Reviews
The Pathogenesis of Glaucoma in the Interplay with the
Immune System
Jochen Rieck
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 autoim-
mune 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 conse-
quences are always the establishment of extensive degenera-
tive 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 pathogen-
esis of glaucoma, with special focus on its interplay with the
immune system. (Invest Ophthalmol Vis Sci. 2013;54:2393–
2409) DOI:10.1167/iovs.12-9781
G laucoma, 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 path-
way, characterized by progressive, irreversible destruction and
death of retinal ganglion cells.2–15 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.13,16–23
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
From the Institut für Zoologie, Johannes Gutenberg-Universität
Mainz, Mainz, Germany.
Submitted for publication March 1, 2012; revised August 19 and
December 17, 2012; accepted January 26, 2013.
Disclosure: J. Rieck, None
Corresponding author: Jochen Rieck, Institut für Zoologie,
Johannes Gutenberg-Universität Mainz, Johannes von Müller-Weg 6,
55099 Mainz, Germany; rieck@uni-mainz.de.
DOI:10.1167/iovs.12-9781
Investigative Ophthalmology & Visual Science, March 2013, Vol. 54, No. 3
Copyright 2013 The Association for Research in Vision and Ophthalmology, Inc.
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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.9,10,25–27 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.25,26,29–34
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.4,13,15,35–39 The reduction
of IOP is obtained by eye drops or systemic application of
glaucoma medications. These include carbonic anhydrase
inhibitors, beta-blockers, cholinergic agonists, a2-adrenoceptor
agonists and prostaglandins.25,27,37,40–43 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, approxi-
mately 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.25,27,45–47 It is worth mentioning that
therapeutic lowering of the IOP leads to a slowing of disease
progression in a subgroup of NTG patients.43,48–50
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
2393
 2394 Rieck
brain is affected.14,26,51–54 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.6,10,12,13,17,19,20,31,36,50,57–64
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.12,15,20,65–67 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 Hyperten-
sion 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.73–77 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).80–85 Immunohistochemical studies demonstrate that
impairing neurotrophin transport from the visual thalamus to
the soma of RCGs results in their destruction by apopto-
sis.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.65,71,72,88–91 Additionally, the cerebrospinal
fluid pressure influences the degree of mechanical stress, due to
a pressure gradient across the tissue of the ONH.92
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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 neurode-
generation. Already documented is the initiation of pro-
grammed cell death of RGCs via tumor suppressor protein
p53, but also through the direct activation of the ‘‘death
receptor’’ CD95 in autoreactive conditions.58,63,93–95
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 b-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 photore-
ceptor apoptosis.98,99
Furthermore, neurotransmitters such as dopamine, seroto-
nin, and glutamate have the potential to drive RGCs into
programmed cell death. As a cause for the triggering of
apoptosis, excitatory mechanisms are suggested.36,43,50,100–110
Regarding the potential excitotoxicity of glutamate, it is
noteworthy that glutamate transporters like GLAST and EEAC1,
as well as glutamate receptors, are downregulated in glau-
comatous eyes following astrocyte activation.102,111,112 As a
consequence, deficient glutamate removal from the extracel-
lular 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.10,79,113–125 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 glauco-
ma.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.15,61,127–131
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
 IOVS, March 2013, Vol. 54, No. 3
review article by Whitmore et al.15 provides detailed informa-
tion 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.139–142 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 apopto-
sis.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-3.147–149 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 a-HSP27 autoantibodies could
protect HSP27 from premature degradation by matrix metal-
loproteinases (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 a-HSP27 autoanti-
bodies.157
On the other hand, the accumulation of MMPs correlates
with the release of TNF-a particularly in patients with NTG, in
which MMPs are involved in the processing of the membrane-
bound TNF-a 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
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A Summary of the Current Knowledge 2395
patients contain antibodies against neuron-specific c-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 c-enolase antibody titers,
none of the elevated autoantibody titers against rhodopsin, a-
crystallin, and HSP60 otherwise commonly detected in
glaucoma patients could be demonstrated.8,146,153,159,160 Fur-
ther studies, published by Grus et al. and Joachim et al., also
revealed significant differences in the antibody profiles of
glaucoma patients.161–163
Furthermore, a significantly increased antibody reactivity
against ONH glycosaminoglycans (GAGs), glutathione S-trans-
ferase, alpha-fodrin, and neurofilament protein has been found
in the sera of patients with glaucoma.163–166 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 phylogeneti-
cally that molecular similarities between host and pathogenic
germs occasionally result in cross-reactivity.137,167–169
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 (intermolec-
ular 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.170–172
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 antibod-
ies), Devic’s syndrome (anti-aquaporin-4 antibodies), and NTG
(antirhodopsin antibodies).173–175 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 autoanti-
bodies is present in every healthy human and seems to be of
great significance during tissue injury when these autoanti-
bodies 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-a through anticytokine antibodies, and an
immune-regulatory function.178–181 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
 2396 Rieck
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.183–186 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-a and nitric oxide synthase-2 (NOS-2).
Apoptotic cells release anti-inflammatory mediators such as
TGF-b 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 mecha-
nisms and a high degree of flexibility to act at the appropriate
place. They destroy microbes by releasing cytotoxic substanc-
es, remove cell debris by phagocytosis, and act as antigen-
presenting cells.189
Apart from the normal motility behavior under physiolog-
ical 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.68,105,136,193–195
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 inflamma-
tory processes within the CNS, is documented in patients with
Alzheimer’s disease, Parkinson’s disease, Huntington’s disease,
MS, and ALS.201–203 Found in serum and cerebrospinal fluid of
these patients are elevated titers of IL-6, IL-1, and TNF-a,
chemokines of innate immunity that are potent initiators of the
extrinsic apoptosis of neurons.201–203 Especially for IL-1 and
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IOVS, March 2013, Vol. 54, No. 3
TNF-a, the activation of caspases has been shown, whereupon
TNF-a 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 profession-
al antigen-presenting cells, activated microglia control the
transition from innate immunity to an adaptive immune
response in the CNS.206–208
However, in glaucoma, TNF-a is of special interest: TNF-a
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-a–
mediated neurodegeneration.210 Thereby the increased TNF-a
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-a
production; and TNF-a causes RGC death.211
Another interesting aspect in this context is the occurrence
of single-nucleotide polymorphisms of the TNF-a 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 pseudoex-
foliative glaucoma with TNF-a polymorphisms, others could
not confirm this correlation.213–216
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, Parkin-
son’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
a-A- and a-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.165,221–223
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.224–232 The cause of inflammatory processes in the CNS
 IOVS, March 2013, Vol. 54, No. 3
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
CD4þ 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 endocy-
tosis, as in the case of a-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 presenta-
tion, 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 cyto-
kines 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 lymphocytes235,236
(Fig. 1).
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 immu-
nity 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.241–246 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
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A Summary of the Current Knowledge 2397
In the case of pathogen recognition, TLR will induce the
coordinated activation of transcription factor NF-jB (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.249–251 Of
the total of 12 isotypes so far identified, TLR 3, 7, 8, and 9
monitor the internal cellular compartments.242,252–254
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.258–260 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.264–266 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.269–271 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 autoanti-
gens.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 in-
creased reactivity in glaucoma and other neurodegenerative
diseases such as MS or Guillain-Barré syndrome.153,155,277,278
 2398 Rieck IOVS, March 2013, Vol. 54, No. 3

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.

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 accumula-
tion 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.7,8,47,161–163,165,172,179,282–292 These au-
toantibodies 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

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 IOVS, March 2013, Vol. 54, No. 3
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.
are significantly increased. Twenty-eight days after experimen-
tal OHT induction, an accumulation of C1q and C3 transcripts
is detected in the RGC layer and the ONH29 (Fig. 2).
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-a, superoxide (O2–), and other effector substances. This
involves glia in the reorganization of the ONH and the
destruction of RGCs.56,294–297 Additionally, the classical com-
plement cascade contributes to development and function
refinement of the CNS and visual system via pruning of
inappropriate synapses.281,298–300 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 histocompa-
tibily 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 comple-
ment 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 CD8þ T cells by
perforin-mediated cytotoxicity and the release of granzyme227
(Fig. 3).
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-a and IL-
1b.57,210,295,307–309 As a consequence, this release of inflam-
matory cytokines have the potential to impair the integrity of
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A Summary of the Current Knowledge 2399
the blood–brain barrier.209,233,234,310,311 The reactivation of the
complement cascade is noticeable by an increased transcrip-
tion 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-a 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 elimina-
tion 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.315–318 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.32,304,312,319–323
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) extracel-
lular signal-regulated kinase (ERK1/2), and the c-Jun N-terminal
kinase (JNK).324 While the mutual reinforcement of comple-
ment cascade and TLR with its increased TNF-a, IL-1b, 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
 2400 Rieck IOVS, March 2013, Vol. 54, No. 3

FIGURE 3. Cytotoxic T cells use three different routes to destroy their target. Initially the CD8þ 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-a. 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.

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 person-
alized ‘‘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 rheuma-
toid 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-a may also be an important factor in the neurodegener-
ative process of glaucoma, a OHT mouse model was used to
investigate the effect of etanercept on glaucoma. In fact, the
therapeutic anti-TNF-a 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

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 IOVS, March 2013, Vol. 54, No. 3
In glaucoma, distinct immunglobulins, such as autoantibod-
ies to alpha-fodrin163 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 superox-
ide dismutase,334–339 glutathione peroxidase,334,337,340 ascor-
bic acid,334,335,340 a-tocopherol,340,341 retinol,228,335 nitric
oxide,43,57,157,210,221,295,296,337,342–346 8-hydroxy-20-deoxygua-
nosine,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 neurotro-
phin 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
1. Quigley HA, Broman AT. The number of people with
glaucoma worldwide in 2010 and 2020. Br J Ophthalmol.
2006;90:262–267.
2. Burgoyne CF. A biomechanical paradigm for axonal insult
within the optic nerve head in aging and glaucoma. Exp Eye
Res. 2010;93:120–132.
3. Fechtner RD, Weinreb RN. Mechanisms of optic nerve
damage in primary open angle glaucoma. Surv Ophthalmol.
1994;39:23–42.
4. Ferrer E. Trabecular meshwork as a new target for the
treatment of glaucoma. Drug News Perspect. 2006;19:151–
158.
Downloaded from iovs.arvojournals.org on 02/05/2019
A Summary of the Current Knowledge 2401
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. Quigley HA. Ganglion cell death in glaucoma: pathology
recapitulates ontogeny. Aust N Z J Ophthalmol. 1995;23:85–
91.
12. Quigley HA. Neuronal death in glaucoma. Prog Retin Eye
Res. 1999;18:39–57.
13. Quigley HA. Glaucoma. Lancet. 2011;377:1367–1377.
14. Weinreb RN, Khaw PT. Primary open-angle glaucoma.
Lancet. 2004;363:1711–1720.
15. 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.
16. Harrington DO. The Bjerrum scotoma. Trans Am Ophthal-
mol Soc. 1964;62:324–348.
17. Garcia-Valenzuela E, Shareef S, Walsh J, Sharma SC. Pro-
grammed cell death of retinal ganglion cells during experi-
mental glaucoma. Exp Eye Res. 1995;61:33–44.
18. Glovinsky Y, Quigley HA, Dunkelberger GR. Retinal ganglion
cell loss is size dependent in experimental glaucoma. Invest
Ophthalmol Vis Sci. 1991;32:484–491.
19. Nickells RW. Retinal ganglion cell death in glaucoma: the
how, the why, and the maybe. J Glaucoma. 1996;5:345–356.
20. 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.
21. Bjerrum J. Om en tilføjelse til den sædvanlige synsfelt –
undersögelse samt om synsfeltet ved glaukom. Nord ophthal
Tidsskrift. 1889;2:141–185.
22. Jay JL, Murray SB. Early trabeculectomy versus conventional
management in primary open angle glaucoma. Br J Oph-
thalmol. 1988;72:881–889.
23. Zur D, Ullman S. Filling-in of retinal scotomas. Vis Res. 2003;
43:971–982.
24. Gloor BP, Sarra GM. Visusverlust und Sehstörung (2. Teil).
Schweiz Med Forum. 2004;4:308–312.
25. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular
Hypertension Treatment Study: a randomized trial deter-
mines that topical ocular hypotensive medication delays or
prevents the onset of primary open-angle glaucoma. Arch
Ophthalmol. 2002;120:701–713.
26. Weber AJ, Chen H, Hubbard WC, Kaufman PL. Experimental
glaucoma and cell size, density, and number in the primate
 2402 Rieck
lateral geniculate nucleus. Invest Ophthalmol Vis Sci. 2000;
41:1370–1379.
27. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular
Hypertension Treatment Study: baseline factors that predict
the onset of primary open-angle glaucoma. Arch Ophthal-
mol. 2002;120:714–720.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.
34. Grehn F, Hollo G, Lachkar Y, Migdal C, Thygesen J.
Terminology and Guidelines for Glaucoma. Vol. 2. Savona,
Italy: European Glaucoma Society; 2003.
35. Weinreb RN, Levin LA. Is neuroprotection a viable therapy
for glaucoma? Arch Ophthalmol. 1999;117:1540–1544.
36. Nickells RW. From ocular hypertension to ganglion cell
death: a theoretical sequence of events leading to glaucoma.
Can J Ophthalmol. 2007;42:278–287.
37. Coleman AL. Glaucoma. Lancet. 1999;354:1803–1810.
38. Mackenzie P, Cioffi G. How does lowering of intraocular
pressure protect the optic nerve? Surv Ophthalmol. 2008;
53(suppl 1):S39–S43.
39. Mozaffarieh M, Flammer J. Is there more to glaucoma
treatment than lowering IOP? Surv Ophthalmol. 2007;
52(suppl 1):S174–S179.
40. Enyedi LB, Freedman SF. Safety and efficacy of brimonidine in
children with glaucoma. J Pediatr Ophthalmol Strabismus.
2001;5:281–284.
41. 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.
42. 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.
43. Chidlow G, Wood JP, Casson RJ. Pharmacological neuropro-
tection for glaucoma. Drugs. 2007;67:725–759.
44. Pfeiffer N. Glaukom und okuläre Hypertension - Grund-
lagen, Diagnostik, Therapie. Vol. 1. Stuttgart, Germany:
Thieme-Verlag; 2001.
45. Aung T, Ocaka L, Ebenezer ND, et al. A major marker for
normal tension glaucoma: association with polymorphisms in
the OPA1 gene. Hum Genet. 2002;110:52–56.
46. Bonomi L, Marchini G, Marraffa M, et al. Prevalence of
glaucoma and intraocular pressure distribution in a defined
population: the Egna-Neumarkt study. Ophthalmology. 1998;
105:209–215.
Downloaded from iovs.arvojournals.org on 02/05/2019
IOVS, March 2013, Vol. 54, No. 3
47. Grus FH, Joachim SC, Pfeiffer N. Analysis of complex
autoantibody repertoires by surface-enhanced laser desorp-
tion/ionization-time of flight mass spectrometry. Proteomics.
2003;3:957–961.
48. CNTGSG. Comparison of glaucomatous progression between
untreated patients with normal-tension glaucoma and pa-
tients with therapeutically reduced intraocular pressures. Am
J Ophthalmol. 1998;126:487–497.
49. CNTGSG. The effectiveness of intraocular pressure reduction
in the treatment of normal-tension glaucoma. Am J Oph-
thalmol. 1998;126:498–505.
50. 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.
51. Crawford ML, Harwerth RS, Smith EL III, Mills S, Ewing B.
Experimental glaucoma in primates: changes in cytochrome
oxidase blobs in V1 cortex. Invest Ophthalmol Vis Sci. 2001;
42:358–364.
52. 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.
53. 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.
54. 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.
55. 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 glaucoma-
tous monkey optic nerve heads. Jpn J Ophthalmol. 2001;45:
592–599.
56. Hernandez MR. The optic nerve head in glaucoma: role of
astrocytes in tissue remodeling. Prog Retin Eye Res. 2000;19:
297–321.
57. Zhong YS, Leung CK, Pang CP. Glial cells and glaucomatous
neuropathy. Chin Med J (Engl). 2007;120:326–335.
58. 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.
59. Calandrella N, Scarsella G, Pescosolido N, Risuleo G.
Degenerative and apoptotic events at retinal and optic
nerve level after experimental induction of ocular hyper-
tension. Mol Cell Biochem. 2007;301:155–163.
60. 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.
61. Libby RT, Li T, Savinova OV, et al. Susceptibility to
neurodegeneration in a glaucoma is modified by Bax gene
dosage. PLoS Genet. 2005;1:17–26.
62. Murakami A, Okisaka S. Neuronal cell death mechanism in
glaucomatous optic neuropathy. Nippon Ganka Gakkai
Zasshi. 1998;102:645–653.
63. Nickells RW. The molecular biology of retinal ganglion cell
death: caveats and controversies. Brain Res Bull. 2004;62:
439–446.
64. Tatton WG, Olanow CW. Apoptosis in neurodegenerative
diseases: the role of mitochondria. Biochim Biophys Acta.
1999;1410:195–213.
65. Pease ME, McKinnon SJ, Quigley HA, Kerrigan-Baumrind LA,
Zack DJ. Obstructed axonal transport of BDNF and its
 IOVS, March 2013, Vol. 54, No. 3
receptor TrkB in experimental glaucoma. Invest Ophthalmol
Vis Sci. 2000;41:764–774.
66. 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.
67. Agar A, Yip SS, Hill MA, Coroneo MT. Pressure related
apoptosis in neuronal cell lines. J Neurosci Res. 2000;60:
495–503.
68. 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.
69. Leske MC. The epidemiology of open angle glaucoma: a
review. Am J Epidemiol. 1983;118:166–191.
70. Pfeiffer N. Results of the ‘‘Ocular Hypertension treatment
study.’’ Ophthalmologe. 2005;102:230–234.
71. Minckler DS, Bunt AH, Johanson GW. Orthograde and
retrograde axoplasmic transport during acute ocular hyper-
tension in the monkey. Invest Ophthalmol Vis Sci. 1977;16:
426–441.
72. Quigley HA, McKinnon SJ, Zack DJ, et al. 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.
73. 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.
74. 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.
75. Klöcker N, Bräunling F, Isenmann S, Bähr M. In vivo
neurotrophic effects of GDNF on axotomized retinal ganglion
cells. Neuroreport. 1997;8:3439–3442.
76. Ji JZ, Elyaman W, Yip HK, et al. 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.
77. Zweifel LS, Kuruvilla R, Ginty DD. Functions and mechanisms
of retrograde neurotrophin signalling. Nat Rev Neurosci.
2005;6:615–625.
78. 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.
79. 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.
80. Eathiraj S, Pan X, Ritacco C, Lambright DG. Structural basis of
family-wide Rab GTPase recognition by rabenosyn-5. Nature.
2005;436:415–419.
81. Nielsen E, Christoforidis S, Uttenweiler-Joseph S, et al.
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.
82. 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.
83. Schnatwinkel C, Christoforidis S, Lindsay MR, et al. The Rab5
effector rabankyrin-5 regulates and coordinates different
endocytic mechanisms. PLoS Biol. 2004;2:e261.
84. Shin H-W, Hayashi M, Christoforidis S, et al. An enzymatic
cascade of Rab5 effectors regulates phosphoinositide turn-
over in the endocytic pathway. J Cell Biol. 2005;170:607–
618.
Downloaded from iovs.arvojournals.org on 02/05/2019
A Summary of the Current Knowledge 2403
85. 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.
86. 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.
87. Morgan JE, Jeffery G, Foss AJE. Axon deviation in the human
lamina cribrosa. Br J Ophthalmol. 1998;82:680–683.
88. Radius RL, Anderson DR. Rapid axonal transport in primate
optic nerve. Distribution of pressure-induced interruption.
Arch Ophthalmol. 1981;99:650–654.
89. 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.
90. 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.
91. Pena JD, Agapova O, Gabelt BT, et al. Increased elastin
expression in astrocytes of the lamina cribrosa in response to
elevated intraocular pressure. Invest Ophthalmol Vis Sci.
2001;42:2303–2314.
92. Jonas JB. Role of cerebrospinal fluid pressure in the pathogen-
esis of glaucoma. Acta Ophthalmol. 2011;89:505–514.
93. 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.
94. 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.
95. Wax MB, Tezel G, Yang J, et al. Induced autoimmunity to heat
shock proteins elicits glaucomatous loss of retinal ganglion
cell neurons via activated T-cell-derived Fas-ligand. J Neuro-
sci. 2008;28:12085–12096.
96. McKinnon SJ. The cell and molecular biology of glaucoma:
common neurodegenerative pathways and relevance to
glaucoma. Invest Ophthalmol Vis Sci. 2012;53:2485–2487.
97. 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.
98. 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.
99. Harada T, Harada C, Nakayama N, et al. Modification of glial
neuronal cell interactions prevents photoreceptor apoptosis
during light-induced retinal degeneration. Neuron. 2000;26:
533–541.
100. Lipton SA. Possible role for memantine in protecting retinal
ganglion cells from glaucomatous damage. Surv Ophthalmol.
2003;48(suppl 1):S38–S46.
101. Schori H, Kipnis J, Yoles E, et al. Vaccination for protection of
retinal ganglion cells against death from glutamate cytotox-
icity and ocular hypertension: implications for glaucoma.
Proc Natl Acad Sci U S A. 2001;98:3398–3403.
102. Vorwerk CK, Naskar R, Schuettauf F, et al. Depression of
retinal glutamate transporter function leads to elevated
intravitreal glutamate levels and ganglion cell death. Invest
Ophthalmol Vis Sci. 2000;41:3615–3621.
103. Honkanen RA, Baruah S, Zimmerman MB, et al. Vitreous
amino acid concentrations in patients with glaucoma
undergoing vitrectomy. Arch Ophthalmol. 2003;121:183–
188.
 2404 Rieck
104. Ullian EM, Barkis WB, Chen S, Diamond JS, Barres BA.
Invulnerability of retinal ganglion cells to NMDA excitotox-
icity. Mol Cell Neurosci. 2004;26:544–557.
105. Bringmann A, Reichenbach A. Role of Muller cells in retinal
degenerations. Front Biosci. 2001;6:E72–E92.
106. Russo R, Rotiroti D, Tassorelli C, et al. Identification of novel
pharmacological targets to minimize excitotoxic retinal
damage. Int Rev Neurobiol. 2009;85:407–423.
107. 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.
108. Bucolo C, Leggio GM, Maltese A, Castorina A, D’Agata V,
Drago F. Dopamine-3 receptor modulates intraocular pres-
sure: implications for glaucoma. Biochem Pharmacol. 2011;
83:680–686.
109. 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.
110. 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.
111. Aronica E, Gorter JA, Ijlst-Keizers H, et al. Expression and
functional role of mGluR3 and mGluR5 in human astrocytes
and glioma cells: opposite regulation of glutamate transport-
er proteins. Eur J Neurosci. 2003;17:2106–2118.
112. Naskar R, Vorwerk CK, Dreyer EB. Concurrent downregula-
tion of a glutamate transporter and receptor in glaucoma.
Invest Ophthalmol Vis Sci. 2000;41:1940–1944.
113. 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.
114. Campenot RB. Local control of neurite development by nerve
growth factor. Proc Natl Acad U S A. 1977;74:4516–4519.
115. Campenot RB. Local control of neurite sprouting in cultured
sympathetic neurons by nerve growth factor. Dev Brain Res.
1987;37:293–301.
116. Castaño A, Bell MD, Perry VH. Unusual aspects of inflamma-
tion in the nervous system: Wallerian degeneration. Neuro-
biol Aging. 1996;17:745–751.
117. Fu QL, Li X, Shi J, et al. Synaptic degeneration of retinal
ganglion cells in a rat ocular hypertension glaucoma model.
Cell Mol Neurobiol. 2009;29:575–581.
118. Gillingwater TH, Ribchester RR. The relationship of neuro-
muscular synapse elimination to synaptic degeneration and
pathology: insights from WldS and other mutant mice. J
Neurocytol. 2003;32:863–881.
119. Hilliard MA. Axonal degeneration and regeneration: a
mechanistic tug-of-war. J Neurochem. 2009;108:23–32.
120. Jellinger K. Recent advances in our understanding of
neurodegeneration. J Neural Transm. 2009;116:1111–1162.
121. 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.
122. 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.
123. Yoles E, Schwartz M. Degeneration of spared axons following
partial white matter lesion: implications for optic nerve
neuropathies. Exp Neurol. 1998;153:1–7.
124. Coleman MP, Freeman MR. Wallerian degeneration, WldS,
and Nmnat. Annu Rev Neurosci. 2010;33:245–267.
125. 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.
Downloaded from iovs.arvojournals.org on 02/05/2019
IOVS, March 2013, Vol. 54, No. 3
126. 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.
127. 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.
128. Schwartz M. Vaccination for glaucoma: dream or reality?
Brain Res Bull. 2004;62:481–484.
129. Ohlsson M, Bellander BM, Langmoen IA, Svensson M.
Complement activation following optic nerve crush in the
adult rat. J Neurotrauma. 2003;20:895–904.
130. 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.
131. 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.
132. Tse MT. Axon degeneration: a new pathway emerges. Nat
Rev Neurosci. 2012;13:516.
133. Beirowski B, Adalbert R, Wagner D, et al. The progressive
nature of Wallerian degeneration in wild-type and slow
Wallerian degeneration (WldS) nerves. BMC Neurosis. 2005;
6:6.
134. de Lima S, Koriyama Y, Kurimoto T, et al. 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.
135. 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.
136. Sofroniew M, Vinters H. Astrocytes: biology and pathology.
Acta Neuropathol. 2010;119:7–35.
137. Wax MB, Tezel G, Saito I, et al. Anti-Ro/SS-a positivity and
heat shock protein antibodies in patients with normal-
pressure glaucoma. Am J Ophthalmol. 1998;125:145–157.
138. Feder ME, Hofmann GE. Heat-shock proteins, molecular
chaperones, and the stress response: evolutionary and
ecological physiology. Annu Rev Physiol. 1999;61:243–282.
139. 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.
140. 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.
141. 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.
142. Tezel G, Wax MB. The mechanisms of hsp27 antibody-
mediated apoptosis in retinal neuronal cells. J Neurosci.
2000;20:3552–3562.
143. 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.
144. 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.
145. 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.
 IOVS, March 2013, Vol. 54, No. 3
146. 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.
147. 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.
148. 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.
149. Whitlock NA, Lindsey K, Agarwal N, Crosson CE, Ma JX. Heat
shock protein 27 delays Ca2þ-induced cell death in a caspase-
dependent and -independent manner in rat retinal ganglion
cells. Invest Ophthalmol Vis Sci. 2005;46:1085–1091.
150. 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.
151. 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.
152. Sisto M, Lisi S, D’Amore S, D’Amore M. Autoantibodies,
human Fcc receptors, and autoimmunity. J Receptor Ligand
Channel Res. 2009;2:45–57.
153. Tezel G, Seigel GM, Wax MB. Autoantibodies to small heat
shock proteins in glaucoma. Invest Ophthalmol Vis Sci.
1998;39:2277–2287.
154. 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.
155. Cauwe B, Martens E, Proost P, Opdenakker G. Multidimen-
sional degradomics identifies systemic autoantigens and
intracellular matrix proteins as novel gelatinase B/MMP-9
substrates. Integr Biol. 2009;1:404–426.
156. Ram M, Sherer Y, Shoenfeld Y. Matrix metalloproteinase-9 and
autoimmune diseases. J Clin Immunol. 2006;26:299–307.
157. Yuan L, Neufeld AH. Activated microglia in the human
glaucomatous optic nerve head. J Neurosci Res. 2001;64:
523–532.
158. Yan X, Tezel G, Wax MB, Edward DP. Matrix metalloprotei-
nases and tumor necrosis factor alpha in glaucomatous optic
nerve head. Arch Ophthalmol. 2000;118:666–673.
159. Meyerhof O, Lohmann K. Über die enzymatische Gleichge-
wichtsreaktion zwischen Hexosediphosphorsäure und Diox-
yacetonphosphorsäure. Naturwissenschaften. 1934;22:220.
160. 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.
161. 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.
162. Grus FH, Joachim SC, Hoffmann EM, Pfeiffer N. Complex
autoantibody repertoires in patients with glaucoma. Mol Vis.
2004;10:132–137.
163. 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.
164. Tezel G, Edward DP, Wax MB. Serum autoantibodies to optic
nerve head glycosaminoglycans in patients with glaucoma.
Arch Ophthalmol. 1999;917–924.
Downloaded from iovs.arvojournals.org on 02/05/2019
A Summary of the Current Knowledge 2405
165. 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.
166. Yano T, Yamada K, Kimura A, et al. Autoimmunity against
neurofilament protein and its possible association with HLA-
DRB1*1502 allele in glaucoma. Immunol Lett. 2005;100:
164–169.
167. Thatcher TH, Gorovsky MA. Phylogenetic analysis of the core
histones H2A, H2B, H3, and H4. Nucleic Acids Res. 1994;22:
174–149.
168. Garsia RJ, Hellqvist L, Booth RJ, et al. Homology of the 70-
kilodalton antigens from Mycobacterium leprae and Myco-
bacterium bovis with the Mycobacterium tuberculosis 71-
kilodalton antigen and with the conserved heat shock
protein 70 of eucaryotes. Infect Immun. 1989;57:204–212.
169. Schlesinger MJ. How the cell copes with stress and the
function of heat shock proteins. Pediatr Res. 1994;36(1, pt
1):1–6.
170. 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.
171. Klareskog L, Rönnelid J, Lundberg K, Padyukov L, Alfredsson
L. Immunity to citrullinated proteins in rheumatoid arthritis.
Annu Rev Immunol. 2008;26:651–675.
172. 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.
173. 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.
174. 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.
175. Kampylafka EI, Routsias JG, Alexopoulos H, Dalakas MC,
Moutsopoulos HM, Tzioufas AG. Fine specificity of antibodies
against AQP4: epitope mapping reveals intracellular epi-
topes. J Autoimmun. 2011;36:221–227.
176. Vyshkina T, Kalman B. Autoantibodies and neurodegenera-
tion in multiple sclerosis. Lab Invest. 2008;88:796–807.
177. 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.
178. Shoenfeld Y, Toubi E. Protective autoantibodies: role in
homeostasis, clinical importance, and therapeutic potential.
Arthritis Rheum. 2005;52:2599–2606.
179. Grus F, Sun D. Immunological mechanisms in glaucoma.
Semin Immunopathol. 2008;30:121–126.
180. Poletaev AB, Stepanyuk VL, Gershwin ME. Integrating
immunity: the immunculus and self-reactivity. J Autoimmun.
2008;30:68–73.
181. Wax MB, Tezel G. Immunoregulation of retinal ganglion cell
fate in glaucoma. Exp Eye Res. 2009;88:825–830.
182. Grus FH, Joachim SC, Wuenschig D, Rieck J, Pfeiffer N.
Autoimmunity and glaucoma. J Glaucoma. 2008;17:79–84.
183. Newman E, Reichenbach A. The Müller cell: a functional
element of the retina. Trends Neurosci. 1996;19:307–312.
184. Newman EA, Zahs KR. Modulation of neuronal activity by
glial cells in the retina. J Neurosci. 1998;18:4022–4028.
185. Ramı́rez JM, Triviño A, Ramı́rez AI, Salazar JJ, Garcı́a-Sánchez
J. Structural specializations of human retinal glial cells. Vis
Res. 1996;36:2029–2036.
 2406 Rieck
186. 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.
187. 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.
188. Napoli I, Neumann H. Microglial clearance function in health
and disease. Neuroscience. 2009;158:1030–1038.
189. 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.
190. Davalos D, Grutzendler J, Yang G, et al. ATP mediates rapid
microglial response to local brain injury in vivo. Nat
Neurosci. 2005;8:752–758.
191. Haynes SE, Hollopeter G, Yang G, et al. The P2Y12 receptor
regulates microglial activation by extracellular nucleotides.
Nat Neurosci. 2006;9:1512–1519.
192. Ladeby R, Wirenfeldt M, Dalmau I, et al. Proliferating resident
microglia express the stem cell antigen CD34 in response to
acute neural injury. Glia. 2005;50:121–131.
193. Meyer-Luehmann M, Spires-Jones TL, Prada C, et al. Rapid
appearance and local toxicity of amyloid-beta plaques in a
mouse model of Alzheimer’s disease. Nature. 2008;451:720–
724.
194. Inman DM, Horner PJ. Reactive nonproliferative gliosis
predominates in a chronic mouse model of glaucoma. Glia.
2007;55:942–953.
195. Prasanna G, Krishnamoorthy R, Yorio T. Endothelin, astro-
cytes and glaucoma. Exp Eye Res. 2011;93:170–177.
196. Rappert A, Bechmann I, Pivneva T, et al. CXCR3-dependent
microglial recruitment is essential for dendrite loss after brain
lesion. J Neurosci. 2004;24:8500–8509.
197. Cardona AE, Pioro EP, Sasse ME, et al. Control of microglial
neurotoxicity by the fractalkine receptor. Nat Neurosci.
2006;9:917–924.
198. Biber K, Neumann H, Inoue K, Boddeke HW. Neuronal On
and Off signals control microglia. Trends Neurosci. 2007;30:
596–602.
199. Tezel GMD, Wax MB. Glial modulation of retinal ganglion dell
death in glaucoma. J Glaucoma. 2003;12:63–68.
200. Tezel G, Chauhan BC, LeBlanc RP, Wax MB. Immunohisto-
chemical assessment of the glial mitogen-activated protein
kinase activation in glaucoma. Invest Ophthalmol Vis Sci.
2003;44:3025–3033.
201. Pasinetti GM. Cyclooxygenase and inflammation in Alz-
heimer’s disease: experimental approaches and clinical
interventions. J Neurosci Res. 1998;54:1–6.
202. Gonzalez-Scarano F, Baltuch G. Microglia as mediators of
inflammatory and degenerative diseases. Annu Rev Neurosci.
1999;22:219–240.
203. Julien J-P. Amyotrophic lateral sclerosis: unfolding the toxicity
of the misfolded. Cell. 2001;104:581–591.
204. Venters HD, Tang Q, Liu Q, VanHoy RW, Dantzer R, Kelley
KW. A new mechanism of neurodegeneration: a proinflam-
matory cytokine inhibits receptor signaling by a survival
peptide. Proc Natl Acad Sci U S A. 1999;96:9879–9884.
205. Friedlander RM. Role of caspase 1 in neurologic disease. Arch
Neurol. 2000;57:1273–1276.
206. González-Scarano F, Baltuch G. Microglia as mediators of
inflammatory and degenerative diseases. Annu Rev Neurosci.
1999;22:219–240.
207. Hickey WF, Kimura H. Perivascular microglial cells of the
CNS are bone marrow-derived and present antigen in vivo.
Science. 1988;239:290–292.
Downloaded from iovs.arvojournals.org on 02/05/2019
IOVS, March 2013, Vol. 54, No. 3
208. Weiner H. A shift from adaptive to innate immunity: a
potential mechanism of disease progression in multiple
sclerosis. J Neurol. 2008;255:3–11.
209. Tezel G. TNF-alpha signaling in glaucomatous neurodegener-
ation. Prog Brain Res. 2008;173:409–421.
210. Yuan L, Neufeld AH. Tumor necrosis factor-a: a potentially
neurodestructive cytokine produced by glia in the human
glaucomatous optic nerve head. Glia. 2000;32:42–50.
211. Bai Y, Shi Z, Zhuo Y, et al. 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.
212. Fan BJ, Liu K, Wang DY, et al. Association of polymorphisms
of tumor necrosis factor and tumor protein p53 with primary
open-angle glaucoma. Invest Ophthalmol Vis Sci. 2010;51:
4110–4116.
213. Khan MI, Micheal S, Rana N, et al. Association of tumor
necrosis factor alpha gene polymorphism G-308A with
pseudoexfoliative glaucoma in the Pakistani population.
Mol Vis. 2009;15:2861–2867.
214. Razeghinejad MR, Rahat F, Kamali-Sarvestani E. Association of
TNFA 308 G/A and TNFRI þ36 A/G gene polymorphisms
with glaucoma. Ophthalmic Res. 2009;42:118–124.
215. Mossböck G, Renner W, El-Shabrawi Y, et al. 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.
216. Tekeli O, Turacli ME, Egin Y, Akar N, Elhan AH. Tumor
necrosis factor alpha-308 gene polymorphism and pseudoex-
foliation glaucoma. Mol Vis. 2008;14:1815–1818.
217. 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.
218. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative
stress in neurodegenerative diseases. Nature. 2006;443:787–
795.
219. Musunuru K, Darnell RB. Paraneoplastic neurologic disease
antigens: RNA-binding proteins and signaling proteins in
neuronal degeneration. Annu Rev Neurosci. 2001;24:239–
262.
220. Solimena M, De Camilli P. Synaptic autoimmunity and the
Salk factor. Neuron. 2000;28:309–316.
221. Maruyama I, Nakazawa M, Ohguro H. Autoimmune mecha-
nisms in molecular pathology of glaucomatous optic
neuropathy [in Japanese]. Nippon Ganka Gakkai Zasshi.
2001;105:205–212.
222. 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.
223. Wax MB, Yang J, Tezel G. Serum autoantibodies in patients
with glaucoma. J Glaucoma. 2001;10(5)(suppl 1):S22–S24.
224. 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.
225. Fearon DT, Locksley RM. The instructive role of innate
immunity in the acquired immune response. Science. 1996;
272:50–53.
226. Li Y, Ucccelli A, Laxer KD, et al. Local-clonal expansion of
infiltrating T lymphocytes in chronic encephalitis of Rasmus-
sen. J Immunol. 1997;158:1428–1437.
227. Neumann H, Medana IM, Bauer J, Lassmann H. Cytotoxic T
lymphocytes in autoimmune and degenerative CNS diseases.
Trends Neurosci. 2002;25:313–319.
 IOVS, March 2013, Vol. 54, No. 3
228. Caspi R. Autoimmunity in the immune privileged eye:
pathogenic and regulatory T cells. Immunol Res. 2008;42:
41–50.
229. Nielsen HH, Ladeby R, Fenger C, et al. Enhanced microglial
clearance of myelin debris in T cell-infiltrated central nervous
system. J Neuropathol Exp Neurol. 2009;68:845–856.
230. Streilein JW. Unraveling immune privilege. Science. 1995;
270:1158–1159.
231. 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.
232. 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.
233. Abbott N. Astrocyte-endothelial interactions and blood-brain
barrier permeability. J Anat. 2002;200:527.
234. Grieshaber MC, Flammer J. Does the blood-brain barrier play
a role in glaucoma? Surv Ophthalmol. 2007;52(6)(suppl 1):
S115–S121.
235. Goverman J. Autoimmune T cell responses in the central
nervous system. Nat Rev Immunol. 2009;9:393–407.
236. Nguyen MD, Julien JP, Rivest S. Innate immunity: the missing
link in neuroprotection and neurodegeneration? Nat Rev
Neurosci. 2002;3:216–227.
237. 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.
238. Huber JD, Egleton RD, Davis TP. Molecular physiology and
pathophysiology of tight junctions in the blood-brain barrier.
Trends Neurosci. 2001;24:719–725.
239. Howell GR, Soto I, Zhu X, et al. 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.
240. 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.
241. Colonna M. TREMs in the immune system and beyond. Nat
Rev Immunol. 2003;3:445–453.
242. Olson JK, Miller SD. Microglia initiate central nervous system
innate and adaptive immune responses through multiple
TLRs. J Immunol. 2004;173:3916–3924.
243. 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.
244. Akira S, Yamamoto M, Takeda K. Role of adapters in Toll-like
receptor signalling. Biochem Soc Trans. 2003;31(pt 3):637–
642.
245. Ford JW, McVicar DW. TREM and TREM-like receptors in
inflammation and disease. Curr Opin Immunol. 2009;21:38–
46.
246. Bouchon A, Dietrich J, Colonna M. Cutting edge: inflamma-
tory responses can be triggered by TREM-1, a novel receptor
expressed on neutrophils and monocytes. J Immunol. 2000;
164:4991–4995.
247. 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.
248. 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.
249. Janeway CA, Medzhitov R. Innate immune recognition. Annu
Rev Immunol. 2002;20:197–216.
250. Choe J, Kelker MS, Wilson IA. Crystal structure of human Toll-
like receptor 3 (TLR3) ectodomain. Science. 2005;309:581–585.
Downloaded from iovs.arvojournals.org on 02/05/2019
A Summary of the Current Knowledge 2407
251. Hajishengallis G, Lambris JD. Crosstalk pathways between
Toll-like receptors and the complement system. Trends
Immunol. 2010;31:154–163.
252. Beutler B. Microbe sensing, positive feedback loops, and the
pathogenesis of inflammatory diseases. Immunol Rev. 2009;
227:248–263.
253. 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.
254. Heil F, Hemmi H, Hochrein H, et al. Species-specific
recognition of single-stranded RNA via Toll-like receptors 7
and 8. Science. 2004;303:1526–1529.
255. 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.
256. Tsan MF, Gao B. Heat shock proteins and immune system. J
Leukoc Biol. 2009;85:905–910.
257. 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.
258. Roelofs MF, Boelens WC, Joosten LA, et al. 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.
259. 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.
260. 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.
261. Johnson JD, Fleshner M. Releasing signals, secretory path-
ways, and immune function of endogenous extracellular heat
shock protein 72. J Leukoc Biol. 2006;79:425–434.
262. Young DB. Heat-shock proteins: immunity and autoimmunity.
Curr Opin Immunol. 1992;4:396–400.
263. Young RA, Elliott TJ. Stress proteins, infection, and immune
surveillance. Cell. 1989;59:5–8.
264. 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.
265. Liu D, Yumoto D, Hirota K, et al. 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.
266. Rajaiah R, Moudgil KD. Heat-shock proteins can promote as
well as regulate autoimmunity. Autoimmun Rev. 2009;8:
388–393.
267. Damian RT. Molecular mimicry in biological adaptation.
Science. 1965;147:824.
268. Damian RT. Molecular mimicry: antigen sharing by parasite
and host and its consequences. Am Naturalist. 1964;98:129–
149.
269. Galloway PH, Warner SJ, Morshed MG, Mikelberg FS.
Helicobacter pylori infection and the risk for open-angle
glaucoma. Ophthalmology. 2003;110:922–925.
270. 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.
271. Kountouras J, Mylopoulos N, Konstas AG, Zavos C, Chatzo-
poulos D, Boukla A. Increased levels of Helicobacter pylori
IgG antibodies in aqueous humor of patients with primary
 2408 Rieck
open-angle and exfoliation glaucoma. Graefes Arch Clin Exp
Ophthalmol. 2003;241:884–890.
272. Cohen IR. Antigenic mimicry, clonal selection and autoim-
munity. J Autoimmun. 2001;16:337–340.
273. Oldstone MB. Molecular mimicry, microbial infection, and
autoimmune disease: evolution of the concept. Curr Top
Microbiol Immunol. 2005;296:1–17.
274. 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.
275. Rodriguez D, Morrison CJ, Overall CM. Matrix metalloprotei-
nases: what do they not do? New substrates and biological
roles identified by murine models and proteomics. Biochim
Biophys Acta. 2010;1803:39–54.
276. Kurien BT, Scofield RH. Autoimmunity and oxidatively
modified autoantigens. Autoimmun Rev. 2008;7:567–573.
277. Chiba S, Yokota S, Yonekura K, et al. Autoantibodies against
HSP70 family proteins were detected in the cerebrospinal
fluid from patients with multiple sclerosis. J Neurol Sci.
2006;241:39–43.
278. Yonekura K, Yokota S, Tanaka S, et al. Prevalence of anti-heat
shock protein antibodies in cerebrospinal fluids of patients
with Guillain-Barre syndrome. J Neuroimmunol. 2004;156:
204–209.
279. Gasque P. Complement: a unique innate immune sensor for
danger signals. Mol Immunol. 2004;41:1089–1098.
280. 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.
281. Stevens B, Allen NJ, Vazquez LE, et al. The classical
complement cascade mediates CNS synapse elimination.
Cell. 2007;131:1164–1178.
282. 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.
283. Buckley C, Vincent A. Autoimmune channelopathies. Nat
Clin Pract Neurol. 2005;1:22–33.
284. Scofield RH. Autoantibodies as predictors of disease. Lancet.
2004;363:1544–1546.
285. Arbuckle MR, McClain MT, Rubertone MV, et al. Develop-
ment of autoantibodies before the clinical onset of systemic
lupus erythematosus. N Engl J Med. 2003;349:1526–1533.
286. Quintana FJ, Cohen IR. The natural autoantibody repertoire
and autoimmune disease. Biomed Pharmacother. 2004;58:
276–281.
287. Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum
autoantibody marker of neuromyelitis optica: distinction
from multiple sclerosis. Lancet. 2004;364:2106–2112.
288. Dziewas R, Kis B, Grus FH, Zimmermann CW. Antibody
pattern analysis in the Guillain-Barré syndrome and patho-
logic controls. J Neuroimmunol. 2001;119:287–296.
289. Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory
autoantibodies to the PDGF receptor in systemic sclerosis.
N Engl J Med. 2006;354:2667–2676.
290. Kubo T, Uchida Y, Watanabe Y, et al. 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.
291. Hueber W, Tomooka BH, Batliwalla F, et al. Blood autoanti-
body and cytokine profiles predict response to anti-tumor
necrosis factor therapy in rheumatoid arthritis. Arthritis Res
Ther. 2009;11:R76.
292. Walport MJ. Complement. N Engl J Med. 2001;344:1058–
1066.
Downloaded from iovs.arvojournals.org on 02/05/2019
IOVS, March 2013, Vol. 54, No. 3
293. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a
key system for immune surveillance and homeostasis. Nat
Immunol. 2010;11:785–797.
294. Kulkarni AP, Kellaway LA, Lahiri DK, Kotwal GL. Neuropro-
tection from complement-mediated inflammatory damage.
Ann N Y Acad Sci. 2004;1035:147–164.
295. Neufeld AH, Liu B. Glaucomatous optic neuropathy: when
glia misbehave. Neuroscientist. 2003;9:485–495.
296. 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 cocul-
tured retinal ganglion cells. J Neurosci. 2000;20:8693–8700.
297. Tezel G, Wax MB. Hypoxia-inducible factor 1alpha in the
glaucomatous retina and optic nerve head. Arch Ophthal-
mol. 2004;122:1348–1356.
298. Boulanger LM. Immune proteins in brain development and
synaptic plasticity. Neuron. 2009;64:93–109.
299. 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.
300. Katz LC, Shatz CJ. Synaptic activity and the construction of
cortical circuits. Science. 1996;274:1133–1138.
301. 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.
302. 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.
303. Neumann H, Cavalié A, Jenne DE, Wekerle H. Induction of
MHC class I genes in neurons. Science. 1995;269:549–552.
304. Stasi K, Nagel D, Yang X, et al. Complement component 1Q
(C1Q) upregulation in retina of murine, primate, and human
glaucomatous eyes. Invest Ophthalmol Vis Sci. 2006;47:
1024–1029.
305. Howell GR, Libby RT, Jakobs TC, et al. Axons of retinal
ganglion cells are insulted in the optic nerve early in DBA/2J
glaucoma. J Cell Biol. 2007;179:1523–1537.
306. Sigal IA, Ethier CR. Biomechanics of the optic nerve head.
Exp Eye Res. 2009;88:799–807.
307. Ambrosini E, Aloisi F. Chemokines and glial cells: a complex
network in the central nervous system. Neurochem Res.
2004;29:1017–1038.
308. Langmann T. Microglia activation in retinal degeneration. J
Leukoc Biol. 2007;81:1345–1351.
309. Nakazawa T, Nakazawa C, Matsubara A, et al. Tumor necrosis
factor-a mediates oligodendrocyte death and delayed retinal
ganglion cell loss in a mouse model of glaucoma. J Neurosci.
2006;26:12633–12641.
310. Hawkins BT, Davis TP. The blood-brain barrier/neurovascular
unit in health and disease. Pharmacol Rev. 2005;57:173–185.
311. Yong VW, Marks S. The interplay between the immune and
central nervous systems in neuronal injury. Neurology. 2010;
74(suppl 1);S9–S16.
312. 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.
313. 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.
314. Botto M, Dell’Agnola C, Bygrave AE, et al. Homozygous C1q
deficiency causes glomerulonephritis associated with multi-
ple apoptotic bodies. Nat Genet. 1998;19:56–59.
 IOVS, March 2013, Vol. 54, No. 3
315. Cowell RM, Plane JM, Silverstein FS. Complement activation
contributes to hypoxic-ischemic brain injury in neonatal rats.
J Neurosci. 2003;23:9459–9468.
316. Rancan M, Morganti-Kossman MC, Barnum SR, et al. Central
nervous system-targeted complement inhibition mediates
neuroprotection after closed head injury in transgenic mice. J
Cereb Blood Flow Metab. 2003;23:1070–1074.
317. 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.
318. Schäfer MK, Schwaeble WJ, Post C, et al. Complement C1q is
dramatically up-regulated in brain microglia in response to
transient global cerebral ischemia. J Immunol. 2000;164:
5446–5452.
319. Dangond F, Hwang D, Camelo S, et al. Molecular signature of
late-stage human ALS revealed by expression profiling of
postmortem spinal cord gray matter. Physiol Genomics.
2004;16:229–239.
320. Fonseca MI, Kawas CH, Troncoso JC, Tenner AJ. Neuronal
localization of C1q in preclinical Alzheimer’s disease. Neuro-
biol Dis. 2004;15:40–46.
321. Stasi K, Nagel D, Yang X, et al. Complement component 1Q
(C1Q) upregulation in retina of murine, primate, and human
glaucomatous eyes. Invest Ophthalmol Vis Sci. 2006;47:
1024–1029.
322. 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.
323. 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.
324. Zhang X, Kimura Y, Fang C, et al. Regulation of Toll-like
receptor-mediated inflammatory response by complement in
vivo. Blood. 2007;110:228–236.
325. Kim DD, Song W-C. Membrane complement regulatory
proteins. Clin Immunol. 2006;118:127–136.
326. Wax MB. The case for autoimmunity in glaucoma. Exp Eye
Res. 2011;93:187–190.
327. Flavell RA, Hafler DA. Autoimmunity: what is the turning
point?: editorial overview. Curr Opin Immunol. 1999;11:
635–637.
328. Hafler DA, Flavell R. Autoimmunity. How to know thy self.
Curr Opin Immunol. 1996;8:805–807.
329. Roh M, Zhang Y, Murakami Y, et al. 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.
330. 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.
331. Golubnitschaja O, Flammer J. What are the biomarkers for
glaucoma? Surv Ophthalmol. 2007;52(suppl 2):S155–S161.
332. Grus FH, Joachim SC, Sandmann S, et al. Transthyretin and
complex protein pattern in aqueous humor of patients with
primary open-angle glaucoma. Mol Vis. 2008;14:1437–1445.
Downloaded from iovs.arvojournals.org on 02/05/2019
A Summary of the Current Knowledge 2409
333. 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.
334. 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.
335. Erdurmus M, Yağcı R, Atis Ö, Karadağ R, Akbas A, Hepsen IF.
Antioxidant status and oxidative stress in primary open angle
glaucoma and pseudoexfoliative glaucoma. Curr Eye Res.
2011;36:713–718.
336. Tezel G. Oxidative stress in glaucomatous neurodegenera-
tion: mechanisms and consequences. Prog Retin Eye Res.
2006;25:490–513.
337. 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.
338. Hinerfeld D, Traini MD, Weinberger RP, et al. Endogenous
mitochondrial oxidative stress: neurodegeneration, proteo-
mic analysis, specific respiratory chain defects, and effica-
cious antioxidant therapy in superoxide dismutase 2 null
mice. J Neurochem. 2004;88:657–667.
339. 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.
340. Wilson JX. Antioxidant defense of the brain: a role for
astrocytes. Can J Physiol Pharmacol. 1997;75:1149–1163.
341. 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.
342. Neufeld AH, Hernandez MR, Gonzalez M. Nitric oxide
synthase in the human glaucomatous optic nerve head. Arch
Ophthalmol. 1997;115:497–503.
343. Ritch R. Neuroprotection: is it already applicable to glaucoma
therapy? Curr Opin Ophthalmol. 2000;11:78–84.
344. 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.
345. 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.
346. Mozaffarieh M, Grieshaber MC, Flammer J. Oxygen and blood
flow: players in the pathogenesis of glaucoma. Mol Vis. 2008;
14:224–233.
347. 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.
348. McElnea EM, Quill B, Docherty NG, et al. Oxidative stress,
mitochondrial dysfunction and calcium overload in human
lamina cribrosa cells from glaucoma donors. Mol Vis. 2011;
17:1182–1191.
349. Pinazo-Durán MD, Zanón-Moreno V, Garcı́a-Medina JJ, Galle-
go-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.