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Multiple Sclerosis and Central Nervous System Demyelination
Article No. jaut.1999.0321, available online at http://www.idealibrary.com on
Journal of Autoimmunity (1999) 13, 297–306
Review Article
Multiple Sclerosis and Central Nervous System Demyelination Sandrine Pouly* and Jack P. Antel Montre´al Neurological Institute, Neuroimmunology Unit, 3801 University Street, Montre´al, Que´bec, H3A 2B4, Canada
Multiple sclerosis (MS) is characterized by multifocal areas within the CNS of demyelination with relative but not absolute axonal sparing. Initial lesion development appears dependent on T cell infiltration into the CNS; however, lesion expansion may reflect tissue injury induced by additional effector mechanisms derived from cells of the immune system and endogenous CNS cells (glial cells). This relative susceptibility to injury in MS of myelin and its cell of origin, the oligodendrocyte (OL), could reflect either the properties of the effectors or the targets. Effector-determined susceptibility could relate to presence of OL/myelin-restricted T cells or antibody. OLs, at least in vitro, express MHC class I molecules and are susceptible to CD8 + T cell-mediated cytotoxicity. OL/myelin-specific antibodies are identified in MS lesions and could induce injury via complement- or ADCC-dependent mechanisms. OLs are susceptible to injury-mediated by non-specific cell effectors including NK cells, NK-like T cells (CD56 + ), and / T cells via perforin/granzymedependent mechanisms. In vitro studies of OL injury mediated via tumor necrosis factor (TNF) and CD95 indicate that differential glial cell susceptibility to injury can depend on cell surface receptor expression and intracellular signaling pathways that are activated. These target-determined susceptibility factors may be amenable to neuroprotective therapies. © 1999 Academic Press
Introduction
receptors and have much less restriction with regard to antigen recognition. Selective target injury mediated by these cells or their soluble products would largely be determined by the properties of the target cells or by interactions with components of the adaptive immune system. The actual mechanisms of target cell injury also need to be elucidated, as a prerequisite for design of neuroprotective therapy. OL death in MS tissue has been ascribed to both apoptosis [1, 2] and necrosis [3].
MS is considered as an autoimmune disease that appears to selectively targets CNS myelin or its cell of origin the oligodendrocyte (OL), although there is also a component of axonal loss which could be primary or secondary to loss of trophic support from myelin. An important issue raised with regard to MS is the basis for such specific injury. We will consider how such selectivity could be determined either by properties of the effectors or the targets of the immune response. The immune effectors can be considered in terms of constituents of the adaptive and innate components of the immune system. The former are comprised of / T cells and of B cells whose receptors undergo rearrangement during cell differentiation providing a high degree of specificity for the antigens which they recognize. The cell constituents of the innate immune system include macrophages, NK cells, and / T cells which continue to express germ line determined
Adaptive Immune Response-mediated Injury MHC-restricted T cell-mediated injury of human OLs CD4 + and CD8 + / T lymphocytes are both present in MS lesions. Their role in autoimmune demyelination has been studied using the animal models experimental allergic encephalomyelitis (EAE) and Theiler’s murine encephalomyelitis virus infection (TMEV). CD4 + T lymphocytes are required for the
Correspondence to: Jack P. Antel, Montre´al Neurological Institute, Neuroimmunology Unit, 3801 University Street, Montre´al, Que´bec H3A 2B4, Canada. Fax: 514 398 7371. E-mail: [email protected] 297 0896–8411/99/070297+10 0$30.00/0
© 1999 Academic Press
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passive transfer of EAE [4]. In TMEV, depletion of CD8 + T cells results in marked reduction in neurologic impairment, although demyelination still occurs [5]. Antigen-specific / T cells recognize antigen on their target cells in the context of MHC molecules expressed by such cells. Although expression of MHC class I or class II molecules on OLs in situ has not yet been clearly demonstrated by conventional immunohistochemical techniques in the normal or inflamed human CNS, in situ expression of MHC class II in OLs has been described in a line of mice overexpressing IFN- specifically in the CNS [6]. Human OLs in vitro, isolated from post-mortem tissues [7] or biopsies [8], have been shown to express MHC class I molecules [9–11], but not MHC class II. The latter have been detected on cultured rat OLs following dexamethasone exposure [12]. The observed expression of MHC class I on human OLs has been coupled with functional cytotoxicity studies involving MHC class I-restricted CD8 + T cells. We demonstrated susceptibility of human OLs to lysis by alloreactive class I-directed CD8 + cytotoxic T lymphocytes, generated by initially co-culturing lymphocytes from a volunteer blood donor with irradiated MNCs derived from the peripheral blood of the individual from whom the OLs were derived [13]. We further observed that CD8 + T cells lines, specifically reactive with MBP peptide 110–118 which sits in the HLA-A2 groove [14], were cytotoxic to HLA-A2 but not to non-HLA-A2 cultured human OLs, even in the absence of exogenous peptide [15]. Such cytotoxic effect was inhibited by anti-MHC class I Abs. To date, myelin reactive CD4 + T cells have not been shown to induce MHC class II-restricted injury of OLs, although these cells do have cytotoxic potential [16]. These observations raise the issue as to whether myelin reactive CD4 + T cells, found in MS lesions, are capable of inducing non MHC-restricted OL injury. CD56 (NCAM) expression was originally thought to be restricted to NK cells, but was subsequently detected on T cell lines and associated with a capacity of these cells to mediate non-MHC-restricted cytotoxicity [17, 18]. CD56-dependent cytotoxicity requires homotypic interaction with CD56 expressed on the target cell [19]. A proportion of human MBP-reactive CD4 + T cells in vitro have also been found to express CD56; such cells are cytotoxic to an array of CD56expressing targets in the absence of added antigen [20]. Cultured human OLs were shown both to express CD56 and be susceptible to lysis induced by CD56-expressing MBP-reactive T cell lines [21]. In our studies, CD56 expression and cytotoxicity was dependent on the activation state of the effector cells, supporting efforts to develop means to reduce activation and modulate adhesion molecule expression of potential immune effector cells as a therapy for MS. Antibody-mediated OL cytotoxicity Intrathecal production of immunoglobulins (Igs) is a characteristic feature of MS. These Igs are of restricted
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heterogeneity as determined by electrophoresis (oligoclonal bands) and by analysis of rearranged gene sequences encoded by mRNA derived from cells present in the cerebro-spinal fluid (CSF) or active CNS lesions of MS patients [22, 23]. Antibodies directed at specific myelin constituents including MOG, MBP, PLP and lipid moieties have been identified in tissue and in CSF of MS patients [24]. The intrathecal Igs in MS are not however restricted to myelin directed antibodies. Titers of antibodies recognizing an array of infectious agents are increased in MS CSF compared to controls. How much of the increased Igs in the CNS in MS results from a specific antigen-driven immune response and how much reflects a more general dysregulation of the immune response within the CNS remains to be resolved. Furthermore, the ongoing tissue injury over time may lead to an expanded range of antigens against which both cellular and humoral immune response can be mounted (determinant spreading) [25]. Studies in the EAE model, especially using myelin/oligodendrocyte glycoprotein (MOG) as immunogen, indicate that myelin specific antibodies can markedly augment the extent of tissue injury [26, 27]. Distinct pathologic forms of MS are now being associated with presence of Igs in the lesions [28]. OL/myelin-directed antibodies could contribute to selective target injury in a number of ways. Antibody acting in conjunction with complement results in lytic injury to cells. Complement products are produced within the CNS and are present in the MS lesion. Myelin is a complement activator [29, 30]. In initial studies, we did not find consistent injury of human OLs when these cells were exposed to sera or CSF derived from MS patients [31]. There are, however, a number of reports of the toxic effects of MS CSF on rodent dissociated CNS tissue [32, 33]. The converse that distinct types of antibodies (IgM antibodies expressing germ line sequences) binding to OLs may promote myelin regeneration needs also to be considered [34]. Target-specific antibody could promote selective tissue injury via an antibody-dependent cell cytotoxicity (ADCC) mechanism [35]. In this process, potential non target-specific immune effector cells bearing Fc receptors (macrophages, microglia, NK cells) would be brought into proximity with a specific target and become activated, as a result of binding to the Fc portion of antibodies which are specifically bound to such targets via their combining sites in the Fab regions of the molecule. Expression of all three Fc receptor classes is upregulated on microglia cells and macrophages present in active MS lesions [36]. Using cells obtained from surgically resected human CNS tissues [8], we could also detect all three classes of Fc receptor on microglial cells in vitro, but not on astrocytes or oligodendrocytes [37]. Incubation of these cultured human microglia with immune complexes enhanced phagocytic activity, production of potential effector cytokines including TNF-, and release of reactive oxygen species (ROS). Scolding et al. showed that macrophage attachment to myelin with subsequent
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phagocytosis could be triggered by presence of antibodies directed at antigens expressed on the surface of myelin (galactocerebroside, MOG) [38]. ADCC illustrates the links that exist between the adaptive and innate immune systems.
Innate Immune Response-mediated Injury In this section, we consider constituents of the innate immune system which are derived from the systemic immune system and which can migrate into the CNS and be found in MS lesions. These include macrophages, NK cells, and / T cells. We will also consider resident cells within the CNS parenchyma that display similar properties. In this category, we include microglia, which are long-lived cells of bone marrow origin and which migrate early in development into the CNS. Unlike perivascular microglia, these parenchymal cells persist without a significant turnover rate. Astrocytes may also acquire some of these properties.
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Macrophages/microglia As mentioned in context of Fc receptor-mediated activation of these cells, activation can be associated with release of an array of potential injury effector molecules which could inflict OL injury [TNF-, ROS, proteases, excitotoxins, nitric oxide (NO)]; the basis for selective injury of OLs by such mediators is discussed below. Activated microglia and macrophages in MS lesions are also reported to express CD95 ligand (CD95L) [47, 48]; CD95 (Fas, Apo-1) signaling and OL injury are discussed in a later section. Microglia and macrophages can be activated via CD40-CD40 ligand interactions with infiltrating T cells [49], and by interactions with an array of endogenous and exogenous antigens which may be present in this compartment under pathologic conditions. Examples of such interactions dependent on expression of innate receptors on these cells include CD14 with the bacterial endotoxin LPS [50], scavenger receptors which may bind proteins such as amyloid [51, 52] and apoptotic cells [53], and chemokine receptors which may be significant for binding HIV [54].
Effector cells / T cells / T cells are found in disproportionately increased numbers in some MS plaques [39] and are also increased in numbers in the CSF of MS patients [40]. Cultured human OLs have been shown to be efficiently lysed in a dose-dependent manner by human / T cells, although such an effect was not restricted to this cell type [41]. This effect is predominantly mediated through the perforin/granzyme system [42]. Members of the heat shock family of molecules are suggested to be recognition targets of these T cells. A number of heat shock proteins (HSP) are readily induced on cultured human OLs by pro-inflammatory cytokines [43]. Alpha B-crystallin, a member of the HSP family present in the OL/myelin complex, is a candidate autoantigen in MS [44]. OLs have been shown to selectively stimulate expansion of the V2 subtype of / T cells; this subtype is particularly reactive to HSP [45]. NK cells NK cells are phenotypically defined by their large granular appearance and expression of the surface molecules CD16 and CD56. These cells do not express CD3, but can express CD8. Cells with this phenotype have been described in the CSF of MS patients [46]. They also express Fc receptors which would allow interaction with antibody in a manner akin to macrophages and thus participate in a combined adaptive/ innate immune response. We can demonstrate that OLs are susceptible to killing mediated by these cells with the apparent mediators being the perforin/ granzyme system [21]. As with / T cells, this susceptibility is not restricted to OLs.
Target-determined Selectivity of Immune-Mediated OL Injury In this section, we consider the selective expression of receptors or induction of specific intracellular signaling events as a basis for selective OL toxicity in response to non-target-selective effector mechanisms.
Receptor-determined injury TNF- death receptor superfamily This family of receptors (R) has a number of members which have been shown to be expressed on OLs, and which may induce intacellular signaling pathways leading to cell injury, or conversely resistance to injury. TNF-R/TNF-. TNF- is readily detected in active MS lesions, largely being produced by macrophages and microglia [55, 56]. In culture, microglia are the major human adult CNS cell source of TNF-, whereas astrocytes are a potent source in the fetal CNS [57, 58]. TNF- could contribute to the pathogenesis of the MS disease process at multiple levels. For example, we demonstrated its role in regulation of the immune response within the CNS by its effects on the Th1 polarizing cytokine interleukin (IL)-12 production [55]. There are two TNF- receptors (TNF-R1 and TNF-R2) which can transduce the signal for apoptosis, but only TNF-R1 is linked to a death domain, making it responsible for the induction of apoptosis in most cases [59]. Human OLs are demonstrated to express the TNF-R1 receptor in vitro [60]; expression is also found on OLs around MS lesions [61]. TNF-R signaling was initially shown to activate caspase-8 [62].
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Subsequently, TNF- induced OL cell death was linked to the caspase-1 pathway [1, 63]. Regarding the direct effects of TNF- on OL and myelin injury, the emerging data from in vivo and in vitro studies indicate that this molecule can exert both neuroprotective and neurotoxic effects. In vivo data are largely derived from mice in which TNF- is overexpressed in the CNS or from mice in which TNF- or one or both of its receptors are deleted. Transgenic overexpression of TNF- within the CNS has resulted in chronic inflammation and demyelination and conversion of acute EAE into a more chronic tissue destructive phenotype [64–66]. Conversely, however, animals in which the TNF- gene was depleted, were more susceptible to CNS inflammation and tissue injury induced by ischemia or trauma [67]. These results implicate a dose effect in determining the balance between cytotoxic and neuroprotective effects of TNF- within the CNS. Such selectivity may also reflect the relative extent of signaling via the TNF-R1 and TNF-R2 receptors, again based on results of receptor knockout mice [68, 69]. In vitro studies related to TNF--induced injury of OLs and myelin have involved evaluating the effects of adding TNF- to an array of culture systems established from mature and immature CNS of a number of species. TNF- was reported to be harmful to aggregating myelinating rodent cultures, to the CG4 OL precursor cell line, and to dissociated rodent, bovine and human primary OL cultures [60, 70–74]. Other studies have not shown such effects [67, 75]. TNF- on OLs also induces retraction of processes [76], modification of ion channels [76–78], and upregulation of death receptors such as CD95 [79]. Our experience with adult human CNS-derived OLs in vitro is that high-dose TNF-, when administered over a relatively long time period (5–7 days), does induce apoptosis, although we have not yet shown that this is TNF-R-dependent [74, 80]. We have observed that TNF- rapidly activates both the c-Jun N-terminal kinases (JNKs) and NFB signaling pathways in these cells. JNKs are p53 N-terminal serine 34 kinases [81] which play a role in p53 stability, transcriptional activities, and apoptotic capacity [82]. We found that treatment of human OLs with TNF- resulted in increased levels of p53 in the cells; overexpression of p53 by adenovirus-mediated gene transfer induced apoptosis [80]. Others consider JNK signaling as protective [83]. The NFB signaling pathway is considered as a protective signaling pathway [84]. The decision as to whether TNF-R signaling will be tipped toward death or survival remains to be defined, but is likely to depend on a balance of the signaling pathways induced. A further potential contribution of TNF- in the injury process is by means of modulating expression of other putative injury mediating receptors such as CD95 on target cells, or of their ligands, e.g. CD95L, on the effector cells. CD95/CD95L. CD95 is a further member of the TNF-R superfamily [85]. Cell death signaling is transduced upon engagement of this receptor by its ligand
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(CD95L), or anti-CD95 antibodies, which then leads to clustering of its death domain and subsequent activation of the caspase cascade [86]. Although CD95 was at first not detected in normal brain, it has now been shown to be expressed during development in murine CNS [87], and on the fetal human astrocytes in vitro [88]. Furthermore, it has been found to be expressed on OLs in MS lesions [47, 48], as well as in the CNS under other pathologic conditions, such as cerebral ischemia and Alzheimer’s disease [89, 90]. CD95L-bearing cells, identified in active MS lesions include macrophages, microglia and lymphocytes [91]. Soluble CD95L can be recovered from MS CSF [48, 92]. To assess the potential role of CD95 signaling as mediator of OL injury, we initially determined that CD95 could be expressed by human OLs in vitro [47] and that engagement of these receptors induced cytotoxicity within a relatively short time period (hours) relative to that observed using TNF-. Recent evidence suggests that pro-inflammatory cytokines, such as TNF- or IFN- within the CNS might upregulate expression of CD95 on a number neural cell types [79, 93, 94]. We were able to show that such an upregulation of CD95 on cultured human OLs rendered them more sensitive to CD95-mediated apoptosis [95]. We did not observe CD95 expression on fetal human neurons or adult astrocytes, providing a basis whereby signaling via this receptor could result in selective target injury. We did observe CD95 expression on both fetal human astrocytes and human glioma cell lines, but only the latter were susceptible to CD95 engagement [88]. These results provide an example whereby selective tissue injury can be dependent on the signaling pathways induced by engagement of a specific surface receptor expressed by an array of cell types. Neurotrophin receptor/NGF. The neurotrophin receptor p75 (p75NTR), another member of the TNF-R superfamily, has been considered to be a co-receptor with the high affinity Trk receptors for neurotrophins [96, 97]. Trk receptors (TrkA, B or C) are tyrosine kinase receptors that mediate suvival effect through neurotrophin-dependent activation [98–100]. P75NTR is able to autonomously signal via neurotrophindependent activation of sphingomyelinase activity and NFB. It contains a death domain in its cytoplasmic region, leading to speculation about its role in cell death signaling in response to neurotrophins, particularly in cells which lack Trk receptors [100]. Levels of the neurotrophin nerve growth factor (NGF) are elevated in the CSF of MS patient [101]. Furthermore, MS lesions contain cells from the OL lineage with elevated p75 neurotrophin receptor (p75NTR) but not Trk expression [48, 102]. OLs within the normal CNS seem to express little or no p75NTR [103]. Neonatal rat OLs in dissociated culture were found to undergo apoptosis in the presence of NGF under conditions in which the cells expressed p75NTR but not TrkA [104, 105]. Under culture conditions that resulted in expression of TrkA on such OLs, NGF supported survival rather than induction of apoptosis [105]. This
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apoptotic effect is now shown to be mediated via a caspase-1 rather than a caspase-8 dependent pathway [106], which, as mentioned before, resembles the actions of TNF- in OLs [1, 63]. Caspase-1 activation has been linked with inflammation [107, 108]. NGF treatment of human adult OLs in culture did not induce apoptosis, even though the cells were expressing p75NTR and not TrkA [80]. It did, however, induce nuclear translocation of NFB, suggesting that at least in human OLs, p75NTR signaling mediates responses other than cell death. Cytokines-mediated OL injury A number of cytokines capable of contributing to tissue injury are present within the inflamed CNS (review in [109, 110]. Specifically implicated cytokines include IFN-, IL-1, -2 and -6 [73]. To date, none of these cytokines have been found to be cytotoxic for human OLs in culture. Whether they indirectly modulate cell death signaling pathways described above remains to be determined. IFN- has been shown in some but not all studies to be cytotoxic for rodent OLs [70, 111, 112]. Overexpression of IFN- in the CNS of transgenic mice can induce spontaneous demyelination [113]. Recent data show that a combination of IFN- and TNF- upregulates the level of CD95 on the surface of neural cells [94], indicating, as mentioned previously in the context of TNF-, another means whereby cytokines can modulate their environment. IL-2 toxicity to OLs in also described [114], an effect ascribed to dimerization of IL-2 by a transglutaminase [115]. The same cytokine was also shown to promote proliferation and maturation of immature oligodendrocytes [116].
Non receptor-mediated injury Oxidative stress Antioxidants belonging to sulfhydryl groups are decreased in the CSF of MS patients, whereas products of lipid peroxidation are increased, pointing out the importance of oxidative stress in MS [117]. Kim and Kim reported that adult bovine OLs were susceptible to the toxic effects of free radicals (reactive oxygen species) generated enzymatically by combinations of glucose with glucose oxidase, and hypoxanthine with xanthine oxidase [118]. They further showed that such damage could be prevented by catalase, but not by superoxide dismutase, vitamin E or glutathione. Protection can also be provided by other resident cells of the CNS, specifically astrocytes [119]. ROS have long been proposed to play a role in bystander demyelination in adult animal [120]. It was shown in EAE that production of ROS regulates the extent of phagocytosis [121]. The sources of free radicals in MS may include not only activated immune cells, such as microglia and macrophages [122], but also neurotransmitters, specifically catecholamines, which generate ROS when they are metabolized [119]. Catecholamines participate in
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the process of neural regulation of the immune response. Many studies have implicated nitric oxide (NO) as an injury mediator within the CNS (review in [123]), including being a key mediator in microglia-induced cytotoxicity of rat OLs [124]. NO was observed to induce necrosis rather than apoptosis in rodent OLs [125]. In the rodent and human CNS, astrocytes rather than microglia would seem to be a major source of NO [126, 127]. Although adult human microglia are shown to produce ROS [128, 129], to date, only fetal human microglia were shown to produce NO [130, 131]. Differential sensitivity of different resident CNS cells to ROS mediated injury has already been demonstrated [132].
Conclusion In summary, the selective injury of OL/myelin that characterizes MS could be determined either by the properties of the effectors of the immune response or the properties of the targets. Many of the effectors implicated in the MS process and the receptors and signaling events involved in the response to these effectors, may have dual roles as related to inducing injury or promoting protection. Opportunities increasingly present themselves to define means to manipulate these responses for the benefit of the individual.
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Journal of Autoimmunity (1999) 13, 297–306
Review Article
Multiple Sclerosis and Central Nervous System Demyelination Sandrine Pouly* and Jack P. Antel Montre´al Neurological Institute, Neuroimmunology Unit, 3801 University Street, Montre´al, Que´bec, H3A 2B4, Canada
Multiple sclerosis (MS) is characterized by multifocal areas within the CNS of demyelination with relative but not absolute axonal sparing. Initial lesion development appears dependent on T cell infiltration into the CNS; however, lesion expansion may reflect tissue injury induced by additional effector mechanisms derived from cells of the immune system and endogenous CNS cells (glial cells). This relative susceptibility to injury in MS of myelin and its cell of origin, the oligodendrocyte (OL), could reflect either the properties of the effectors or the targets. Effector-determined susceptibility could relate to presence of OL/myelin-restricted T cells or antibody. OLs, at least in vitro, express MHC class I molecules and are susceptible to CD8 + T cell-mediated cytotoxicity. OL/myelin-specific antibodies are identified in MS lesions and could induce injury via complement- or ADCC-dependent mechanisms. OLs are susceptible to injury-mediated by non-specific cell effectors including NK cells, NK-like T cells (CD56 + ), and / T cells via perforin/granzymedependent mechanisms. In vitro studies of OL injury mediated via tumor necrosis factor (TNF) and CD95 indicate that differential glial cell susceptibility to injury can depend on cell surface receptor expression and intracellular signaling pathways that are activated. These target-determined susceptibility factors may be amenable to neuroprotective therapies. © 1999 Academic Press
Introduction
receptors and have much less restriction with regard to antigen recognition. Selective target injury mediated by these cells or their soluble products would largely be determined by the properties of the target cells or by interactions with components of the adaptive immune system. The actual mechanisms of target cell injury also need to be elucidated, as a prerequisite for design of neuroprotective therapy. OL death in MS tissue has been ascribed to both apoptosis [1, 2] and necrosis [3].
MS is considered as an autoimmune disease that appears to selectively targets CNS myelin or its cell of origin the oligodendrocyte (OL), although there is also a component of axonal loss which could be primary or secondary to loss of trophic support from myelin. An important issue raised with regard to MS is the basis for such specific injury. We will consider how such selectivity could be determined either by properties of the effectors or the targets of the immune response. The immune effectors can be considered in terms of constituents of the adaptive and innate components of the immune system. The former are comprised of / T cells and of B cells whose receptors undergo rearrangement during cell differentiation providing a high degree of specificity for the antigens which they recognize. The cell constituents of the innate immune system include macrophages, NK cells, and / T cells which continue to express germ line determined
Adaptive Immune Response-mediated Injury MHC-restricted T cell-mediated injury of human OLs CD4 + and CD8 + / T lymphocytes are both present in MS lesions. Their role in autoimmune demyelination has been studied using the animal models experimental allergic encephalomyelitis (EAE) and Theiler’s murine encephalomyelitis virus infection (TMEV). CD4 + T lymphocytes are required for the
Correspondence to: Jack P. Antel, Montre´al Neurological Institute, Neuroimmunology Unit, 3801 University Street, Montre´al, Que´bec H3A 2B4, Canada. Fax: 514 398 7371. E-mail: [email protected] 297 0896–8411/99/070297+10 0$30.00/0
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passive transfer of EAE [4]. In TMEV, depletion of CD8 + T cells results in marked reduction in neurologic impairment, although demyelination still occurs [5]. Antigen-specific / T cells recognize antigen on their target cells in the context of MHC molecules expressed by such cells. Although expression of MHC class I or class II molecules on OLs in situ has not yet been clearly demonstrated by conventional immunohistochemical techniques in the normal or inflamed human CNS, in situ expression of MHC class II in OLs has been described in a line of mice overexpressing IFN- specifically in the CNS [6]. Human OLs in vitro, isolated from post-mortem tissues [7] or biopsies [8], have been shown to express MHC class I molecules [9–11], but not MHC class II. The latter have been detected on cultured rat OLs following dexamethasone exposure [12]. The observed expression of MHC class I on human OLs has been coupled with functional cytotoxicity studies involving MHC class I-restricted CD8 + T cells. We demonstrated susceptibility of human OLs to lysis by alloreactive class I-directed CD8 + cytotoxic T lymphocytes, generated by initially co-culturing lymphocytes from a volunteer blood donor with irradiated MNCs derived from the peripheral blood of the individual from whom the OLs were derived [13]. We further observed that CD8 + T cells lines, specifically reactive with MBP peptide 110–118 which sits in the HLA-A2 groove [14], were cytotoxic to HLA-A2 but not to non-HLA-A2 cultured human OLs, even in the absence of exogenous peptide [15]. Such cytotoxic effect was inhibited by anti-MHC class I Abs. To date, myelin reactive CD4 + T cells have not been shown to induce MHC class II-restricted injury of OLs, although these cells do have cytotoxic potential [16]. These observations raise the issue as to whether myelin reactive CD4 + T cells, found in MS lesions, are capable of inducing non MHC-restricted OL injury. CD56 (NCAM) expression was originally thought to be restricted to NK cells, but was subsequently detected on T cell lines and associated with a capacity of these cells to mediate non-MHC-restricted cytotoxicity [17, 18]. CD56-dependent cytotoxicity requires homotypic interaction with CD56 expressed on the target cell [19]. A proportion of human MBP-reactive CD4 + T cells in vitro have also been found to express CD56; such cells are cytotoxic to an array of CD56expressing targets in the absence of added antigen [20]. Cultured human OLs were shown both to express CD56 and be susceptible to lysis induced by CD56-expressing MBP-reactive T cell lines [21]. In our studies, CD56 expression and cytotoxicity was dependent on the activation state of the effector cells, supporting efforts to develop means to reduce activation and modulate adhesion molecule expression of potential immune effector cells as a therapy for MS. Antibody-mediated OL cytotoxicity Intrathecal production of immunoglobulins (Igs) is a characteristic feature of MS. These Igs are of restricted
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heterogeneity as determined by electrophoresis (oligoclonal bands) and by analysis of rearranged gene sequences encoded by mRNA derived from cells present in the cerebro-spinal fluid (CSF) or active CNS lesions of MS patients [22, 23]. Antibodies directed at specific myelin constituents including MOG, MBP, PLP and lipid moieties have been identified in tissue and in CSF of MS patients [24]. The intrathecal Igs in MS are not however restricted to myelin directed antibodies. Titers of antibodies recognizing an array of infectious agents are increased in MS CSF compared to controls. How much of the increased Igs in the CNS in MS results from a specific antigen-driven immune response and how much reflects a more general dysregulation of the immune response within the CNS remains to be resolved. Furthermore, the ongoing tissue injury over time may lead to an expanded range of antigens against which both cellular and humoral immune response can be mounted (determinant spreading) [25]. Studies in the EAE model, especially using myelin/oligodendrocyte glycoprotein (MOG) as immunogen, indicate that myelin specific antibodies can markedly augment the extent of tissue injury [26, 27]. Distinct pathologic forms of MS are now being associated with presence of Igs in the lesions [28]. OL/myelin-directed antibodies could contribute to selective target injury in a number of ways. Antibody acting in conjunction with complement results in lytic injury to cells. Complement products are produced within the CNS and are present in the MS lesion. Myelin is a complement activator [29, 30]. In initial studies, we did not find consistent injury of human OLs when these cells were exposed to sera or CSF derived from MS patients [31]. There are, however, a number of reports of the toxic effects of MS CSF on rodent dissociated CNS tissue [32, 33]. The converse that distinct types of antibodies (IgM antibodies expressing germ line sequences) binding to OLs may promote myelin regeneration needs also to be considered [34]. Target-specific antibody could promote selective tissue injury via an antibody-dependent cell cytotoxicity (ADCC) mechanism [35]. In this process, potential non target-specific immune effector cells bearing Fc receptors (macrophages, microglia, NK cells) would be brought into proximity with a specific target and become activated, as a result of binding to the Fc portion of antibodies which are specifically bound to such targets via their combining sites in the Fab regions of the molecule. Expression of all three Fc receptor classes is upregulated on microglia cells and macrophages present in active MS lesions [36]. Using cells obtained from surgically resected human CNS tissues [8], we could also detect all three classes of Fc receptor on microglial cells in vitro, but not on astrocytes or oligodendrocytes [37]. Incubation of these cultured human microglia with immune complexes enhanced phagocytic activity, production of potential effector cytokines including TNF-, and release of reactive oxygen species (ROS). Scolding et al. showed that macrophage attachment to myelin with subsequent
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phagocytosis could be triggered by presence of antibodies directed at antigens expressed on the surface of myelin (galactocerebroside, MOG) [38]. ADCC illustrates the links that exist between the adaptive and innate immune systems.
Innate Immune Response-mediated Injury In this section, we consider constituents of the innate immune system which are derived from the systemic immune system and which can migrate into the CNS and be found in MS lesions. These include macrophages, NK cells, and / T cells. We will also consider resident cells within the CNS parenchyma that display similar properties. In this category, we include microglia, which are long-lived cells of bone marrow origin and which migrate early in development into the CNS. Unlike perivascular microglia, these parenchymal cells persist without a significant turnover rate. Astrocytes may also acquire some of these properties.
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Macrophages/microglia As mentioned in context of Fc receptor-mediated activation of these cells, activation can be associated with release of an array of potential injury effector molecules which could inflict OL injury [TNF-, ROS, proteases, excitotoxins, nitric oxide (NO)]; the basis for selective injury of OLs by such mediators is discussed below. Activated microglia and macrophages in MS lesions are also reported to express CD95 ligand (CD95L) [47, 48]; CD95 (Fas, Apo-1) signaling and OL injury are discussed in a later section. Microglia and macrophages can be activated via CD40-CD40 ligand interactions with infiltrating T cells [49], and by interactions with an array of endogenous and exogenous antigens which may be present in this compartment under pathologic conditions. Examples of such interactions dependent on expression of innate receptors on these cells include CD14 with the bacterial endotoxin LPS [50], scavenger receptors which may bind proteins such as amyloid [51, 52] and apoptotic cells [53], and chemokine receptors which may be significant for binding HIV [54].
Effector cells / T cells / T cells are found in disproportionately increased numbers in some MS plaques [39] and are also increased in numbers in the CSF of MS patients [40]. Cultured human OLs have been shown to be efficiently lysed in a dose-dependent manner by human / T cells, although such an effect was not restricted to this cell type [41]. This effect is predominantly mediated through the perforin/granzyme system [42]. Members of the heat shock family of molecules are suggested to be recognition targets of these T cells. A number of heat shock proteins (HSP) are readily induced on cultured human OLs by pro-inflammatory cytokines [43]. Alpha B-crystallin, a member of the HSP family present in the OL/myelin complex, is a candidate autoantigen in MS [44]. OLs have been shown to selectively stimulate expansion of the V2 subtype of / T cells; this subtype is particularly reactive to HSP [45]. NK cells NK cells are phenotypically defined by their large granular appearance and expression of the surface molecules CD16 and CD56. These cells do not express CD3, but can express CD8. Cells with this phenotype have been described in the CSF of MS patients [46]. They also express Fc receptors which would allow interaction with antibody in a manner akin to macrophages and thus participate in a combined adaptive/ innate immune response. We can demonstrate that OLs are susceptible to killing mediated by these cells with the apparent mediators being the perforin/ granzyme system [21]. As with / T cells, this susceptibility is not restricted to OLs.
Target-determined Selectivity of Immune-Mediated OL Injury In this section, we consider the selective expression of receptors or induction of specific intracellular signaling events as a basis for selective OL toxicity in response to non-target-selective effector mechanisms.
Receptor-determined injury TNF- death receptor superfamily This family of receptors (R) has a number of members which have been shown to be expressed on OLs, and which may induce intacellular signaling pathways leading to cell injury, or conversely resistance to injury. TNF-R/TNF-. TNF- is readily detected in active MS lesions, largely being produced by macrophages and microglia [55, 56]. In culture, microglia are the major human adult CNS cell source of TNF-, whereas astrocytes are a potent source in the fetal CNS [57, 58]. TNF- could contribute to the pathogenesis of the MS disease process at multiple levels. For example, we demonstrated its role in regulation of the immune response within the CNS by its effects on the Th1 polarizing cytokine interleukin (IL)-12 production [55]. There are two TNF- receptors (TNF-R1 and TNF-R2) which can transduce the signal for apoptosis, but only TNF-R1 is linked to a death domain, making it responsible for the induction of apoptosis in most cases [59]. Human OLs are demonstrated to express the TNF-R1 receptor in vitro [60]; expression is also found on OLs around MS lesions [61]. TNF-R signaling was initially shown to activate caspase-8 [62].
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Subsequently, TNF- induced OL cell death was linked to the caspase-1 pathway [1, 63]. Regarding the direct effects of TNF- on OL and myelin injury, the emerging data from in vivo and in vitro studies indicate that this molecule can exert both neuroprotective and neurotoxic effects. In vivo data are largely derived from mice in which TNF- is overexpressed in the CNS or from mice in which TNF- or one or both of its receptors are deleted. Transgenic overexpression of TNF- within the CNS has resulted in chronic inflammation and demyelination and conversion of acute EAE into a more chronic tissue destructive phenotype [64–66]. Conversely, however, animals in which the TNF- gene was depleted, were more susceptible to CNS inflammation and tissue injury induced by ischemia or trauma [67]. These results implicate a dose effect in determining the balance between cytotoxic and neuroprotective effects of TNF- within the CNS. Such selectivity may also reflect the relative extent of signaling via the TNF-R1 and TNF-R2 receptors, again based on results of receptor knockout mice [68, 69]. In vitro studies related to TNF--induced injury of OLs and myelin have involved evaluating the effects of adding TNF- to an array of culture systems established from mature and immature CNS of a number of species. TNF- was reported to be harmful to aggregating myelinating rodent cultures, to the CG4 OL precursor cell line, and to dissociated rodent, bovine and human primary OL cultures [60, 70–74]. Other studies have not shown such effects [67, 75]. TNF- on OLs also induces retraction of processes [76], modification of ion channels [76–78], and upregulation of death receptors such as CD95 [79]. Our experience with adult human CNS-derived OLs in vitro is that high-dose TNF-, when administered over a relatively long time period (5–7 days), does induce apoptosis, although we have not yet shown that this is TNF-R-dependent [74, 80]. We have observed that TNF- rapidly activates both the c-Jun N-terminal kinases (JNKs) and NFB signaling pathways in these cells. JNKs are p53 N-terminal serine 34 kinases [81] which play a role in p53 stability, transcriptional activities, and apoptotic capacity [82]. We found that treatment of human OLs with TNF- resulted in increased levels of p53 in the cells; overexpression of p53 by adenovirus-mediated gene transfer induced apoptosis [80]. Others consider JNK signaling as protective [83]. The NFB signaling pathway is considered as a protective signaling pathway [84]. The decision as to whether TNF-R signaling will be tipped toward death or survival remains to be defined, but is likely to depend on a balance of the signaling pathways induced. A further potential contribution of TNF- in the injury process is by means of modulating expression of other putative injury mediating receptors such as CD95 on target cells, or of their ligands, e.g. CD95L, on the effector cells. CD95/CD95L. CD95 is a further member of the TNF-R superfamily [85]. Cell death signaling is transduced upon engagement of this receptor by its ligand
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(CD95L), or anti-CD95 antibodies, which then leads to clustering of its death domain and subsequent activation of the caspase cascade [86]. Although CD95 was at first not detected in normal brain, it has now been shown to be expressed during development in murine CNS [87], and on the fetal human astrocytes in vitro [88]. Furthermore, it has been found to be expressed on OLs in MS lesions [47, 48], as well as in the CNS under other pathologic conditions, such as cerebral ischemia and Alzheimer’s disease [89, 90]. CD95L-bearing cells, identified in active MS lesions include macrophages, microglia and lymphocytes [91]. Soluble CD95L can be recovered from MS CSF [48, 92]. To assess the potential role of CD95 signaling as mediator of OL injury, we initially determined that CD95 could be expressed by human OLs in vitro [47] and that engagement of these receptors induced cytotoxicity within a relatively short time period (hours) relative to that observed using TNF-. Recent evidence suggests that pro-inflammatory cytokines, such as TNF- or IFN- within the CNS might upregulate expression of CD95 on a number neural cell types [79, 93, 94]. We were able to show that such an upregulation of CD95 on cultured human OLs rendered them more sensitive to CD95-mediated apoptosis [95]. We did not observe CD95 expression on fetal human neurons or adult astrocytes, providing a basis whereby signaling via this receptor could result in selective target injury. We did observe CD95 expression on both fetal human astrocytes and human glioma cell lines, but only the latter were susceptible to CD95 engagement [88]. These results provide an example whereby selective tissue injury can be dependent on the signaling pathways induced by engagement of a specific surface receptor expressed by an array of cell types. Neurotrophin receptor/NGF. The neurotrophin receptor p75 (p75NTR), another member of the TNF-R superfamily, has been considered to be a co-receptor with the high affinity Trk receptors for neurotrophins [96, 97]. Trk receptors (TrkA, B or C) are tyrosine kinase receptors that mediate suvival effect through neurotrophin-dependent activation [98–100]. P75NTR is able to autonomously signal via neurotrophindependent activation of sphingomyelinase activity and NFB. It contains a death domain in its cytoplasmic region, leading to speculation about its role in cell death signaling in response to neurotrophins, particularly in cells which lack Trk receptors [100]. Levels of the neurotrophin nerve growth factor (NGF) are elevated in the CSF of MS patient [101]. Furthermore, MS lesions contain cells from the OL lineage with elevated p75 neurotrophin receptor (p75NTR) but not Trk expression [48, 102]. OLs within the normal CNS seem to express little or no p75NTR [103]. Neonatal rat OLs in dissociated culture were found to undergo apoptosis in the presence of NGF under conditions in which the cells expressed p75NTR but not TrkA [104, 105]. Under culture conditions that resulted in expression of TrkA on such OLs, NGF supported survival rather than induction of apoptosis [105]. This
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apoptotic effect is now shown to be mediated via a caspase-1 rather than a caspase-8 dependent pathway [106], which, as mentioned before, resembles the actions of TNF- in OLs [1, 63]. Caspase-1 activation has been linked with inflammation [107, 108]. NGF treatment of human adult OLs in culture did not induce apoptosis, even though the cells were expressing p75NTR and not TrkA [80]. It did, however, induce nuclear translocation of NFB, suggesting that at least in human OLs, p75NTR signaling mediates responses other than cell death. Cytokines-mediated OL injury A number of cytokines capable of contributing to tissue injury are present within the inflamed CNS (review in [109, 110]. Specifically implicated cytokines include IFN-, IL-1, -2 and -6 [73]. To date, none of these cytokines have been found to be cytotoxic for human OLs in culture. Whether they indirectly modulate cell death signaling pathways described above remains to be determined. IFN- has been shown in some but not all studies to be cytotoxic for rodent OLs [70, 111, 112]. Overexpression of IFN- in the CNS of transgenic mice can induce spontaneous demyelination [113]. Recent data show that a combination of IFN- and TNF- upregulates the level of CD95 on the surface of neural cells [94], indicating, as mentioned previously in the context of TNF-, another means whereby cytokines can modulate their environment. IL-2 toxicity to OLs in also described [114], an effect ascribed to dimerization of IL-2 by a transglutaminase [115]. The same cytokine was also shown to promote proliferation and maturation of immature oligodendrocytes [116].
Non receptor-mediated injury Oxidative stress Antioxidants belonging to sulfhydryl groups are decreased in the CSF of MS patients, whereas products of lipid peroxidation are increased, pointing out the importance of oxidative stress in MS [117]. Kim and Kim reported that adult bovine OLs were susceptible to the toxic effects of free radicals (reactive oxygen species) generated enzymatically by combinations of glucose with glucose oxidase, and hypoxanthine with xanthine oxidase [118]. They further showed that such damage could be prevented by catalase, but not by superoxide dismutase, vitamin E or glutathione. Protection can also be provided by other resident cells of the CNS, specifically astrocytes [119]. ROS have long been proposed to play a role in bystander demyelination in adult animal [120]. It was shown in EAE that production of ROS regulates the extent of phagocytosis [121]. The sources of free radicals in MS may include not only activated immune cells, such as microglia and macrophages [122], but also neurotransmitters, specifically catecholamines, which generate ROS when they are metabolized [119]. Catecholamines participate in
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the process of neural regulation of the immune response. Many studies have implicated nitric oxide (NO) as an injury mediator within the CNS (review in [123]), including being a key mediator in microglia-induced cytotoxicity of rat OLs [124]. NO was observed to induce necrosis rather than apoptosis in rodent OLs [125]. In the rodent and human CNS, astrocytes rather than microglia would seem to be a major source of NO [126, 127]. Although adult human microglia are shown to produce ROS [128, 129], to date, only fetal human microglia were shown to produce NO [130, 131]. Differential sensitivity of different resident CNS cells to ROS mediated injury has already been demonstrated [132].
Conclusion In summary, the selective injury of OL/myelin that characterizes MS could be determined either by the properties of the effectors of the immune response or the properties of the targets. Many of the effectors implicated in the MS process and the receptors and signaling events involved in the response to these effectors, may have dual roles as related to inducing injury or promoting protection. Opportunities increasingly present themselves to define means to manipulate these responses for the benefit of the individual.
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