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G. Meyer Zu Hö
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C Kieseierr, MD
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ABSTRACT: Schwann cells are the myelinating glial cells of the peripheral
nervous system that support and ensheath axons with myelin to enable rapid
saltatory signal propagation in the axon. Immunocompetence, however, has
only recently been recognized as an important feature of Schwann cells. An
autoimmune response against components of the peripheral nervous system triggers disabling inflammatory neuropathies in patients and corresponding animal models. The immune system participates in nerve damage
and disease manifestation even in non-inflammatory hereditary neuropathies. A growing body of evidence suggests that Schwann cells may modulate local immune responses by recognizing and presenting antigens and
may also influence and terminate nerve inflammation by secreting cytokines.
This review summarizes current knowledge on the interaction of Schwann
cells with the immune system, which is involved in diseases of the peripheral
nervous system.
Muscle Nerve 37: 3–13, 2008
THE IMMUNOCOMPETENCE OF SCHWANN CELLS
GERD MEYER ZU HÖRSTE, MD, WEI HU, MD, HANS-PETER HARTUNG, MD,
HELMAR C. LEHMANN, MD, and BERND C. KIESEIER, MD
Department of Neurology, Heinrich-Heine-University, Moorenstrasse 5,
40225 Düsseldorf, Germany
Accepted 26 July 2007
Schwann cells myelinate and support axons of the
peripheral nervous system (PNS) and they can become targets of a primary and secondary immune
response. We review pathogenetic concepts and
models of immune reactions in the PNS and elaborate on specific immune functions of Schwann cells
in greater detail.
Human inflammatory neuropathies are caused
by an immune response mounted against still incompletely characterized autoantigens within the PNS.
The clinical picture ranges from Guillain–Barré syndrome (GBS)35 to chronic inflammatory demyelinating polyneuropathy (CIDP).37 Different subforms
and distinct regional variants have been defined.
Available for Category 1 CME credit through the AANEM at www.
aanem.org.
Abbreviations: BDNF, brain-derived neurotrophic factor; CIDP, chronic inflammatory demyelinating polyneuropathy; CMT, Charcot–Marie–Tooth (disease); EAN, experimental autoimmune neuritis; FasL, Fas ligand; GBS, Guillain–Barré syndrome; IL, interleukin; LPS, lipopolysaccharide; MAG, myelinassociated glycoprotein; MBP, myelin basic protein; MHC, major
histocompatibility complex; NF-␬B, nuclear transcription factor-␬B; P0, myelin protein zero; PNS, peripheral nervous system; Rag-1, recombination
activating gene-1; TLR, toll-like receptors; TNF, tumor necrosis factor
Key words: antigen presentation; Charcot–Marie–Tooth disease; experimental autoimmune neuritis; Guillain–Barré syndrome; inflammatory neuropathy; Schwann cells
Correspondence to: B. C. Kieseier; e-mail: [email protected]
© 2007 Wiley Periodicals, Inc.
Published online 6 September 2007 in Wiley InterScience (www.interscience.
wiley.com). DOI 10.1002/mus.20893
Immunocompetence of Schwann Cells
Depending on the primary target of the autoimmune reaction, acute inflammatory neuropathies
are classified either as the most common acute inflammatory demyelinating polyneuropathy (AIDP)
or as the less frequent acute motor (and sensory)
axonal neuropathies (AMAN and AMSAN, respectively). Miller Fisher syndrome (MFS) denotes the
acute regional variant involving predominantly cranial nerves. Multifocal motor neuropathy (MMN) is
a multifocal variant of CIDP involving mainly motor
fibers.61
A consistent model of how these disorders develop has been established for certain subforms.
Even under normal conditions, there may be autoreactive T lymphocytes recognizing peripheral nerve
antigens in the systemic immune compartment, but
their continuous suppression ensures self-tolerance.
During a minor infectious disease these lymphocytes
become activated upon encountering microbial
epitopes. The hallmark finding that microbial
epitopes can resemble endogenous peripheral nerve
antigens has been termed “molecular mimicry.”133,134,136 Autoreactive T lymphocytes stimulate B
cells to produce autoantibodies, which in turn can
block nerve conduction,119,128 activate complement,102,115 and facilitate a macrophage attack in the
peripheral nerve. Activated T cells transgress the
blood–nerve barrier and provoke local inflammation
by proinflammatory cytokines.54 Attracted macro-
MUSCLE & NERVE
January 2008
3
phages act as antigen-presenting cells, release toxic
mediators, and directly damage myelinating
Schwann cells and axons.52 Long-term disability is
mainly determined by the degree of axonal degeneration. The immune response may eventually be
terminated by increased T-cell apoptosis, as demonstrated in animal models of inflammatory neuropathies.31,32
PATHOMECHANISMS OF AUTOIMMUNE DISORDERS
OF THE PNS
The pathological hallmark of the demyelinating subtypes of inflammatory neuropathies is the infiltration
of the PNS by lymphocytes and macrophages, which
results in multifocal demyelination, predominantly
around blood vessels.33 Macrophages actively strip
off myelin lamellae from axons, induce vesicular
disruption of the myelin sheath, and phagocytose
both intact and damaged myelin, as shown by electron microscopy.34,52 Macrophages, numerous as resident cells in the endoneurium, represent the predominant cell population in the inflamed PNS, and
they reside in spinal roots as well as in more distal
segments of the affected nerves.51
Pathological studies suggest that the early invasion of the PNS by leukocytes is crucial in the pathogenesis of inflammatory demyelination. Circulating
autoreactive T cells need to be activated in the periphery in order to cross the blood–nerve barrier
and incite a local inflammatory response. Breakdown of the blood–nerve barrier is one of the earliest morphologically demonstrable events in lesion
development in the animal model of demyelinating
GBS.32
It remains elusive how the cascade of autoimmune responses targeting PNS structures is ignited.
One pathogenic mechanism of special relevance to
autoimmune neuropathies is “molecular mimicry.”
In a proportion of patients with GBS, epitopes
shared between the enteropathogen Campylobacter
jejuni, cytomegalovirus, or Haemophilus influenzae
and nerve fibers have been identified as targets for
aberrant cross-reactive B-cell responses.53 In a recent
study, antibody responses to the ganglioside GM1
were linked to axonal and motor injury, as seen in
one clinical variant of GBS136 and in an experimental model induced in rabbits by active immunization
with this glycoconjugate.135 This provides a conclusive pathomechanism of axonal subtypes of GBS.
Despite long-term efforts, no such conclusive
mechanistic models have been confirmed in the demyelinating GBS subtypes. Myelin protein–like structures have not been proven to exist in microbes.
4
Immunocompetence of Schwann Cells
Antibodies against various components of the myelin
sheath are found in only a fraction of demyelinating
GBS patients and even in some healthy subjects.
There may be several explanations for this observation. First, myelin components may not be the target
of the immune response in demyelinating GBS. Second, antibodies against myelin components are important, but may not be the main orchestrators of
the immune response in demyelinating GBS. A primarily cellular immune response may not be controlled sufficiently by screening for antibodies.
Thus, it is impossible to prove that an animal
model of demyelinating GBS actually reflects human
disease, because the definite immunopathogenetic
mechanisms and target antigens of this disease in
humans still have not been identified. From a pathological, electrophysiological, and clinical point of
view, myelin-induced experimental autoimmune
neuritis (EAN) is a good model of acute demyelinating GBS. Furthermore, plasma exchange and intravenous immunoglobulins, the clinical mainstays of
human GBS therapy, are effective in myelin-induced
EAN.
GBS should be defined as an organ-specific immune-mediated disorder emerging from a synergistic interaction of cell-mediated and humoral immune responses to still incompletely characterized
peripheral nerve antigens.36,106 Schwann cells represent one of the major targets in immune-mediated
disorders of the PNS.
ANIMAL MODELS OF INFLAMMATORY
NEUROPATHIES
Many features of human inflammatory neuropathies
are accurately recapitulated in EAN, an animal
model of GBS that has greatly extended our knowledge of the underlying pathological mechanisms.
Table 1 provides an overview of the available animal
models. These models are explained in what follows.
A variety of antigens can induce immunological
responses against peripheral nerves in different species, including rats, mice, rabbits, monkeys, and
guinea pigs (Table 1). Immunization with Schwanncell or myelin components generates demyelinating
neuropathy models, whereas axonal components
elicit axonal damage representing axonal GBS subtypes (Table 1). In the most widely used GBS model,
Lewis rats are immunized with peripheral myelin
homogenates, myelin proteins, or derived peptides
to develop EAN (Table 1).76 Like entire myelin homogenates, the major myelin adhesion molecule
P0,82 and the fatty acid– binding protein P2,47
and their immunogenic peptides, elicit marked im-
MUSCLE & NERVE
January 2008
Table 1. Animal models of inflammatory neuropathies.
Reference
nos.
Animal model
Transfer
Possible antigens
Description
Rat
Lewis
Active
PNS myelin, P0, P2, P0(180–199),
P2(53–78), P2(57–81)
PMP22
PNS myelin ⫹ cyclosporine
PNS myelin
PNS myelin
P0, P2, P0(180–199), P2(61–70), MAG
Frequently used EAN models
1, 23, 76, 83
Mild course EAN
CIDP-like chronic relapsing, not robust
Less severe EAN course
CIDP-like relapsing
Rapid-onset EAN, CIDP-like relapsing
if transferred repeatedly
28
78
41
46
76, 64
Varying effectiveness reported
Mild course EAN
Severe course EAN
Peripheral and central demyelination
Spontaneous autoimmune neuropathy
CIDP-like
81, 137
121, 14
AT
Spontaneous
P0(180–199), P0(106–125) ⫹ PTx
P2
Myelin ⫹ PTx (⫹IL-12)
MBP
—
Active
PNS myelin, P2 galactocerebroside
First EAN model
Chronic inflammation
Active
Active
GM1
GD1b
Acute motor axonal neuropathy
Ataxic sensory neuronopathy
Active
Active
PNS myelin
PNS myelin, P2
BN, SD, BUF, Wistar
Dark Agouti
Lewis
Mouse
C57/B6
SJL
BALB/c
B7-2⫺/⫺ NOD
Rabbit
Rabbit
Rabbit (axonal)
Other
Guinea pig
Monkey
Active
Active
Active
Active
AT
Active
Active
2
100
76
48
114
135
63
109
24
PNS, peripheral nervous system; EAN, experimental autoimmune neuritis; CIDP, chronic inflammatory neuropathy; P0, myelin protein zero; P2, myelin protein 2;
PMP22, peripheral myelin protein of 22 kDa; BN, Brown–Norway rats; SD, Sprague–Dawley rats; BUF, Buffalo rats; MAG, myelin-associated glycoprotein;
MBP, myelin basic protein; PTx, pertussis toxin; AT, adoptive transfer.
munological responses. Less severe forms of rat EAN
are triggered by peripheral myelin protein of 22
kDa.28,59 Alternatively, transfer of stimulated T lymphocytes that are reactive toward various myelin antigens, including myelin proteins P2,98 P0,68 and derived peptides, evokes adoptive transfer EAN in host
animals (Table 1). Adoptive transfer of lymphocytes
that are reactive against myelin-associated glycoprotein (MAG) generates mild peripheral nerve inflammation.129
Unlike rats, mice were generally thought not to
be susceptible to immunization with peripheral myelin, but recent studies have challenged this view.
Although myelin protein P2 induced only subclinical
EAN in SJL mice, extended immunization protocols
have allowed the induction of severe EAN by myelin
homogenates in this strain (Table 1).14 Adoptive
transfer EAN in BALB/c mice identified myelin basic protein (MBP) as an alternative neuritogenic
antigen. The number of regulatory T cells differs
between mouse strains,17 which might explain their
differential autoimmune susceptibility, and a similar
concept might be relevant for human autoimmune
diseases.22 Generation of active EAN by two different
Immunocompetence of Schwann Cells
P0 peptides, P0(180 –199)137 and P0(106 –125),81 together with pertussis toxin adjuvant in C57/B6 mice,
has recently been reported. This protocol might enable the study of peripheral nerve inflammation in
genetically modified animals, which are mostly generated on this background, allowing us to further
extend our knowledge of inflammatory neuropathies.
The present data clearly highlight the fact that
immunization with myelin components derived from
Schwann cells as the cellular source can be used to
induce an immune reponse against the PNS.
SECONDARY IMMUNE REACTIONS IN NONINFLAMMATORY HEREDITARY NEUROPATHIES
Even hereditary disorders of the peripheral nervous
system trigger immune responses in the peripheral
nerve. These responses have been suggested to be an
important determinant of disease manifestation.
Charcot–Marie–Tooth (CMT) disease, clinically
termed hereditary motor and sensory neuropathy
(HMSN), is the most common inherited peripheral
neuropathy. Animal models of many subtypes of
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January 2008
5
CMT have been generated and have vastly extended
our knowledge of the underlying disease mechanisms.80 In the more frequent demyelinating CMT
forms, a genetic defect results in progressive destruction of myelin sheaths and secondary axonal loss.117
One may easily conceive that such genetically determined defects of myelination can trigger a secondary
immune response. Indeed, infiltration of lymphocytes and macrophages has been demonstrated in
peripheral nerves of some human CMT patients,27,125 and corresponding animal models.7,57,104
Apart from this secondary immune response,
however, a series of experimental studies have suggested immune cells as a primary cause for disease
manifestation in genetically determined neuropathies. Mouse models of CMT subtypes CMT1B72 and
CMTX5,80 were crossbred with mouse strains lacking
functional T lymphocytes or with impaired macrophage function. Surprisingly, immune deficiency
ameliorated mild, chronic demyelination in these
models of inherited neuropathies. Impairment of
immune function was achieved by abolishing functional T lymphocytes in mouse strains carrying null
mutations of the recombination activating gene-1
(Rag-1)56,104 or the T-cell-receptor ␣-subunit gene.77
Macrophage function was impeded in mice lacking
functional genes of macrophage colony stimulating
factor16 and adhesion protein sialoadhesin preferentially expressed in macrophages.58 Demyelination in
the Rag-1– deficient CMT1B model could be reconstituted by transfer of wild-type bone marrow,75
which excludes Schwann-cell intrinsic effects of
Rag-1 deficiency.
This effect, however, has not been shown in the
most common CMT subtype, 1A, and, in contrast to
its effect on mild chronic demyelination, immune
deficiency was found to aggravate early-onset severe
dysmyelination.7 Furthermore, myelinating cell cultures generated from a CMT1A animal model develop defects of myelination despite the obvious absence of immune cells in such a model.88 The
efficacy of an anti-inflammatory treatment in CMT
remains controversial.73
One possible explanation for the increased immune reaction in the CMT1B animal model may be
reduced intrathymic induction of tolerance. A heterozygous knockout of the myelin protein zero (P0)
gene determines this CMT subtype and this reduction in gene dose was demonstrated to increase Tcell reactivity to a P0 peptide.84 Genetically determined P0 deficiency in mice abolishes tolerance and
causes the P0 protein to be recognized as a foreign
antigen,124 which further supports autoimmune
mechanisms in hereditary neuropathies.
6
Immunocompetence of Schwann Cells
Finally, we have learned that macrophages and
lymphocytes are required for myelin loss in models
of at least certain forms of hereditary neuropathies.
This raises the question of how immune cells “sense”
the defectiveness of the myelin sheath and why they
participate in its gradual destruction. Increased immunogenity due to altered protein composition or
mechanical instability of the myelin sheath has been
suggested. Molecules required for antigen presentation could communicate this information from
Schwann cells to immune cells and one may speculate that a myelin protein mutant Schwann cell
would not demyelinate if it lacked the molecules
required for antigen processing and presentation.
We have described the intimate interaction between myelinating Schwann cells and immune cells
and its importance for various peripheral nerve disorders. In what follows, we specifically elaborate on
the expanding recognition of Schwann cells as immunocompetent cells that form part of the local
immune circuitry within the peripheral nerve. The
present data suggest that the entire spectrum of an
immune response can be displayed by Schwann cells,
which includes recognition of antigens; presentation
of antigens; mounting of an immune response; and,
finally, terminating the immune response within the
inflamed peripheral nerve (Fig. 1).
ANTIGEN RECOGNITION BY SCHWANN CELLS
Two types of responses to invading organisms can
take place in the mammalian immune system: an
acute response launched within hours and a delayed
response occurring within days. The immediately
responding system is called the innate immune system,
and it evolves stereotypically and at the same intensity regardless of how often the infectious agent is
encountered. The strategy of the innate immune
response is not to recognize every possible antigen,
but rather to focus on a few highly conserved structures present in large groups of microorganisms.
These structures are referred to as pathogen-associated
molecular patterns, and the corresponding receptors
of the innate immune system are called patternrecognition receptors.45 Examples of pathogen-associated molecular patterns are bacterial lipopolysaccharide (LPS), peptidoglycan, and bacterial DNA.
Although chemically quite distinct, these molecules
display common features. They are only produced by
microbial pathogens and not by their host. They
generally represent invariant structures shared by
large classes of pathogens, and they are usually relevant for the survival or pathogenicity of microorganisms.79
MUSCLE & NERVE
January 2008
FIGURE 1. Immunocompetence of Schwann cells. (a) Facultative antigen presentation: Schwann cells are able to process and present
endogenous antigens to immune cells. Schwann cells can express the major histocompatibility (MHC) class I molecules as well as MHC
class II molecules; in addition, co-stimulatory molecules are expressed on the cell surface. (b) Facultative antigen recognition: via toll-like
receptors, Schwann cells can recognize antigens, such as LPS, activating the nuclear transcription factor NF-␬B. (c) Regulation of an
immune response: Schwann cells, after stimulation, secrete various soluble factors, such as cytokines, growth factors, and other immune
mediators. (d) Termination of an immune response: via the interaction of Fas and FasL, Schwann cells can drive inflammatory T cells into
apoptosis. LPS, lipopolysaccharide; GDNF, glial cell line– derived neurotrophic factor; PGE2, prostaglandin E2; IL, interleukin; TNF, tumor
necrosis factor; TGF, transforming growth factor.
The family of toll-like receptors (TLRs) belongs
to the group of pattern-recognition receptors that
recognize specific conserved components of microbes,118 such as LPS, and that have been implicated to play a critical role in various inflammatory
disorders.20,40 To date, 11 TLRs have been identified
in humans and 7 in rats.43 LPS, a major component
of the outer membrane of gram-negative bacteria,
which appears to be a relevant antigen triggering
immune-mediated demyelination of the PNS,53,60 is
recognized by TLR-4.
TLRs are usually found on antigen-presenting
cells, such as dendritic cells. TLR-2 has been shown
to be expressed constitutively on primary human
and rat Schwann cells and has been invoked as a
target receptor for Mycobacterium leprae.38,89 Under
inflammatory conditions, expression of various
TLRs, especially TLR-4, is inducible on rat Schwann
cells in vitro. Selective stimulation of TLR-4 on
Immunocompetence of Schwann Cells
Schwann cells with LPS has been shown to elicit the
production of various inflammatory mediators such
as chemokines, protease inhibitors, and growth factors.42 Thus, in aggregate, these findings suggest that
Schwann cells can detect LPS fragments and may act
as a link between innate and acquired immunity via
TLR-4 activation in the inflamed PNS. Recent studies
have also revealed that inflammatory Schwann-cell
activation can be induced via TLR-2 and TLR-3.65
SCHWANN CELLS AS FACULTATIVE ANTIGENPRESENTING CELLS
The task of displaying the antigens of cell-associated
microbes for recognition by T lymphocytes is performed by specific molecules that are encoded by
genes comprising the major histocompatibility complex (MHC). The physiological function of MHC
molecules is the presentation of peptides to T cells.
MUSCLE & NERVE
January 2008
7
Two types of MHC gene products can be distinguished, class I MHC molecules and class II MHC
molecules, which differ functionally. Each MHC
molecule consists of an extracellular peptide-binding cleft or groove and a pair of immunoglobulinlike domains, containing binding sites for the T-cell
surface markers CD4 and CD8.71,122 By transmembrane domains, MHC molecules are anchored to the
cell surface. MHC molecules exhibit a broad specificity for peptide binding, whereas the fine specificity
of antigen recognition resides mostly in the T-cell
receptor.13 In general, endogenous cytosolic peptides are presented via MHC class I molecules to
CD8⫹ T cells, whereas mainly exogenously derived
peptides generated in vesicles are bound to MHC
class II molecules and recognized by CD4⫹ T lymphocytes.97,127 The two classes of MHC molecules are
expressed differentially on cells. All nucleated cells
exhibit MHC class I molecules, although hematopoietic cells express them at the highest densities. MHC
class II molecules, in contrast, are normally only
expressed on professional antigen-presenting cells,
such as macrophages, dendritic cells, and B lymphocytes. The levels of both class I and II molecules can
be markedly upregulated by cytokines, particularly
interferon-␥ and tumor necrosis factor (TNF)-␣.
Macrophages are the predominant professional antigen-presenting cells in EAN. These macrophages in
EAN shift from resident endoneural in the early
disease stages to a hematopoietic origin in later
stages.85
Apart from such professional antigen-presenting
cells, other cell types may acquire the ability to process and present antigens in inflammatory conditions, thus representing facultative antigen-presenting cells. Human and rat Schwann cells in vitro
constitutively express low levels of MHC class I but
not MHC class II.6,9,30,66,101 Significant numbers of
MHC class II molecules can be detected on Schwann
cells in the presence of activated T lymphocytes
upon stimulation with the proinflammatory cytokine
interferon-␥, which can be synergistically increased
by the addition of TNF-␣.6,30,55,66,123 Moreover, a
number of molecules that are prominent in the
intracellular processing cascade of peptides prone to
MHC presentation can be visualized in Schwann
cells in vitro and in vivo (Meyer zu Hörste and
Kieseier, unpublished observations). In human
nerve biopsies from patients with GBS and its
chronic variant CIDP, Schwann cells stained positive
for MHC class II, suggesting that these cells may
indeed act as facultative antigen-presenting cells in
immune-mediated disorders of the PNS.92,93 Antigen-presenting cells are characterized by their ability
8
Immunocompetence of Schwann Cells
to phagocytose exogenous antigen and its degradation to antigenic peptides, which can be expressed in
the cleft of the MHC molecule.15,122 Schwann cells in
vitro have been shown to present foreign and exogenous antigens, such as MBP, to antigen-specific syngeneic T-cell lines.10,130 Moreover, the presentation
of endogenous antigen, such as the myelin component P2, by Schwann cells via MHC class II can
restimulate resting antigen-specific CD4⫹ T-cell
lines.67
Non-endogenous antigen can also be presented
by Schwann cells, which may be of special relevance
in leprosy. On a global scale, leprosy is one of the
major causes of peripheral neuropathy, with sensory
loss being its foremost symptom. Neuropathy in leprosy mainly affects pain and temperature sensation
from small cutaneous nerves, resulting in painless
injury and mutilation.99 The causal agent of the
disease, Mycobacterium leprae, shows a remarkable
preference for invading and proliferating in nonmyelinating Schwann cells.96 Schwann cells present
M. leprae– derived antigens to lymphocytes in an
MHC II– dependent manner,26 whereas CD8⫹ lymphocytes lyse M. leprae–infected Schwann cells in
vitro.112 A different study showed M. leprae– derived
antigen presentation by Schwann cells to CD4⫹ lymphocytes.110 This MHC II–mediated interaction resulted in Schwann-cell destruction. Thus, apart from
other mechanisms described,95,120 antigen presentation by Schwann cells evolves as an important mechanism of nerve damage in this infectious neuropathy.
For optimal T-cell activation and differentiation
to occur, at least two distinct signals delivered during
the interaction with an antigen-presenting cell are
required. These include antigen-specific signaling
via MHC and signaling through costimulatory molecules. If the T cell does not receive adequate costimulation, it is rendered anergic or undergoes apoptosis. Thus, the costimulation signal is central to
T-cell activation and survival.21,105 Recent data suggest that BB-1, a member of the family of costimulatory molecules, can be detected on non-myelinating
Schwann cells and appears to be upregulated on
myelinating Schwann cells in nerve biopsies from
CIDP patients. This further indicates that Schwann
cells possess the cellular components required to act
as facultative antigen-presenting cells in the inflamed PNS.86,94 The extent to which these cells may
propagate a T-cell response via antigen presentation
in situ needs to be elucidated in greater detail. It
needs to be investigated whether Schwann cells can
suppress such a response in vivo as well as in vitro.70
In any case, it is an appealing concept that Schwann
MUSCLE & NERVE
January 2008
cells actively control the local T-cell response within
the peripheral nerve by acting as facultative antigenpresenting cells.
SCHWANN CELLS AS REGULATORS OF AN
AUTOIMMUNE RESPONSE
For a long time, cytokines, as mediators of an immune response within the peripheral nerve, were
considered to be the exclusive product of inflammatory cells. Nowadays, there is a large body of evidence implying that Schwann cells can produce and
secrete a wide variety of cytokines, which could act as
immunomodulators.70 Interleukin (IL)-1, a cytokine
relevant in the initiation of an immune response,
can be produced by cultured Schwann cells.8 Other
proinflammatory cytokines, such as IL-6,8,12,29,87
TNF-␣,8,12,29,87,116,126 and transforming growth factor␤,103,113 are generated and released by Schwann cells
under certain conditions, some in vitro and others in
vivo.50,74,108 Schwann cells are able to regulate the
production of proinflammatory cytokines, at least in
part, in a specific autocrine manner, as shown for
IL-1.107,108 The specific receptors for some of the
cytokines, such as TNF receptor, are constitutively
expressed on Schwann cells, rendering these cells
susceptible to, for example, a TNF-␣ response.11,90
Other proinflammatory and immunoregulatory mediators, such as prostaglandin E2, thromboxane A2,
and leukotriene C4, are synthesized in large amounts
by Schwann cells, and may regulate the immune
cascade within the inflamed PNS.18,19 Further mediators produced by Schwann cells include osteopontin, which is constitutively expressed and can be
easily induced in Schwann cells,3 as well as glial cell
line– derived neurotrophic factor, a known survival
factor for neurons, and glial cell line– derived neurotrophic factor family receptor ␣-1, displayed on
the surface of Schwann cells.39,44
Nuclear transcription factor-␬B (NF-␬B) plays a
pivotal role in the regulation of the host innate
antimicrobial response. It governs the expression of
many immunological mediators, including cytokines, their receptors, and components of their signal transduction. Recent studies have suggested that
two NF-␬B complexes, p65/p50 and p50/p50, can
be activated and regulated in human Schwann cells
under certain conditions.91 Interestingly, the natural
inhibitor of NF-␬B, I␬B, can be detected in large
amounts in Schwann cells.4 These observations further point to an active rather than a passive role for
Schwann cells in the inflamed PNS. Apart from engaging such cellular factors, Schwann cells can modulate local immune reactivity by humoral mecha-
Immunocompetence of Schwann Cells
nisms. One pathway may operate through the
production and release of nitric oxide (NO), a multipotential mediator with neurotoxic and immunosuppressive properties. Schwann cells are endowed
with inducible nitrite oxide synthase, which is upregulated after the stimulation with proinflammatory cytokines.131
Taken together, a large number of pro- and antiinflammatory mediators can be induced and released by Schwann cells. The extent to which these
mediators have a significant impact on the clinical
course of an immune-mediated disorder in the PNS
clearly warrants further investigation.
In animal models of inflammatory diseases of the
central nervous system, neurotrophic cytokines and
neurotrophins have been suggested as important
regulators of axonal degeneration and of resulting
clinical impairment.69 Most interestingly, brainderived neurotrophic factor (BDNF), originating
from inflammatory cells, has been demonstrated to
mediate neuroprotective effects,49,111 which emphasizes the concept of neuroprotective autoimmunity.
Few studies, however, support a comparable concept
in inflammatory diseases of the peripheral nervous
system. Except for reduced urinary bladder weight as
a possible indirect sign of reduced autonomic dysregulation, BDNF treatment did not significantly influence clinical disease manifestation in rat EAN.25
SCHWANN CELLS AS TERMINATORS OF THE
AUTOIMMUNE RESPONSE
In order to control the massive expansion of cellular
and soluble immune mediators within the target
tissue, certain mechanisms must operate with high
fidelity to regulate the immune response. Once the
target antigen has been eliminated or infection
abated, the activated effector cells are no longer
needed. When the antigenic stimulus is no longer
present, the cells will succumb to programmed cell
death or apoptosis.32
The survival of lymphocytes depends on a delicate balance between death-promoting and deathinhibiting factors. Various mechanisms can induce
apoptosis. It can, for example, be affected through
the interaction of the cell surface receptor Fas on T
cells with its ligand, FasL, a member of the TNF
family.62 Schwann cells reveal surface expression of
FasL after stimulation with proinflammatory cytokines in vitro. Functional analysis indicates that the
interaction between Fas on T cells and FasL on
Schwann cells promotes apoptosis of T lymphocytes.
This raises the possibility that Schwann cells are
MUSCLE & NERVE
January 2008
9
important in terminating the immune response in
the inflamed PNS.132
11.
SCHWANN CELLS AS IMMUNOCOMPETENT CELLS
In summary, our current knowledge of the potential
immunocompetence of Schwann cells suggests that
these cells can induce an immune response within
the peripheral nerve via pattern-recognition receptors, but can also trigger a T-cell response via the
presentation of antigen fragments on MHC class II
molecules in the context of costimulatory molecules.
Through the release of immunomodulators,
Schwann cells could regulate the immune reaction
in situ and, by inducing apoptosis, appear even to
terminate an ongoing immune response. This evidence collected in recent years indicates that the
many functions of Schwann cells go far beyond forming the myelin sheath.
This work was supported by grants from the German Research
Foundation (GRK320) and the Research Commission of the
Heinrich-Heine-University, Düsseldorf (FoKo) (to G.M.z.H, H.L.,
and B.C.K.).
12.
13.
14.
15.
16.
17.
18.
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