Immunocompetence of Schwann Cells

G. Meyer Zu Hörste, MD; W. Hu, MD; Hans-P. Hartung, MD; H. C. Lehmann, MD; B. C. Kieseier, MD

No one involved in the planning of this CME activity has anyy relevant financial relationships to discllose. Authors/faculty have nothing to disclose.

CME is available 1/15/2011 - 1/5/2014

Copyright: 20008

American Association of Neuromuscular and Electrodiagnostic Medicine

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The ideas and opinions in this Journal Review are solely thhose of the author and do not necessariily represent those of the AANEM

Product: JR16 INVITED REVIEW 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 sys- tem triggers disabling inflammatory neuropathies in patients and corre- sponding animal models. The immune system participates in nerve damage and disease manifestation even in non-inflammatory hereditary neuropa- thies. A growing body of evidence suggests that Schwann cells may mod- ulate 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 HO¨ RSTE, 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 Du¨sseldorf, Germany

Accepted 26 July 2007

Schwann cells myelinate and support axons of the Depending on the primary target of the autoim- peripheral nervous system (PNS) and they can be- mune reaction, acute inflammatory neuropathies come targets of a primary and secondary immune are classified either as the most common acute in- response. We review pathogenetic concepts and flammatory demyelinating polyneuropathy (AIDP) models of immune reactions in the PNS and elabo- or as the less frequent acute motor (and sensory) rate on specific immune functions of Schwann cells axonal neuropathies (AMAN and AMSAN, respec- in greater detail. tively). Miller Fisher syndrome (MFS) denotes the Human inflammatory neuropathies are caused acute regional variant involving predominantly cra- by an immune response mounted against still incom- nial nerves. Multifocal motor neuropathy (MMN) is pletely characterized autoantigens within the PNS. a multifocal variant of CIDP involving mainly motor The clinical picture ranges from Guillain–Barre´ syn- fibers.61 drome (GBS)35 to chronic inflammatory demyelinat- A consistent model of how these disorders de- ing polyneuropathy (CIDP).37 Different subforms velop has been established for certain subforms. and distinct regional variants have been defined. Even under normal conditions, there may be auto- reactive T lymphocytes recognizing peripheral nerve antigens in the systemic immune compartment, but Available for Category 1 CME credit through the AANEM at www. their continuous suppression ensures self-tolerance. aanem.org. During a minor infectious disease these lymphocytes Abbreviations: BDNF, brain-derived neurotrophic factor; CIDP, chronic in- flammatory demyelinating polyneuropathy; CMT, Charcot–Marie–Tooth (dis- become activated upon encountering microbial ease); EAN, experimental autoimmune neuritis; FasL, Fas ligand; GBS, Guil- epitopes. The hallmark finding that microbial lain–Barre´ syndrome; IL, interleukin; LPS, lipopolysaccharide; MAG, myelin- associated glycoprotein; MBP, myelin basic protein; MHC, major epitopes can resemble endogenous peripheral nerve histocompatibility complex; NF-␬B, nuclear transcription factor-␬B; P0, my- antigens has been termed “molecular mimic- elin protein zero; PNS, peripheral nervous system; Rag-1, recombination 133,134,136 activating gene-1; TLR, toll-like receptors; TNF, tumor necrosis factor ry.” Autoreactive T lymphocytes stimulate B Key words: antigen presentation; Charcot–Marie–Tooth disease; experi- cells to produce autoantibodies, which in turn can mental autoimmune neuritis; Guillain–Barre´ syndrome; inflammatory neurop- 119,128 athy; Schwann cells block nerve conduction, activate comple- Correspondence to: B. C. Kieseier; e-mail: bernd.kieseier@uni-duessel- ment,102,115 and facilitate a macrophage attack in the dorf.de peripheral nerve. Activated T cells transgress the © 2007 Wiley Periodicals, Inc. Published online 6 September 2007 in Wiley InterScience (www.interscience. blood–nerve barrier and provoke local inflammation wiley.com). DOI 10.1002/mus.20893 by proinflammatory cytokines.54 Attracted macro-

Immunocompetence of Schwann Cells MUSCLE & NERVE January 2008 3 phages act as antigen-presenting cells, release toxic Antibodies against various components of the myelin mediators, and directly damage myelinating sheath are found in only a fraction of demyelinating Schwann cells and axons.52 Long-term disability is GBS patients and even in some healthy subjects. mainly determined by the degree of axonal degen- There may be several explanations for this observa- eration. The immune response may eventually be tion. First, myelin components may not be the target terminated by increased T-cell apoptosis, as demon- of the immune response in demyelinating GBS. Sec- strated in animal models of inflammatory neuropa- ond, antibodies against myelin components are im- thies.31,32 portant, but may not be the main orchestrators of the immune response in demyelinating GBS. A pri- PATHOMECHANISMS OF AUTOIMMUNE DISORDERS marily cellular immune response may not be con- OF THE PNS trolled sufficiently by screening for antibodies. Thus, it is impossible to prove that an animal The pathological hallmark of the demyelinating sub- model of demyelinating GBS actually reflects human types of inflammatory neuropathies is the infiltration disease, because the definite immunopathogenetic of the PNS by lymphocytes and macrophages, which mechanisms and target antigens of this disease in results in multifocal demyelination, predominantly humans still have not been identified. From a patho- around blood vessels.33 Macrophages actively strip logical, electrophysiological, and clinical point of off myelin lamellae from axons, induce vesicular view, myelin-induced experimental autoimmune disruption of the myelin sheath, and phagocytose neuritis (EAN) is a good model of acute demyelinat- both intact and damaged myelin, as shown by elec- ing GBS. Furthermore, plasma exchange and intra- tron microscopy.34,52 Macrophages, numerous as res- venous immunoglobulins, the clinical mainstays of ident cells in the endoneurium, represent the pre- human GBS therapy, are effective in myelin-induced dominant cell population in the inflamed PNS, and EAN. they reside in spinal roots as well as in more distal GBS should be defined as an organ-specific im- segments of the affected nerves.51 mune-mediated disorder emerging from a synergis- Pathological studies suggest that the early inva- tic interaction of cell-mediated and humoral im- sion of the PNS by leukocytes is crucial in the patho- mune responses to still incompletely characterized genesis of inflammatory demyelination. Circulating peripheral nerve antigens.36,106 Schwann cells repre- autoreactive T cells need to be activated in the pe- sent one of the major targets in immune-mediated riphery in order to cross the blood–nerve barrier disorders of the PNS. and incite a local inflammatory response. Break- down of the blood–nerve barrier is one of the earli- est morphologically demonstrable events in lesion ANIMAL MODELS OF INFLAMMATORY NEUROPATHIES development in the animal model of demyelinating GBS.32 Many features of human inflammatory neuropathies It remains elusive how the cascade of autoim- are accurately recapitulated in EAN, an animal mune responses targeting PNS structures is ignited. model of GBS that has greatly extended our knowl- One pathogenic mechanism of special relevance to edge of the underlying pathological mechanisms. autoimmune neuropathies is “molecular mimicry.” Table 1 provides an overview of the available animal In a proportion of patients with GBS, epitopes models. These models are explained in what follows. shared between the enteropathogen Campylobacter A variety of antigens can induce immunological jejuni, cytomegalovirus, or Haemophilus influenzae responses against peripheral nerves in different spe- and nerve fibers have been identified as targets for cies, including rats, mice, rabbits, monkeys, and aberrant cross-reactive B-cell responses.53 In a recent guinea pigs (Table 1). Immunization with Schwann- study, antibody responses to the ganglioside GM1 cell or myelin components generates demyelinating were linked to axonal and motor injury, as seen in neuropathy models, whereas axonal components one clinical variant of GBS136 and in an experimen- elicit axonal damage representing axonal GBS sub- tal model induced in rabbits by active immunization types (Table 1). In the most widely used GBS model, with this glycoconjugate.135 This provides a conclu- Lewis rats are immunized with peripheral myelin sive pathomechanism of axonal subtypes of GBS. homogenates, myelin proteins, or derived peptides Despite long-term efforts, no such conclusive to develop EAN (Table 1).76 Like entire myelin ho- mechanistic models have been confirmed in the de- mogenates, the major myelin adhesion molecule myelinating GBS subtypes. Myelin protein–like struc- P0,82 and the fatty acid–binding protein P2,47 tures have not been proven to exist in microbes. and their immunogenic peptides, elicit marked im-

4 Immunocompetence of Schwann Cells MUSCLE & NERVE January 2008 Table 1. Animal models of inflammatory neuropathies. Reference Animal model Transfer Possible antigens Description nos. Rat Lewis Active PNS myelin, P0, P2, P0(180–199), Frequently used EAN models 1, 23, 76, 83 P2(53–78), P2(57–81) Active PMP22 Mild course EAN 28 Active PNS myelin ϩ cyclosporine CIDP-like chronic relapsing, not robust 78 BN, SD, BUF, Wistar Active PNS myelin Less severe EAN course 41 Dark Agouti Active PNS myelin CIDP-like relapsing 46 Lewis AT P0, P2, P0(180–199), P2(61–70), MAG Rapid-onset EAN, CIDP-like relapsing 76, 64 if transferred repeatedly

Mouse C57/B6 Active P0(180–199), P0(106–125) ϩ PTx Varying effectiveness reported 81, 137 SJL Active P2 Mild course EAN 121, 14 Myelin ϩ PTx (ϩIL-12) Severe course EAN BALB/c AT MBP Peripheral and central demyelination 2 B7-2Ϫ/Ϫ NOD Spontaneous — Spontaneous autoimmune neuropathy 100 CIDP-like Rabbit Rabbit Active PNS myelin, P2 galactocerebroside First EAN model 76 Chronic inflammation 48 114 Rabbit (axonal) Active GM1 Acute motor axonal neuropathy 135 Active GD1b Ataxic sensory neuronopathy 63 Other Guinea pig Active PNS myelin 109 Monkey Active PNS myelin, P2 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 P0 peptides, P0(180–199)137 and P0(106–125),81 to- are triggered by peripheral myelin protein of 22 gether with pertussis toxin adjuvant in C57/B6 mice, kDa.28,59 Alternatively, transfer of stimulated T lym- has recently been reported. This protocol might en- phocytes that are reactive toward various myelin an- able the study of peripheral nerve inflammation in tigens, including myelin proteins P2,98 P0,68 and de- genetically modified animals, which are mostly gen- rived peptides, evokes adoptive transfer EAN in host erated on this background, allowing us to further animals (Table 1). Adoptive transfer of lymphocytes extend our knowledge of inflammatory neuropa- that are reactive against myelin-associated glycopro- thies. tein (MAG) generates mild peripheral nerve inflam- The present data clearly highlight the fact that mation.129 immunization with myelin components derived from Unlike rats, mice were generally thought not to Schwann cells as the cellular source can be used to be susceptible to immunization with peripheral my- induce an immune reponse against the PNS. elin, but recent studies have challenged this view. Although myelin protein P2 induced only subclinical SECONDARY IMMUNE REACTIONS IN NON- EAN in SJL mice, extended immunization protocols INFLAMMATORY HEREDITARY NEUROPATHIES have allowed the induction of severe EAN by myelin homogenates in this strain (Table 1).14 Adoptive Even hereditary disorders of the peripheral nervous transfer EAN in BALB/c mice identified myelin ba- system trigger immune responses in the peripheral sic protein (MBP) as an alternative neuritogenic nerve. These responses have been suggested to be an antigen. The number of regulatory T cells differs important determinant of disease manifestation. between mouse strains,17 which might explain their Charcot–Marie–Tooth (CMT) disease, clinically differential autoimmune susceptibility, and a similar termed hereditary motor and sensory neuropathy concept might be relevant for human autoimmune (HMSN), is the most common inherited peripheral diseases.22 Generation of active EAN by two different neuropathy. Animal models of many subtypes of

Immunocompetence of Schwann Cells MUSCLE & NERVE January 2008 5 CMT have been generated and have vastly extended Finally, we have learned that macrophages and our knowledge of the underlying disease mecha- lymphocytes are required for myelin loss in models nisms.80 In the more frequent demyelinating CMT of at least certain forms of hereditary neuropathies. forms, a genetic defect results in progressive destruc- This raises the question of how immune cells “sense” tion of myelin sheaths and secondary axonal loss.117 the defectiveness of the myelin sheath and why they One may easily conceive that such genetically deter- participate in its gradual destruction. Increased im- mined defects of myelination can trigger a secondary munogenity due to altered protein composition or immune response. Indeed, infiltration of lympho- mechanical instability of the myelin sheath has been cytes and macrophages has been demonstrated in suggested. Molecules required for antigen presenta- peripheral nerves of some human CMT pa- tion could communicate this information from tients,27,125 and corresponding animal models.7,57,104 Schwann cells to immune cells and one may specu- Apart from this secondary immune response, late that a myelin protein mutant Schwann cell however, a series of experimental studies have sug- would not demyelinate if it lacked the molecules gested immune cells as a primary cause for disease required for antigen processing and presentation. manifestation in genetically determined neuropa- We have described the intimate interaction be- thies. Mouse models of CMT subtypes CMT1B72 and tween myelinating Schwann cells and immune cells CMTX5,80 were crossbred with mouse strains lacking and its importance for various peripheral nerve dis- functional T lymphocytes or with impaired macro- orders. In what follows, we specifically elaborate on phage function. Surprisingly, immune deficiency the expanding recognition of Schwann cells as im- ameliorated mild, chronic demyelination in these munocompetent cells that form part of the local models of inherited neuropathies. Impairment of immune circuitry within the peripheral nerve. The immune function was achieved by abolishing func- present data suggest that the entire spectrum of an tional T lymphocytes in mouse strains carrying null immune response can be displayed by Schwann cells, mutations of the recombination activating gene-1 which includes recognition of antigens; presentation (Rag-1)56,104 or the T-cell-receptor ␣-subunit gene.77 of antigens; mounting of an immune response; and, Macrophage function was impeded in mice lacking finally, terminating the immune response within the functional genes of macrophage colony stimulating inflamed peripheral nerve (Fig. 1). factor16 and adhesion protein sialoadhesin preferen- 58 tially expressed in macrophages. Demyelination in ANTIGEN RECOGNITION BY SCHWANN CELLS the Rag-1–deficient CMT1B model could be recon- stituted by transfer of wild-type bone marrow,75 Two types of responses to invading organisms can which excludes Schwann-cell intrinsic effects of take place in the mammalian immune system: an Rag-1 deficiency. acute response launched within hours and a delayed This effect, however, has not been shown in the response occurring within days. The immediately most common CMT subtype, 1A, and, in contrast to responding system is called the innate immune system, its effect on mild chronic demyelination, immune and it evolves stereotypically and at the same inten- deficiency was found to aggravate early-onset severe sity regardless of how often the infectious agent is dysmyelination.7 Furthermore, myelinating cell cul- encountered. The strategy of the innate immune tures generated from a CMT1A animal model de- response is not to recognize every possible antigen, velop defects of myelination despite the obvious ab- but rather to focus on a few highly conserved struc- sence of immune cells in such a model.88 The tures present in large groups of microorganisms. efficacy of an anti-inflammatory treatment in CMT These structures are referred to as pathogen-associated remains controversial.73 molecular patterns, and the corresponding receptors One possible explanation for the increased im- of the innate immune system are called pattern- mune reaction in the CMT1B animal model may be recognition receptors.45 Examples of pathogen-asso- reduced intrathymic induction of tolerance. A het- ciated molecular patterns are bacterial lipopolysac- erozygous knockout of the myelin protein zero (P0) charide (LPS), peptidoglycan, and bacterial DNA. gene determines this CMT subtype and this reduc- Although chemically quite distinct, these molecules tion in gene dose was demonstrated to increase T- display common features. They are only produced by cell reactivity to a P0 peptide.84 Genetically deter- microbial pathogens and not by their host. They mined P0 deficiency in mice abolishes tolerance and generally represent invariant structures shared by causes the P0 protein to be recognized as a foreign large classes of pathogens, and they are usually rel- antigen,124 which further supports autoimmune evant for the survival or pathogenicity of microor- mechanisms in hereditary neuropathies. ganisms.79

6 Immunocompetence of Schwann Cells 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 Schwann cells with LPS has been shown to elicit the to the group of pattern-recognition receptors that production of various inflammatory mediators such recognize specific conserved components of mi- as chemokines, protease inhibitors, and growth fac- crobes,118 such as LPS, and that have been impli- tors.42 Thus, in aggregate, these findings suggest that cated to play a critical role in various inflammatory Schwann cells can detect LPS fragments and may act disorders.20,40 To date, 11 TLRs have been identified as a link between innate and acquired immunity via in humans and 7 in rats.43 LPS, a major component TLR-4 activation in the inflamed PNS. Recent studies of the outer membrane of gram-negative bacteria, have also revealed that inflammatory Schwann-cell which appears to be a relevant antigen triggering activation can be induced via TLR-2 and TLR-3.65 immune-mediated demyelination of the PNS,53,60 is recognized by TLR-4. SCHWANN CELLS AS FACULTATIVE ANTIGEN- TLRs are usually found on antigen-presenting PRESENTING CELLS cells, such as dendritic cells. TLR-2 has been shown to be expressed constitutively on primary human The task of displaying the antigens of cell-associated and rat Schwann cells and has been invoked as a microbes for recognition by T lymphocytes is per- target receptor for Mycobacterium leprae.38,89 Under formed by specific molecules that are encoded by inflammatory conditions, expression of various genes comprising the major histocompatibility com- TLRs, especially TLR-4, is inducible on rat Schwann plex (MHC). The physiological function of MHC cells in vitro. Selective stimulation of TLR-4 on molecules is the presentation of peptides to T cells.

Immunocompetence of Schwann Cells MUSCLE & NERVE January 2008 7 Two types of MHC gene products can be distin- to phagocytose exogenous antigen and its degrada- guished, class I MHC molecules and class II MHC tion to antigenic peptides, which can be expressed in molecules, which differ functionally. Each MHC the cleft of the MHC molecule.15,122 Schwann cells in molecule consists of an extracellular peptide-bind- vitro have been shown to present foreign and exog- ing cleft or groove and a pair of immunoglobulin- enous antigens, such as MBP, to antigen-specific syn- like domains, containing binding sites for the T-cell geneic T-cell lines.10,130 Moreover, the presentation surface markers CD4 and CD8.71,122 By transmem- of endogenous antigen, such as the myelin compo- brane domains, MHC molecules are anchored to the nent P2, by Schwann cells via MHC class II can ϩ cell surface. MHC molecules exhibit a broad speci- restimulate resting antigen-specific CD4 T-cell ficity for peptide binding, whereas the fine specificity lines.67 of antigen recognition resides mostly in the T-cell Non-endogenous antigen can also be presented receptor.13 In general, endogenous cytosolic pep- by Schwann cells, which may be of special relevance tides are presented via MHC class I molecules to in leprosy. On a global scale, leprosy is one of the ϩ CD8 T cells, whereas mainly exogenously derived major causes of peripheral neuropathy, with sensory peptides generated in vesicles are bound to MHC loss being its foremost symptom. Neuropathy in lep- ϩ class II molecules and recognized by CD4 T lym- rosy mainly affects pain and temperature sensation phocytes.97,127 The two classes of MHC molecules are from small cutaneous nerves, resulting in painless expressed differentially on cells. All nucleated cells injury and mutilation.99 The causal agent of the exhibit MHC class I molecules, although hematopoi- disease, Mycobacterium leprae, shows a remarkable etic cells express them at the highest densities. MHC preference for invading and proliferating in non- class II molecules, in contrast, are normally only myelinating Schwann cells.96 Schwann cells present expressed on professional antigen-presenting cells, M. leprae–derived antigens to lymphocytes in an ϩ such as macrophages, dendritic cells, and B lympho- MHC II–dependent manner,26 whereas CD8 lym- cytes. The levels of both class I and II molecules can phocytes lyse M. leprae–infected Schwann cells in be markedly upregulated by cytokines, particularly vitro.112 A different study showed M. leprae–derived ϩ interferon-␥ and tumor necrosis factor (TNF)-␣. antigen presentation by Schwann cells to CD4 lym- Macrophages are the predominant professional an- phocytes.110 This MHC II–mediated interaction re- tigen-presenting cells in EAN. These macrophages in sulted in Schwann-cell destruction. Thus, apart from EAN shift from resident endoneural in the early other mechanisms described,95,120 antigen presenta- disease stages to a hematopoietic origin in later tion by Schwann cells evolves as an important mech- stages.85 anism of nerve damage in this infectious neuropa- Apart from such professional antigen-presenting thy. cells, other cell types may acquire the ability to pro- For optimal T-cell activation and differentiation cess and present antigens in inflammatory condi- to occur, at least two distinct signals delivered during tions, thus representing facultative antigen-present- the interaction with an antigen-presenting cell are ing cells. Human and rat Schwann cells in vitro required. These include antigen-specific signaling constitutively express low levels of MHC class I but via MHC and signaling through costimulatory mole- not MHC class II.6,9,30,66,101 Significant numbers of cules. If the T cell does not receive adequate co- MHC class II molecules can be detected on Schwann stimulation, it is rendered anergic or undergoes ap- cells in the presence of activated T lymphocytes optosis. Thus, the costimulation signal is central to upon stimulation with the proinflammatory cytokine T-cell activation and survival.21,105 Recent data sug- interferon-␥, which can be synergistically increased gest that BB-1, a member of the family of costimula- by the addition of TNF-␣.6,30,55,66,123 Moreover, a tory molecules, can be detected on non-myelinating number of molecules that are prominent in the Schwann cells and appears to be upregulated on intracellular processing cascade of peptides prone to myelinating Schwann cells in nerve biopsies from MHC presentation can be visualized in Schwann CIDP patients. This further indicates that Schwann cells in vitro and in vivo (Meyer zu Ho¨rste and cells possess the cellular components required to act Kieseier, unpublished observations). In human as facultative antigen-presenting cells in the in- nerve biopsies from patients with GBS and its flamed PNS.86,94 The extent to which these cells may chronic variant CIDP, Schwann cells stained positive propagate a T-cell response via antigen presentation for MHC class II, suggesting that these cells may in situ needs to be elucidated in greater detail. It indeed act as facultative antigen-presenting cells in needs to be investigated whether Schwann cells can immune-mediated disorders of the PNS.92,93 Anti- suppress such a response in vivo as well as in vitro.70 gen-presenting cells are characterized by their ability In any case, it is an appealing concept that Schwann

8 Immunocompetence of Schwann Cells MUSCLE & NERVE January 2008 cells actively control the local T-cell response within nisms. One pathway may operate through the the peripheral nerve by acting as facultative antigen- production and release of nitric oxide (NO), a mul- presenting cells. tipotential mediator with neurotoxic and immuno- suppressive properties. Schwann cells are endowed SCHWANN CELLS AS REGULATORS OF AN with inducible nitrite oxide synthase, which is up- AUTOIMMUNE RESPONSE regulated after the stimulation with proinflamma- 131 For a long time, cytokines, as mediators of an im- tory cytokines. mune response within the peripheral nerve, were Taken together, a large number of pro- and anti- considered to be the exclusive product of inflamma- inflammatory mediators can be induced and re- tory cells. Nowadays, there is a large body of evi- leased by Schwann cells. The extent to which these dence implying that Schwann cells can produce and mediators have a significant impact on the clinical secrete a wide variety of cytokines, which could act as course of an immune-mediated disorder in the PNS immunomodulators.70 Interleukin (IL)-1, a cytokine clearly warrants further investigation. relevant in the initiation of an immune response, In animal models of inflammatory diseases of the can be produced by cultured Schwann cells.8 Other central nervous system, neurotrophic cytokines and proinflammatory cytokines, such as IL-6,8,12,29,87 neurotrophins have been suggested as important TNF-␣,8,12,29,87,116,126 and transforming growth factor- regulators of axonal degeneration and of resulting ␤,103,113 are generated and released by Schwann cells clinical impairment.69 Most interestingly, brain- under certain conditions, some in vitro and others in derived neurotrophic factor (BDNF), originating vivo.50,74,108 Schwann cells are able to regulate the from inflammatory cells, has been demonstrated to production of proinflammatory cytokines, at least in mediate neuroprotective effects,49,111 which empha- part, in a specific autocrine manner, as shown for sizes the concept of neuroprotective autoimmunity. IL-1.107,108 The specific receptors for some of the Few studies, however, support a comparable concept cytokines, such as TNF receptor, are constitutively in inflammatory diseases of the peripheral nervous expressed on Schwann cells, rendering these cells system. Except for reduced urinary bladder weight as susceptible to, for example, a TNF-␣ response.11,90 a possible indirect sign of reduced autonomic dys- Other proinflammatory and immunoregulatory me- regulation, BDNF treatment did not significantly in- 25 diators, such as prostaglandin E2, thromboxane A2, fluence clinical disease manifestation in rat EAN. and leukotriene C4, are synthesized in large amounts by Schwann cells, and may regulate the immune SCHWANN CELLS AS TERMINATORS OF THE cascade within the inflamed PNS.18,19 Further medi- AUTOIMMUNE RESPONSE ators produced by Schwann cells include osteopon- tin, which is constitutively expressed and can be In order to control the massive expansion of cellular easily induced in Schwann cells,3 as well as glial cell and soluble immune mediators within the target line–derived neurotrophic factor, a known survival tissue, certain mechanisms must operate with high factor for neurons, and glial cell line–derived neu- fidelity to regulate the immune response. Once the rotrophic factor family receptor ␣-1, displayed on target antigen has been eliminated or infection the surface of Schwann cells.39,44 abated, the activated effector cells are no longer Nuclear transcription factor-␬B (NF-␬B) plays a needed. When the antigenic stimulus is no longer pivotal role in the regulation of the host innate present, the cells will succumb to programmed cell antimicrobial response. It governs the expression of death or apoptosis.32 many immunological mediators, including cyto- The survival of lymphocytes depends on a deli- kines, their receptors, and components of their sig- cate balance between death-promoting and death- nal transduction. Recent studies have suggested that inhibiting factors. Various mechanisms can induce two NF-␬B complexes, p65/p50 and p50/p50, can apoptosis. It can, for example, be affected through be activated and regulated in human Schwann cells the interaction of the cell surface receptor Fas on T under certain conditions.91 Interestingly, the natural cells with its ligand, FasL, a member of the TNF inhibitor of NF-␬B, I␬B, can be detected in large family.62 Schwann cells reveal surface expression of amounts in Schwann cells.4 These observations fur- FasL after stimulation with proinflammatory cyto- ther point to an active rather than a passive role for kines in vitro. Functional analysis indicates that the Schwann cells in the inflamed PNS. Apart from en- interaction between Fas on T cells and FasL on gaging such cellular factors, Schwann cells can mod- Schwann cells promotes apoptosis of T lymphocytes. ulate local immune reactivity by humoral mecha- This raises the possibility that Schwann cells are

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