MS发病机制的研究进展

NATURE REVIEWS | NEUROLOGY ADVANCE ONLINE PUBLICATION | 1 Centre for Brain Research, Medical University of Vienna, Spitalgasse 4, A‑1090 Wien, Austria (H. Lassmann). Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center Amsterdam, PO Box 7057, 1007 MB Amsterdam, The Netherlands (J. van Horssen). The Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK (D. Mahad). Correspondence to: H. Lassmann hans.lassmann@ meduniwien.ac.at Progressive multiple sclerosis: pathology and pathogenesis Hans Lassmann, Jack van Horssen and Don Mahad Abstract | Major progress has been made during the past three decades in understanding the inflammatory process and pathogenetic mechanisms in multiple sclerosis (MS). Consequently, effective anti‑inflammatory and immunomodulatory treatments are now available for patients in the relapsing–remitting stage of the disease. This Review summarizes studies on the pathology of progressive MS and discusses new data on the mechanisms underlying its pathogenesis. In progressive MS, as in relapsing–remitting MS, active tissue injury is associated with inflammation, but the inflammatory response in the progressive phase occurs at least partly behind the blood–brain barrier, which makes it more difficult to treat. The other mechanisms that drive disease in patients with primary or secondary progressive MS are currently unresolved, although oxidative stress resulting in mitochondrial injury might participate in the induction of demyelination and neurodegeneration in both the relapsing–remitting and progressive stages of MS. Oxidative stress seems to be mainly driven by inflammation and oxidative burst in microglia; however, its effects might be amplified in patients with progressive MS by age‑dependent iron accumulation in the brain and by mitochondrial gene deletions, triggered by the chronic inflammatory process. Lassmann, H. et al. Nat. Rev. Neurol. advance online publication 25 September 2012; doi:10.1038/nrneurol.2012.168 Introduction Multiple sclerosis (MS) is a chronic, inflammatory, demye linating disease of the CNS.1 In early disease, active bouts of demyelination are followed by periods of remission, and relapses are associated with the appear- ance of new lesions or reactivation of old lesions in the white matter of the brain and spinal cord.2 This relapsing– remitting stage is followed by a phase of uninterrupted disease progression, termed secondary progressive MS (SPMS). However, 10–20% of patients do not present with relapsing–remitting MS (RRMS), but instead experi ence unremitting disease progression (primary progressive MS, or PPMS).2 In addition, during the period of transi- tion from RRMS to progressive MS, continuous clinical deterioration can be interspersed with new bouts of the disease (relapsing progressive MS).2 Major progress has been made during the past three decades in understanding disease mechanisms in the relapsing–remitting phase of MS. This knowledge has led to effective anti-inflammatory and immunomodula- tory treatments that reduce the severity and frequency of new demyelinating episodes.3,4 However, once patients have entered the progressive stage of MS, therapeutic options are currently limited to symptomatic treatments and physiotherapy. The reason for this unsatisfactory situation is that the disease mechanisms driving pro- gressive MS remain unresolved, and there is currently no animal model available that accurately reproduces this stage of MS. Several mechanisms have been proposed to explain the pathogenesis of progressive MS.5 The first postulates that brain damage is driven by inflammatory processes similar to those in RRMS, but that inflammation differs in such a way that it is no longer treatable by current therapeutic strategies.6 In the second, MS starts as an inflammatory disease but, after several years of chronic inflamma- tion, neurodegeneration results in disease progression, a process that occurs independently from the inflammatory response. As an example, microglial activation is under the control of intact neurons, and this control might be lost as a consequence of neuro degeneration.7–9 Finally, MS might be primarily a neuro-degenerative disease, progres- sion of which is modified or amplified by inflammation in the early disease stage. Support for this view comes from experimental models, such as transgenic mice in which oligodendrocytes are deficient for peroxisomes10 or overexpress proteolipid protein,11 causing inflammation that contributes to disease progression.10,11 However, gene association studies in patients with MS did not provide evidence for an association between genes implicated in neuro degeneration and MS incidence.12 Although these different concepts are not necessarily exclusive, the rational design of therapeutic strategies for progressive MS depends on understanding which patho- genetic pathways dominate the disease process. In this Review, we discuss current data on the pathophysiology of progressive MS, and present a pathogenetic concept that involves oxidative stress and mitochondrial injury, Competing interests J. van Horssen declares an association with the following company: Biogen Idec. See the online article for full details of the relationship. The other authors declare no competing interests. REVIEWS © 2012 Macmillan Publishers Limited. All rights reserved dell 附注工具 多发性硬化的研究进展：病理和发病机制 概要： 过去60年对于多发性硬化的病理及发病机制的研究所取得的重大进步，主要表现在对其炎症过程的研究。因此给予RRMS阶段行抗炎治疗和免疫治疗是合适的。 对于进展性的MS，比如RR型MS，炎症的能导致组织损伤，然而进展期炎症应答的部分在血脑屏障内，这增加了治疗的难度。 尽管在复发缓解型及继发进展型MS患者中，氧化应激导致线粒体损伤可能会诱导脱髓鞘和神经变性，但目前这种机制仍不明确。 小胶质细胞的炎症和氧化反应可能驱动氧化应激的主要因素；并且，这种效应在继发进展型MS患者中得以放大，这可能相关于 dell 文本高亮工具 dell 文本高亮工具 2 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneurol which could be applicable to the relapsing–remitting stage as well as to progressive MS. Clinical course of MS In the relapsing–remitting stage of MS, clinical disease seems to be driven by the development of new inflamma- tory demyelinating lesions in the CNS. The accumulation of irreversible neurological symptoms, therefore, largely depends on the number and severity of relapses and the location of these lesions.13 However, after several years of disease, when the patients have reached a threshold level of irreversible neurological symptoms, and when functional compensation may be exhausted, the clini- cal features of the disease change, heralding the onset of SPMS.14,15 Further clinical deterioration generally devel- ops at a constant and predicable speed after this point, and is independent of the previous disease course, number of relapses and relapse severity. The rate of clinical deteriora- tion is similarly predictable in patients with PPMS, who do not go through the relapsing– remitting stage.13,15 Intriguingly, the conversion from RRMS to progres- sive MS tends to occur in a well-defined age window of 35–50 years, which is the same as the typical age of disease onset in patients with PPMS.16 Evidence from families affected by MS does not support the view that PPMS is a separate disease entity from RRMS or SPMS.12,17 Moreover, pathological studies show similar alterations in the CNS in RRMS, PPMS and SPMS.1 Taken together, these findings suggest that MS is a single disease entity with several distinct clinical phenotypes. Conversion of MS from the relapsing–remitting stage to SPMS seems to be related to prolonged chronic inflammation in the CNS and—as discussed below—to the age of the patient. Hallmarks of MS pathology The pathological hallmarks of MS are inflammation, demyelination, remyelination, neurodegeneration and glial scar formation, which occur either focally or dif- fusely throughout the white and grey matter in the brain and spinal cord (Figure 1).1 These pathological features are present in both RRMS and SPMS, as well as in PPMS, Key points ■ In all stages of multiple sclerosis (MS), active demyelination and neurodegeneration are associated with inflammation mediated by T cells, B cells, macrophages and activated microglia ■ The basic pathological alterations in the brain are similar between early relapsing and progressive stages of MS, but are increased in their extent in progressive disease ■ Multiple mechanisms contribute to neurodegeneration in progressive MS, including exhaustion of functional compensation, lack of trophic support, chronic microglial activation and altered expression of ion channels in demyelinated axons ■ Mitochondrial injury induced by oxidative stress might underlie the pathological features of MS lesions, such as oligodendrocyte apoptosis, demyelination, destruction of thin‑calibre axons, and lack of remyelination ■ Age‑related iron accumulation in the human brain and release of iron in lesioned tissue might amplify oxidative damage, particularly in progressive MS ■ Treatment of progressive MS is hindered by the presence of inflammation ‘trapped’ behind the blood–brain barrier, and might require a combination of anti‑inflammatory and neuroprotective strategies although they vary over time both quantitatively and qualitatively between these three forms of MS and among individuals with the same form (Figure 2). Inflammation Inflammation is invariably present at all stages of MS.6 Inflammatory lesions in patients with MS consist of perivascular and parenchymal infiltrates of lympho- cytes and macrophages.18 CD8+ T cells are present in greater numbers than are other T-cell subsets, B cells or plasma cells.6,19 In active lesions, which dominate in the re lapsing–remitting stage of MS, low numbers of T cells are present at sites of initial tissue injury during the pre- phagocytic stage of lesion formation,20 and ongoing tissue injury is associated with infiltration of macrophages and/or activation of resident microglia.18 Invasion of the majority of these inflammatory cells into the tissue occurs after the initial destruction of myelin.21,22 This observation suggests that two different types of inflammation occur within active plaques: the initial response, consisting mainly of CD8+ T cells and abundant micro glial activa- tion; and secondary recruitment of T cells, B cells and macrophages as a consequence of myelin destruction. Inflammation in the relapsing–remitting stage of MS is indicated by the infiltration of inflammatory cells into the CNS, resulting in profound damage to the blood– brain barrier (BBB), which has been demonstrated with gadolinium-enhanced MRI of lesions.23–25 In PPMS and SPMS, active demyelination and neuro- degeneration are also invariably associated with inflam- mation.6 However, the relationship between inflammation and damage to the BBB is less obvious than in RRMS.26 First, mild BBB impairment, indicated pathologically by serum-protein leakage,26, 27 can occur in conjunction with chronic lesions, irrespective of the presence or absence of inflammatory infiltrates.27,28 However, the extent of BBB damage is too limited to be detected by gadolinium- enhanced MRI. The inflammatory process in the brains of patients with PPMS or SPMS also becomes, at least in part, dissociated from BBB damage, with the result that inflammatory infiltrates are frequently encountered around small veins and venules without evidence of loss of BBB integrity.26 In the connective tissue spaces of the brain, such as the meninges and the large Virchow–Robin spaces, large aggregates of inflammatory cells have been observed, which display structural features of lymphatic follicles (Figure 1), such as T-cell-and-B-cell germinal areas and the presence of follicular dendritic cells.29–31 This observation demonstrates that as the disease pro- gresses, inflammation becomes partly compartmentalized behind an intact BBB. Focal plaques of demyelination Focal plaques of demyelination are the diagnostic hall- mark of MS pathology.1 In the brain, such plaques are pre sent in the grey and white matter at all stages of the dis ease. In progressive MS, however, the pathology shifts in quantitative terms from new and active white matter lesions to slow expansion of pre-existing lesions, which leads to pronounced cortical demyelination and is REVIEWS © 2012 Macmillan Publishers Limited. All rights reserved dell 附注工具 要点： MS的各个阶段，脱髓鞘及神经变性相关于由T细胞介导的炎性反应。 MS早期和晚期的神经病理改变是相同的，但晚期比早前的病变程度要更重一些。 多种机制参与多发性硬化的进展过程，包括代偿功能的衰竭、营养支持的缺乏、长期小胶质细胞活化以及脱髓鞘病变轴突上例子通道的改变 dell 文本高亮工具 dell 文本高亮工具 NATURE REVIEWS | NEUROLOGY ADVANCE ONLINE PUBLICATION | 3 associated with extensive diffuse injury throughout the normal-appearing white and grey matter (Figure 1). As a consequence of this shift, patients can exhibit a mixture of lesion types—classic active lesions, slowly expanding lesions, inactive lesions and remyelinated shadow plaques (Box 1). The types of lesions that are present depends on the stage of MS, speed of plaque development, and extent of remyelination. Axonal injury is most pronounced in the initial, early active and late active zones of classic active lesions, and the extent of axonal damage correlates significantly with the number of lymphocytes and activated microglia in the surrounding tissue.32–34 This finding suggests that axonal injury is extensive even in the earliest bouts of RRMS.35 However, in the progressive stage of MS, axonal injury also occurs in the active zone of slowly expanding lesions, and even within their inactive centres.36 Focal demyelinated plaques are not restricted to the white matter, but are also present in the cortex and deep grey matter nuclei.37,38 In the first bouts of RRMS, they are (like white matter lesions) associated with profound inflammation, consisting of perivascular inflammatory infiltrates, dispersion of lymphocytes throughout the tissue, and substantial macrophage and microglial acti- vation.39 Moreover, damage and loss of neurons, axons and synapses is more pronounced in early-stage corti- cal plaques than in those arising during the progressive phase of the disease.39,40 Cortical lesions are most abun- dant in the progressive stage of MS, at which time they are most prominent in the subpial cortical layers40 and, when active, are linked to local inflammation (T-cell and B-cell infiltrates) in the meninges.31 Active demyelina- tion and neurodegeneration are associated with activated microglia.30,41 This pattern of pathology, together with the characteristic accumulation of lesions in the corti- cal sulci, suggest that active tissue injury is driven by a soluble factor produced by meningeal inflammatory aggregates.31,40 This factor diffuses into the cortex and induces demyelination and neurodegeneration either directly or indirectly through microglial activation.31,40 Diffuse global tissue injury Besides focal lesions, the brains of patients with MS also show diffuse and global changes, including widespread inflammation, microglial activation, astrocytic gliosis, and mild demyelination and axonal loss in normal- appearing white matter.40,42 Widespread loss of tissue volume is also seen in the normal-appearing cortex.43 These changes collectively result in extensive brain atrophy with dilatation of the ventricles. Focal demyelination: white matter Focal remyelination: white matter Demyelination: deep grey matter nuclei Demyelination: cortex a c d e f b * Figure 1 | Characteristic brain pathology in secondary progressive multiple sclerosis. a | Brain section immunostained for proteolipid protein. Coloured areas indicate the locations of different lesion types. Marked atrophy with dilatation of cerebral ventricles and outer cerebrospinal fluid spaces is also evident. b | Normal‑appearing white matter with microglial activation and microglial nodule, revealed by immunostaining for p22phox (brown). c | Proteolipid protein immunostaining (brown) reveals a broad band of subpial demyelination together with a small intracortical demyelinated lesion (pale regions). d | Low‑power image of active demyelinating white matter lesion, showing macrophages with myelin degradation products (arrows) and reactive gliosis (arrowheads). e | Higher‑magnification image of the active lesions shown in (d) reveals demyelinated axons (arrows), macrophages with myelin debris (arrowheads) and dystrophic axons (asterisk) within the myelin sheath. f | Double immunostaining for p22phox and CD8 shows activated microglia (brown) and T lymphocytes (black) accumulating in perivascular cuffs and dispersed within the lesion. REVIEWS © 2012 Macmillan Publishers Limited. All rights reserved 4 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneurol The extent and severity of diffuse white matter injury increases with disease duration, and is most pronounced in the progressive stage of MS. However, partly preserved axons can be found in all MS lesions and, when axons are destroyed, the small-calibre fibres are predomi nantly affected.44,45 The extent of diffuse white matter injury does not correlate with the number, size or destruc- tiveness of focal white matter lesions.40,46 How ever, diffuse white matter injury shows a moderate (but still statistically significant) correlation with the extent of cortical demyelination.40 Mechanisms underlying MS pathology Many different components of adaptive and innate immunity induce demyelination, oligodendrocyte death and axonal or neuronal injury in patients with MS, including antigen-specific cytotoxic T cells,47,48 and autoantibodies directed against neuronal or glial antigens.49,50 Furthermore, myelin sheaths are par- ticularly vulnerable to nonspecific products released by activated macrophages and microglia that cause tissue destruction, such as cytotoxic cytokines, excito- toxins or reactive oxygen or nitric oxide species. In the highly inflammatory lesions seen in RRMS, distinct immune processes might con tribute to demyelination and neurodegeneration in different patients or differ- ent disease subgroups, as reflected by distinct patterns of demyelination and tissue injury.51 The most fre- quently observed patterns of demyelina tion are antibody and complement- associated changes (pattern II), and hypoxia-like tissue injury (pattern III). In hypoxia-like tissue injury, demyelina tion is initiated by degeneration of the most distal oligo dendrocyte processes and apopto- sis of oligodendrocytes, as also seen in the initial stages of white matter stroke lesions,20,51 and astrocytes show loss of polarity, resulting in a disturbance of the struc- tural organization of the peri vascular glia limitans.52,53 In other patients with RRMS, active demyelina tion is associated with T cells and activated microglia alone (pattern I).51 In patients with either PPMS or SPMS, the patterns of tissue injury are, in general, homogeneous, showing the essential criteria of demyelination, oligo- dendrocyte loss, preferential destruction of small-calibre axons, lack of remyelina tion, and astrocytic gliosis.6,54,55 The absence of different patterns of tissue injury within lesions arising in the progressive stage of MS might be a result of their slow expansion, which in turn might pre- clude identification of immunopathological pathways specific to different lesion types.56 Several different mechanisms have been proposed to underlie neurodegeneration in progressive MS. Chronic neurodegenerative changes are well-established to accu- mulate over time as a result of axonal injury in focal white matter lesions.32,33 However, several studies have failed to show a correlation between diffuse brain and spinal cord atrophy and focal white matter lesions,40,46 suggesting that neurodegeneration in white matter plaques does not hav