multiple sclerosis pathologyperspectivesinmedicine.cshlp.org/content/8/3/a028936.full.pdf ·...

Multiple Sclerosis Pathology

Hans Lassmann

Center for Brain Research, Medical University of Vienna, A-1090 Wien, Austria

Correspondence: [email protected]

Multiple sclerosis (MS) is achronic inflammatory demyelinating disease of the central nervoussystem (CNS), which gives rise to focal lesions in the gray and white matter and to diffuseneurodegeneration in the entire brain. In this review, the spectrum of MS lesions and theirrelation to the inflammatory process is described. Pathology suggests that inflammation drivestissue injury at all stages of the disease. Focal inflammatory infiltrates in the meninges and theperivascular spaces appear to produce soluble factors,which induce demyelination or neuro-degeneration either directly or indirectly through microglia activation. The nature of thesesoluble factors, which are responsible for demyelinating activity in sera and cerebrospinalfluid of the patients, is currently undefined. Demyelination and neurodegeneration is finallyaccomplished by oxidative injury and mitochondrial damage leading to a state of “virtualhypoxia.”

Multiple sclerosis (MS) has historically beendefined as a chronic inflammatory disease

of the central nervous system (CNS), which leadsto large focal lesions in the white matter of thebrain and spinal cord, characterized by primarydemyelination with a variable extent of axonalloss (Charcot 1880). Demyelination and neuro-degeneration in theMS brain is associatedwith aprofound astroglia reaction, forming a dense gli-al scar in long-standing established lesions. Forsome time, the view on MS pathology centeredon focal demyelinated plaques in the white mat-ter. Later it became clear that lesions are alsopresent in the gray matter, including the cortex,the basal ganglia, brain stem, and the graymatterof the spinal cord (Brownell and Hughes 1962).Furthermore, there is neurodegeneration, whichaffects the brain and spinal cord in a globalsense, giving rise to axonal loss in the normal-

appearing white matter, and diffuse neurode-generation in the entire gray matter. Thesechanges finally result in profound brain tissueloss and atrophy, which is most pronounced inthe progressive stage of the disease (Mahad et al.2015). The general pathology of MS has beendescribed in detail in several recent reviews(Lassmann et al. 2007; Kutzelnigg and Lass-mann 2014) and, therefore, this article focuseson some essential features. In addition, newfindings related to inflammation and its relationto demyelination and neurodegeneration will bediscussed in more detail.

BASIC PATHOLOGY OF MULTIPLESCLEROSIS

The diagnostic hallmark of MS is the presenceof large confluent demyelinated lesions in the

Editors: Howard L. Weiner and Vijay K. KuchrooAdditional Perspectives on Multiple Sclerosis available at www.perspectivesinmedicine.org

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white and graymatter of the CNS (Fig. 1) (Char-cot 1880). The most important feature is theselective and primary nature of demyelinationwith the destruction and loss of oligodendro-cytes (Babinski 1885; Prineas 1985). Althoughmyelin is completely lost, axons are preserved to

a large extent, and the amount of axonal de-struction is variable between different patientsand even between lesions in the same patient(Ferguson et al. 1997; Trapp et al. 1998; for ahistorical review, see Kornek and Lassmann1999). Lesions occur on the background of in-

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Figure 1. Pathological changes in the brain of a patient with secondary progressive multiple sclerosis (MS). Largeconfluent focal demyelinated lesions are present in the white matter (A). In addition, there is extensive subpialcortical demyelination, which can only be seen when sensitive immunocytochemistry for myelin proteins (e.g., pro-teolipid protein) is used (B). In contrast to the normal pattern ofmyelin in the cerebral cortex, as shown inC, thereis complete loss ofmyelin in subpial lesions (D). Demyelinated plaques in thewhitemattermay appear as inactivedemyelinated lesions ([DMs] in E), as early remyelinated lesions with a low density of thin myelin sheaths onlyvisible by immunocytochemistry for myelin proteins (ERM in F) or as remyelinated shadow plaques (G andH ).

H. Lassmann

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flammation, consisting of T lymphocytes, Blymphocytes, and plasma cells (Fig. 2). The in-flammatory reaction is initiated around post-capillary venoles and veins (Charcot 1880).Thus, in the initial stages of lesions, perivenousdemyelination is seen and these lesions fuse toconfluent demyelinated plaques, which expandat their border into the surrounding normal-appearing white matter. This gives rise to thetypical perivenous extensions of established le-sions, the so-called Dawson fingers (Dawson1916). The demyelinating process is associatedwith activation of astrocytes during the state ofactive tissue injury and the formation of glioticscars in inactive lesions. MS lesions can in partbecome remyelinated as a result of recruitmentand differentiation of oligodendrocyte progeni-tor cells (Prineas et al. 1993).

Similar perivenous and confluent demyeli-nated lesions are also formed in the gray matter(Fig. 1), including the cerebral (Kidd et al. 1999)and cerebellar cortex (Kutzelnigg et al. 2007), thedeep brain stem nuclei (Cifelli et al. 2002; Ver-cellino et al. 2009; Haider et al. 2014), and thegray matter of the spinal cord (Fog 1950). In ad-dition, in the cerebral cortex, widespread subpialcortical demyelination is present, in particular inthe progressive stage of the disease, and activesubpial demyelination isoriented toward inflam-matory infiltrates in the leptomeninges (Bo et al.2003; Kutzelnigg et al. 2005). Inflammation inand around MS lesions is seen in all stages ofthe disease, thus being present not only in thebrain of patients who died in early (relapsing)MS but also in primary or secondary progressiveMS. It is most pronounced within actively de-

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Figure 2. Inflammation in the multiple sclerosis (MS) brain. Meningeal inflammatory infiltrates are composed ofCD3+ T cells, CD20+ B cells (A), and immunoglobulin-positive plasma cells (B). The inflammatory infiltratesappear as aggregates with separated domains for T cells, B cells, and plasma cells (A and B). No lymphocytes arepresent in the underlying cortical tissue (A). In white matter lesions, profound inflammatory infiltrates are seenin the perivascular space, which contain T cells and B cells (C). In addition, there is a diffuse infiltration of T cells,but not of B cells in the lesioned tissue (C). The diffuse infiltrates in the lesions nearly exclusively consist of CD8+

T lymphocytes (D).


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myelinating lesions, but is also seen in inactive orremyelinated plaques as well as in the normal-appearing white matter (Frischer et al. 2009).

The selective perivenous and confluent pri-mary demyelination with oligodendrocyte lossdistinguishes MS from other diseases with focalwhite and gray matter lesions. As examples, inneuromyelitis optica, focal demyelinated lesionswith severe axonal destruction follow a primaryastrocyte damage triggered by specific antibod-ies against aquaporin 4 (Misu et al. 2013). Inother inflammatory conditions, primary demye-lination may follow virus infection of oligoden-drocytes (e.g., progressive multifocal leukoence-phalopathy). In this situation, demyelinationinitially affects the territories of single oligoden-drocytes, but does not reflect the MS typicalperivenous pattern (Bauer et al. 2015). Focalwhite matter lesions in other inflammatory dis-eases or stroke are mainly destructive with par-allel loss ofmyelin, oligodendrocytes, and axons.

Active Lesions

Active demyelination or tissue injury is associ-ated with densely populated phagocytic cells,which reveal a morphological phenotype of acti-vatedmicroglia ormacrophages (Fig. 3) (Prineas1985). Microglia activation is most pronouncedat the edge of actively demyelinating lesions butalso abundant in the periplaque or even in thedistant normal-appearing white matter. In theperiplaque, whitematter clusters of activatedmi-croglia are frequently encountered, which in partsurround degenerating axons (Prineas et al.2001). In the demyelinated center of active le-sions, cells with a microglia phenotype are rare,but the majority of phagocytic cells present asmacrophages (Fig. 3A). Whether the macro-phages in the plaque center are derived fromthe pool of activatedmicroglia or fromhematog-enous monocytes is unresolved. Macrophagescontain remnants of the destroyed myelinsheaths and the immunocytochemical profileof different minor and major myelin proteinswithin the degradation products allow an exactstaging of the activity of the lesion (Brück et al.1995). Microglia and macrophages in the MSbrain present with a phenotype, which is inter-

mediate between proinflammatory (M1) or anti-inflammatory(M2)cells (Vogeletal.2013).How-ever, at sites of active demyelination and tissueinjury, they highly express nicotinamide adeninedinucleotide phosphate (NADPH) oxidase, indi-cating oxidative tissue damage. NADPH oxidaseexpression is reduced or lost in later stages ofactive lesions when macrophages have taken upmyelin or tissue debris (Fischer et al. 2012).

Such classical active lesions, describedabove, are mainly seen in patients who havedied in early disease stages, such as acute MSor relapsing remitting MS (Frischer et al.2015); they can be distinguished from slowlyexpanding active lesions, which are most fre-quently seen in patients with progressive MS(Fig. 3C,D) (Prineas et al. 2001). The slowly ex-panding lesions show an inactive demyelinatedcenter and a rim of activated microglia at theedge with some intermingled cells with a mac-rophage phenotype, which contain myelin deg-radation products. In addition, acute axonal in-jury, reflected by the presence of axons withdisturbed fast axonal transport or of axonalend bulbs, is not only seen in classical activelesions but also at the active edge of slowly ex-panding plaques (Frischer et al. 2015).

Inactive Lesions

Inactive lesions are most abundant in the MSbrain. They are sharply demarcated and showprimary demyelination, partial axonal preserva-tion, and reactive gliosis (Fig. 1E). A variabledegree of microglia activation is present in theperiplaque white matter, whereas the number ofmicroglia is profoundly reduced in the center ofthe demyelinated plaque. A dense fibrillary scartissue fills the space between the demyelinatedaxons. Importantly, there is a low degree of on-going acute axonal injury, reflected by the dis-turbance of fast axonal transport also in inactivelesions, indicating the ongoing demise of chron-ically demyelinated axons (Kornek et al. 2000).

Remyelinated Shadow Plaques

Like inactive lesions, remyelinated shadowplaques are sharply demarcated from the sur-

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rounding normal-appearing white matter (Fig.1F–H). Axons within these lesions have uni-formly thin myelin sheaths with shortened in-ternodes (Prineas et al. 1993). Remyelinationmay be present in the entire lesion or coveronly focal areas within the plaque or the plaquemargin. The extent of remyelination varies pro-foundly between different MS patients and de-pends in part on lesion location. As an example,remyelinated plaques are more frequent in thesubcortical compared to the periventricularwhite matter (Patrikios et al. 2006). Remyelina-tion is accomplished by new oligodendrocytesderived from the progenitor cell pool, and the

extent of remyelination appears to be deter-mined by several factors, such as the presenceof progenitor cells, their potential to differenti-ate into mature myelinating oligodendrocytes(Chang et al. 2002), the presence and functionalproperties of axons, and the occurrence of repeat-ed demyelination of remyelinated areas (Bramowet al. 2010). Furthermore, in rare lesions, whichare affected by pronounced damage of astrocytes,remyelination may also be accomplished bySchwann cells (Itoyama et al. 1985). However,in light of recent knowledge, some of the patientsdescribed in this study may have suffered fromneuromyelitis optica and not from MS.

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Figure 3. Macrophages and microglia in active multiple sclerosis (MS) lesions. Classical active white matterlesions are densely infiltrated by macrophages and show massive microglia activation with expression of thephagocytosis-associatedmarker CD68 at the lesionmargin and in the adjacent periplaquewhitematter (PPWM)(A). Active cortical lesions are associated with inflammation in the meninges, whereas the zone of activedemyelination is infiltrated by activated microglia with some intermingled macrophages (B). The cortical andwhite matter areas are labeled as Cortex and WM, respectively. Slowly expanding lesions in the white matter arecharacterized by a dense rim of activated microglia with some intermingled macrophages at the lesion edge,stained with the microglia marker Iba1. In the lesion center, there is a very low microglia density (C). Similarly,slowly expanding lesions are also seen in the cortex, associated with meningeal inflammation and the presence ofactivated Iba1-positivemicroglia at the zone of activemyelin injury. As in chronic whitematter lesions also in thecortex, the demyelinated zones are nearly completely devoid of microglia (D).



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Demyelination in the Gray Matter

As in white matter lesions, oligodendrocyte de-struction and primary demyelination is thepathological hallmark that distinguishes themfrom brain damage in other diseases of theCNS (Fig. 1B–D). However, the degree of in-flammation, edema, microglia activation, andmacrophage recruitment is much less comparedwith that in white matter (Peterson et al. 2001).Demyelination is associated with a variable de-gree of loss of axons, neurons, and glia cells, andthis is accompanied by an even greater loss ofsynapses (Wegner et al. 2006; Dutta et al. 2011).Remyelination is more extensive in the cortexcompared with the white matter (Albert et al.2007).

Types of Cortical Lesions

Different types of cortical lesions are found inthe MS brain, and their incidence is differentbetween early relapsing and progressive MS(Kidd et al. 1999; Peterson et al. 2001; Bo et al.2003). Type 1 lesions are present at the cortico–subcortical border and affect the gray as well asthe white matter. Type 2 lesions are small peri-venous intracortical lesions. Type 3 lesions arelocated in the subpial layers of the cortex (Fig.1B,D). They are most abundant, in particular, inthe progressive stage of the disease and aremain-ly located in the cortical sulci and the deep in-vaginations of the brain surface, such as the in-sular cortex or the cingulate cortex. They areassociated with inflammation in the meningesand expand from the pial surface into the deepercortical layers. A special type of cortical type 3lesions has been classified as type 4 when it af-fects the entire cortex but does not pass the bor-der between the cortex and the white matter.

Diffuse Changes in Normal-Appearing Whiteand Gray Matter

Such alterations aremostpronounced inpatientswith progressive MS. They consist of perivascu-lar inflammatory infiltrates, moderate brain ede-ma, diffuse microglia activation, diffuse axonalinjury, and astrocytic gliosis (Kutzelnigg et al.

2005). Part of these changes is secondary to ax-onal and neuronal damage within focal lesions,which gives rise to anterograde (Wallerian) andretrograde degeneration (Dziedzic et al. 2010).Retrograde degeneration induces the accumula-tion of phosphorylated neurofilamentwithin thecytoplasm of affected neurons, which is a goodindicator of the severity of this process (Haideret al. 2016). However, diffuse changes in the nor-mal-appearing white and graymatter also devel-ops independent from focal lesions. They corre-late, in part, to inflammation in the meningescovering the spinal cord or the cortex (Andro-dias et al. 2010; Haider et al. 2016).

Differences in Pathology among Acute,Relapsing, and Progressive MS

All typical pathological features of MS are seenin all stages of the disease (Haider et al. 2014,2016). Thus, there is no qualitative difference inthe pathology between relapsing and progressiveMS, including primary progressive MS. Howev-er, the contribution of the pathological processesand alterations differs quantitatively. Focal newand active white matter lesions are most nu-merous in early (acute and relapsing) MS andbecome rare when patients have entered theprogressive stage. Instead, many plaques inprogressive MS fulfill the criteria of slowly ex-panding lesions, as described above. Cortical de-myelination is already present in the earlieststages of MS (Lucchinetti et al. 2011), but itsextent massively increases when patients reachthe progressive stage (Kutzelnigg et al. 2005). Inextreme examples of primary progressive MS,white matter lesions may be very rare and small,whereas demyelination may affect >60% of theentire cortical area (Haider et al. 2014). Diffusechanges in the normal-appearing white matterare sparse in early MS but very pronounced inpatients with progressive MS (Kutzelnigg et al.2005).

Focal lesions in the MS brain arise aroundinflamed veins and venoles and, thus, areas ofhigh venous density are more likely to be affect-ed (Charcot 1880). In the progressive stage of thedisease, however, chronic demyelinated plaquesaccumulate in brain areas, which have a lower

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perfusion and oxygen tension in normal indi-viduals (the so-called watershed areas markingthe borders of the territories of large cerebralarteries) (Brownell and Hughes 1962; Haideret al. 2016). This indicates that in brain regionswith high-perfusion and oxygen tension, lesionsformed in the early disease stages may becomerepaired, whereas tissue destruction, leading topermanent lesions, is more pronounced in areasof low blood perfusion (Holland et al. 2012;Haider et al. 2016). Interestingly, permanentand destructive lesions in progressive MS alsoaccumulate in those areas, which are mainly af-fected by the consequences of age-related vascu-lar disturbances such as periventricular leuko-arayosis (Haider et al. 2016). These features ofpathology in the progressive stage of MS are inline with the concept that oxidative injury, fol-lowed by mitochondrial injury and genetic de-letions of mitochondrial DNA, are key mecha-nisms of tissue damage inMS, leading to “virtualhypoxia.” This appears to result in energy defi-ciency and subsequent ionic imbalance in oligo-dendrocytes, axons, and neurons, which can beamplified by age-related hypoxic tissue injury(Trapp and Stys 2009; Mahad et al. 2015).

INFLAMMATION

MS has originally been defined as a chronic in-flammatory disease of the CNS, which leads todemyelination and subsequent neurodegenera-tion (Babinski 1885). However, this view hasbeen challenged by clinical observations thatin the progressive stage, ongoing tissue damageis not associated with magnetic resonance im-aging (MRI) evidence for inflammation (the de-tection of blood–brain barrier disturbance byGd-leakage) and the lack of effectiveness ofanti-inflammatory treatments in this stage ofthe disease. Furthermore, analysis of initialstages of white matter lesions showed surpris-ingly little inflammation in comparison to thatseen in later, more advanced lesion stages (Bar-nett and Prineas 2004). For these reasons, it hasbeen proposed that MS may be the result of aprimary neurodegenerative process, which ismodified or amplified by the inflammatoryreaction (Stys et al. 2012). However, a detailed

pathological analysis provides a different view,which will be discussed in detail below.

The nature of the inflammatory response inthe MS brain has been in the center of interestfor decades of MS research. As described above,the formation of MS lesions around veins andvenoles, the association of active demyelinationwith inflammatory infiltrates around these ves-sels, as well as the diffuse spread of the inflam-matory process into the affected tissue have al-ready been noted in the earliest descriptions ofthis disease. Perivascular inflammatory infil-trates were found to consist mainly of lympho-cytes and plasma cells, whereas active tissuedamage was associated with macrophages andactivated microglia. The lymphocyte populationhas later been defined to representmainly T cellswith a smaller contribution of B cells and plasmacells (Fig. 2C) (Esiri et al. 1980; Booss et al. 1983;Hayashi et al. 1988; Franciotta et al. 2008). Theinflammatory process is associated with theexpression of proinflammatory as well as anti-inflammatory cytokines (Cannella and Raine1995; Mycko et al. 2003) and adhesion mole-cules (Dore-Duffy et al. 1993; Ifergan et al.2011; Larochelle et al. 2012, 2015) or chemo-kines and their receptors (Balashov et al. 1999;Holman et al. 2011), which are involved in therecruitment of different lymphocyte subsets andmonocytes.

Regarding cells of the adaptive immune sys-tem,CD3-positiveT cells are themost numerouslymphocytes in theMS brain in all lesions and atall stages of the disease. CD8+ T cells by far out-number CD4+ cells (Fig. 2D) (Booss et al. 1983;Hayashi et al. 1988), CD20+ B cells, or plasmacells (Frischer et al. 2009). Clonal expansion hasbeenmainly observed in the population of CD8+

T cells and plasma cells, being much less abun-dant in the CD4+ population (Babbe et al. 2000;Skulina et al. 2004; Hohlfeld et al. 2016). How-ever, there are differences in the composition ofinflammatory cells in the perivascular ormenin-geal space and in the diffuse infiltrates in theparenchyme of the CNS. CD8+ T cells outnum-ber other lymphocytes in all locations, but in theperivascular and meningeal cuffs, a substantialbut variable number of CD4+ T cells, CD20+ Bcells, and plasma cells are present (Fig. 2A,C)



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(Babbe et al. 2000; Frischer et al. 2009). In themeninges, inflammatory cells form large aggre-gates, which show features of tertiary lymphatictissue (Serafini et al. 2004; Franciotta et al. 2008;Pikor et al. 2016). This is reflected by separationof T cells, B cells, and plasma cells in distinctdomains of the aggregates (Fig. 2A,B), and thisprocess is associated with B-cell proliferationand the presence of cells expressing markers offollicular dendritic cells (Serafini et al. 2004).Such inflammatory follicle-like structures inthemeninges are associated with particularly se-vere active demyelination in the underlying cor-tex (Magliozzi et al. 2007). Similar, but less im-pressive, aggregates are also found within thelarge perivascular Virchow–Robin spaces of thebrain. In contrast, diffuse infiltration of the brainparenchyme in lesions and the normal-appear-ing white matter nearly exclusively consist ofCD8+ T cells (Fig. 2D) and, in some cases, im-munoglobulin-containing plasma cells (Babbeet al. 2000; Frischer et al. 2009). Little is knownso far regarding the presence of T-cell subsets inthe lesions. Some studies report high numbers ofT cells expressing the transcription factor T-bet,thus suggesting the presence of T cells polarizedinto a γ-interferon-producing subset (Bsibsiet al. 2014). One study reported Il17 expressionin CD4+ and CD8+ lymphocytes (Tzartos et al.2008, 2011), but functional interpretation ofthese findings was complicated by the abun-dance of the expression of Il17 in astrocytes.Il21 was found in CD4+ cells, but the Il21 recep-tor was broadly expressed in all lymphocyte sub-populations. In addition, Il21 and its receptorwere abundantly expressed in neurons. Thefunctional role of the expression of these cyto-kines inCNScells andhow it influences lympho-cyte function in the nervous system is current-ly unresolved. There is good agreement thatFoxP3-positive regulatory cells are very sparseor even absent in MS lesions (Tzartos et al.2008; Fritzsching et al. 2011).

Inflammation in Active MS Lesions

As mentioned above, it is still controversial as towhether the inflammatory process in MS is theprimary driving force of tissue damage inMS, or

whether the lesions are initiated by a neurode-generative process that is modified or amplifiedby the inflammatory reaction. The latter view issupported by a highly recognized study, whichproposed that initial MS lesions are formed inthe absence of inflammation by T cells and Bcells, although these cells accumulate in ad-vanced lesion stages after the initial destructionof oligodendrocytes by apoptosis and demyeli-nation (Barnett and Prineas 2004). However,detailed quantitative studies following this pri-mary observation showed that in the earlieststages of lesions there are already perivascularinflammatory infiltrates containing T cells andB cells in close proximity to the site of activetissue damage and that there is a diffuse infiltra-tion of the initial lesions by a low number ofCD8+ T cells, which significantly outnumberthose seen in the periplaque and normal-ap-pearing white matter of MS patients or in thewhite matter of controls (Marik et al. 2007; Hen-derson et al. 2009). In more advanced lesions inwhich myelin has already been destroyed andthe fragments have been taken up by macro-phages, a massive increase of inflammationwas seen, containing not only CD8+ T cells butalso CD4+ cells, B cells, and monocytes. Thesedata suggest that cells of the adaptive immunesystem are already present in initial lesions, al-though in relatively small numbers, but that de-myelination and tissue damage leads to a secondwave of inflammation that may be caused byadhesion molecule and chemokine expressionin response to tissue injury (Marik et al. 2007;Henderson et al. 2009).

Inflammation in the Brain of Patients withProgressive MS

Quantitative data of T- and B-cell infiltration inthe MS brain showed the most pronounced in-flammation in classical active lesions in patientswith acute or relapsing MS. However, there wasa lower extent of inflammation also present ininactive lesions, the normal-appearing whitematter, and the meninges. In patients with pro-gressive MS, classical active lesions are sparse orabsent. In contrast, a significant number of le-sions show signs of slow and chronic expansion.

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When T cells and B cells were counted in thebrain of patients with progressiveMS, the degreeof inflammatory infiltration was very similarcompared to that seen in the normal-appearingwhite matter, in inactive lesions, or in the me-ninges of patients with early (acute or relapsing)MS (Frischer et al. 2009). Furthermore, in theprogressive stage of MS, lymphocyte infiltrationinto the tissue is 10–100 times higher than thatseen in age-matched controls or in the brain ofpatients with stroke or neurodegenerative dis-ease. Inflammation in progressive MS is pro-nounced in the meninges and the perivascularVirchow–Robin spaces, where it gives rise tolarge inflammatory aggregates.

Several observations suggest that in the pro-gressive stage of MS the inflammatory responseis, at least in part, trapped within the CNS be-hind a closed or repaired blood–brain barrier.Contrast enhancement inMRI is rare in patientswith progressive MS, despite the fact that pa-tients from a similar disease stage and with asimilar disease course have substantial inflam-mation in the brain and spinal cord seen bypathological analysis; in many instances, peri-vascular and diffuse parenchymal infiltrates oflymphocytes are present in the absence of serumprotein leakage (Hochmeister et al. 2006). Fur-thermore, the formation of inflammatory aggre-gates with features of tertiary lymphoid tissue islikely to be driven by the local environment orthe presence of a specific antigen within thecompartment of the CNS (Pikor et al. 2016).

In a subset of patients with progressive MS,the inflammatory response in the brain is com-parable to that which is present in age-matchedcontrols. This is mainly the case in patients withhigh-age and long-disease duration but some-times also in younger patients with a short-dis-ease course. Interestingly, in these patients, noactive demyelination was found and the extentof acute axonal injury was similar to that seenin age-matched controls (Frischer et al. 2009).These data suggest that in MS patients in whominflammation has ceased, demyelination andactive tissue injury declines to the levels associ-ated with brain aging. Thus, such patientsmay reflect a stage of “burnt-out”MS. However,in such patients with severe MS-related pathol-

ogy, which has passed the threshold of function-al compensation, even minor age-related neuro-degeneration may increase clinical disability,thus giving rise to further clinical diseaseprogression.

All of the above-described findings supportthe view that inflammation drives demyelina-tion and neurodegeneration in MS. Whetherthere are, however, differences in the nature ofthe inflammatory response between early andlate MS, which additionally may explain the dif-ference in the effectiveness of anti-inflammatorytreatments between patients in these two differ-ent disease stages, remains unresolved.

HOW IS INFLAMMATION CONNECTEDTO DEMYELINATION ANDNEURODEGENERATION IN THE MS BRAIN?

As mentioned above, the key feature of MS pa-thology is the selective primary nature of thedemyelinating process. Based on knowledgefrom experimental models, there are many dif-ferent immunological mechanisms that may beinvolved in this process, and the question arises,which of these mechanisms are relevant for MS(Lucchinetti et al. 2000; Lassmann et al. 2012).Because subpial cortical lesions in the MS brainare the most specific pathological feature of thedisease, their detailed analysis in comparison tocortical damage in other human diseases mayprovide information regarding disease mecha-nisms.

Demyelination in MS is Not a Nonspecific(Bystander) Consequence of theInflammatory Process

Subpial cortical lesions are not seen in any otherinflammatory brain disease that affects the cor-tex (Moll et al. 2008). This is the case even inchronic inflammatory diseases such as tuber-culous or luetic meningoencephalitis diseases,which have meningeal and cortical inflammato-ry infiltrates with a composition that is very sim-ilar to that seen in MS. Subpial cortical demyeli-nation is also absent in Rasmussen’s encephalitisor paraneoplastic encephalitis, diseases with adominant (or even exclusive) CD8+ T-cell-me-



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diated pathogenesis. Furthermore, no demyeli-nation is detected in patients with meningeal ordiffuse infiltration by neoplastic B cells in caseswith B-cell lymphoma (Fischer et al. 2013).These observations clearly show that primarydemyelination in MS is not a nonspecific (by-stander) consequence of brain inflammation.

Demyelination and Neurodegeneration MayBe Triggered by a Soluble Factor Produced byLymphocytes

Active subpial cortical lesions in MS show acharacteristic architecture. T lymphocytes, Blymphocytes, and plasma cells are located inthe meninges and their presence is clearly asso-ciated with activity of demyelination and neuro-degeneration in the underlying cortex (Figs. 2A,B and 3B,D). However, active demyelinationwithin the cortex in most cases occurs in theabsence of diffuse T-cell, B-cell, and plasma-cell infiltration in the cortical tissue, but is asso-ciated with activated microglia at sites distantfrom the cells of the adaptive immune response.The best explanation for such a pattern of tissuedamage is that soluble factors are produced inthe meningeal inflammatory infiltrates, whichdiffuse into the cortex and induce demyelina-tion either directly or indirectly throughmicrog-lia activation (Magliozzi et al. 2007). Such apathogenic cascade of events could also resolvethe controversy regarding the relation betweeninflammation and neurodegeneration at othersites of the MS brain. The low-tissue infiltrationof actively demyelinating lesions by lympho-cytes, as seen not only in the cortex but also ininitial white matter lesions, makes it unlikelythat demyelination and axonal damage is in-duced by a direct contact between the target cellsand lymphocytes. The inflammatory cells are,however, present in the perivascular space with-in and around active lesions and these inflam-matory cells may trigger tissue damage throughthe action of a soluble factor.

A similar pattern of cortical demyelination,as seen in MS patients, is well reflected in pri-mates and rats with experimental autoimmuneencephalomyelitis when the disease is inducedby the combination of an encephalitogenic

T-cells response and the presence of specificdemyelinating antibodies (Pomeroy et al. 2005;Storch et al. 2006). In this case, encephalitogenicT cells induce inflammation, blood–brain bar-rier damage, activation of macrophages ormicroglia, and the accumulation of B cells andplasma cells in the meninges and perivascularspaces. Demyelination, however, is triggered bythe binding of specific demyelinating antibodiesand accomplished through complement activa-tion or antibody-dependent cellular cytotoxici-ty. These observations stimulated an intense in-ternational effort to search for demyelinating orcytotoxic autoantibodies in the serum and cere-brospinal fluid (CSF) of MS patients. In an invitro study, antibodies binding to oligodendro-cytes or myelin have been observed in 30%–50%of theMS sera tested (Lily et al. 2004; Elliott et al.2012). So far, however, the identification of anMS-specific target for such antibodies has failed.Myelin oligodendrocyte glycoprotein would bean obvious candidate, but antibodies against thisprotein have only been identified in patients(mainly children) with acute or relapsing dis-seminated encephalomyelitis, and the presenceof such antibodies may indicate that the patientsdo not have MS but a newly defined myelinoligodendrocyte glycoprotein antibody–associ-ated autoimmune syndrome (Kim et al. 2015).Analysis of antibodies derived from clonally ex-panded plasma cells from the patient’s CSFshowed some binding to neurons, astrocytes,and oligodendrocytes and induced demyelina-tion in vitro, but, so far, the specific target anti-gens have not been identified (Blauth et al.2015). Furthermore, demyelinating or cytotoxicactivity of serum or CSF ofMS patients may alsobe caused by as-yet-unidentified factors, whichare produced by B cells but are still present whenimmunoglobulins are removed from the sam-ples (Grundke Iqbal and Bornstein 1980; Lisaket al. 2012). A recent study identified ceramideas a potential cytotoxic factor in the MS CSF,which may induce neuronal injury through ox-idative damage in vitro (Vidaure et al. 2014).Although this is a very interesting candidate, itcannot explain how such a lipid factor will beable to diffuse from the meningeal inflammato-ry infiltrates to the site of active demyelination in

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the cortex. Overall, these data indicate that thereare one or several soluble demyelinating and/orcytotoxic factors produced in the inflammatoryprocess in MS, but their biochemical nature willhave to be defined in future studies.

Demyelination and Neurodegeneration IsFinally Accomplished by Microglia Activation,Oxidative Injury, and “Virtual Hypoxia”

Asdescribed so far, inflammatory demyelinatinglesions inMS are specific for the disease and notseen in other inflammatory or neurodegenera-tive diseases affecting the cerebral cortex. Thismade it possible todirectly compare gene expres-sion in active corticalMS lesionswith that seen incontrol populations, including tuberculous me-ningoencephalitis (as an inflammatory control),Alzheimer’s disease (as a control for neurode-generation), and normal controls without neu-rological disease or brain lesions (Fischer et al.2013). A limited numberof genes, which showeddifferential expression in activeMS lesions, wereidentified. The differentially expressed genescoded for proteins involved in inflammation, ac-tive tissue injury, and demyelination or neuro-degeneration. Regarding active tissue injury, themolecules that appeared in this analysis weremainly related to oxidative burst in microglia,mitochondrial damage, and cell degeneration.The gene expression changeswere thenvalidatedby pathological analysis and immunocytochem-istry. These investigations showed that degener-ating neurons, myelin, and oligodendrocytesidentifiedby the fragmentationof their processesand apoptosis show profound lipid oxidation(Fischer et al. 2013). This process is associatedwith mitochondrial damage reflected by thepresence of respiratory-deficient cells and theaccumulation of mitochondrial gene deletions(Dutta et al. 2006; Mahad et al. 2008; Campbellet al. 2011). Profound oxidative injury is alsoseen in active white matter lesions in early MS(Fischer et al. 2012). Mitochondrial injury ap-pears to be in the center of the pathogenic cas-cade, giving rise to a state of “virtual hypoxia”and to the amplification of oxidative injurythrough electron leakage (Mahad et al. 2015).A consequence of “virtual hypoxia” is energy

deficiency, which results in ionic dysbalance inaffected cells and cell degeneration throughCa2+-dependent pathways (Stys et al. 2012). Asdiscussed above, such a pathogenetic cascademay explain the distribution of lesions in theMS brain, and it will also be amplified in theprogressive stage of the disease by brain agingand mechanisms related to the accumulation oflesion burden in the CNS (Haider et al. 2016).Key questions, however, remain unresolved. It iscurrently not clear why such a profound oxida-tive injury specifically occurs in MS lesions incomparison to other inflammatory diseases oftheCNS. It alsomust be determined in the futurewhether this exaggerated oxidative injury is re-lated to anMS-specific inflammatory process or,in part, is influenced by mechanisms that regu-late the susceptibility of the target tissue in theMS brain and spinal cord.

CONCLUSIONS

Experimental studies performed during the lastdecade have identified a large number of immu-nological and neurobiological mechanisms thatmay be involved in the regulation of inflamma-tion inMS and in the induction of tissue damagein the CNS. Which of these mechanisms arerelevant for the disease process in MS patientscan, in part, be identified in pathological studiesof the lesions in the CNS of the patients. On thebasis of such a pathological analysis, a numberof mechanistic insights are suggested, which ap-pear to be relevant for the understanding of thedisease process in MS:

1. The pathological data provide strong supportfor the concept that inflammation drives de-myelination and tissue injury in all stages ofthe disease. However, demyelination andneurodegeneration is not a nonspecific (by-stander) consequence of the inflammatoryprocess, but is MS-specific.

2. The low number of lymphocytes at the sitesof active demyelination and neurodegenera-tion makes it unlikely that tissue injury istriggered by a direct interaction of these cellswith the target tissue, but that it is mediatedby soluble factors produced by lymphocytes



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that induce damage either directly or indi-rectly through microglia activation.

3. Although demyelinating and cytotoxic activ-ity is present in the sera and CSF of the pa-tients, the nature of this soluble factor is cur-rently undefined.

4. A dominant mechanism finally leading todemyelination and neurodegeneration is acascade of oxidative injury, mitochondrialdamage, “virtual hypoxia,” and its down-stream molecular consequences. This mech-anism becomes particularly prominent inpatients with progressive MS, because it isamplified by factors related to brain agingand the accumulation of lesion burden inthe CNS.What primarily causes this exagger-ated oxidative and mitochondrial injury inMS patients is currently unresolved.

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January 22, 20182018; doi: 10.1101/cshperspect.a028936 originally published onlineCold Spring Harb Perspect Med

Hans Lassmann Multiple Sclerosis Pathology

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