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Therapeutic Potential of Intravenous Immunoglobulin in Acute Brain Injury

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Acute ischemic and traumatic injury of the central nervous system (CNS) is known to induce a cascade of inflammatory events that lead to secondary tissue damage. In particular, the sterile inflammatory response in stroke has been intensively investigated in the last decade, and numerous experimental studies demonstrated the neuroprotective potential of a targeted modulation of the immune system. Among the investigated immunomodulatory agents, intravenous immunoglobulin (IVIg) stand out due to their beneficial therapeutic potential in experimental stroke as well as several other experimental models of acute brain injuries, which are characterized by a rapidly evolving sterile inflammatory response, e.g., trauma, subarachnoid hemorrhage. IVIg are therapeutic preparations of polyclonal immunoglobulin G, extracted from the plasma of thousands of donors. In clinical practice, IVIg are the treatment of choice for diverse autoimmune diseases and various mechanisms of action have been proposed. Only recently, several experimental studies implicated a therapeutic potential of IVIg even in models of acute CNS injury, and suggested that the immune system as well as neuronal cells can directly be targeted by IVIg. This review gives further insight into the role of secondary inflammation in acute brain injury with an emphasis on stroke and investigates the therapeutic potential of IVIg.
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July 2017 | Volume 8 | Article 8751
REVIEW
published: 31 July 2017
doi: 10.3389/fimmu.2017.00875
Frontiers in Immunology | www.frontiersin.org
Edited by:
Robert Weissert,
University of Regensburg,
Germany
Reviewed by:
Arthur Liesz,
Ludwig-Maximilians-Universität
München, Germany
Anna Fogdell-Hahn,
Karolinska Institutet, Sweden
Andreas Meisel,
Charité Universitätsmedizin Berlin,
Germany
*Correspondence:
Mathias Gelderblom
m.gelderblom@uke.de
Specialty section:
This article was submitted to
Multiple Sclerosis and
Neuroimmunology,
a section of the journal
Frontiers in Immunology
Received: 21March2017
Accepted: 10July2017
Published: 31July2017
Citation:
ThomV, ArumugamTV, MagnusT
and GelderblomM (2017)
Therapeutic Potential of Intravenous
Immunoglobulin in Acute Brain Injury.
Front. Immunol. 8:875.
doi: 10.3389/mmu.2017.00875
Therapeutic Potential of Intravenous
Immunoglobulin in Acute Brain Injury
Vivien Thom1, Thiruma V. Arumugam2, Tim Magnus1 and Mathias Gelderblom1*
1 Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 2 Department of Physiology,
Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Acute ischemic and traumatic injury of the central nervous system (CNS) is known to
induce a cascade of inflammatory events that lead to secondary tissue damage. In
particular, the sterile inflammatory response in stroke has been intensively investigated in
the last decade, and numerous experimental studies demonstrated the neuroprotective
potential of a targeted modulation of the immune system. Among the investigated immu-
nomodulatory agents, intravenous immunoglobulin (IVIg) stand out due to their beneficial
therapeutic potential in experimental stroke as well as several other experimental models
of acute brain injuries, which are characterized by a rapidly evolving sterile inflammatory
response, e.g., trauma, subarachnoid hemorrhage. IVIg are therapeutic preparations
of polyclonal immunoglobulin G, extracted from the plasma of thousands of donors. In
clinical practice, IVIg are the treatment of choice for diverse autoimmune diseases and
various mechanisms of action have been proposed. Only recently, several experimental
studies implicated a therapeutic potential of IVIg even in models of acute CNS injury, and
suggested that the immune system as well as neuronal cells can directly be targeted
by IVIg. This review gives further insight into the role of secondary inflammation in acute
brain injury with an emphasis on stroke and investigates the therapeutic potential of IVIg.
Keywords: acute brain injury, ischemic stroke, Fcγ receptors, sterile inammation, treatment, intravenous
immunoglobulin
STERILE INFLAMMATION OF THE CENTRAL NERVOUS
SYSTEM (CNS)
Acute tissue damage is known to trigger a highly conserved cascade of inammatory events. is
inammation is vital for the immediate response of the host to invasive pathogens in the settings
of acute infection and it is characterized by a rapid recruitment of neutrophils to the side of injury.
Similar to the inammation in response to microorganisms, trauma, ischemia, or chemically induced
tissue damage elicit a rapid inammatory reaction. Due to the absence of microorganisms, this inam-
matory response is termed “sterile inammation” (1). Sterile inammation shows several similarities
with innate immune responses toward microorganisms. Both microbially induced inammation
and sterile inammation are characterized by the initial generation of danger-associated patterns
(DAMPs), production of inammatory cytokines as well as chemokines, and subsequent recruit-
ment of leukocytes. In the CNS, sterile inammation is mainly associated with an exacerbation
of the tissue damage, induced by the initial event. In the case of cerebral ischemia, inammation
of the peri-infarct area contributes to a subsequent growth of the infarct core in the rst days and is
thereby contributing to a secondary worsening of the neurological outcome (2). However, at later
stages inammation might also be important for the resolution of the tissue damage and long-term
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recovery, even though these processes are currently only poorly
understood (3). In addition to inammation associated with acute
injuries, there is also convincing evidence for the importance of
chronic inammatory processes in degenerative diseases of the
brain, including Parkinsons and Alzheimers disease (4).
Development and Consequences
of Inammation in Stroke
Pathophysiology of Cerebral Ischemia
Ischemic stroke is a devastating disease and represents the most
common cause of long-term disability in adults as well as the third
leading cause of death in the western world. Due to the improv-
ing management of risk factors, the incidence of stroke in the
western world has decreased over the past decades. Nevertheless,
the prevalence has risen based on a reduced mortality (5). is
shi will probably become even more prominent in the future due
to improved treatment, but particularly on the basis of an increase
in life expectancy and a net aging population. Considering the
annual direct and indirect costs emerging for the treatment of
stroke patients an enormous economic burden is emerging.
Typically, an occlusion of a major artery, leading to disruption of
blood supply, causes an ischemic stroke and the only treatment
option is the early restoration of blood ow. Available treatment
strategies include drug-induced thrombolysis as well as endovas-
cular treatment with thrombectomy, but the major limiting factor
is the onset-to-treatment time.
Focal disruption of cerebral circulation (ischemia) as well as
the subsequent reperfusion contributes to brain injury. Initially,
the restriction of blood ow leads to a rapid decrease of oxygen
and glucose. Since brain tissue and particularly neurons are almost
exclusively dependent on these substrates, they cease to function
within minutes. Subsequently, activation of numerous signaling
cascades, oxidative stress, mitochondrial dysfunction, and peri-
infarct depolarization are initiated among other cellular events
and cause neuronal necrosis as wells as apoptosis (6). Cells in
the ischemic core are irreversibly damaged and quickly undergo
necrosis. e surrounding tissue, the so-called penumbra, is still
viable, but dysfunctional and extremely vulnerable. Aer the
initial restriction of blood supply, reperfusion and reoxygena-
tion lead to an aggravation of tissue damage particularly in the
penumbra area, through the induction of a severe inammatory,
albeit sterile response (7).
Postischemic Inammation
Apart from early excitotoxic mechanisms promoting neuronal
and glial cell death, the initial lesion enlarges within few hours
and days aer the ischemic event. is results in deterioration
of the neurological decit and poor functional outcome. A large
number of reports support the hypothesis that inammation is
rather a cause than merely a consequence of brain injury. Infarct
growth resulting from activation of the immune system by
ischemia and subsequent reperfusion is recognized as a major
element in all stages of the pathophysiology of ischemic stroke
(as illustrated in Figure1), including long-lasting regenerative
processes (3). A reduction of infarct size as well as brain edema
and improvement of neurological impairment could by achieved
in the middle cerebral artery occlusion (MCAO) animal model
by implementing various immunological alterations, such as
using immuno-decient mice, blocking antibodies against
pro-inammatory cytokines, and adhesion-molecules as well as
anti-inammatory treatment (813).
In response to the initial brain damage dying cells in the infarct
core region release, DAMPs such as adenosin triphosphate (ATP)
(14, 15) heat shock proteins (16), and high mobility group box 1
protein (HMGB1) (17), which activate pro-inammatory mem-
brane receptors, such as toll-like receptors (TLRs) and the recep-
tor for advanced glycation end products (RAGE) in the penumbra
region. Microglia are among the rst immune cells to be activated
by DAMPs aer stroke (18). e rapid proliferation of resident
microglia as well as subsequent inltration of macrophages can
be observed within the rst hours following ischemia (19). Both
cell types can produce inammatory cytokines, such as tumor
necrosis factor α (TNFα) and Interleukin (IL)-1β (8, 20) upon
activation of TLRs, RAGE (21), and non-obese diabetic (NOD)-
like receptor family pyrin domain containing protein (NLRP) 1
and NLPR3. It is well established that activation of TLR2 (22),
TLR 4 (21), TLR 8 (23), and NLRP inammasomes (24, 25) have
been implicated in the context of postischemic inammation. In
addition, it was also shown that ATP as a DAMP activates the
purinergic receptor such as P2X7 and contributes to postisch-
emic infarct development (26, 27).
In addition to the hypoxia and ROS-induced breakdown of
the blood–brain barrier (BBB), upregulation of endothelial adhe-
sion molecules and pro-inammatory cytokines, such as IL-1β
and TNFα, promote further migration of leukocytes to the site of
inammation through the induction of chemoattractant signals
(28). Lymphocytes only constitute a small fraction of inltrating
cells, but still play a prominent role in the evolvement of pos-
tischemic inammation, although the temporal sequence does
not correspond to established concepts of adaptive immunity.
Mice decient in lymphocytes have smaller infarcts (29) and
specic depletion of the dierent Tcell subpopulations T helper
cells, cytotoxic T cells, and γδ T cells also revealed protective
eects (12, 13). Whereas CD8 cells are important for perforin-
mediated cytotoxicity (30), interferon γ (IFNγ) secreted by CD4
cells enhances the TNFα production of inltrating macrophages
(8). γδ T cells, in turn, produce large amounts of IL-17 in an
IL-23-dependent manner (13), which synergistically with TNFα
promotes neutrophil recruitment via the chemokine C-X-C motif
ligand 1 (CXCL-1) (8). Conversely, administration of anti-IL-17
antibodies diminishes infarct size and improves neurological out-
come. Just recently, the role of the inammatory cytokine IL-21,
which is mainly produced by CD4 cells, was also highlighted in
the evolvement of postischemic inammation (31). However,
the role of regulatory Tcells (Tregs) is more controversial. It was
shown that the depletion of Tregs via the administration of anti-
CD25 increased lesion size and neurological decit (32), which
led to the hypothesis that Tregs are protective in stroke and that
their benecial function depends on IL-10 (33). Contrary to these
ndings, Treg depletion through diphteria toxin injection in the
DEREG mouse, a model to exclusively deplete Tregs, did not
show an eect on lesion size (34). Furthermore, cells of the innate
immune system are also involved in the processes of postischemic
FIGURE 1 | Depiction of the evolvement and amplification of postischemic inflammation. Hypoxia and glucose deprivation cause severe cell damage and dying cells
release DAMPS and ROS, which activate resident immune cells. Subsequent production of inflammatory cytokines contributes to the breakdown of the blood–brain-
barrier (BBB) and promotes the infiltration of cells of the adaptive as well as innate immunity, which cause a severe inflammatory response and deteriorate the initial
brain damage.
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inammation. e presence of DCs in the ischemic lesion, for
instance, is a well-documented feature aer stroke, although the
functional relevance remains unknown so far (35). Neutrophils
account for a substantial number of inltrating cells (19) and
blockade of the IL-17 axis diminishes neutrophil invasion and pro-
tects from ischemic stroke (8). Generally, preventing neutrophil
migration to the brain has a benecial eect (36) and neutrophils
contribute to further brain damage by producing ROS, proteases,
and inammatory cytokines. Still, they also might have anti-
inammatory and neuroprotective functions and a more detailed
understanding regarding their role in postischemic inammation
is needed (37). In contrast to the detrimental activation of the
immune system in the CNS, a systemic immunosuppression
caused by overactivation of the sympathetic nervous system
is a common phenomenon following stroke (38). e clinical
relevance is underlined by an increased frequency of pulmonary
as well as urinary tract infections and can be partially attributed
to a long-lasting lymphopenia and impaired cytokine production
(39). Furthermore, a loss of innate-like B cells in the spleen,
which can rapidly produce immunoglobulin G (IgG) and IgM in
a Tcell-independent manner and are important in the rst-line
of antibacterial defense, can be observed (40). Consistent with the
loss of Bcells murine and human studies have found that ischemic
stroke can lead to decreased levels of IgG (41) and IgM (40).
Apart from the deleterious eects, the immunological pro-
cesses are also a prerequisite for the structural and functional
reorganization of the injured brain tissue (3). e inammatory
processes aer stroke are self-limiting within the rst week aer
the initial events. Microglia as well as inltrating macrophages
are important for the phagocytosis of dead cells and debris
(18, 42). ey are a source of tropic factors, growth factors (43),
and IL-10 (44), thereby facilitating tissue repair. Furthermore,
there is evidence that production of growth factors, such as
insulin-like growth factor 1 (45) and vascular endothelial
growth factor (VEGF) (46), are conducive to neuronal repair.
Controversially, some molecules comprise destructive as well
as protective capacity. Matrix metallopeptidase 9 (MMP-9), for
example, not only exacerbates brain damage in the early phase
aer stroke (47) but also contributes to neurovascular remodeling
and promotes poststroke recovery by converting pro-VEGF into
an active form (48). Taken together, activation of the immune
system contributes to poststroke inammation and augments
secondary brain damage aer stroke. Furthermore, a systemic
immunosuppression and an increased susceptibility to infections
are observed aer stroke. However, it is also important to note
that postischemic inammation may also be involved in regen-
erative processes. erefore, it is important to dissect specic
detrimental and protective mechanisms when developing new
immunomodulatory treatment strategies.
The Postischemic Inammatory Response in Human
Stroke and Translational Approaches
Most of our current pathophysiological knowledge of the
postischemic inammatory mechanisms derives from murine
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experimental models employing the temporary MCAO mouse
model. Despite the diculty of obtaining postischemic human
brain tissue, there is growing evidence of a similar critical inam-
matory reaction following stroke in humans, which is based on
histopathological postmortem studies and radiological nd-
ings. Repetitive magnetic resonance imaging (MRI) showed an
enlargement of the ischemic lesion over time by 20% in selected
patients (49) as well as the existence of a penumbra area (50).
Migration patterns of inltrating leukocytes were observed
by single photon emission computed tomography and MRI.
Neutrophils (51) as well as monocular phagocytes (52) inltrated
the ischemic hemisphere and also microglia were shown to be
activated in the human brain following ischemic stroke (53).
Brain autopsies validated these ndings and showed an inltra-
tion of neutrophils in the ischemic hemisphere within the rst
48h (54). Furthermore, inltrating macrophages (52, 55), DCs,
and Tcells (56) could be found 3days aer stroke onset. Apart
from the presence of immune cells, there is also evidence for
poststroke inammation. e pro-inammatory transcription
factor nuclear factor kappa-light-chain-enhancer of activated
Bcells (NFκb) and chemokines such as CXCL2 were upregulated
(57). Furthermore, activated microglia could be detected in the
penumbra area (58). Supporting the importance of IL-17, an enor-
mous increase of IL-17 positive cells was found in the ischemic
hemisphere (59), mostly in co-localization with inltrated Tcells
(8). In addition, IL-17 messenger ribonucleic acid (mRNA) was
found to be elevated in leukocytes from stroke patients (60).
In summary, there is substantial preclinical and clinical
evidence for a pivotal role of postischemic inammation in the
pathophysiology of ischemic stroke and subsequent induction of
further damage to the brain. Considering the limited time win-
dow of the available therapies, solely aiming at the restoration of
blood supply, there is an urgent need of new treatment strategies.
ese should not only be applicable in a less restricted period of
time but also target the inammatory and regenerative processes
aer stroke. Despite the promising results in the mouse model,
clinical trials testing neuroprotective and anti-inammatory
agents have largely failed so far (3, 61). e underlying cause of
the translational roadblock can be attributed to the experimental
model. First of all, dierent genetic backgrounds and signicant
dierence in the composition and the function of the immune
system exist between human and mouse (62). Furthermore,
there are important varieties in brain morphology, anatomy of
cerebral vasculature, and metabolism (6, 63, 64). Other relevant
factors inuencing the translation of preclinical studies concern
the experimental model regarding the age of the animals and
comorbidities, the stroke model in terms of distal versus proximal
occlusion as well as transient versus permanent ischemia, out-
come measurements, study quality, and selection of patients (65).
A recent example partly elucidating these issues is the
investigation of the ability of natalizumab to reduce the detri-
mental eects of postischemic inammation. Natalizumab is a
monoclonal antibody against CD49d, an α4-integrin, preventing
the migration of leukocytes into the brain in a very late antigen-
4-dependent manner and is approved for the treatment of multi-
ple sclerosis (MS). Anti-CD49d treatment was tested in dierent
animals and distinct models of MCAO with varying periods
of ischemia regarding the transient model. One group found a
reduction of infarct size in the focal permanent model (30), in
general resulting in small cortical infarcts, whereas another group
could not reproduce these results (66). Comparable results were
published for the transient model, where lesion size increases
with the duration of ischemia. Short as well as extended periods
of occlusion resulted in protection in some studies (30, 67, 68) but
not exclusively (30, 66). In response to those deviating results a
preclinical randomized controlled multicentre trial was initiated,
which found that anti-CD49d treatment signicantly reduced
lesion size in the permanent model, but only when data from all
centers were analyzed together, whereas there were no dierences
in the transient model (69). Nevertheless, a clinical study testing
a single intravenous injection of natalizumab was conducted
from December 2013 to April 2015, showing that natalizumab
did not reduce infarct volume, but improved clinical outcome as
measured by the modied Rankin Scale (mRS) (70).
Similar controversial is the published data on the immu-
nomodulatory drug ngolimod, which acts as a functional analog
of sphingosin-1-phosphate and, therefore, inhibits lymphocyte
migration from the lymph nodes to the CNS. Conicting data
are published, mostly describing an impact of ngolimod (13,
7174) but also challenging the eectiveness (75). Lately, how-
ever, two clinical pilot trials succeeded in showing a benecial
eect. Initially, they found in an open-label, evaluator-blinded
fashion that ngolimod treatment is safe, attenuated the primary
end point infarct growth and improved neurological outcome
measured with the National Institutes of Health Stroke Scale and
mRS in a cohort of 22 matched patients, who were not eligible
for thrombolysis, given at a mean time of 22h aer symptom
onset (76). e follow-up randomized, open-label, evaluator-
blind multicenter trial investigated the eect of early ngolimod
treatment in addition to thrombolysis (77). 47 patients, with 22
receiving ngolimod and rt-PA, were enrolled in the study and
signicant benecial eects for the primary endpoints changes in
lesion volume and extent of clinical improvement from baseline
to day 1 as well as for the secondary endpoints extent of lesion vol-
ume growth and clinical improvement from day 1 to day 7 were
observed. However, an unusual high rate of reperfusion of more
than 60% was described in the second study and it needs to be
considered that these studies have a proof of principle character
and further multicenter, randomized, double-blind, and placebo-
controlled trials will be necessary to conrm these results.
FcγRs AND INTRAVENOUS
IMMUNOGLOBULIN (IVIg)
Among many other immunomodulatory drugs, IVIg have been
shown to be benecial in experimental stroke in recent studies.
IVIg contain polyclonal IgG and many dierent mechanisms of
action have been proposed, of which the Fc fragment-dependent
pathways seem to be of major signicance. IVIg are established
as a rst-line therapy in dierent kinds of autoimmune disease.
Although the mechanisms in stroke are not well understood so
far, they possess promising therapeutic potential through neuro-
protective and immunomodulatory pathways.
FIGURE 2 | Illustration of the different FcγRs in human and mice. All activating FcγRs in mice as well as human FcγRI and FcγRIIIA express a common γ and a
ligand binding a chain. After phosphorylation of the immunoreceptor tyrosin-based activating motif (ITAM), a signal cascade involving spleen tyrosin kinases (SYK),
Bruton’s tyrosine kinase (BTK), and phospholipase Cγ (PLCγ) becomes initiated, leading to intracellular calcium influx and cell activation. Upon engagement of the
inhibitory receptor, in turn, phosphorylation of the immunoreceptor tyrosin-based inhibitory motif (ITIM) leads to suppression of BTK and PLCγ. Since activating and
inhibiting receptors are co-expressed and affect the same signaling pathways, the ratio of the different FcγRs sets a threshold for cell activation.
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Fcγ Receptors
Fc receptors are found on the surface of a variety of cells and
specically bind to the Fc region of immunoglobulins (Igs).
Four dierent subclasses of Fc receptors for IgG (FcγRs) have
been identied in mice, including the activating receptors FcγRI,
FcγRIII, and FcγRIV as well as the inhibitory receptor FcγRIIB
(78). All FcγRs belong to the Ig superfamily. e activating recep-
tors share a common γ-chain that comprises an immunoreceptor
tyrosin-based activating motif (ITAM) (79) and express an indi-
vidual ligand-binding α-chain, whereas the inhibitory FcγRIIB is
a single chain receptor containing an immunoreceptor tyrosin-
based inhibitory motif (as illustrated in Figure2).
Besides microglial, endothelial, and mesangial cells as well as
osteoclasts (78), FcγRs are particularly expressed by leukocytes.
e majority of immune cells co-express activating and inhibitory
FcγRs and the ratio of these receptors expressed by individual
cells set a threshold for cell activation. Apart from distinct FcγRs,
four dierent subclasses of IgG, in mice IgG1, IgG2a, IgG2b, and
IgG3, with varying anities toward the FcγRs are known. FcγRI
shows high anity and specicity for the dierent IgG isotypes,
in contrast to FcγRIIB and FcγRIII that have lower binding
capacities but recognize a broader spectrum (80). FcγRIV, in turn,
seems to be the most important receptor for eector function
of IgG2a and IgG2b (81). Moreover, it needs to be considered
that the low-anity receptors FcγRIIB, FcγRIII, and FcγRIV can
only interact with multimeric IgG, which is present in immune
complexes (ICs). is prevents unspecic binding, whereas FcγRI
is saturated with monomeric serum IgG, but also requires ICs for
activation (82). ese kinetics suggest that the low-anity recep-
tors can regulate immunity more eective since the high-anity
binding to monomeric IgG of FcγRI hampers interaction with ICs
(78). Apart from FcγRs IgG also binds to the neonatal Fc recep-
tor (FcRn), which is expressed by vascular endothelium. FcRn
prevents catabolism of IgG and is important for IgG half-life (83).
Triggered by the crosslinking of ICs with the α-chain of the
activating FcγRs, the ITAM becomes phosphorylated, leading
to the activation of members of the family of spleen tyrosin
kinases (SYK) (78, 84). Subsequently, SYK-dependent phospho-
inositides increase the activity of phospholipase Cγ (PLCγ) and
Bruton’s tyrosine kinase (BTK) (78, 84) leading to an increase
of intracellular calcium levels. Upon activation of FcγRIIB, in
turn, the SH2-containing inositol polyphosphate 5-phosphatase
(SHIP) hydrolyzes phosphoinositides (85). is events lead to
a reduction of the activity of kinases, such as PLCγ and BTK,
and, therefore, diminish the increase of intracellular calcium
(78, 84). Hereby, activating as wells as inhibitory receptors aect
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the same signaling pathway and FcγRIIB exhibits important nega-
tive regulatory function in this manner. e loss or impairment
of this inhibitory receptor can lead to autoimmunity as well as a
prolonged immune response (86). e balance of activating and
inhibitory receptors can be altered by the surrounding cytokine
environment. e diverse role of Fc receptors in autoimmunity is
elucidated by the fact that Fc receptor common γ-chain (FcRγ)
knockout mice are resistant to the induction of autoimmune
disease or show a milder course of disease, whereas FcγRIIB
knockout mice oen show worse outcome compared to wild-type
mice (8789). Mechanistically, it could be shown in nephrotoxic
nephritis that DCs from FcγRIIB knockout animals show a
more pronounced expression prole of cytokines associated
with Tcell activation that is absent in FcRγ-decient mice (90).
Furthermore, autoimmune-prone mouse-strains show a reduced
expression of FcγRIIB, which is due to a promoter polymorphism
in the Fcgr2 region (91). However, it needs to be considered that
the FcRγ-chain is not only expressed by activating FcγRs but is
also associated with a variety of other receptors, such as the Tcell
receptor (TCR)-CD3 (cluster of dierentiation) complex, FcαR,
FcεR, Nkp46, and IL3 (79, 92), when using the FcRγ knockout
animals.
Human Fc receptors have a similar nomenclature and sign-
aling pathways, but possess dierent expression patterns and
binding anities. So far, six dierent FcγRs have been identied.
e high-anity receptor FcγRI and the low-anity recep-
tors FcγRIIA, FcγRIIC, and FcγRIIIA are activating receptors,
whereas FcγRIIB is inhibitory and the function of FcγRIIIB is yet
unknown (93). e dierent IgG isotypes in humans are named
IgG1, IgG2, IgG3, and IgG4, which bind to the dierent FcγRs in a
concentration-dependent manner (94). Functionally, in humans
IgG1 and IgG3 are the most pro-inammatory IgG subclasses,
whereas in mice IgG2a and IgG2b show a high inammatory
activity (78).
Taken together, humans and mice possess a similar repertoire
of dierent FcγRs regarding their function and share common
pathways. However, an important characteristic is the high rate
of FcγR polymorphisms in humans (95), which aect binding
anities for IgG (94) and are associated with dierent kinds of
autoimmune disease as well as immunological function (96).
Immunomodulatory Effects of IVIg in
Autoimmune Disease
Intravenous immunoglobulins are therapeutic preparations of
polyclonal IgG, which are extracted from the plasma of thousands
of donors. e dierent IgG subclasses are similarly distributed
in IVIg preparations like in the blood of healthy individuals.
Dierent mechanisms of action for IVIg in diseases models have
been proposed. e Fc-mediated eects are most likely of major
signicance (97), which is supported by the fact that infusion of
IgG preparations only containing the Fc fragment can protect
mice as wells as humans from disease (98, 99). First of all IVIg
can compete for activating FcγRs and, therefore, limit the access
of activating ICs (100). In a similar manner, IVIg can inhibit
complement deposition (101). e inhibitory receptor FcγRIIB
seems to be essential for the protective eects, since protection by
IVIg is lost in FcγRIIB-decient mice and FcγRIIB is upregulated
following IVIg treatment (88, 99). Mechanistically, FcγRIIB
signaling can suppress Bcell-mediated Tcell-dependent immune
responses (102). Specic intracellular adhesion molecule grab-
bing none-integrin receptor 1(SIGN-R1) and its human homolog
dendritic cell-specic intracellular adhesion molecule-3 grabbing
non-integrin, which is among others expressed by macrophages
(103), have also been proposed to be important in IVIg function
mediated by FcγRIIB. ese two receptors can directly recognize
specic sialic acid rich isoforms of IgG, which leads to an up to
tenfold increase of eectiveness of IVIg (104) and induces a non-
inammatory phenotype in a specialized subset of macrophages.
Conversely, macrophage colony-stimulating factor 1 (M-CSF-1)-
decient mice also loose IVIg protection, which might be due
to a lack of M-CSF-1-dependent regulatory SIGN-R1 expressing
macrophages (105). Furthermore, inhibition of BTK, a kinase
downstream of FcγRs, whose activity is reduced upon FcγRIIB
activation, leads to reduced mature IL-1β in the context of inam-
mation (25), as well as preventing IL-1β, IL-17, IFNγ, and TNFα
production upon FcγR stimulation (106).
Another proposed functional pathway is the ability of IVIg
to neutralize anti-ideotypic antibodies in a F(ab)2 fragment-
dependent manner and, therefore, protect from disease (107).
Other F(ab)2 fragment-dependent mechanisms include blockade
of specic receptors, such as the Fas receptor via anti-Fas anti-
bodies (108), the binding of cytokines such as IL-5 as wells as
granulocyte macrophage colony-stimulating factor (109) and
the inhibition of TCR-mediated T cell proliferation (110). In
addition, IVIg do not only hemper Tcell proliferation but can
also inuence the dierentiation of T helper cells into 17cells
via interference with the retinoic acid-related orphan receptor C
(111) and can induce a shi toward a 2 phenotype in childhood
ITP and women with recurrent spontaneous abortion (112, 113).
Furthermore, there is evidence that IVIgs increase the expression
of IL-10 as wells as TGF-β in Tregulatory cells (114) via specic
epitopes in the Fc region of IgG (115). Interestingly, IVIg were
also able to bind to peripheral blood Tcells, which do not express
FcγRs, through yet unknown receptors (116) and can reduce the
production of inammatory cytokines, such as IL-2, IL-3, IL-4,
IL-5, IFNγ, and TNF in invitro setting (117).
Taken together IVIg can act through a variety of dierent
pathways. Apart from Fc and F(ab)2 fragment-dependent eects,
IVIgs can either indirectly or even directly address cells that do
not express FcγRs. e individual roles and mechanisms need to
be explored individually in the dierent autoimmune diseases,
also considering that there are probably joint eects.
FcγRs and IVIg in Neurological Disease
Expression of FcγRs in the CNS
ere is growing evidence for a pivotal role of Fc receptors in
the pathophysiology of disorders of the CNS, but the existence
of the distinct FcγRs within the cell types of the CNS are still not
fully explored. Especially the functionality and expression prole
of FcγRs in neurons remains controversial. Nevertheless, mRNA
of all FcγRs has been found in primary mouse superior cervical
ganglion cultures and an intracellular calcium increase upon
stimulation with IgG could be detected (118). Considering that
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FcγR signaling in immune cells causes an intracellular calcium
increase via SYK and subsequent activation of BTK and PLCγ,
it is conceivable that the same pathway is enabled in neurons.
FcγRI has also been found on dorsal root ganglions, similarly
causing intracellular calcium increase (119), whereas FcγRIII
was expressed by primary neuronal cell cultures (120). FcγRIV
could be detected in the hippocampal area and temporal cortex
in mice brain (121). Likewise, the inhibitory receptor FcγRIIB
is expressed by neurons (122) and has an important function in
the cerebellum during development (123). Little is known about
the regulation of these receptors in neurons, but elevated mRNA
levels of all FcγRs could be found in response to an increase of
intracerebral IgG in a model of experimental hypercholester-
olemia (121).
Microglia express all FcγRs (124) and their expression levels
are upregulated in response to inammation and cytokines,
such as IFNγ, TNF, and IL-1β (125128). Upon stimulation with
monoclonal antibodies against the FcRγ-chains I, IIA, III, but not
IIB human microglia can produce inammatory cytokines such
as macrophage inammatory protein 1α (129). Furthermore, it
could be shown that the expression of FcγRIV increases with age
and upon lipopolysaccharide stimulation (130). An upregulation
of all FcγRs in models of chronic neurodegeneration in response
to inammatory stimuli was also observed (131), whereas
FcγRI and FcγRIIb were downregulated on microglia of AD
patients aer immunotherapy (132, 133). Apart from microglia,
astrocytes and oligodendrocytes are also known to contribute
to postischemic inammation, but only limited data on the
expression of FcRs are available in these cell types. Astrocytes
have been reported to express FcγRI and FcγRIIB (134), whereas
oligodendrocyte precursor cells (OPCs) express FcRγ as well as
the alpha chain of FcγRI and FcγRIII (134). Stimulation with
anti-FcRγ as well as IgG induces dierentiation into myelinating
oligodendrocytes, suggesting that FcγRs are expressed on cells of
the oligodendrocytes lineage and are important for myelination.
Conversely, the FcRγ mice show hypomyelination (135).
In summary, there is much evidence that all FcγRs are
expressed in neurons, microglial as well as other glial cells of
the CNS. Particularly the inhibitory receptor FcγRIIB could be
found on all cell types. eir existence seems to be not exclusively
important in immunological processes but also in the context of
development of the CNS.
Immunomodulatory Effects of IVIg
in Neurological Disease
Intravenous immunoglobulins are established as a rst-line
therapy in a variety of neurological disease. ey are used in the
treatment of CIDP, Guillain–Barré syndrome (GBS), myasthenia
gravis, and inammatory myopathies as well as in autoimmune
encephalitis and neuromyelitis optica (136, 137). CIDP, for exam-
ple, is a heterogeneous autoimmune-mediated inammatory
demyelinating disease of peripheral nerves and several clinical
trials showed that IVIg are benecial (138). e pathophysiol-
ogy of disease remains unknown; but in a subset of patients, it
appears to be mediated by IgG-autoantibodies against myelin.
IgG isolated from this group of patients was able to induce disease
in rats (91), suggesting that IgG can play an important role in
the development of CIDP. Furthermore, the NODmouse strain,
which has a promoter polymorphism in the Fcgr2 region (139),
can develop spontaneous autoimmune peripheral polyneuropa-
thy under certain circumstances (140, 141). Conversely, FcγRIIB
expression is impaired in B cells of patients with CIDP but is
upregulated following IVIg treatment (142). Likewise, for GBS,
another disease of the peripheral nervous system (PNS), IVIg
represent an established therapeutic regime. In approximately
50% of patients with the GBS, autoantibodies against gangliosides
can be found (143). One of the proposed mechanisms of IVIg
action in GBS as wells as CIDP is the presence of anti-ideotypic
antibodies that are able to bind and neutralize pathogenic autoan-
tibodies (144). Another exemplary IgG-mediated neurological
disorder is myasthenia gravis, in which autoantibodies against the
acetylcholine receptor are produced in a T helper cell-dependent
manner. Mechanistically, IVIg protection in myasthenia gravis is
also most likely promoted by anti-ideotypic antibodies.
Apart from the ecacy to treat PNS aecting diseases, data
for IVIg on diseases of the CNS is more controversial. Although
benecial eects and potential therapeutic pathways have been
observed in the mouse model of MS (145) and AD, for example,
translation into the human system remains dicult so far.
A major limiting factor in the context of diseases of the CNS
is the BBB, which controls access of IVIg to the brain. In the
healthy brain, IgG is present in small amounts and is able to
cross the BBB in a controlled manner through yet unknown
mechanism. e clearance from the CNS is mediated by the
FcRn (146), which is expressed by brain endothelial cells (147,
148). In the context of inammation, when the BBB is disrupted,
IVIg are able to enter the brain in a less restricted manner.
Accordingly, following administration of IVIg in a model of
experimental stroke, increased intracerebral IgG was observed
in the ischemic brain (147, 148). IVIg is also able to cross the
intact BBB in a saturation-dependent process and were found
to co-localize with neurons as well as endothelial cells (149).
Interestingly, administration of IVIg reduced the amount of
endogenous IgG in this model, suggesting a competition for
brain access. A positive impact of IVIg on the integrity of the
BBB has also been reported, since IVIg treatment was able to
prevent BBB-breakdown in sepsis (150).
For MS, which is suggested to be primarily a Tcell-mediated
disease, there is experimental evidence from the experimental
autoimmune encephalitis (EAE) model that treatment with IVIg
is benecial. It could be shown that IVIg decreased the produc-
tion of inammatory cytokines such as IFNγ and TNF (144, 151)
on one side and led to an expansion of peripheral Tregulatory
cells and subsequent suppression of conventional T helper cells
in an Fc-fragment independent manner on the other side (152).
Apart from the impact on the cells of the adaptive immunity,
there is also evidence for a direct involvement of FcγRs. It could
be shown that FcRγ-decient mice develop milder EAE (89),
although this eect was attributed to γδ Tcells that use this chain
in other receptors than the FcγR. In addition, the FcRγ can be
detected on OPCs in remyelinating plaques in MS as well as on
microglia in inactive plaques (153). Despite the benecial action
in the experimental setting, the eect of treatment in humans is
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controversial. Some small studies were able to show protection,
whereas a large multicentre, randomized, double-blind, placebo-
controlled trial failed to reproduce the previous results (154).
IVIg IN ACUTE BRAIN INJURY
Current Knowledge of Fc Receptors
and IVIg in Stroke
Only little is known about the role of FcγRs in the context of
postischemic inammation, but various experimental studies
emphasize a promising therapeutic eect of IVIgs in the invivo
stroke model as well as in invitro settings by reducing infarct size
and improving neurological outcome. e direct mechanisms
remain unknown so far. First of all, it could be shown in the
MCAO model that the common γ-chain knockout, which lacks
all activating FcγRs, is protected from stroke (155). Compared
to WT mice, the common γ-chain-decient mice showed sig-
nicant reduction of infarct volume at 24, 72h, and 14days aer
stroke as well as an improved neurological outcome aer being
subjected to 60min of transient focal ischemia. Mechanistically,
it was assumed that FcγRs are important for the activation of
microglia and induction of the inducible nitric oxide synthase
(iNOS). Hence, microglia of the common γ-chain KO mice
expressed fewer ionized calcium-binding adapter molecule 1, a
protein that is upregulated in microglia upon activation, as well
as less iNOS in immunohistochemistry and on protein level.
In addition to the eects mediated by inhibition of the acti-
vating FcγRs, it was recently shown that IVIg treatment likewise
protects the brain from ischemia-induced reperfusion injury and
the subsequent inammatory response. Administration of IVIg,
3h post reperfusion signicantly reduced the amount of inltrat-
ing leukocytes 24h aer MCAO, which were identied as CD45
high cells in ow cytometry (156). In line with recent preclinical
studies showing a benecial eect of the α4-integrin-inhibitor
natalizumab in experimental stroke, the reduction of inltrating
leukocytes by IVIg could be mediated in an α4-integrin-inhibitor-
dependent manner as it has been shown in the EAE model
(157). Of note, this study concluded that IVIg treatment is even
detrimental in stroke, since they found more leukocytes occupy-
ing pial vessels, which is thought to be due to platelet-mediated
pro-adhesive eects. Still, it needs to be considered that they did
not examine the actual number of inltrating cells.
Furthermore, IVIg treatment of primary neuronal cultures
subjected to oxygen and glucose deprivation, an invitro model
of ischemic stroke, inhibited upregulation of TLR2, TLR4, and
TLR8 (158). ese ndings could also be reproduced in vivo
where IVIg administration aer transient MCAO signicantly
reduced ischemia-induced upregulation of TLR2, TLR4, and
TLR8. e authors also observed an IVIg-dependent suppres-
sion of HMGB1-mediated TLR activation, which is released by
dying cells as a danger signal in the context of ischemic stroke. In
addition, it was found that IVIg attenuated the ischemia-induced
increase of complement factor C3b, which is known to contrib-
ute to ischemic injury (159) and among others upregulates the
intracellular adhesion molecule 1 (ICAM-1) invivo and invitro.
In line with these ndings, IVIg also specically aect endothelial
cells and diminish the upregulation of VCAM-1 and ICAM-1 in
invitro settings (160).
Another immunomodulatory IVIg mechanism includes the
suppression of the NLPR1 and NLPR3 inammasome-mediated
neuronal cell death (24, 25). Treatment of primary neuronal
cultures with IVIg subjected to simulated ischemia as well as
mice subjected to MCAO, reduced levels of inammasome com-
ponents such as NLRP1, NLRP3, and apoptosis-associated speck-
like protein containing a caspase recruitment domain (ACS).
is, in turn, led to a reduction of caspase-1 and mature IL-1β as
well as IL-18. Moreover, it was shown that selective inhibition of
BTK with ibrutinib, whose activity is reduced aer engagement
of the inhibitory receptor FcγRIIB, diminishes ischemic injury
by decreasing inammasome NLPR3 activity and, therefore,
conversion of pro-IL-1β (25). Conversely, the inhibition of SYK,
a kinase upstream of BTK was also able to decrease lesion size in
the MCAO model (161). Interestingly, IVIg protection in other
autoimmune disease is lost in M-CSF-1-decient (op/op) mice.
Apart from an enormous reduction of microglia proliferation,
these M-CSF-1-decient mice show an enhanced sensitivity to
ischemia-induced neuronal injury and cell death (162). M-CSF-1
overexpression, in turn, leads to microglia proliferation, which
does not show a dierence in phenotype regarding the M1/M2
model, but shows altered immune responses (163). Importantly,
M-CSF-1 treatment of mice subjected to MCAO decreases infarct
size (162) and the presence of M-CSF-1-dependent macrophages
correlates with an increased expression of FcγRIIB (164).
Apart from ameliorating the inammatory response aer
stroke the protective capacity of IVIg includes the induction of
neuroprotective pathways. For instance, neuronal structure was
more intact and had less ischemia-associated alterations on a
histopathological level in IVIg-treated rats (165). IVIg treatment
of primary neuronal cultures subjected to simulated ischemia
for 12h signicantly reduced protein levels of factors involved
in neuronal cell death like the phospho-SAPK c-Jun NH2-
terminal kinase (p-JNK) and phospho-p65 NFκB and inhibited
the loss of the neuronal marker microtubulin associated protein
2 (MAP2) (147, 158). ese ndings could be conrmed by
immunoblots and immunohistochemistry, respectively, in vivo
in the transient MCAO model. Furthermore, IVIg could prevent
simulated ischemia-induced endothelial disintegration in a
brain endothelial cell line and increased the protective protein
B-cell lymphoma 2 produced by these endothelial cells as well as
by neurons (156). In line with these ndings it could be shown
that ischemia-induced decrease and reduced phosphorylation
of low-density lipoprotein receptor-related protein 1, which is
abundantly expressed by neurons, can be inhibited by IVIgs and,
subsequently, prevents activation of cell death signaling proteins
as NFκB and p-JNK (166).
Apart from the already described pathways, there are multiple
other conceivable mechanism how IVIg facilitate protection in
the context of ischemic stroke (Figure 3). ey could inhibit
complement deposition and induce a regulatory phenotype in
macrophages in an Fc-fragment manner, as well as targeting
the inhibitory receptor FcγRIIB, subsequently supressing Tcell-
mediated immune responses. Similary, the production of inam-
matory cytokines, such as IL-1β and TNFα, could be diminished
FIGURE 3 | Keyplayers in acute brain injury and their expression of FcγRs as well as their proposed role in intravenous immunoglobulin (IVIg)-mediated protective
effects.
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in FcγRs expressing cells. In addition, the F(ab)2 fragment could
block receptors such as Fas (167) or inhibit TCR-mediated Tcell
proliferation. Also indirect eect such as increased IL-10 and
TGF-β expression as well as a reduced production of inam-
matory cytokine by Tcells need to be considered. Ultimately, it
remains unsolved wheter IVIg primarily operate via the Fc or
F(ab)2 fragment, or if indirect mechanisms such as Tcell inhibi-
tion predominate.
IVIg in Other Models of Acute CNS- and
Ischemia-Reperfusion Injury
Besides experimental evidence for positive IVIg eects in pos-
tischemic inammation, there are other models of acute CNS
injury in which IVIg have been shown to be benecial. Similar to
inammatory processes following ischemic stroke, neuroinam-
mation exacerbates the tissue damage in acute spinal cord trauma
(168). Accordingly, several hallmarks of sterile inammation
have been observed following trauma: (i) microglia activation;
(ii) upregulation of proinammatory cytokines, including IL-1β,
TNFα, and IL-6 as well as ROS and MMP-9; and (iii) inltration of
neutrophils, monocytes, and lymphocytes. e importance of the
local inammation is underlined by studies showing that immu-
nosuppressive treatment approaches with steroids have favorable
eect on functional outcome. Nevertheless, the disadvantage of
unspecic immunosuppressive agents is demonstrated by studies
showing an increased risk of infection following steroid treatment
in models of traumatic spinal cord injury. Consequently, more
specic immunomodulatory treatment strategies are needed. e
feasibility of immunmodulatory treatments in acute spinal cord
injury was recently demonstrated by Gok etal. (169), describing
that the treatment with IgG had signicant benecial eects on
motor function in a rat model. Furthermore, electron microscopy
revealed a signicant decrease of intraneuronal vacuoles, as an
indicator for more preserved neuronal ultrastructure. Another
study on IgG in acute spinal cord injury also showed reduced scar
formation and tissue preservation on a histopathological level
(170). In addition, the authors detected a reduction in proinam-
matory cytokines, such as TNFα, IL-1β, and IL-6 as well as MMP9,
and showed that the IgG is able to enter the injured spinal cord
while it mainly co-localized to astrocytes. Furthermore, protective
IVIg eects were associated with reduced numbers of inltrating
neutrophils as wells as a diminished MPO activity. Overall, the
reduction of inammation showed improved functional recovery
assessed by neurobehavioral test as well as signicantly enhanced
conduction velocity in electrophysiological measurements.
Sterile inammation is also a well-known feature aer
traumatic brain injury (171). As a consequence of the initial
trauma a tremendous release of DAMPs can be observed, which
induced production of proinammatory cytokines and inltra-
tion of various immune cells. Incidentally, it was found that IgG
signicantly improved motor test scores compared to saline and
reduced MPO activity, as it was used as an additional vehicle
control in a study investigating the eect of ICAM-1 blockage in
traumatic brain injury (172). Furthermore, it could be shown that
IVIg treatment stabilized the BBB and reduced edema formation
(173). ese eects were accompanied by reduced amounts of
IL-6 upon IVIg administration as well as less inltrating mac-
rophages and increased neuronal density. Moreover, endothelial
protection by IVIg was detected in a model of subarachnoidal
hemorrhage (174).
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Intravenous immunoglobulin have also been investigated in
other models of ischemia-reperfusion injury and a protective
eect on the evolving inammatory cascades has been observed.
In mesenteric ischemia, a condition that can be associated with
hypovolaemic shock, sepsis, and cardiac arrest (175), pretreat-
ment with IVIg reduced complement-mediated tissue damage
(176). IVIg also signicantly reduced mucosal injury on a histo-
pathological level and diminished C3 deposition in the intestinal
mucosa. Interestingly, the number of inltrating leukocytes was
not altered by IVIg administration. Similarly, in a model of liver
ischemia, sinusoidal congestion and cytoplasmatic vacuolation
were diminished in IVIg-treated mice (177). ese eects were
associated with a reduced mortality in the IVIg-treated group.
Taken together, there are multiple pieces of evidence from
experimental studies that IVIg have signicant protective eects
on acute injuries of the CNS and other organs, in which sterile
inammation is part of the pathology.
Implications for the Clinical Use of IVIg
in Acute Brain Injury
Reecting the available preclinical data on IVIg in acute brain
injury, it seems promising to also use IVIg in a clinical setting.
However, possible rheologic disadvantages need to be considered.
It does not appear intuitively that an agent, which could possibly
deteriorate perfusion due to the high viscosity, is suitable to treat
diseases with reduced blood ow and impairment of microcircu-
lation. Indeed, IVIg-related thrombosis has been described in the
literature sporadically (178). Nevertheless, the positive impact of
IVIg seems to predominate these negative eects. Overall, these
drawbacks might be overcome in future studies, if specic thera-
peutic eects can be attributed to single IVIg fractions, thereby
allowing to reduce the necessary dosage.
Considering that peripheral immunosuppression and an
increased risk of urinary tract as well as upper airway infec-
tions is a common epiphenomenon aer stroke IVIg treatment
shows another promising potential. Apart from reducing the
inammatory reactions aer stroke, IVIg administration could
also compensate for the transient decrease of IgG aer stroke
(41) and possibly reduce the risk of infections that deteriorates
the outcome of stroke patients. In line with this assumption,
it could be shown that IVIg can even enhance microbial-specic
immune responses in preterm infants (179) and do not increase
mortality in sepsis (180). One clinical trial exploring the eect
of IVIg in human stroke was already initiated (clinicaltrials.
gov NCT01628055), but had to be stopped due to diculties in
patient recruitment.
CONCLUSION
Taken together, there is growing evidence that the rapid activation
of the immune system in response to acute sterile tissue damage
can be detrimental for the aected organ. Particularly, posti-
schemic inammation following stroke has been investigated
extensively and multiple preclinical studies emphasize benecial
IVIg eects in models of acute brain injury, i.e., ischemic stroke,
spinalcord, and traumatic brain injury. e already established
use of IVIg in various neurological diseases is a major advantage.
Furthermore, available data suggest that IVIg are specically
modulating harmful inammatory processes, without relevant
immunosuppressive side eects.
In general, IVIg exert protective eects in autoimmune disease
via multiple mechanisms. Similarly, in acute brain injury, it is most
likely that IVIg protection is mediated by the interaction with
dierent targets concomitantly, which merge to a mutual eect.
In this context, immunomodulatory pathways are among the
most promising candidates. IVIg can target microglia as resident
immune cells of the CNS as well as immune cells from the systemic
immune compartment and endothelial cells. Furthermore, it is
important to mention that IVIg can stabilize the BBB and even
facilitate direct neuroprotection. Eventually, it currently remains
concealed if IVIg eects are Fc or F(ab)2 fragment dependent and
if IVIg can modulate cells indirectly, which are not expressing
Fc receptors in this context. Although the currently existing data
are promising, further research is needed to gain more insight
into protective IVIg-dependent mechanisms and to explore the
therapeutic potential of IVIg in acute brain injury.
AUTHOR CONTRIBUTIONS
VT, TM, TA, and MG contributed to the concept design, writing,
and nal approval of the manuscript; VT drew the gures.
FUNDING
is study was funded by Hermann und Lilly Schilling-Stiung
für Medizinische Forschung.
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... 28 The primary injury is caused by direct mechanical damage and the injured neuronal tissue releases intracellular damageassociated molecular patterns (DAMPs) as HMGB1 and heat shock protein, which activate macrophage/microglia via pro-inflammatory membrane receptors such as Tolllike receptors (TLRs) and the receptor for advanced glycation end products (RAGE). [29][30][31] The activated cells mediate neuroinflammation by secreting nitrite and cytokines such as TNF-α, IL-1β, and IL-6, thereby inducing necrosis of other neurons and resulting in further DAMP release. Thus, the secondary injury is a chemical damage exacerbated by a positive feedback circuit between DAMPs and pro-inflammatory cytokines. ...
... [16][17][18] Rather, high-dose IgG has been shown neuroprotective efficacy against brain edema, ischemia, and subarachnoid hemorrhage in acute brain injury. 24,31 It is also useful for prevention of septic infection, 36 while anti-IL-6 antibody and TNF-α blocker sometimes aggravate infectious diseases because of oversuppression of the immune system. 19,20 Since highdose IgG is efficacious against other brain damages occurring together with olfactory dysfunction, it can be a preferable agent to use in severe head injury cases. ...
Full-text available
Article
Objective: Head trauma can be a cause of refractory olfactory dysfunction due to olfactory nervous system injury. Anti-inflammatory treatment using steroids or anti-cytokine agents is known to contribute to functional recovery of the central and peripheral nervous systems in injury models, while there is a concern that they can induce adverse reactions. The present study examines if high-dose immunoglobulin G (IgG) can facilitate olfactory functional recovery following injury. Methods: Olfactory nerve transection (NTx) was performed in OMP-tau-lacZ mice to establish injury models. High-dose IgG was intraperitoneally injected immediately after the NTx and histological assessment of recovery within the olfactory bulb was performed at 5, 14, 42, and 100 days after the drug injection. X-gal staining labeled degenerating and regenerating olfactory nerve fibers and immunohistochemical staining detected the presence of reactive astrocytes and macrophages/microglia. Olfactory function was assessed using an olfactory avoidance behavioral test. Results: High-dose IgG-injected mice showed significantly smaller areas of injury-associated tissue, fewer astrocytes and macrophages/microglia, and an increase in regenerating nerve fibers. An olfactory avoidance behavioral test showed improved functional recovery in the IgG-injected mice. Interpretation: These findings suggest that high-dose IgG could provide a new therapeutic strategy for the treatment of olfactory dysfunction following head injuries.
... The process of neural injury consists of two phases, the primary injury and the secondary injury [28]. The primary injury is caused by direct mechanical damage and the injured neuronal tissue releases intracellular damage-associated molecular patterns (DAMPs) as HMGB1 and heat shock protein, which activate macrophage/microglia via proin ammatory membrane receptors such as toll-like receptors (TLRs) and the receptor for advanced glycation end products (RAGE) [29][30][31]. The activated cells mediate neuroin ammation by secreting nitrite and cytokines such as TNF-α, IL-1β and IL-6, thereby inducing necrosis of other neurons and resulting in further DAMP release. ...
... There have been no or few clinical and experimental reports showing serious adverse effects due to in vivo administration of high-dose IgG [35], compared with steroids, which are not recommended for patients with head injury because of no signi cant effects on morbidity and mortality and concerns about their adverse effects [16][17][18]. Rather, high-dose IgG has been shown neuroprotective e cacy against brain edema, ischemia and subarachnoid hemorrhage in acute brain injury [24,31]. It is also useful for prevention of septic infection [36], while anti-IL-6 antibody and TNF-α blocker sometimes aggravate infectious diseases because of oversuppression of the immune system [19,20]. ...
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Background Head trauma can be a cause of refractory olfactory dysfunction due to olfactory nervous system injury. Anti-inflammatory treatment using steroids or anti-cytokine agents is known to contribute to functional recovery of the central and peripheral nervous systems in injury models, while there is a concern that they can induce adverse reactions. The present study examines if high-dose immunoglobulin G (IgG) can facilitate olfactory functional recovery following injury. Methods Olfactory nerve transection (NTx) was performed in OMP-tau-lacZ mice to establish injury models. High-dose IgG was intraperitoneally injected immediately after the NTx and histological assessment of recovery within the olfactory bulb was performed at 5, 14, 42 and 100 days after the drug injection. X-gal staining labeled degenerating and regenerating olfactory nerve fibers and immunohistochemical staining detected the presence of reactive astrocytes and macrophages/microglia. Olfactory function was assessed using an olfactory avoidance behavioral test. Results High-dose IgG-injected mice showed significantly smaller areas of injury-associated tissue, fewer astrocytes and macrophages/microglia, and an increase in regenerating nerve fibers. An olfactory avoidance behavioral test showed improved functional recovery in the IgG-injected mice. Conclusions These findings suggest that high-dose IgG could provide a new therapeutic strategy for the treatment of olfactory dysfunction following head injuries.
... Purified polyclonal immunoglobulin G (>98%) from human plasma, called intravenous immunoglobulin (IVIg), has been approved by the Food and Drug Administration at high doses (≥1 g/kg) for the treatment of various inflammatory and autoimmune diseases, such as Kawasaki's disease, immune thrombocytopenia, humoral immunodeficiency, and bone marrow transplantation [19][20][21]. Additionally, IVIg has shown promise in treating ischemic stroke by directly targeting the immune system and neuronal cells [22][23][24][25]. However, patients are more likely to have adverse reactions, such as thromboembolic events and skin reactions, to IVIg at high doses [19]. ...
... All data are presented as the mean ± S.D. ns, nonsignificant, *P < 0.05, **P < 0.01, or ***P < 0.001. Furthermore, IVIg prevents the post-ischemic infiltration of monocytes/macrophages (Mo/MΦ) [45], suppresses glial cell activation [24], and induces a protective phenotype in microglia [46,47]. We studied the effect of MPC-n(IVIg) on the migration of macrophages using a transwell assay to mimic the migration of macrophages in vivo ( Figure 7A). ...
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Ischemic stroke is an acute and severe neurological disease, which leads to disability and death. Immunomodulatory therapies exert multiple remarkable protective effects during ischemic stroke. However, patients suffering from ischemic stroke do not benefit from immunomodulatory therapies due to the presence of the blood-brain barrier (BBB) and their off-target effects. Methods: We presented a delivery strategy to optimize immunomodulatory therapies by facilitating BBB penetration and selectively delivering intravenous immunoglobulin (IVIg) to ischemic regions using 2-methacryloyloxyethyl phosphorylcholine (MPC)-nanocapsules, MPC-n(IVIg), synthesized using MPC monomers and ethylene glycol dimethyl acrylate (EGDMA) crosslinker via in situ polymerization. In vitro and in vivo experiments verify the effect and safety of MPC-n(IVIg). Results: MPC-n(IVIg) efficiently crosses the BBB and IVIg selectively accumulates in ischemic areas in a high-affinity choline transporter 1 (ChT1)-overexpression dependent manner via endothelial cells in ischemic areas. Moreover, earlier administration of MPC-n(IVIg) more efficiently deliver IVIg to ischemic areas. Furthermore, the early administration of low-dosage MPC-n(IVIg) decreases neurological deficits and mortality by suppressing stroke-induced inflammation in the middle cerebral artery occlusion model. Conclusion: Our findings indicate a promising strategy to efficiently deliver the therapeutics to the ischemic target brain tissue and lower the effective dose of therapeutic drugs for treating ischemic strokes.
... Immune globulin, the interferon system, and the complement system play an indispensable role in the regulation of immune capacity [47][48][49]. In this study, dietary histidine deficiency inhibited the level of C3 compared with that after appropriate histidine supplementation, indicating that dietary histidine deficiency has a negative effect on immune regulation in largemouth bass. ...
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This 56-day study aimed to evaluate the effects of histidine levels on intestinal antioxidant capacity and endoplasmic-reticulum stress (ERS) in largemouth bass (Micropterus salmoides). The initial weights of the largemouth bass were (12.33 ± 0.01) g. They were fed six graded levels of histidine: 0.71% (deficient group), 0.89%, 1.08%, 1.26%, 1.48%, and 1.67%. The results showed that histidine deficiency significantly suppressed the intestinal antioxidant enzyme activities, including SOD, CAT, GPx, and intestinal level of GSH, which was supported by significantly higher levels of intestinal MDA. Moreover, histidine deficiency significantly lowered the mRNA level of nrf2 and upregulated the mRNA level of keap1, which further lowered the mRNA levels of the downstream genes sod, cat, and gpx. Additionally, histidine-deficiency-induced intestinal ERS, which was characterized by activating the PEPK-signalling pathway and IRE1-signalling pathway, including increased core gene expression of pepk, grp78, eif2α, atf4, chopα, ire1, xbp1, traf2, ask1, and jnk1. Dietary histidine deficiency also induced apoptosis and necroptosis in the intestine by upregulating the expressions of proapoptotic genes, including caspase 3, caspase 8, caspase 9, and bax, and necroptosis-related genes, including mlkl and ripk3, while also lowering the mRNA level of the antiapoptotic gene bcl-2. Furthermore, histidine deficiency activated the NF-κB-signalling pathway to induce an inflammatory response, improving the mRNA levels of the proinflammatory factors tnf-α, hepcidin 1, cox2, cd80, and cd83 and lowering the mRNA levels of the anti-inflammatory factors tgf-β1 and ikbα. Similarly, dietary histidine deficiency significantly lowered the intestinal levels of the anti-inflammatory factors TGF-β and IL-10 and upregulated the intestinal levels of the proinflammatory factor TNF-α, showing a trend similar to the gene expression of inflammatory factors. However, dietary histidine deficiency inhibited only the level of C3, and no significant effects were observed for IgM, IgG, HSP70, or IFN-γ. Based on the MDA and T-SOD results, the appropriate dietary histidine requirements of juvenile largemouth bass were 1.32% of the diet (2.81% dietary protein) and 1.47% of the diet (3.13% dietary protein), respectively, as determined by quadratic regression analysis.
... Immunity is an important factor in the maintenance of healthy growth and disease resistance in animals (42). Immunoglobulins, the complement system and interferons play important roles in immune regulation in humans and animals (43)(44)(45). Hence, we also investigated the effect of TB on immunity. ...
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The present study aimed to assess the role of tributyrin (TB) in regulating the growth and health status of juvenile blunt snout bream ( Megalobrama amblycephala ) through an 8-week feeding experiment. Six groups were fed experimental diets with added TB percentages of 0% (control group), 0.03%, 0.06%, 0.09%, 0.12% and 0.15%. The present results showed that TB supplementation in feed had some positive impacts on FW, WG, FCR and SGR, and the best results were found in the 0.06% TB group ( P<0.05 ). However, TB supplementation in feed had no significant effects on SR, CF, VSI or whole-body composition ( P>0.05 ). TB supplementation in feed increased antioxidant capacity and immunological capacity and attenuated the inflammatory response by increasing the activity of T-SOD, GPx, CAT and the levels of anti-inflammatory cytokines (IL-10 and TGF-β) and decreasing the levels of MDA and anti-inflammatory cytokines (TNF-α) ( P<0.05 ). Furthermore, TB supplementation improved immunity by increasing the levels of immunoglobulins (IgM and IgG), C3 and IFN-γ ( P<0.05 ). Surprisingly, 0.06%-0.12% TB supplementation significantly increased the content of IL-1β ( P<0.05 ). However, TB supplementation in feed had no significant effects on the plasma content of GSH, HSP70, IL-8 and the activity of T-AOC ( P>0.05 ). The possible mechanism was that TB activated PI3K/Akt/Nrf2 and inhibits the NF-κB signaling pathway, further regulating the mRNA levels of key genes with antioxidant capacity and the inflammatory response; for example, it increased the mRNA levels of Nrf2, Cu/Zn-SOD, HO-1, CAT, Akt, PI3K, GPx, IL-10, and TGF-β and decreased the mRNA levels of NF-κB and TNF-α ( P<0.05 ). In addition, 0.06%-0.15% TB supplementation significantly increased the mRNA levels of IL-1β ( P<0.05 ). TB supplementation in feed had no significant effects on the mRNA levels of HSP70, Mn-SOD and IL-8 ( P>0.05 ). Evidence was presented that TB supplementation decreased the mortality rate caused by Aeromonas hydrophila challenge. In pathological examination, TB supplementation prevented hepatic and intestinal damage. Generally, TB supplementation improved the growth performance of juvenile blunt snout bream. Furthermore, TB supplementation activated PI3K/Akt/Nrf2 and inhibited the NF-κB signaling pathway, regulating health status and preventing hepatic and intestinal damage.
... Immunotherapy is one way of targeting B cells to provide a neuroprotective effect. For example, intravenous IgG administration (IVIG), which is a therapeutic preparation of polyclonal immunoglobulin G extracted from the plasma of donors [144], has neuroprotective roles and immunomodulatory effects via inhibition of inflammatory cytokine production, complement activation in the CNS, and pathogenic autoantibody production [145]. The administration of IVIG into animal models of SCI and TBI enhances the CNS functional recovery and improves the neurobehavioral and histological outcomes [146À148]. ...
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Biomarkers for Traumatic Brain Injury provides a comprehensive overview on the selection and implementation of serum-based biomarkers for traumatic brain injury. The book presents an economic analysis for implementing TBI biomarkers into clinical practice. In addition, it discusses the analytical tools needed to implement TBI biomarkers, including specifications for testing instruments and interpretative software. Neurologists, emergency department physicians, intensivists, and clinical laboratorians will find this book a great resource from which to familiarize themselves with the issues and processes regarding TBI biomarkers. Approximately 2 million people in the U.S. sustain a traumatic brain injury (TBI) each year with over 250,000 hospitalizations and 50,000 deaths. There has been a significant rise in interest in diagnosing mild concussions, particularly in the sports world. While imaging has been the gold standard, these procedures are costly and not always available. There is great potential in using serum-based biomarkers, hence the book seeks to enlighten readers on new possibilities.
... Ig treatment has been used in different forms of the intractable childhood epilepsy with promising results (up to 70% of patients obtaining a seizure-free status) (27,28), and the fact that plasma levels of IgG are positively correlated with gestational age increase (1), one should consider Ig as possible neuromodulators, which regulate excitability of neuronal membranes and protect the immature brain of newborn infants against over excitation. Furthermore, Ig have been shown to be taken up by neurons (20), causing direct neuroprotective effects via the modulation of NF-kB and MAPK activities, through the reduced expression and activation of neuronal tolllike receptors, as well as by decreasing caspase-3 cleavage leading to decreased apoptosis of neurons (29)(30)(31)(32). ...
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In the present review, we highlight the possible "extra-immunological" effects of maternal immunoglobulins (Ig) transferred to the blood circulation of offspring, either via the placenta before birth or via the colostrum/milk across the gut after birth in different mammalian species. Using the newborn pig as a model, since they are naturally born agammaglobulinemic, intravenously (i.v.) infused purified serum Ig rapidly improved the vitality, suckling behavior, and ensured the survival of both preterm and term piglets. In further studies, we found that proper brain development requires i.v. Ig supplementation. Studies have reported on the positive effects of i.v. Ig treatment in children with epilepsy. Moreover, feeding newborn pigs an elementary diet supplemented with Ig improved the gut structure, and recently a positive impact of enteral or parenteral Ig supplementation on the absorption of polyunsaturated fatty acids (PUFAs) was observed in the newborn pig. Summarized, our own results and those found in the literature, indicate the existence of important extra-immune effects of maternal Ig, in addition to the classical protective effects of transferred maternal passive immunity, including effects on the development of the brain, gut, and possibly other organ systems in the neonate. These additional properties of circulating Ig could have an impact on care guidelines for human neonates, especially those born prematurely with low plasma Ig levels.
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Intravenous immunoglobulin (IVIg) is used as treatment for several autoimmune and inflammatory conditions, but its specific mechanisms are not fully understood. Herein, we aimed to evaluate, using systems biology and artificial intelligence techniques, the differences in the pathophysiological pathways of autoimmune and inflammatory conditions that show diverse responses to IVIg treatment. We also intended to determine the targets of IVIg involved in the best treatment response of the evaluated diseases. Our selection and classification of diseases was based on a previously published systematic review, and we performed the disease characterization through manual curation of the literature. Furthermore, we undertook the mechanistic evaluation with artificial neural networks and pathway enrichment analyses. A set of 26 diseases was selected, classified, and compared. Our results indicated that diseases clearly benefiting from IVIg treatment were mainly characterized by deregulated processes in B cells and the complement system. Indeed, our results show that proteins related to B-cell and complement system pathways, which are targeted by IVIg, are involved in the clinical response. In addition, targets related to other immune processes may also play an important role in the IVIg response, supporting its wide range of actions through several mechanisms. Although B-cell responses and complement system have a key role in diseases benefiting from IVIg, protein targets involved in such processes are not necessarily the same in those diseases. Therefore, IVIg appeared to have a pleiotropic effect that may involve the collaborative participation of several proteins. This broad spectrum of targets and ‘non-specificity’ of IVIg could be key to its efficacy in very different diseases.
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Traumatic spinal cord injury (SCI) elicits a complex cascade of cellular and molecular inflammatory events. Although certain aspects of the inflammatory response are essential to wound healing and repair, on balance, it is thought to be detrimental to recovery by causing bystander damage and spread of pathology into spared but vulnerable regions of the spinal cord. Much of the research to date has therefore focused on understanding inflammatory drivers of secondary tissue loss after SCI in order to define therapeutic targets and positively modulate this response. Numerous experimental studies have demonstrated that modulation of the inflammatory response to SCI can indeed lead to significant neuroprotection and improved recovery. However, it is now also recognised that broad-scale immunosuppression is not necessarily beneficial and may even carry the risk of contributing to the development of serious adverse events. Immune modulation as opposed to suppression is therefore now considered as a more promising approach to target harmful post-traumatic inflammation following a major neurotraumatic event like SCI. One promising immunomodulatory agent is intravenous immunoglobulin (IVIG), a plasma product that contains mostly immunoglobulin G (IgG) from thousands of healthy donors. IVIG is currently already widely used to treat a range of autoimmune diseases, but recent studies have found that it also holds great promise for treating acute neurological conditions, including SCI. This review provides an overview of the inflammatory response to SCI, immunomodulatory approaches that are currently being trialled, proposed mechanisms of action for IVIG therapy and the putative relevance of these in the context of neurotraumatic events.
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The conditions required for effective immune responses to viral or bacterial organisms and chemicals of exogenous origin and to intrinsic molecules of abnormal configuration, are briefly outlined. This is followed by a discussion of endocrine and environmental factors that can lead to excessive continuation of immune activity and persistent elevation of inflammatory responses. Such disproportionate activity becomes increasingly pronounced with aging and some possible reasons for this are considered. The specific vulnerability of the nervous system to prolonged immune events is involved in several disorders frequently found in the aging brain. In addition of being a target for inflammation associated with neurodegenerative disease, the nervous system is also seriously impacted by systemically widespread immune disturbances since there are several means by which immune information can access the CNS. The activation of glial cells and cells of non-nervous origin that form the basis of immune responses within the brain, can occur in differing modes resulting in widely differing consequences. The events underlying the relatively frequent occurrence of derangement and hyperreactivity of the immune system are considered, and a few potential ways of addressing this common condition are described.
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Pharmaceutical preparations of normal human immunoglobulin (IgG) are known to contain high-avidity and neutralizing antibodies (Ab) to the cytokines interleukin (IL)-1α, IL-6, and interferon (IFN)α. To test for other cytokine Ab, 23 batches of IgG were tested for saturable binding to eight 125I-labeled recombinant cytokines. All batches bound granulocyte-macrophage colony-stimulating factor (GM-CSF) with high avidity (Kav ≈ 10 pmol/L) and capacities of up to 5 μmol GM-CSF/mol IgG. Only 1 of 15 batches bound IL-5, also with high avidity, whereas 13 of 15 batches bound to IL-10 but with lower capacities and avidities. None of the IgG preparations bound IL-1 receptor antagonist (IL-1ra), IL-2, IL-3, IL-4, or G-CSF. Cross-binding and absorption analyses revealed identical or slightly stronger binding of recombinant GM-CSF, IL-5, and IL-10 than their native counterparts. GM-CSF–IgG complexes did not bind to cellular GM-CSF receptors, but Fc-dependent binding occurred to blood polymorphonuclear cells. Increased binding of GM-CSF to patient sera correlated positively with the binding capacities of infused IgG preparations. Patient and normal sera did not interfere with the binding of Ab to GM-CSF. From these and previous experiments, we conclude that pools of normal human IgG contain variable amounts of specific and high-avidity Ab to some cytokines, and that Ab to GM-CSF constitute a dominant anti-cytokine activity in these preparations. These Ab are available for reactionin vivo following IgG therapy.
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Infection is a major complication of acute stroke and causes increased mortality and morbidity; however, current interventions do not prevent infection and improve clinical outcome in stroke patients. The mechanisms that underlie susceptibility to infection in these patients are unclear. Splenic marginal zone (MZ) B cells are innate-like lymphocytes that provide early defence against bacterial infection. Here we show experimental stroke in mice induces a marked loss of MZ B cells, deficiencies in capturing blood-borne antigen and suppression of circulating IgM. These deficits are accompanied by spontaneous bacterial lung infection. IgM levels are similarly suppressed in stroke patients. β-adrenergic receptor antagonism after experimental stroke prevents loss of splenic MZ B cells, preserves IgM levels, and reduces bacterial burden. These findings suggest that adrenergic-mediated loss of MZ B cells contributes to the infection-prone state after stroke and identify systemic B-cell disruption as a target for therapeutic manipulation.
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Fcγ-receptors (FcγR) provide a critical link between humoral and cellular immunity. The genes of the low-affinity receptors for IgG and their isoforms, namely, FcγRIIa, FcγRIIb, FcγRIIIa, FcγRIIIb, and SH-FcγRIIIb, are located in close proximity on chromosome 1q22. Variant alleles may differ in biologic activity and a number of studies have reported the frequencies of variant FcγR alleles in both disease and control populations. No large study has evaluated the possibility of a nonrandom distribution of variant genotypes. We analyzed 395 normal individuals (172 African Americans [AA] and 223 Caucasians [CA]) at the following loci: FcγRIIa, FcγRIIIa, and FcγRIIIb, including the SH-FcγRIIIb. The genotypic distributions of FcγRIIa, FcγRIIIa, and FcγRIIIb conform to the Hardy-Weinberg law in each group. There was no strong evidence that combinations of 2-locus genotypes of the 3 loci deviated from random distributions in these healthy control populations. The distribution of SH-FcγRIIIb is underrepresented in CA compared with AA (P < .0001) controls. A previously reported variant FcγRIIb was not detected in 70 normal individuals, indicating that this allele, if it exists, is very rare (<1%). In conclusion, we present data that should serve as the foundation for the interpretation of association studies involving multiple variant alleles of the low-affinity FcγR.
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Background: In animal models of acute ischaemic stroke, blocking of the leukocyte-endothelium adhesion by antagonism of α4 integrin reduces infarct volumes and improves outcomes. We assessed the effect of one dose of natalizumab, an antibody against the leukocyte adhesion molecule α4 integrin, in patients with acute ischaemic stroke. Methods: In this double-blind, phase 2 study, patients with acute ischaemic stroke (aged 18-85 years) from 30 US and European clinical sites were randomly assigned (1:1) to 300 mg intravenous natalizumab or placebo with stratification by treatment window and baseline infarct size. Patients, investigators, and study staff were masked to treatment assignments. The primary endpoint was the change in infarct volume from baseline to day 5 and was assessed in the modified intention-to-treat population. Secondary endpoints were the change in infarct volume from baseline to day 30, and from 24 h to days 5 and 30; the National Institute of Health Stroke Scale (NIHSS) at baseline, 24 h, and at days 5 (or discharge), 30, and 90; and modified Rankin Scale (mRS) and Barthel Index (BI) at days 5 (or discharge), 30, and 90. This trial is registered with ClinicalTrials.gov, number NCT01955707. Findings: Between Dec 16, 2013, and April 9, 2015, 161 patients were randomly assigned to natalizumab (n=79) or placebo (n=82). Natalizumab did not reduce infarct volume growth from baseline to day 5 compared with placebo (median absolute growth 28 mL [range -8 to 303] vs 22 mL [-11 to 328]; relative growth ratio 1·09 [90% CI 0·91-1·30], p=0·78) or to day 30 (4 mL [-43 to 121] vs 4 mL [-28 to 180]; 1·05 [0·88-1·27], p=0·68), from 24 h to day 5 (8 mL [-30 to 177] vs 7 mL [-13 to 204]; 1·00 [0·89-1·12], p=0·49), and from 24 h to day 30 (-5 mL [-93 to 81] vs -5 mL [-48 to 48]; 0·98 [0·87-1·11], p=0·40). No difference was noted between the natalizumab and placebo groups in the NIHSS (score ≤1 or ≥8 point improvement) from baseline at 24 h, day 5 (or discharge), day 30 (27 [35%] vs 36 [44%]; odds ratio 0·69 [90% CI 0·39-1·21], p=0·86), and day 90 (36 [47%] vs 37 [46%]; 1·10 [0·63-1·93], p=0·39). More patients in the natalizumab group than in the placebo group had mRS scores of 0 or 1 at day 30 (13 [18%] vs seven [9%]; odds ratio 2·88 [90% CI 1·20-6·93], p=0·024) and day 90 (18 [25%] vs 16 [21%]; 1·48 [0·74-2·98], p=0·18); and BI (score ≥95) at day 90 (34 [44%] vs 26 [33%]; 1·91 [1·07-3·41], p=0·033) but not significantly at day 5 or day 30 (26 [34%] vs 26 [32%]; 1·13 [0·63-2·00], p=0·37). Natalizumab and placebo groups had similar incidences of adverse events (77 [99%] of 78 patients vs 81 [99%] of 82 patients), serious adverse events (36 [46%] vs 38 [46%]), and deaths (14 [18%] vs 13 [16%]). Two patients in the natalizumab group died because of adverse events assessed as related to treatment by the investigator (pneumonia, and septic shock and multiorgan failure). Interpretation: Natalizumab administered up to 9 h after stroke onset did not reduce infarct growth. Treatment-associated benefits on functional outcomes might warrant further investigation. Funding: Biogen.
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The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional and multi-ligand endocytic receptor abundantly expressed in neurons. Intravenous immunoglobulin (IVIg) is a purified preparation of plasma-derived human immunoglobulin used for the treatment of several neurological inflammatory disorders, and proposed for the treatment of stroke for its potent neuroprotective effects. LRP1 has been shown to be involved in the transcytosis of IVIg, and IVIg-LRP1 interaction leads to LRP1 tyrosine phosphorylation, which may contribute to the anti-inflammatory effects of IVIg. However, the question remains whether IVIg could induce its neuroprotective effects via LRP1 in neurons under ischemic stroke conditions. In cultured neurons and in a transient ischemic mouse model, ischemia decrease LRP1 levels and phosphorylation, and IVIg blocks these effects. In ischemic neurons, LRP1 antagonism by receptor associated protein (RAP) enhances the activation of pro-death signaling pathways such as nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs), and caspase-3, and IVIg reduces these effects. When applied to ischemic neuronal cultures, RAP induces a dramatic drop in Akt activation, and IVIg reverses this effect, as it does with the decrease in Bcl-2 levels caused by ischemic injury in the presence of RAP. Altogether, these results show evidence of LRP1 expression and activity modulation by IVIg, and support the role of LRP1 as a partner of IVIg in the execution of its neuroprotective effects.
Article
Treatments for acute ischaemic stroke continue to evolve after the superior value of endovascular thrombectomy was confirmed over systemic thrombolysis. Unfortunately, numerous neuroprotective drugs have failed to show benefit in the treatment of acute ischaemic stroke, making the search for new treatments imperative. Increased awareness of the relevance of rigorous preclinical testing, and appropriate selection of study participants, might overcome the barriers to progress in stroke research. Relevant areas of interest include the search for safe and effective treatment strategies that combine neuroprotection reperfusion, better use of advanced brain imaging for patient selection, and wider implementation of prehospital conducted clinical trials. Randomised controlled trials of combination treatments completed within the past 5 years have included growth factors, hypothermia, minocycline, natalizumab, fingolimod, and uric acid; the latter two drugs with alteplase produced encouraging results. Blocking of excitotoxicity is also being reassessed in clinical trials with new approaches, such as the postsynaptic density-95 inhibitor NA-1, or peritoneal dialysis to remove excess glutamate. The findings of these randomised trials are anticipated to improve treatment options and clinical outcomes in of patients with acute stroke.
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Background The complement cascade plays a deleterious role in multiple models of ischemia/reperfusion (I/R) injury, including stroke. Investigation of the complement cascade may provide a critical approach to identifying neuroprotective strategies that can be effective at clinically relevant time points in cerebral ischemia. This review of the literature describes the deleterious effects of complement activation in systemic I/R models and previous attempts at therapeutic complement inhibition, with a focus on the potential role of complement inhibition in ischemic neuroprotection. Translation of these concepts into ischemic stroke models and exploration of related neuroprotective strategies are also reviewed. Summary of ReviewWe performed a MEDLINE search to identify any studies published between 1966 and 2001 dealing with complement activation in the setting of I/R injury. We also searched for studies demonstrating up-regulation of any complement components within the central nervous system during inflammation and/or ischemia. Conclusions The temporal and mechanistic overlap of the complement cascade with other biochemical events occurring in cerebral I/R injury is quite complex and is only beginning to be understood. However, there is compelling evidence that complement is quite active in the setting of acute stroke, suggesting that anticomplement strategies should be further investigated through genetic analysis, nonhuman primate models, and clinical investigations.