi F. Chemokines and glial cells: a complex network in the central nervous system. Neurochem Res . 2004; 29: 1017–1038. [CrossRef] [PubMed]
Langmann T. Microglia activation in retinal degeneration. J Leukoc Biol . 2007; 81: 1345–1351. [CrossRef] [PubMed]
Nakazawa T Nakazawa C Matsubara A Tumor necrosis factor-α mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma. J Neurosci . 2006; 26: 12633–12641. [CrossRef] [PubMed]
Hawkins BT Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev . 2005; 57: 173–185. [CrossRef] [PubMed]
Yong VW Marks S. The interplay between the immune and central nervous systems in neuronal injury. Neurology . 2010; 74 (suppl 1); S9–S16. [CrossRef] [PubMed]
Ahmed F Brown KM Stephen DA Morrison JC Johnson EC Tomarev SI. Microarray analysis of changes in mRNA levels in the rat retina after experimental elevation of intraocular pressure. Invest Ophthalmol Vis Sci . 2004; 45: 1247–1258. [CrossRef] [PubMed]
Taylor PR Carugati A Fadok VA. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med . 2000; 192: 359–366. [CrossRef] [PubMed]
Botto M Dell'Agnola C Bygrave AE Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet . 1998; 19: 56–59. [CrossRef] [PubMed]
Cowell RM Plane JM Silverstein FS. Complement activation contributes to hypoxic-ischemic brain injury in neonatal rats. J Neurosci . 2003; 23: 9459–9468. [PubMed]
Rancan M Morganti-Kossman MC Barnum SR . Central nervous system-targeted complement inhibition mediates neuroprotection after closed head injury in transgenic mice. J Cereb Blood Flow Metab . 2003; 23: 1070–1074. [CrossRef] [PubMed]
Yamada K Miwa T Liu J Nangaku M Song WC. Critical protection from renal ischemia reperfusion injury by CD55 and CD59. J Immunol . 2004; 172: 3869–3875. [CrossRef] [PubMed]
Schäfer MK Schwaeble WJ Post C Complement C1q is dramatically up-regulated in brain microglia in response to transient global cerebral ischemia. J Immunol . 2000; 164: 5446–5452. [CrossRef] [PubMed]
Dangond F Hwang D Camelo S Molecular signature of late-stage human ALS revealed by expression profiling of postmortem spinal cord gray matter. Physiol Genomics . 2004; 16: 229–239. [CrossRef] [PubMed]
Fonseca MI Kawas CH Troncoso JC Tenner AJ. Neuronal localization of C1q in preclinical Alzheimer's disease. Neurobiol Dis . 2004; 15: 40–46. [CrossRef] [PubMed]
Stasi K Nagel D Yang X Complement component 1Q (C1Q) upregulation in retina of murine, primate, and human glaucomatous eyes. Invest Ophthalmol Vis Sci . 2006; 47: 1024–1029. [CrossRef] [PubMed]
Johnson EC Jia L Cepurna WO Doser TA Morrison JC. Global changes in optic nerve head gene expression after exposure to elevated intraocular pressure in a rat glaucoma model. Invest Ophthalmol Vis Sci . 2007; 48: 3161–3177. [CrossRef] [PubMed]
Miyahara T Kikuchi T Akimoto M Kurokawa T Shibuki H Yoshimura N. Gene microarray analysis of experimental glaucomatous retina from cynomologus monkey. Invest Ophthalmol Vis Sci . 2003; 44: 4347–4356. [CrossRef] [PubMed]
Zhang X Kimura Y Fang C Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood . 2007; 110: 228–236. [CrossRef] [PubMed]
Kim DD Song W-C. Membrane complement regulatory proteins. Clin Immunol . 2006; 118: 127–136. [CrossRef] [PubMed]
Wax MB. The case for autoimmunity in glaucoma. Exp Eye Res . 2011; 93: 187–190. [CrossRef] [PubMed]
Flavell RA Hafler DA. Autoimmunity: what is the turning point?: editorial overview. Curr Opin Immunol . 1999; 11: 635–637. [CrossRef] [PubMed]
Hafler DA Flavell R. Autoimmunity. How to know thy self. Curr Opin Immunol . 1996; 8: 805–807. [CrossRef] [PubMed]
Roh M Zhang Y Murakami Y Etanercept, a widely used inhibitor of tumor necrosis factor-alpha (TNF-alpha), prevents retinal ganglion cell loss in a rat model of glaucoma. PLoS One . 2012; 7: e40065. [CrossRef] [PubMed]
Ognibene A Ciuti R Tozzi P Messeri G. Maternal serum superoxide dismutase (SOD): a possible marker for screening Down syndrome affected pregnancies. Prenat Diagn . 1999; 19: 1058–1060. [CrossRef] [PubMed]
Golubnitschaja O Flammer J. What are the biomarkers for glaucoma? Surv Ophthalmol . 2007; 52 (suppl 2): S155–S161. [CrossRef] [PubMed]
Grus FH Joachim SC Sandmann S Transthyretin and complex protein pattern in aqueous humor of patients with primary open-angle glaucoma. Mol Vis . 2008; 14: 1437–1445. [PubMed]
Ghaffariyeh A Honarpisheh N Heidari MH Puyan S Abasov F. Brain-derived neurotrophic factor as a biomarker in primary open-angle glaucoma. Optom Vis Sci . 2011; 88: 80–85. [CrossRef] [PubMed]
Ferreira SM Lerner SF Brunzini R Evelson PA Llesuy SF. Oxidative stress markers in aqueous humor of glaucoma patients. Am J Ophthalmol . 2004; 137: 62–69. [CrossRef] [PubMed]
Erdurmuş M Yağcı R Atiş Ö Karadağ R Akbaş A Hepşen IF. Antioxidant status and oxidative stress in primary open angle glaucoma and pseudoexfoliative glaucoma. Curr Eye Res . 2011; 36: 713–718. [CrossRef] [PubMed]
Tezel G. Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences. Prog Retin Eye Res . 2006; 25: 490–513. [CrossRef] [PubMed]
Moreno MC Campanelli J Sande P Sánez DA Keller Sarmiento MI Rosenstein RE. Retinal oxidative stress induced by high intraocular pressure. Free Radic Biol Med . 2004; 37: 803–812. [CrossRef] [PubMed]
Hinerfeld D Traini MD Weinberger RP . Endogenous mitochondrial oxidative stress: neurodegeneration, proteomic analysis, specific respiratory chain defects, and efficacious antioxidant therapy in superoxide dismutase 2 null mice. J Neurochem . 2004; 88: 657–667. [CrossRef] [PubMed]
Miyara N Shinzato M Yamashiro Y Iwamatsu A Kariya K Sawaguchi S. Proteomic analysis of rat retina in a steroid-induced ocular hypertension model: potential vulnerability to oxidative stress. Jpn J Ophthalmol . 2008; 52: 84–90. [CrossRef] [PubMed]
Wilson JX. Antioxidant defense of the brain: a role for astrocytes. Can J Physiol Pharmacol . 1997; 75: 1149–1163. [CrossRef] [PubMed]
Engin KN Engin G Kucuksahin H Oncu M Engin G Guvener B. Clinical evaluation of the neuroprotective effect of alpha-tocopherol against glaucomatous damage. Eur J Ophthalmol . 2007; 17: 528–533. [PubMed]
Neufeld AH Hernandez MR Gonzalez M. Nitric oxide synthase in the human glaucomatous optic nerve head. Arch Ophthalmol . 1997; 115: 497–503. [CrossRef] [PubMed]
Ritch R. Neuroprotection: is it already applicable to glaucoma therapy? Curr Opin Ophthalmol . 2000; 11: 78–84. [CrossRef] [PubMed]
Liu B Neufeld AH. Nitric oxide synthase-2 in human optic nerve head astrocytes induced by elevated pressure in vitro. Arch Ophthalmol . 2001; 119: 240–245. [PubMed]
Liu B Neufeld, Arthur H. Expression of nitric oxide synthase-2 (NOS-2) in reactive astrocytes of the human glaucomatous optic nerve head. Glia . 2000; 30: 178–186. [CrossRef] [PubMed]
Mozaffarieh M Grieshaber MC Flammer J. Oxygen and blood flow: players in the pathogenesis of glaucoma. Mol Vis . 2008; 14: 224–233. [PubMed]
Sacca S Pascotto A Camicione P Capris P Izzotti A. Oxidative DNA damage in the human trabecular meshwork: clinical correlation in patients with primary open-angle glaucoma. Arch Ophthalmol . 2005; 123: 458–463. [CrossRef] [PubMed]
McElnea EM Quill B Docherty NG Oxidative stress, mitochondrial dysfunction and calcium overload in human lamina cribrosa cells from glaucoma donors. Mol Vis . 2011; 17: 1182–1191. [PubMed]
Pinazo-Durán MD Zanón-Moreno V García-Medina JJ Gallego-Pinazo R. Evaluation of presumptive biomarkers of oxidative stress, immune response and apoptosis in primary open-angle glaucoma. Curr Opin Pharmacol . 2012; 13: 98–107. [CrossRef] [PubMed]
Footnotes
 Disclosure: J. Rieck, None
Figure 1
 
Hypothetical mechanism of neurodegeneration in the CNS involving innate and adaptive immunity. Damage of peripheral organs leads to the activation of immunological processes involving antigen-presenting cells (APC). The APC float to local lymph nodes where activation of the adaptive immune response takes place. (3, 4) The following clonal expansion of B cells leads to the production of antigen-specific antibodies. (5) These antibodies pass through the permeable blood–brain barrier. (6) In the CNS, the antibodies bind to neuronal antigens, interfering with their function, and cause cellular stress and finally apoptosis of the neuron. (7) The apoptosis of neurons leads to activation of microglia. (8) Activated microglia phagocytose the apoptotic cells and present their antigens on their surface. (9) Microglia secrete proinflammatory cytokines. Increased titers of vascular endothelial growth factor (VEGF) and the intercellular adhesion molecule 1 (ICAM 1) lead to increased permeability of the blood–brain barrier. (11) This leads to further influx of T lymphocytes. (12, 13) T cells and neuronal antigens activate microglia, which also leads to the destruction of neurons. (14) Alternatively, cellular damage or pathogens can cause chronic immune responses of the nonadaptive immune defense. Reprinted with permission from Nguyen MD, Julien JP, Rivest S. Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci. 2002;3:216–227. Copyright 2002 Macmillan Publishers Ltd: Nature Reviews Neuroscience.
Figure 1
 
Hypothetical mechanism of neurodegeneration in the CNS involving innate and adaptive immunity. Damage of peripheral organs leads to the activation of immunological processes involving antigen-presenting cells (APC). The APC float to local lymph nodes where activation of the adaptive immune response takes place. (3, 4) The following clonal expansion of B cells leads to the production of antigen-specific antibodies. (5) These antibodies pass through the permeable blood–brain barrier. (6) In the CNS, the antibodies bind to neuronal antigens, interfering with their function, and cause cellular stress and finally apoptosis of the neuron. (7) The apoptosis of neurons leads to activation of microglia. (8) Activated microglia phagocytose the apoptotic cells and present their antigens on their surface. (9) Microglia secrete proinflammatory cytokines. Increased titers of vascular endothelial growth factor (VEGF) and the intercellular adhesion molecule 1 (ICAM 1) lead to increased permeability of the blood–brain barrier. (11) This leads to further influx of T lymphocytes. (12, 13) T cells and neuronal antigens activate microglia, which also leads to the destruction of neurons. (14) Alternatively, cellular damage or pathogens can cause chronic immune responses of the nonadaptive immune defense. Reprinted with permission from Nguyen MD, Julien JP, Rivest S. Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci. 2002;3:216–227. Copyright 2002 Macmillan Publishers Ltd: Nature Reviews Neuroscience.
Figure 2
 
Distribution of C1q transcripts in the retina. Compared to the control (A) strong signals for C1q can be detected in OHT patients in the ganglion cell layer (B) and the optic nerve head (ONH, [C]) strong signals for C1q (arrow). Reprinted with permission from Kuehn MH, Kim CY, Ostojic J, et al. Retinal synthesis and deposition of complement components induced by ocular hypertension. Exp Eye Res. 2006;83:620–628. Copyright 2006 Elsevier.
Figure 2
 
Distribution of C1q transcripts in the retina. Compared to the control (A) strong signals for C1q can be detected in OHT patients in the ganglion cell layer (B) and the optic nerve head (ONH, [C]) strong signals for C1q (arrow). Reprinted with permission from Kuehn MH, Kim CY, Ostojic J, et al. Retinal synthesis and deposition of complement components induced by ocular hypertension. Exp Eye Res. 2006;83:620–628. Copyright 2006 Elsevier.
Figure 3
 
Cytotoxic T cells use three different routes to destroy their target. Initially the CD8+ T cell recognizes the target via the interaction of its T-cell receptor (TCR) with the target cell's MHC-I complex, including presented peptide (square). The destruction of the target cell is performed by either (i) release of cytotoxic granules and the resulting perforation of the cell membrane, (ii) activation of the target cell's Fas/CD95 receptor by Fas ligand/CD95 ligand, or (iii) the release of cytokines such as TNF-α. Reprinted with permission from Neumann H, Medana IM, Bauer J, Lassmann H. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci. 2002;25:313–319. Copyright 2002 Elsevier.
Figure 3
 
Cytotoxic T cells use three different routes to destroy their target. Initially the CD8+ T cell recognizes the target via the interaction of its T-cell receptor (TCR) with the target cell's MHC-I complex, including presented peptide (square). The destruction of the target cell is performed by either (i) release of cytotoxic granules and the resulting perforation of the cell membrane, (ii) activation of the target cell's Fas/CD95 receptor by Fas ligand/CD95 ligand, or (iii) the release of cytokines such as TNF-α. Reprinted with permission from Neumann H, Medana IM, Bauer J, Lassmann H. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci. 2002;25:313–319. Copyright 2002 Elsevier.
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