Glutamate is the major excitatory neurotransmitter of the Central
Nervous System (CNS), and it is crucially needed for numerous key
neuronal functions. Yet, excess glutamate causes massive neuronal death
and brain damage by excitotoxicity-detrimental over activation of
glutamate receptors. Glutamate-mediated excitotoxicity is the main
pathological process taking place in many types of acute and chronic CNS
diseases and injuries. In recent years, it became clear that not only
excess glutamate can cause massive brain damage, but that several types
of anti-glutamate receptor antibodies, that are present in the serum and
CSF of subpopulations of patients with a kaleidoscope of human
neurological diseases, can undoubtedly do so too, by inducing several
very potent pathological effects in the CNS. Collectively, the family of
anti-glutamate receptor autoimmune antibodies seem to be the most
widespread, potent, dangerous and interesting anti-brain autoimmune
antibodies discovered up to now. This impression stems from taking
together the presence of various types of anti-glutamate receptor
antibodies in a kaleidoscope of human neurological and autoimmune
diseases, their high levels in the CNS due to intrathecal production,
their multiple pathological effects in the brain, and the unique and
diverse mechanisms of action by which they can affect glutamate
receptors, signaling and effects, and subsequently impair neuronal
signaling and induce brain damage. The two main families of autoimmune
anti-glutamate receptor antibodies that were already found in patients
with neurological and/or autoimmune diseases, and that were already
shown to be detrimental to the CNS, include the antibodies directed
against ionotorpic glutamate receptors: the anti-AMPA-GluR3 antibodies,
anti-NMDA-NR1 antibodies and anti-NMDA-NR2 antibodies, and the
antibodies directed against Metabotropic glutamate receptors: the
anti-mGluR1 antibodies and the anti-mGluR5 antibodies. Each type of
these anti-glutamate receptor antibodies is discussed separately in this
very comprehensive review, with regards to: the human diseases in which
these anti-glutamate receptor antibodies were found thus far, their
presence and production in the nervous system, their association with
various psychiatric/behavioral/cognitive/motor impairments, their
possible association with certain infectious organisms, their
detrimental effects in vitro as well as in vivo in animal models in
mice, rats or rabbits, and their diverse and unique mechanisms of
action. The review also covers the very encouraging positive responses
to immunotherapy of some patients that have either of the
above-mentioned anti-glutamate receptor antibodies, and that suffer from
various neurological diseases/problems. All the above are also
summarized in the review's five schematic and useful figures, for each
type of anti-glutamate receptor antibodies separately. The review ends
with a summary of all the main findings, and with recommended guidelines
for diagnosis, therapy, drug design and future investigations. In the
nut shell, the human studies, the in vitro studies, as well as the in
vivo studies in animal models in mice, rats and rabbit revealed the
following findings regarding the five different types of anti-glutamate
receptor antibodies: (1) Anti-AMPA-GluR3B antibodies are present in
~25-30 % of patients with different types of Epilepsy. When these
anti-glutamate receptor antibodies (or other types of autoimmune
antibodies) are found in Epilepsy patients, and when these autoimmune
antibodies are suspected to induce or aggravate the seizures and/or the
cognitive/psychiatric/behavioral impairments that sometimes accompany
the seizures, the Epilepsy is called 'Autoimmune Epilepsy'. In some
patients with 'Autoimmune Epilepsy' the anti-AMPA-GluR3B antibodies
associate significantly with psychiatric/cognitive/behavior
abnormalities. In vitro and/or in animal models, the anti-AMPA-GluR3B
antibodies by themselves induce many pathological effects: they activate
glutamate/AMPA receptors, kill neurons by 'Excitotoxicity', and/or by
complement activation modulated by complement regulatory proteins, cause
multiple brain damage, aggravate chemoconvulsant-induced seizures, and
also induce behavioral/motor impairments. Some patients with 'Autoimmune
Epilepsy' that have anti-AMPA-GluR3B antibodies respond well (although
sometimes transiently) to immunotherapy, and thanks to that have reduced
seizures and overall improved neurological functions. (2) Anti-NMDA-NR1
antibodies are present in patients with autoimmune 'Anti-NMDA-receptor
Encephalitis'. In humans, in animal models and in vitro the
anti-NMDA-NR1 antibodies can be very pathogenic since they can cause a
pronounced decrease of surface NMDA receptors expressed in hippocampal
neurons, and also decrease the cluster density and synaptic localization
of the NMDA receptors. The anti-NMDA-NR1 antibodies induce these
effects by crosslinking and internalization of the NMDA receptors. Such
changes can impair glutamate signaling via the NMDA receptors and lead
to various neuronal/behavior/cognitive/psychiatric abnormalities.
Anti-NMDA-NR1 antibodies are frequently present in high levels in the
CSF of the patients with 'Anti-NMDA-receptor encephalitis' due to their
intrathecal production. Many patients with 'Anti-NMDA receptor
Encephalitis' respond well to several modes of immunotherapy. (3)
Anti-NMDA-NR2A/B antibodies are present in a substantial number of
patients with Systemic Lupus Erythematosus (SLE) with or without
neuropsychiatric problems. The exact percentage of SLE patients having
anti-NMDA-NR2A/B antibodies varies in different studies from 14 to 35 %,
and in one study such antibodies were found in 81 % of patients with
diffuse 'Neuropshychiatric SLE', and in 44 % of patients with focal
'Neuropshychiatric SLE'. Anti-NMDA-NR2A/B antibodies are also present in
subpopulations of patients with Epilepsy of several types, Encephalitis
of several types (e.g., chronic progressive limbic Encephalitis,
Paraneoplastic Encephalitis or Herpes Simplex Virus Encephalitis),
Schizophrenia, Mania, Stroke, or Sjorgen syndrome. In some patients, the
anti-NMDA-NR2A/B antibodies are present in both the serum and the CSF.
Some of the anti-NMDA-NR2A/B antibodies cross-react with dsDNA, while
others do not. Some of the anti-NMDA-NR2A/B antibodies associate with
neuropsychiatric/cognitive/behavior/mood impairments in SLE patients,
while others do not. The anti-NMDA-NR2A/B antibodies can undoubtedly be
very pathogenic, since they can kill neurons by activating NMDA
receptors and inducing 'Excitotoxicity', damage the brain, cause
dramatic decrease of membranal NMDA receptors expressed in hippocampal
neurons, and also induce behavioral cognitive impairments in animal
models. Yet, the concentration of the anti-NMDA-NR2A/B antibodies seems
to determine if they have positive or negative effects on the activity
of glutamate receptors and on the survival of neurons. Thus, at low
concentration, the anti-NMDA-NR2A/B antibodies were found to be positive
modulators of receptor function and increase the size of NMDA
receptor-mediated excitatory postsynaptic potentials, whereas at high
concentration they are pathogenic as they promote 'Excitotoxcity'
through enhanced mitochondrial permeability transition. (4) Anti-mGluR1
antibodies were found thus far in very few patients with Paraneoplastic
Cerebellar Ataxia, and in these patients they are produced intrathecally
and therefore present in much higher levels in the CSF than in the
serum. The anti-mGluR1 antibodies can be very pathogenic in the brain
since they can reduce the basal neuronal activity, block the induction
of long-term depression of Purkinje cells, and altogether cause
cerebellar motor coordination deficits by a combination of rapid effects
on both the acute and the plastic responses of Purkinje cells, and by
chronic degenerative effects. Strikingly, within 30 min after injection
of anti-mGluR1 antibodies into the brain of mice, the mice became
ataxic. Anti-mGluR1 antibodies derived from patients with Ataxia also
caused disturbance of eye movements in animal models. Immunotherapy can
be very effective for some Cerebellar Ataxia patients that have
anti-mGluR1 antibodies. (5) Anti-mGluR5 antibodies were found thus far
in the serum and CSF of very few patients with Hodgkin lymphoma and
Limbic Encephalopathy (Ophelia syndrome). The sera of these patients
that contained anti-GluR5 antibodies reacted with the neuropil of the
hippocampus and cell surface of live rat hippocampal neurons, and
immunoprecipitation from cultured neurons and mass spectrometry
demonstrated that the antigen was indeed mGluR5. Taken together, all
these evidences show that anti-glutamate receptor antibodies are much
more frequent among various neurological diseases than ever realized
before, and that they are very detrimental to the nervous system. As
such, they call for diagnosis, therapeutic removal or silencing and
future studies. What we have learned by now about the broad family of
anti-glutamate receptor antibodies is so exciting, novel, unique and
important, that it makes all future efforts worthy and essential.

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