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R E V I E W S
The central nervous system (CNS) mounts an
organized INNATE IMMUNE RESPONSE during systemic bac-
terial/viral infection. This inflammatory response
is characterized by the expression ofvarious immuno-
logical proteins in the CIRCUMVENTRICULAR ORGANS
(CVOs) and other structures devoid of blood–brain
barrier (BBB).The response extends progressively to
affect microglia across the brain parenchyma and may
lead to the onset of an ADAPTIVE IMMUNE RESPONSE.
Molecules of both the innate and adaptive immune
responses are induced in a wide diversity ofneurologi-
cal disorders, including Alzheimer’s disease,
Parkinson’s disease,Huntington’s disease,multiple
sclerosisand amyotrophic lateral sclerosis(ALS).The
recent discovery ofthis immune response in the brain
revives the idea that immunological challenges might
be aetiological factors in sporadic cases of neuro-
degeneration,and indicates that primary causes ofsuch
degeneration could originate outside the CNS.Indeed,
the mechanisms that underlie 90% of ALS cases,
sporadic Parkinson’s disease and Alzheimer’s disease
remain elusive,and bacterial/viral infections have been
proposed as a primary cause.Furthermore,peripheral
antibodies generated by damaged peripheral tissues in
neurological conditions that include STIFF-MAN SYNDROME
and RASSMUSSEN ENCEPHALITIScan induce neuronal death
by targeting specific antigens.
Progress in the use ofanti-inflammatory therapies
and immunization in animal models ofneurodegener-
ative disorders points to the importance ofthe immune
response in neurodegeneration.Whereas regulation of
the innate immune response could be decisive in the
development ofboth sporadic and familial forms of
neurological disorders,molecules ofthe innate immune
response can also trigger the production of neuro-
trophic factors,and promote repair and remyelination
in response to injury, trauma and toxin-induced
demyelination.Here,we review the mechanisms that
underlie the dichotomous role of the inflammatory
response ofthe brain,a response that can,on the one
hand,protect neurons and,on the other,be a direct
Host organisms detect the presence ofinfection by recog-
nizing specific elements produced by microorganisms1.
These elements — the so-called PATHOGEN-ASSOCIATED
MOLECULAR PATTERNS(PAMPs) — are recognized by spe-
cific cells ofthe immune system as inducers ofinnate
responses to bacterial infection.The reaction to endo-
toxin lipopolysaccharide (LPS),an important com-
ponent of the outer membranes of GRAM-NEGATIVE
BACTERIA,is the best-characterized example of innate
recognition that leads to a robust inflammatory
INNATE IMMUNITY:THE MISSING
LINK IN NEUROPROTECTION AND
Minh Dang Nguyen*,Jean-Pierre Julien* and Serge Rivest‡
Innate immunity was previously thought to be a nonspecific immunological programme that was
engaged by peripheral organs to maintain homeostasis after stress and injury. Emerging
evidence indicates that this highly organized response also takes place in the central nervous
system. Through the recognition of neuronal fingerprints, the long-term induction of the innate
immune response and its transition to an adaptive form might be central to the pathophysiology
and aetiology of neurodegenerative disorders. Paradoxically, this response also protects neurons
by favouring remyelination and trophic support afforded by glial cells.
The early response ofa host to
infection.One ofits main
features is the pro-inflammatory
response induced by antigen-
presenting cells —
and,in the brain,microglial
cells.This response is followed
by an adaptive response that is
mediated by the clonal selection
oflymphocytes,which leads to
long-term immune protection.
*Centre for Research in
General Hospital Research
and Laval University,
2705 Boulevard Laurier,
Correspondence to S.R.
NATURE REVIEWS | NEUROSCIENCE
VOLUME 3 | MARCH 2002 | 2 1 7
R E V I E W S
Brain regions that have a rich
vascular plexus with a
specialized arrangement ofthe
blood vessels.The junctions
between the capillary endothelial
cells are not tight in the blood
vessels ofthese regions,allowing
the diffusion oflarge molecules.
These organs include the
organum vasculosum ofthe
subfornical organ,the median
eminence and the area
included as circumventricular
organs,the choroid plexus and
leptomeninges are also highly
vascularized and are rapidly
activated by circulating
multiple leucine-rich repeats,whereas TLR cytoplasmic
domains are similar to the cytoplasmic portion ofthe
interleukin 1 (IL-1) receptor (IL-1R),commonly known
as Toll/IL-1R homologous regions (TIR domains)1,3,4.
Distinct TLRs have been proposed as key molecules in the
selective recognition ofthe main PAMPs that are pro-
duced by either Gram-negative or Gram-positive bacteria
(FIG.1).The observations that mutations ofthe mouse Lps
locus abolish the response to LPS,and that this locus
encodes TLR4,provided the first evidence that this partic-
ular receptor might be involved in the innate immune
response to Gram-negative bacteria5,6.By contrast,TLR2-
deficient mice show a normal inflammatory response
to LPS7,but macrophages from these animals are less
responsive to Gram-positive bacterial cell walls and
peptidoglycan7.These results are evidence ofTLR selec-
tivity in PAMP recognition,although other TLRs can
recognize the same components ofboth Gram-negative
and Gram-positive bacteria (see below).
response by phagocytic cells2.Peptidoglycan and lipotei-
choic acid from GRAM-POSITIVE BACTERIA are other PAMPs
that have the ability to activate the NUCLEAR FACTOR κB
(NFκB) signalling pathways and the production of
CYTOKINES. The secretion of cytokines by circulating
monocytes/neutrophils and tissue macrophages in
response to PAMPs requires a cascade of signalling
events,the details ofwhich have been clarified in recent
years.In particular,the involvement of TOLL-LIKE RECEPTORS
(TLRs) has received significant attention.
The Tollprotein was first discovered as an essential
molecule for the establishment ofthe dorsoventral axis in
the Drosophilaembryo.TLRsare mammalian homo-
logues ofthis protein,which are expressed at the surface
ofa specific group ofimmune cells known as the ANTIGEN-
PRESENTING CELLS(APCs).These cells are rapidly activated
by pathogens that bind to specific TLRs.Members ofthe
TLR family share characteristic extracellular and cyto-
plasmic domains3.Their extracellular domains include
Figure 1 |The family of TLRs and pro-inflammatory signal-transduction pathways that recruit NFκB. The extracellular domains of Toll-like receptors (TLRs)
include multiple leucine-rich repeats; TLR cytoplasmic domains are similar to the cytoplasmic portion of the interleukin 1 (IL-1) receptor (IL-1R). TLR2 recognizes the
pathogen-associated molecular patterns that are produced by Gram-positive (Gram+) bacterial cell wall components. TLR4, in association with CD14 and a molecule
known as MD-2, is crucial for the recognition of lipopolysaccharide (LPS) from Gram-negative (Gram–) bacteria. Flagellin, the principal element of bacterial flagella, is a
highly virulent molecule that is recognized by TLR5. TLR9 is required for the inflammatory response that is triggered by bacterial DNA. TLR3 engages the innate immune
response in the presence of viruses that produce double-stranded RNA (dsRNA). The broad spectrum of components recognized by these receptors indicates that
TLRs form heteromeric complexes. The cytoplasmic domain of TLR2 can form functional pairs with TLR6 and TLR1, leading to signal transduction and cytokine gene
expression. All TLRs activate signalling pathways that are similar to those activated by IL-1, because they share a Toll/IL-1R homology domain that can interact with the
adaptor protein MyD88. p50 and p65 are the two most common DNA-binding subunits of the nuclear factor κB (NFκB) dimer, and have the ability to trigger the
transcription of target genes that encode cytokines, chemokines, proteins of the complement system, enzymes, adhesion molecules, immune receptors and others. See
main text for details of the kinases involved in the NFκB nuclear translocation. ACP1, accessory protein 1; IKAP, IκB kinase complex (IKK-αβγ)-associated protein; IκB,
inhibitor of NFκB; IRAK, IL-1R-associated kinase; LTA, lipoteichoic acid; NIK, NFκB-inducing kinase; PGN, peptidoglycan; RIP, receptor-interacting protein; TNF, tumour
necrosis factor; TNFR, TNF receptor; TRADD, TNFR1-associated protein with death domain; TRAF, TNFR-associated factor; Ub, ubiquitin.
2 1 8 | MARCH 2002 | VOLUME 3
R E V I E W S
Also known as acquired
immunity,it describes the
lymphocytes to antigen and the
memory.It is mediated by the
clonal selection oflymphocytes.
A neuromuscular disorder that
is characterized by progressive
rigidity and a hyperactive startle
reflex that results in the
A childhood disease that is
characterized by seizures,
Specific elements that are
produced by microorganisms
and can induce innate immune
responses.These elements are
recognized by specific receptors
that are expressed at the surface
Bacteria that do not retain a
basic blue dye during the Gram-
stain procedure.Their cell walls
are thin,consisting ofa layer of
lipopolysaccharide outside a
activation of NFκB by many stimuli, although only
IKK-βis essential for activating NFκB in response to
cytokines and PAMPs.Indeed,IKK-β is the target of
upstream signals generated by pro-inflammatory stim-
uli that give rise to phosphorylation ofthe inhibitor of
NFκB (IκB) at Ser32/36 and proteasomal degradation
after polyubiquitination13,14.This event frees NFκB,and
allows its nuclear translocation and the subsequent acti-
vation of target genes (FIG. 1). Recruitment of the
MyD88/IRAK/TRAF6 complex can also activate mito-
gen-activated protein kinase (MAPK) kinases (MKKs);
in particular,the JUN kinase pathway that leads to acti-
vation ofthe activator protein 1 (AP-1) transcription
factor.A well-known consequence ofthe nuclear trans-
location ofAP-1 and NFκB is the transcriptional activa-
tion of numerous pro-inflammatory genes, which
encode cytokines,CHEMOKINES,proteins ofthe COMPLEMENT
SYSTEM, enzymes (such as cyclooxygenase 2 and the
inducible form ofnitric oxide synthase),adhesion mole-
cules and immune receptors.All ofthese molecules are
involved in engaging and controlling the innate immune
response,which is essential for pathogen elimination,
and in orchestrating the transition to an adaptive
immune response (BOX 1).
Innate immune response in the CNS
For a long time,the brain was considered to be a privi-
leged organ from an immunological point of view,
owing to its inability to mount an immune response
and process antigens.Although this is partly true,the
CNS shows a well-organized innate immune reaction
in response to systemic bacterial infection and cerebral
injury.The CD14 and TLR4 receptors are constitutively
expressed in the CVOs15,16.Circulating LPS also causes
a rapid increase in CD14in these brain regions,and a
delayed response takes place in cells located at the
boundaries of the CVOs and in microglia across
the brain parenchyma.A similar expression pattern was
recently found for the gene that encodes TLR2 in the
brains ofmice after a single systemic injection ofLPS17.
The signal was first detected in regions devoid ofBBB
(FIG.2).A second wave ofTLR2 expression was detected
in the surrounding parenchymal cells, which also
expressed the microglial marker Iba1.The rapid induc-
tion of IκB and the upregulation of MyD88 indicate
that LPS-induced TLR2 transcription is dependent on
the NFκB pathway17.
The activation of parenchymal microglia during
endotoxaemia is associated with a robust induction of
genes that encode cytokines,chemokines and proteins
of the complement system18–23.This phenomenon is
surprising,because access ofcirculating endotoxins to
cerebral tissue is limited by the BBB.However,there
are structures that are devoid ofBBB that seem to act
as immune sentinels for the brain.These include the
organum vasculosum ofthe lamina terminalis,subfor-
nical organ,median eminence,area postrema, CHOROID
PLEXUSand LEPTOMENINGES.The basal expression ofCD14
and TLR4 is likely to be central to the pro-inflamma-
tory signal-transduction events that originate in these
regions during the innate immune response.Indeed,
Eight further members ofthe TLR family have been
characterized so far.Flagellin,the principal element of
bacterial flagella,is a highly virulent molecule that is rec-
ognized by the TLR5 receptor8, whereas TLR9 is
required for the inflammatory response that is triggered
by bacterial DNA9.TLRs also trigger an innate immune
response to viruses that produce double-stranded RNA.
For example, TLR3-deficient mice show reduced
responses to the synthetic double-stranded-RNA ana-
logue polyinosine-polycytidylic acid10. In addition,
TLRs can form multimeric complexes to increase the
spectrum ofmolecules that they recognize.So,dimer-
ization ofthe cytoplasmic domain ofTLR2 does not
induce cytokine production in macrophages,whereas
similar dimerization ofthe TLR4 cytoplasmic domain is
associated with pro-inflammatory signalling11.Also,the
cytoplasmic domain ofTLR2 can form functional pairs
with TLR6 and TLR1,leading to signal transduction
and cytokine expression11. So, whereas the TLR4
homodimer is responsible for triggering NFκB in
response to cell wall components ofGram-negative bac-
teria, a more complex combinatorial repertoire is
needed to discriminate between PAMPs found in
Because ofthe presence ofthe TIR domain,TLRs
activate signalling pathways that are similar to those
engaged by IL-1.The TIR domain can interact with
MyD88 (FIG. 1). This adaptor protein has an amino-
terminal DEATH DOMAIN that associates with the IL-1R-
associated kinase (IRAK),a serine kinase that activates
another adaptor molecule — tumour necrosis factor
(TNF) receptor (TNFR)-associated factor 6 (TRAF6).
Recruitment ofTRAF6 leads to activation ofthe protein
kinase IKK (IκB kinase), which is composed of two
catalytic subunits (IKK-αand IKK-β) and one regula-
tory subunit (IKK-γ/NEMO)12.IKK-γis required for the
Box 1 |Transition from innate to adaptive immune response
Although long considered as nonspecific,the innate immune reaction might be crucial in
the transmission ofappropriate information to the immune cells that are involved in
acquired immunity.Macrophages and DENDRITIC CELLSexpress as many as ten different
Toll-like receptors (TLRs),which recognize specific components ofbacteria and viruses3.
The identification ofthese receptors provided evidence that pathogen-associated
molecular patterns (PAMPs) recognize specific endogenous receptors that are expressed
on the surface ofantigen-presenting cells.Cytokines that act on the macrophage itselfare
produced minutes after TLR activation,whereas those that mediate the transition from
innate to adaptive immune response appear after a few hours.Binding ofPAMPs to their
respective TLRs leads to the release ofinterleukin 12 (IL-12),a cytokine that is involved in
the transition from innate to adaptive immunity.Indeed,macrophage-derived IL-12
stimulates the differentiation ofa subset ofT lymphocytes (CD4+) into TH1 helper cells,
which produce interferon-γ(IFN-γ).TH1 cells are believed to be crucial to the
pathogenesis ofmultiple sclerosis,especially during the demyelinating episodes.Helper
T lymphocytes can also differentiate into TH2 cells,but this phenomenon requires IL-4
production from antigen-activated T cells,and the contribution ofthe innate immune
response in this process remains unclear.The balance between TH1 (pro-inflammatory)
and TH2 (anti-inflammatory) cytokines in the brain might have a profound impact on
neuronal elements.Although the link between the innate immune reaction and acquired
immunity has been better clarified in recent years,there are many questions about
whether defects in this fine interplay are direct causes ofautoimmune diseases in
different organs and in the central nervous system.
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Bacteria that retain a basic blue
dye during the Gram-stain
procedure.Their cell wall is
thicker than that ofGram-
NUCLEAR FACTOR κB
A family oftranscription factors
that are important for pro-
inflammatory and anti-apoptotic
In general terms,cytokines are
proteins made by cells that affect
the behaviour ofother cells.
They are produced mainly by the
A large family ofreceptors that
are expressed at the surface of
leukocytes and microglial cells.
They are responsible for
engaging the innate immune
system in response to pathogens.
Specialized cells that present
specific antigens to T cells.
Macrophages and dendritic cells
are the main antigen-presenting
cells;in the CNS,the antigen-
presenting cells are the microglia.
A protein–protein interaction
domain found in many proteins
that are involved in signalling
Small,secreted proteins that
stimulate the motile behaviour
A set ofplasma proteins that
attack extracellular pathogens.
The pathogen becomes coated
with complement proteins that
facilitate pathogen removal by
The first lipopolysaccharide
receptor to be characterized.It
exists two forms:membrane
CD14 (mCD14) and soluble
CD14 (sCD14).mCD14 is
present at the surface ofmyeloid
cells and acts as a
lacks the GPI anchor,but can
bind LPS to activate cells that are
devoid ofmCD14,such as
itself acts as an autocrine and paracrine factor to
upregulate the LPS receptor.The binding ofTNF to its
type 1 receptor — TNFR1(p55) — leads to the activa-
tion and translocation of NFκB into the nucleus,an
event that modulates CD14 expression.TNF-α can
induce a transient increase in plasma CD14 levels,
which is accompanied by increased CD14 mRNA
in lung, liver and kidney24. Pre-treatment of mice
with anti-TNF-α antibodies significantly prevents
LPS-induced CD14 transcription25.
TNF can also induce its own production by auto-
crine stimulation,which is followed by the synthesis of
the TLR4/CD14-positive cells of the CVOs might
selectively recognize cell wall components of Gram-
negative bacteria to allow LPS signalling and rapid
transcription of pro-inflammatory cytokines during
endotoxaemia, first within these organs and later
across the brain parenchyma.Interestingly,systemic
injection ofthe bacterial endotoxin causes expression
ofCD14 messenger RNA in the brain in a pattern that
is closely related to the induction of TNF-α,with both
rapid and delayed responses15,20.Although a large body
ofevidence indicates that CD14 is necessary for LPS to
trigger cytokine transcription,it is possible that TNF-α
6 h1.5 h
12 h12 h3 h
24 h24 h24 h
Figure 2 |Response wave of TLR2-expressing cells across the mouse brain to bacterial endotoxin LPS. After a single
systemic injection of lipopolysaccharide (LPS), induction of Toll-like receptor 2 (TLR2) starts in the circumventricular organs,
choroid plexus (Chp), leptomeninges and blood vessels. Six hours after injection, a localized hybridization signal is detected in the
median eminence (ME)/arcuate nucleus (left column), and at the edge of the fimbria, stria terminalis and optic tract (middle
column). The choroid plexus and subfornical organ (SFO) already show a strong signal 3 h after the injection (right column). Later
on, the message spreads over these structures, reaching deeper parenchymal regions 24 h after the challenge (bottom panels).
Magnification, x10. 3V, third ventricle; LHA, lateral hypothalamic area; Veh, vehicle injection. Adapted with permission from REF.17
© 2001 International Society for Neurochemistry.
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A site ofproduction of
cerebrospinal fluid in the adult
brain.It is formed by the
invagination ofependymal cells
into the ventricles,which
become richly vascularized.
Also known as interdigitating
reticular cells because oftheir
cells are the most potent
stimulators ofT-cell responses.
The pia mater and the arachnoid
Tumour necrosis factor-α.
A cytokine produced by
macrophages that has multiple
functions in the immune
Dual nature of innate immunity in the CNS
The roles of TLR2, TLR4 and CD14 in the CNS are
unknown.The constitutive expression ofCD14 in the
CVOs and its upregulation in the brain parenchyma
after LPS injection indicate a potential role for this
molecule in protecting nerve cells against LPS particles.
The macrophages and microglia in the CVOs are
strategically positioned to respond rapidly to circulat-
ing endotoxin or bacteria, whereas parenchymal
microglia serve as the phagocytic population ofcells in
the brain in case ofinvasion.The BBB is altered during
severe endotoxaemia and neurodegeneration. This
alteration might allow the diffusion ofmolecules that
normally have no access to the parenchymal elements.
Although activation of microglial cells could rapidly
eliminate this foreign material,sustained activity of
these cells might have detrimental effects and be associ-
ated with neurodegenerative disorders.In this regard,
robust and rapid transcriptional activation of TLR2
and CD14 takes place in the brains ofmice with EXPERI-
MENTAL AUTOIMMUNE ENCEPHALOMYELITIS(EAE),an experi-
mental model ofmultiple sclerosis26.This observation
is in agreement with the fact that this demyelinating
disease has a well-known immune aetiology, being
associated with the chronic induction ofinflammatory
molecules.However,a similar induction ofTLR2 was
found after stab injury,viral meningitis and,surpris-
ingly, in transgenic mice that overexpress a mutant
form of superoxide dismutase 1 that is found in ALS
(REF.27,and S.R.and colleagues,unpublished observa-
tions).So,proteins ofthe innate immune system can be
induced not only by PAMPs,but also by brain injury
and during some neurodegenerative disorders.What
happens first remains unknown,and the role of this
innate immune response in the brain has yet to be
unravelled.It is possible that,in addition to its well-
known role as a sensor ofPAMPs and as an OPSONIZATION
factor ofLPS particles,CD14 might also have a role in
priming and sustaining the activity ofmicroglial cells
within the brain parenchyma.This could contribute to
an exaggerated immune response and be potentially
detrimental for neurons.
LPS-induced pro-inflammatory signal-transduction
pathways are generally not associated with neurodegen-
eration,although a few studies have provided evidence
ofLPS-induced neurotoxicity28,29.Such discrepancies
could be explained by the use ofdifferent techniques to
assay neurodegeneration and/or by differences in the
regions under scrutiny.So,injection ofbacterial endo-
toxin in the hippocampus,cortex or substantia nigra of
adult rats produced neurodegeneration only in the sub-
stantia nigra29.The authors ofthis study suggested that
the differential susceptibility to LPS might be attribut-
able to differences in the number ofmicroglial cells in
each region,and might reflect the levels ofinflamma-
tion-related factors produced by these cells29.Moreover,
it is possible that specific populations ofneurons are
more susceptible to inflammatory molecules than oth-
ers and that,despite their role in eliminating pathogens
from the CNS,microglia and their secreted products are
harmful to some neurons.
other pro-inflammatory cytokines,such as IL-1β and
IL-6.In the brain,TNF seems to activate parenchymal
microglia in a paracrine manner during endotox-
aemia.Indeed,central injection ofrat TNF-αcauses a
robust expression of the genes that encode IκB-α,
TNF-α and CD14 within microglial cells across the
brain parenchyma20.Systemic injection with endo-
toxin LPS causes a similar microglial activation that is
prevented by inhibiting the activity of TNF-α in the
CNS20.We suggest that circulating LPS might bind its
transmembrane receptors on macrophages and
microglia of the CVOs,stimulating NFκB signalling
and triggering TNF-α transcription.This cytokine
could,in turn,activate NFκB signalling and gene tran-
scription in adjacent microglial cells (FIG.3).So,cen-
trally produced TNF-α is probably essential for the
activation of parenchymal microglial cells during
severe endotoxaemia.These events might be central to
the orchestration of coordinated inflammatory
responses that activate the resident phagocytic cells
Figure 3 |Autocrine and paracrine roles of TNF-α in the synthesis of CD14 in microglial
cells during endotoxaemia. Cell wall components of Gram-negative bacteria might be
recognized by TLR4/CD14-positive cells of the circumventricular organs (CVOs), allowing LPS
signalling and rapid transcription of pro-inflammatory cytokines, first within these organs and
later across the brain parenchyma. We suggest that circulating LPS targets its receptors in
CVO macrophages and microglia, stimulating the NFκB signalling pathway and triggering
TNF-α transcription. The cytokine might in turn bind its cognate receptor (TNFR1) and lead to
the formation of the TRADD/TRAF2/RIP complex, which could activate NFκB signalling in
adjacent microglia. Such events probably contribute to transcriptional activation of CD14,
TNF-α and TLR2 in the brains of endotoxin-treated animals. Expression levels of genes that
are constitutively expressed in the CVOs increase in response to circulating LPS, whereas
expression of TLR4 is decreased. This downregulation of the endotoxin receptor is central to
the control of LPS tolerance. LBP, LPS-binding protein; LPS, lipopolysaccharide; MEKK3,
mitogen-activated protein kinase kinase kinase 3; NFκB, nuclear factor κB; RIP, receptor-
interacting protein; TLR, Toll-like receptor; TNF-α, tumour necrosis factor-α; TRADD, TNFR1-
associated protein with death domain; TRAF2, TNFR-associated factor 2.
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A rodent model ofmultiple
sclerosis that is characterized by
episodes ofspasticity and
The alteration ofthe surface ofa
pathogen so that it can be
ingested by a phagocyte.
HELPER T CELLS
At least two distinct subsets of
activated CD4+T lymphocytes
have been described.TH1 cells
and TNF-α,and support cell-
mediated immunity.TH2 cells
produce IL-4,IL-5 and IL-13,
support humoural immunity,
and downregulate TH1
A transmembrane protein that
mediates apoptosis and might be
involved in the negative selection
ofautoreactive T cells in the
cytokine promotes IGF1 receptor resistance in neurons
and inhibits IGF1-receptor-mediated phosphorylation
of the docking molecule insulin receptor substrate 2
and activation of the downstream survival enzyme
phosphatidylinositol 3-kinase37.Despite this evidence,
there are conflicting results on the role ofTNF in either
exacerbating or attenuating brain damage in different
pathological situations. In an elegant study, Arnett
et al.38used mice that lack TNF-α and its associated
receptors to study demyelination and remyelination.
Lack ofTNF-αled to a significant delay in remyelina-
tion,which was associated with a reduction in the pool
of proliferating oligodendrocyte progenitors and a
reduction in the number ofmature oligodendrocytes.
TNFR2,but not TNFR1,mediated this reparative role
ofTNF,indicating that the dual role ofthis cytokine in
demyelination and remyelination depends partly on
cytokine receptor type38.
But the role ofTNF and other cytokines in myelina-
tion and demyelination could be more complex.HELPER
T CELLS also produce TNF, together with interferon-γ
(IFN-γ), and migrate in the CNS of EAE animals.
Although it is not known how this phenomenon takes
place,a subset ofhelper T cells — activated TH1 cells —
and their secreted cytokines are believed to have a signif-
icant involvement in the aetiology ofmultiple sclerosis
and demyelination.It is therefore possible that TNF and
IFN-γact synergistically to damage neurons and other
cells ofthe CNS.Moreover,transgenic mice that express
IFN-γ in the hippocampus show an enhanced
microglial reactivity to lesion-induced neuronal injury,
indicating that IFN-γmight act as an amplifier ofthe
response39.Treatment with IFN-γfailed to alter cell sur-
vival or expression ofmyelin basic protein in cultured
human oligodendrocytes,but these cells are more sus-
ceptible to FAS-mediated apoptosis, an effect that is
augmented by TNF40.On the other hand,acute admin-
istration ofTNF into the cerebral tissue is not generally
associated with demyelination,despite the robust and
transient inflammatory reaction that occurs across the
brain parenchyma20.We therefore propose that recep-
tors and cytokines that are involved in the innate
immune response (such as TNF) are beneficial to cere-
bral tissue and crucial in protecting against pathogens
and toxin-induced demyelination.By contrast,mol-
ecules ofthe adaptive immune system,especially those
produced by the TH1 subset ofhelper T cells (such as
IFN-γ) might promote demyelination.
Innate immunity and neurodegeneration
The activation of microglia and astrocytes, which is
indicative ofinflammation,occurs in theCNS ofpatients
with Alzheimer’s,Parkinson’s and Huntington’s diseases,
multiple sclerosis and ALS41–43.The serum and cere-
brospinal fluid ofthese patients show elevated levels of
molecules ofthe innate immune system,such as IL-6,IL-
1β and TNF-α41–43.IL-1β and TNF-α are secreted by
activated parenchymal microglia and can be potent
inducers ofcell death in models ofneurodegeneration,
which can be alleviated by anti-inflammatory drugs and
neutralizing antibodies41,44–47.Although this effect depends
A detrimental effect ofthis sort might be observed
when the cerebral tissue is exposed to very high concen-
trations ofLPS and other PAMPs;for example,in cases
ofbacterial meningitis in children.It is interesting to
note that immature brains are more susceptible to the
inflammatory response:LPS administration to 7-day-old
rats markedly sensitizes the brain to injury and induces
cerebral infarction in response to short periods of
hypoxia/ischaemia that cause little or no injury by
themselves30.Although the expression ofboth CD14
and TLR4 was altered in these brains, there was no
direct evidence ofa contribution ofthese receptors in
hypoxia/ischaemia-induced cerebral injury.
Although the innate immune response might have a
detrimental effect in the nervous system,it is clear that it
also has a beneficial role.Pro-inflammatory cytokines
are produced as early as 15 minutes after acute trauma
to the CNS31.This form oftraumatic injury is typically
accompanied by the migration ofinflammatory cells
into the damaged tissue.However,it takes several hours
for this phenomenon to take place,and parenchymal
elements ofthe brain produce molecules ofthe innate
immune response at early time points.Indeed,we have
provided anatomical evidence that cytokine transcripts
appear in microglia 3 and 12 hours after cortical
lesions31.Activated microglia have also been observed
within and adjacent to the primary traumatic injury site
within one hour,whereas infiltration ofmononuclear
cells became prominent only 48 hours after injury32,33.
The temporal profile ofneurotrophic factor induction
that follows the endogenous production ofpro-inflam-
matory cytokines after injury points to a potential role
of the inflammatory response in mediating neuro-
trophic responses.TNF and IL-1 are two ofthe main
cytokines that are detected within parenchymal
microglia along the lesion site31,and a role for IL-1βin
the induction of nerve growth factor expression by
astrocytes has been reported34,35.Microglial-derived IL-1
is also required for the astrocytic production ofciliary
neurotrophic factor (CNTF)31and insulin-like growth
factor 1 (IGF1)36,both ofwhich promote repair ofthe
injured CNS.Remyelination is impaired in mice that
lack IL-1β,and there is also a profound delay in the differ-
entiation ofoligodendrocyte progenitors36.This indicates
that early production ofIL-1βby parenchymal micro-
glial cells might be essential for triggering the release of
neurotrophic factors by astrocytes and facilitating the
maturation ofprecursor cells (FIG.4).
Although TNF and IL-1 have numerous overlap-
ping activities in the immune system,TNF does not
seem to be required for the release ofneurotrophic fac-
tors,at least not for that of CNTF.The production of
CNTF is totally abolished in IL-1β-deficient mice,
although TNF expression remains comparable to that
ofwild-type animals after CNS injury31.Whereas IL-1
might be crucial in increasing the production ofneuro-
trophic factors by astrocytes,TNF might act on microglia
in an autocrine and paracrine manner (FIGS 3and 4).
Paradoxically,TNF-induced microglial activity might
be detrimental to the brain by promoting apoptosis of
oligodendrocytes and preventing remyelination.This
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R E V I E W S
Cysteine proteases involved in
apoptosis,which cleave at
specific aspartate residues.
Biologically active metabolites of
arachidonic acid and other
lipids.Prostaglandins have many
functions;for example,they are
involved in vasodilation,
reactions and the regulation of
cell proliferation.They are also
involved in the control of
Enzymes that phosphorylate
proteins that are involved in
DNA synthesis and mitosis.
They require a cyclin partner for
activity and substrate specificity.
Molecules that are associated
with B-cell leukaemia and
lymphoma.Bcl2 is a
mitochondrial protein ofthe
inner membrane that can block
immunity in neurodegeneration raises questions about
the fundamental capability ofthe CNS to control exces-
sive inflammation and to drive adequately the innate
immune response for neuroprotection.
Common stressors (such as oxidative damage,mito-
chondrial dysfunction and excitotoxicity) and down-
stream effector molecules (such as CYCLIN-DEPENDENT
KINASES,caspases,BCL2 FAMILY MEMBERSand nitric oxide) are
involved in the death ofselective neuronal populations
in animal models ofALS,and in Alzheimer’s,Parkinson’s
and Huntington’s diseases43,49,50.It is unlikely that these
are the sole factors that dictate the specificity ofneuro-
degeneration or that trigger the inflammation process.
on the model and the cellular environment,IL-1βhas
the ability to activate CASPASES,whereas,in addition to
activating caspases (such as IL-1), TNF-αalso inhibits
the IGF1-dependent survival ofneurons37,47.In addition
to the secretion ofcytokines,microglial cells produce
toxic molecules such as nitric oxide and PROSTAGLANDINS,
which might further contribute to the degenerative cas-
cade41–43.By acting as APCs and controlling the transition
to the adaptive immune response,microglial cells are
mediators ofthe innate response in the CNS42,48(BOX 1).
However,it remains unclear whether the innate mecha-
nisms in the CNS are fine-tuned to handle chronic
immune challenges.The long-term induction ofinnate
(e.g. NGF, CNTF)
Figure 4 |Potential beneficial roles of pro-inflammatory cytokines during the innate immune reaction. Pathogens
(including bacteria and viruses), injury and stressors stimulate Toll-like receptors (TLRs) that are expressed at the surface of microglial
cells, the antigen-presenting cells of the central nervous system (CNS). This allows the recruitment of adaptor proteins and activation
of the pro-inflammatory signal-transduction pathways that ultimately trigger cytokine transcription. Tumour necrosis factor-α (TNF-α)
and interleukin 1β (IL-1β) are the two main cytokines involved in the early innate immune response. Once released, these cytokines
act on different cell types in the CNS. TNF-α acts as an autocrine and paracrine factor through its type 1 receptor (TNFR1) to activate
the microglia further, whereas IL-1β binds to its type 1 receptor (IL-1R1) in astrocytes, leading to the production of neurotrophins
(NTs), such as nerve growth factor (NGF) and ciliary neurotrophic factor (CNTF). These NTs might act on progenitors to favour
remyelination after mechanical or toxin-induced injury. TNF-α could also bind to TNFR2 at the surface of specific progenitors to
promote their differentiation into mature and functional oligodendrocytes. MEKK3, mitogen-activated protein kinase kinase kinase 3;
NFκB, nuclear factor κB; PAMPs, pathogen-associated molecular patterns; RIP, receptor-interacting protein; TRADD, TNFR1-
associated protein with death domain; TRAF, TNFR-associated factor.
NATURE REVIEWS | NEUROSCIENCE
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R E V I E W S
There are two classes ofMHC
molecules.MHC class I
molecules are found on the
surface ofmost cells and present
proteins that are generated in the
cytosol to T lymphocytes.MHC
class II molecules are expressed
only at the surface ofactivated
they present peptides that have
been degraded in cellular vesicles
to T cells.
A distinct set ofproteins
expressed by a given population
account for the specialized
biochemical properties ofthese
neurons,and make them
vulnerable to an immune
challenge by acting as antigens.
A set ofneurodegenerative
disorders that arise in the
context ofcancer and are
believed to be mediated by the
harbour autoantibodies that are
targeted to specific tumour and
neuronal antigens (onconeural
During splicing,introns are
excised from RNA after
transcription and the cut ends
are rejoined to form a
splicing allows the production of
different messages from the
same DNA molecule.
A cytosolic protein that clusters
glycine and GABAAreceptors at
A molecule located at the
presynaptic terminal that
interacts with several proteins
that are important in the
been proposed that peripheral antibodies recognize the
neuronal antigen and disrupt its normal function,lead-
ing to cell death.NOVA1(neuro-oncological ventral
antigen 1),the POMA antigen,a protein expressed exclu-
sively in neurons of the ventral horn and hindbrain,
binds the pre-mRNAs of the glycine receptor α2and
GABAA(γ-aminobutyric acid type A) receptorγ2sub-
units,and regulates their ALTERNATIVE SPLICING62–64.POMA
antibodies disrupt the binding ofNOVA1 to these pre-
mRNAs62,63.Mice that are null for Nova1 show abnormal
splicing of the glycine α2 receptor subunit, develop
motor defects and neurological features ofPOMA,and
undergo neuronal apoptotic death in ventral,but not
dorsal,spinal cord and brainstem65.
In the case ofALS,the administration ofimmuno-
globulin G (IgG) that is isolated from patients induces
toxicity in motor neurons ofmice and in a hybrid cell
line ofmotor neurons by disrupting calcium homeo-
stasis60,66–68.Mice injected intraperitoneally with IgG
from ALS patients also recruit activated microglial cells
in the ventral horn ofspinal cord,emphasizing the close
relationship between peripheral challenge,microglial
activation and selective neuronal degeneration69.
Circulating antibodies produced by damaged periph-
eral tissues could cross the BBB and target complexes of
antigens that are found exclusively in motor neurons.So,
in Rasmussen encephalitis,peripheral antibodies are
directed against the AMPA (α-amino-3-hydroxy-
5-methyl-4-isoxazole propionic acid) receptor subunit
GluR3and the synaptic protein Munc-18.These anti-
bodies have been suggested to induce neuronal death by
excitotoxicity and altered synaptic activity, respec-
tively59,70,71.In stiff-man syndrome,antibodies are directed
against GEPHYRIN,glutamic acid decarboxylase (GAD) and
AMPHIPHYSIN, indicating that the disorder might arise
from disturbances in neurotransmission72–74(TABLE 1).
Moreover,stereotaxic injection of IgG from patients
with Alzheimer’s disease induces immune-mediated
Emerging evidence indicates that neurons are immuno-
logically complex;for example,they express class I mol-
ecules ofthe MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)51–53.
In the nervous system,these molecules mediate neuronal
functions that are distinct from their usual roles in
peripheral tissues53.However,it is possible that they also
participate in the immune response by presenting anti-
gens53,54.How might immunity in the CNS contribute to
selective degeneration? It seems that different popula-
tions ofneurons express distinct sets ofmacromolecular
protein complexes,which account for their specialized
biochemical properties.These molecular FINGERPRINTS
(TABLE 1) might be involved in determining the specific
functions ofdifferent neuronal populations,but they
might also make neurons prone to selective vulnerability
by acting as antigens for peripheral antibodies55.For
example,medium spiny neurons in the basal ganglia,
which selectively express the protein DARPP-32, are
selectively killed in Huntington’s disease.
A synergistic action ofinnate and adaptive immunity
in selective neurodegeneration is particularly well illus-
trated in a group ofCNS disorders known as PARANEO-
PLASTIC NEUROLOGICAL DISEASES(PNDs)43,55,56.The serum of
patients that suffer from these diseases commonly har-
bours high titres ofcirculating cytokines and antibodies
that cross-react in most cases with neuronal popu-
lations43,55–57.Antibodies isolated from these patients are
neurotoxic in vitroand in vivo58–61.
PNDs are characterized by the presence oftumours
outside the CNS55.So,patients with paraneoplastic opso-
clonus-myoclonus ataxia (POMA) show deficient
inhibitory motor control ofthe eyes,limbs and trunk,as
well as gynaecological or small-cell lung cancer.The
high-titre peripheral antibodies ofthese patients stain
their systemic tumours,but also recognize neuronal anti-
gens55.These antigens are termed ‘onconeural’owing to
their cross-reactivity with tumour tissues,and are recog-
nized by the immune system as foreign proteins.It has
Table 1 |Neuronal antigens in neurodegeneration and associated systemic challenges
Aberrant RNA splicing of GABAAγ2 and
glycine α2 receptor subunits
Deficient RNA binding
Cell-cycle signalling in neurons by
disruption of Cdr2/c-Myc binding and
Impaired cerebellar plasticity and motor
Excitotoxicity; Ca2+-induced toxicity
Lymphoma, virus?L-type Ca2+
Amphiphysin Defects in presynaptic activity
Defective synaptic activity
Defects in neurotransmission
Defects in GABA synthesis; excitotoxicity
Cdr2, cerebellar-degeneration-related protein 2; c-Myc, myelocytomatosis oncogene; GABA, γ-aminobutyric acid; GAD, glutamic
acid decarboxylase; GluR3, ionotropic glutamate receptor 3; mGluR1, metabotropic glutamate receptor 1; NOVA1, neuro-oncological
ventral antigen 1.
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R E V I E W S
SUPPRESSOR T CELLS
Lymphocytes that can suppress
the activity ofnaive or effector
T cells.They produce TGF-β,
which inhibits T-cell
CYTOTOXIC T CELLS
Lymphocytes that can kill other
cells and are important in host
defence against cytosolic
pathogens.They are commonly
MHC class I CD8 cells.
Most T lymphocytes express one
oftwo antigens — CD4 and
CD8.CD4 is expressed by helper
and inflammatory T cells and is
a co-receptor for MHC class II
molecules.CD8 is expressed by
cytotoxic T cells and is a
co-receptor for MHC class I
CD4/CD8 ratio commonly
indicates heightened immune
function,whereas a decreased
ratio is indicative ofprevalent
reaction42,75–78.Indeed,in ALS for example,increases in
MHC II proteins and human leukocyte antigens in the
corticospinal tracts/anterior horns and elevation ofthe
CD4/CD8 RATIO in serum have been reported, whereas
B cells are conspicuously absent79–82.
On the basis of findings on the role of innate and
adaptive immunity and BBB leakage,we propose a model
to explain the selective vulnerability of neurons that
occurs in neurodegenerative disorders (FIG.5).According
to this model,peripheral tissues express antigens that cor-
respond to proteins found in macromolecular complexes
ofspecific neuronal populations.These tissues undergo
apoptosis and recruit at their site components ofadaptive
immunity.APCs recruited at the inflammatory site act as
phagocytes,clearing up apoptotic debris,and present the
antigen in association with the MHC I complex.Together
with co-stimulatory T cells,the APCs can activate anti-
gen-specific CD8+cells and CD4+cells to help B cells to
produce antibodies.Some ofthese antibodies might cross
the BBB passively and bind to a neuronal antigen,
inflammatory injury to cholinergic neurons in the rat
basal forebrain,whereas injection ofIgG from patients
with Parkinson’s disease causes selective damage to
neurons ofthe substantia nigra58,61.
Although peripheral antibodies might disrupt the
normal role of these neuronal antigens,they are not
sufficient to induce pathology.Indeed,reducing the
titre ofantibodies in cases ofPNDs does not slow down
progression ofdisease,and immunization ofanimals
with antibodies from patients with Rasmussen
encephalitis or PNDs fails to induce pathology with
fidelity55,56.It seems that toxicity of peripheral anti-
bodies requires secretion ofmolecules ofinnate immu-
nity in the CNS,increasing the permeability ofthe BBB
and thereby favouring infiltration of components of
the adaptive immune response in the brain.The find-
ing of many diffusely scattered SUPPRESSOR/CYTOTOXIC
T CELLSmixed with macrophages in specific CNS tissues
ofpatients with neurological disorders is indicative of
BBB leakage and the presence ofan acquired immune
Increase neuronal MHC I
Chronic induction of
Figure 5 |Hypothetical mechanism of selective neurodegeneration involving components of innate and adaptive
immunity. Damage to peripheral organs initiates immune processes at the periphery, recruiting antigen-presenting cells (APCs) at
the inflammatory site (1). These APCs migrate into lymphoid organs, where the transition to an adaptive immune response takes
place (2). As a consequence, the clonal expansion of T cells leads to the priming of B cells to produce antibodies (3,4). These
antibodies diffuse into the central nervous system (CNS) through the blood–brain barrier (BBB), or the circumventricular organs and
other structures devoid of BBB (5). In the CNS, these antibodies target specific antigens and disrupt their function, causing neuronal
death (6). Neuronal loss activates microglial cells that act as immune mediators in the CNS (7). The activated microglial cells
phagocytose the proteins of dead neurons and present this neuronal fingerprint at their surface (8). Simultaneously, they produce
pro-inflammatory cytokines and toxic molecules that compromise neuron survival (9). Eventually, in conjunction with the secretion of
cytokines, microglia disturb astroglial functions, levels of vascular endothelial growth factor (VEGF) and intercellular adhesion
molecule 1 (ICAM1) (10), increasing the permeability of the BBB and favouring T-cell infiltration (11). T cells have a synergistic effect
on selective neuronal death by targeting neuronal antigens and priming microglia to consolidate the acquired immune response in
the CNS (12,13). Alternatively, damage or pathogens within the CNS can initiate a noxious chronic innate immune response without
components of systemic adaptive immunity (black arrows) (14) that can eventually promote infiltration through BBB leakage,
resulting in an acquired immune response. MHC, major histocompatibility complex.
NATURE REVIEWS | NEUROSCIENCE
VOLUME 3 | MARCH 2002 | 2 2 5
R E V I E W S
A term that is generally used to
define ischaemic but still viable
cerebral tissue that surrounds a
core ischaemic zone.
Secondary bleeding that can
occur after an ischaemic episode.
A brain disorder that affects the
control ofgait and balance.The
most obvious sign ofthe disease
is an inability to direct the eyes
properly,reflecting lesions in
brainstem regions that
coordinate eye movements.
Patients often show alterations
ofmood and behaviour,
and mild dementia.
In summary, the recognition of neuronal finger-
prints might lead to the degeneration ofspecific neu-
ronal populations in neurological disorders.The chronic
stimulation ofthe innate immune response by microglia
might directly cause neuronal death.By producing pro-
inflammatory molecules,this persistent response in the
CNS might also promote site-specific leakage across the
BBB, and the establishment of a noxious peripheral
adaptive immune response by targeting neuronal anti-
gens.Alternatively,a peripheral challenge might initiate
systemic inflammation,leading to selective neurodegen-
eration.Although our understanding ofthe inflamma-
tory mechanisms ofneurodegeneration has improved,a
knowledge ofthe peripheral sources that initiate CNS
degeneration is lacking.
Viral/bacterial aetiology in CNS degeneration
Although best known for their detrimental effects on
the homeostasis ofthe whole organism,viral and bacte-
rial infections can induce neuronal death and have
therefore been proposed as an aetiological factor in spo-
radic cases ofneurodegeneration.RNA and DNA from
infectious agents,and antibodies against viral proteins
have been found in the serum and CNS tissues of
patients with neurological disorders.A role for viruses in
the pathogenesis ofmotor neuron disease is supported
by reports that phenotypes associated with ALS can
occur secondary to viral infections such as AIDS.In this
case,the motor symptoms can be treated with antiviral
agents89,90. Moreover, elevated titres of IgG against
human retroviral antigens,enterovirus RNA sequences
and human spuma retrovirus proteins have been found
in more than 50 patients with ALS91–95.The hypothesis
ofa viral aetiology in neurodegeneration is further sup-
ported by findings that HIV can induce encephalitis and
dementia,a syndrome that is found in Alzheimer’s dis-
ease, frontotemporal dementia,ALS-parkinsonism/
dementia complex of Guamand PROGRESSIVE SUPRANU-
CLEAR PALSY96.In addition,microbial and viral infections
ofgenetically susceptible hosts have been proposed as a
primary cause ofRasmussen encephalitis97.
Other lines ofevidence indicate that viruses and bac-
teria might contribute to neurodegeneration.Human
foamy virus proteins affect cerebellar granule cells in mice
and produce an ataxic phenotype98,whereas experimen-
tal pneumococcal meningitis in mice causes persistent
spatial-learning deficits despite normal motor func-
tions99.Mice infected with LP-BM5 murine leukaemia
virus generate antibodies that activate AMPA receptors100,
supporting the idea that peripheral antibodies that arise
from viral infection can induce neuronal death.Further-
more,immunosuppressed mice that are genetically sus-
ceptible to,and challenged with,lactate-dehydrogenase-
elevating virus develop age-dependent poliomyelitis — a
neuroparalytic disorder — and respiratory failure101.
These animals show the important relationship between
genetic factors,the immune response and infections in
neurodegeneration.Together,these observations indicate
that viruses and bacteria,in conjunction with other envi-
ronmental factors,such as trauma,chemical exposure
and stress,might trigger selective neurodegeneration in
impairing its normal function.As a consequence,apop-
tosis might occur in a subset ofneurons.The apoptotic
debris would then be engulfed and presented to other
invading T cells by parenchymal microglial cells.
Microglia stimulate the production of molecules of
innate immunity,such as cytokines,which increase the
permeability of the BBB and/or upregulate the neu-
ronal MHC I complex.These events lead to the presen-
tation ofproteins specific to the degenerating neuronal
population,and might induce the selective killing of
this population after T-cell infiltration.The initial chal-
lenge will not necessarily come from the peripheral
damage. The stress could originate in the CNS and
might trigger a chronic innate immune response that
eventually promotes infiltration and establishment of
acquired immunity in the CNS.
According to this model, the permeability of the
BBB is crucial for the infiltration ofboth antibodies and
lymphocytes.Perturbations in the stability ofthe BBB
have been reported in disease states such as Alzheimer’s
disease,stroke and HIV encephalitis42,83.The induction
ofintercellular adhesion molecule 1 (ICAM1) by pro-
inflammatory cytokines from the innate or the acquired
immune reaction has a potent action on the permeabil-
ity of the BBB,and β-amyloid deposits — one of the
main agents involved in Alzheimer’s disease — cause
alterations in the BBB83,84.Another important factor
that controls the integrity of the BBB is vascular
endothelial growth factor (VEGF)85.After a systemic
challenge,levels ofVEGF are modulated to avoid the
exacerbation ofdamage.The abnormal regulation of
VEGF levels might be a factor that predisposes the brain
to uncontrolled inflammation.Indeed,administration
of recombinant human VEGF to rats 48 hours after
an ischaemic episode increased angiogenesis in the
ISCHAEMIC PENUMBRA and significantly attenuated neuro-
logical recovery86.However,administration ofVEGF
one hour after the lesion significantly enhanced BBB
leakage, HAEMORRHAGIC TRANSFORMATION and ischaemic
lesions86. Chronic overexposure of normal brain to
VEGF also increases the expression of ICAM1 and
MHC complexes I and II,thereby favouring infiltra-
tion87.The involvement ofVEGF in immunity and neu-
ronal survival is further supported by data showing that
targeted disruption ofthe hypoxia response element on
the VEGF gene in mice resulted in an inability to induce
VEGF in hypoxic conditions.Mutant mice developed
profound progressive motor deficits between five and
seven months ofage,which were accompanied by the
classical hallmarks of ALS: accumulation of neuro-
filament proteins in spinal cord and brainstem motor
neurons,selective degeneration of motor axons,and
denervation-induced muscle atrophy88.Remarkably,a
strong astrocytosis,reminiscent ofthe intense inflam-
mation and excitotoxicity that is found in ALS patients,
occurred in the ventral horn ofthese mice88.Although
VEGF is not inflammatory by itself,it is possible that
this factor modulates immune responses in the CNS by
controlling the permeability ofthe BBB,allowing expo-
sure ofnormally sequestered CNS antigens to peripheral
immune effector molecules.
2 2 6 | MARCH 2002 | VOLUME 3
R E V I E W S
detrimental to the CNS,because it takes place rapidly in
response to systemic and cerebral insults.The endoge-
nous expression ofCD14 and numerous TLRs might
engage pro-inflammatory signal-transduction pathways
and the production ofcytokines by microglia.One ofthe
beneficial consequences ofsuch microglial reactivity is
the release ofneurotrophic factors and other molecules
that have important roles in brain homeostasis,neuro-
protection and repair in the case ofinjury.Once engaged
in severe infections,sustained microglial reactivity can
overproduce inflammatory molecules and alter the BBB,
a mechanism that seems to be central to several neurode-
generative disorders and demyelinating diseases. As
microglial cells are the APCs ofthe brain,they are proba-
bly crucial for cell-specific immunity against neuronal
elements.A better understanding ofthe innate immune
response in cerebral tissue could lead us to the funda-
mental mechanisms that underlie the capability ofthe
brain to mount an inflammatory response that either
protects against or contributes to neuronal damage.
humans.Accordingly,a single infection would be able to
trigger an innate immune response that can eventually
progress to a noxious adaptive immune response.
There is substantial evidence that molecules of the
innate immune reaction can be harmful to neurons and
oligodendrocytes,whereas other observations indicate
that inflammation is actually beneficial to recovery.The
cellular source ofthe cytokines that are involved and the
nature oftheir cognate receptors might help to explain
the discrepancies betweenstudies.The chronic produc-
tion ofinnate immune proteins and the presence ofcells
ofthe adaptive immune system in the cerebral environ-
ment could be essential features ofneurodegeneration.
However,this possibility has to be placed in a context of
causes or consequences that involve many players,
including genetic background,gender and environment.
The innate immune response that takes place in
the CNS during systemic infection is unlikely to be
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Our work is supported by the Canadian Institutes of Health
Research (CIHR) and the Neuromuscular Research Partnership.
M.D.N. is a recipient of a K. M. Hunter–CIHR Ph.D. Scholarship.
J .-P.J . holds a CIHR Senior Investigator Award. S.R. is a
CIHR Scientist and holds a Canadian Research Chair in
Neuroimmunology. We thank G. Chabot, S. Nadeau and
N. LaFlamme for assistance with the illustrations.
The following terms in this article are linked online to:
CD14 | GABAAreceptor γ2 | GluR3 | glycine receptor α2 | Iba1 |
IFN-γ | IKAP | IκB | IKK | IL-1 | IL-1R | IL-12 | IRAK | Munc-18 |
MyD88 | NFκB | NIK | NOVA1 | RIP | TLRs | TNF-α | TNFR1 |
TNFR2 | TRADD | TRAF2 | TRAF6
ALS-parkinsonism/dementia complex of Guam | Alzheimer’s
disease | amyotrophic lateral sclerosis | frontotemporal dementia |
Huntington’s disease | multiple sclerosis | Parkinson’s disease |
Encyclopedia of Life Sciences: http://www.els.net/
antigen presentation to lymphocytes | blood–brain barrier |
microglia | nervous and immune system interactions |
Access to this interactive links box is free online.