Multiple Sclerosis — The Plaque And Its Pathogenesis

The new england journal of medicineABFigure 1. Cross Section of White-Matter Lesions Targeting the Myelin Sheath and Oligodendrocytes.In Panel A, light microscopy reveals myelin sheaths(dark blue rings) around axons in a cross section ofmyelinated white matter (toluidine blue). Two darkerstaining oligodendrocytes, the cells that make andmaintain myelin, lie to the right of center (arrow). InPanel B, an electron micrograph reveals the myelinsheath in cross section to be a spirally wrapped membrane beginning in the lower left as an outer (oligodendroglial) “tongue” of cytoplasm and spiraling counterclockwise to terminate at an inner tongue inside themyelin sheath to the right of the axon. Microtubulesand neurofilaments can be seen cut in cross sectionwithin the axoplasm.gest that inflammatory immune responses ordelayed hypersensitivity responses are primarilymediated by inflammatory Th1 cells, which produce lymphotoxin and interferon-γ, but littleinterleukin-4.18 Alternatively, CD4 type 2 helperT cells (Th2) represent an antiinflammatory population of lymphocytes that produce large amounts944n engl j med 354;9of immunoregulatory cytokines (e.g., interleukin-4 and interleukin-5). Myelin-reactive T cellsfrom patients with multiple sclerosis produce cytokines more consistent with a Th1-mediated response, whereas myelin-reactive T cells fromhealthy persons are more likely to produce cytokines that characterize a Th2-mediated response.13Cytokines such as interleukin-12 and type 1 interferons such as interferon-β can activate the transcription factor Stat-4 in human T cells, thus causing the cells to differentiate into pathogenic Th1lymphocytes.19 Interferon beta, which has beenused to treat patients with multiple sclerosis (Table1), was thought to cause a shift from a Th1-mediated to a Th2-mediated response.20 However, microarray studies indicated that a number of genesin patients with multiple sclerosis that are upregulated by this cytokine are associated withdifferentiation into Th1 rather than Th2 lymphocytes, suggesting that such a shift may not be themechanism of action of interferon beta.21Certain members of the interleukin-12 familyof proteins probably have a role in the regulationof T-cell responses that have potential relevanceto multiple sclerosis.22 In experimental models ofinflammatory demyelination, such as experimental autoimmune encephalomyelitis in mice, thelikelihood of disease development depends onwhich interleukins are functional. For example,experimental autoimmune encephalomyelitis didnot develop in mice deficient in both interleukin-12and interleukin-23, but severe disease developedin animals with a deficiency of interleukin-12alone. Other studies indicate that interleukin-23probably has an essential role in brain inflammation.23 For instance, interleukin-23–deficient miceare resistant to experimental autoimmune encephalomyelitis but have a normal Th1 response.24Such studies in mice may be directly relevant topatients with multiple sclerosis. Interleukin-23causes T cells to produce interleukin-17, whichsome investigators believe is the chief determinant of brain inflammation, rather than interferon-γ. Recent microarray studies of lesions ofmultiple sclerosis from patients demonstrated increased expression of interleukin-17, suggestingthat it may be an important factor in the development of inflammatory demyelination.25 Studies of experimental autoimmune encephalomyelitis in mice have recently shown that the T-betand Stat-4 (necessary for Th1 differentiation)transcription factors are important in the differentiation of autoimmune T cells.26-28 Studies inwww.nejm.orgmarch 2, 2006The New England Journal of MedicineDownloaded from nejm.org at REPRINTS DESK INC on September 14, 2016. For personal use only. No other uses without permission.Copyright 2006 Massachusetts Medical Society. All rights reserved.

medical progresshumans are now needed to determine whethersimilar transcriptional programs determine themechanism underlying the pathogenic potentialof myelin-reactive T cells in multiple sclerosis.B CellsIt has long been recognized that intrathecal synthesis of immunoglobulins is increased in patientswith multiple sclerosis, as evidenced by the presence of oligoclonal bands on agarose-gel electrophoresis and an increased IgG index or synthesisrate. Many studies have suggested that these antibodies recognize myelin antigens, but onlyrecently has it become possible to characterizethe antibody response on a molecular level in thecerebrospinal fluid of patients with multiple sclerosis. Perhaps not surprisingly, the demonstrationin the cerebrospinal fluid of B-cell proliferationand increased mutations in B-cell receptors, a process called somatic hypermutation, suggest thata B-cell response to a specific antigen is occurring in the central nervous system, whereas corresponding clones are absent from the peripheralcirculation.29,30 Examination of these B-cell clonesalso indicated that some B cells had undergonea process called receptor revision, or editing, inwhich these cells recognize the body’s misguidedcapability to manufacture autoantibodies and sub-sequently remove this capacity.31 Investigationsare now under way to determine which specificcentral nervous system antigens are recognized bythe autoantibodies generated by clonally expanded B cells in patients with multiple sclerosis. Theobserved overexpression of immunoglobulin genesand Fc receptors in lesions of this disease suggests that targeting the B-cell component of theimmune response (e.g., with rituximab) may represent an attractive therapeutic strategy (Table 2).Other Immune CellsIt is likely that still other types of cells play a rolein the pathogenesis of multiple sclerosis. For example, regulatory cells, such as CD4 /CD25 andCD8 regulatory T cells, appear to be deficient inpatients with this disease.32,33 Glatiramer acetate,a treatment for multiple sclerosis that may increase the numbers of these regulatory cells, mayprovide a means of reconstituting tolerance toself-antigens (Table 1).Dise a se Ini t i at iona nd Patho gene sisThere is substantial evidence to support the hypothesis that genetics has an important role in aperson’s susceptibility to multiple sclerosis, prob-Table 2. Neuroprotective and Restorative Strategies for Multiple Sclerosis.*StrategyRationale or MechanismPreliminary ObservationsCombinations of approved agentsTargets multiple injury mechanismsEvidence of reduced activity on MRIReduced relapsesRituximabDepletes B cellsClinical trials under wayChemokine-receptor antagonistsReduce entry of lymphocytes into CNSClinical trials under wayRiluzoleBlocks N-methyl-d-aspartate and sodium channelsReduced spinal-cord atrophyReduced number of hypointense lesionson T1-weighted MRIPhenytoin and flecainideBlock sodium channelsNeuroprotective in animalsClinical trials under wayBlockers of neurite outgrowth inhibitorPromote axonal sproutingStudies in animals under wayBlockers of NG2, LINGO-1, Notch, and JaggedPromote oligodendrocyte differentiationStudies in animals under wayActivation of oligodendrite transcriptionfactor 1Promotes oligodendrocyte differentiationUnder developmentStem cellsInitiate myelin repairEstablished efficacy in animal modelsEarly trials in humans under wayGrowth factorsPromote neuronal survivalUnder developmentAntiapoptosis factorsPromote survival of neurons and oligodendrocytesStudies in animals under way* CNS denotes central nervous system, NG2 neuron-glia antigen 2, and LINGO-1 leucine-rich–repeat and immunoglobulin-domain–containing neurite outgrowth inhibitor receptor–interacting protein 1.n engl j med 354;9www.nejm.orgmarch 2, 2006The New England Journal of MedicineDownloaded from nejm.org at REPRINTS DESK INC on September 14, 2016. For personal use only. No other uses without permission.Copyright 2006 Massachusetts Medical Society. All rights reserved.945

The new england journal of medicineably in conjunction with environmental factors.Although some investigators argue for a directcausal link between various infectious agents andthis disorder, such agents may merely provide theappropriate milieu for the development of an autoreactive immune response directed against centralnervous system myelin. Recent work in experimental autoimmune encephalomyelitis has focused on pathogens that can stimulate toll-likereceptors, highly conserved receptors that recognize pathogen-associated molecular patterns.These patterns are important for the initiation ofdisease and the production of interleukins, specifically interleukin-12 and interleukin-23, whichlead to the differentiation of T cells into autoreactive effectors.34,35 Infectious agents may alsohave a role in the central mechanism that culminates in the interaction between T cells and thecerebrovascular endothelium by up-regulating adhesion molecules important for immune-cell recruitment into the central nervous system.36Studies of experimental autoimmune encephalomyelitis in mice demonstrated the importanceof T-cell expression of a family of cell-surface receptors (the integrins) that promote adhesion andtransport mechanisms. Such studies led to thedevelopment of a therapeutic antagonist of integrin, natalizumab, a monoclonal antibody specifically against α4 integrin.37 This agent significantlyreduced both clinical relapses and the formationof gadolinium-enhancing lesions in patients withmultiple sclerosis.38 Despite its early promise, thedevelopment of progressive multifocal leukoencephalopathy in a few patients receiving natalizumab in combination with interferon, or withazathioprine and infliximab, resulted in its withdrawal from the market and a halting of all clinicaltrials in February 2005; whether it will return tothe market is unknown as of January 2006.39-41These observations underscore the principle thatstrategies interfering with the recruitment of leukocytes in the pathogenesis of multiple sclerosismay also interfere with routine immunosurveillance functions of the central nervous system.Several additional targets for potential studyand therapeutic intervention have been identifiedwith the use of microarray techniques. For instance, this approach led to the discovery thatosteopontin was overexpressed in multiple sclerosis lesions and subsequently to the finding thatit has an important role in the progression of experimental autoimmune encephalomyelitis.42946n engl j med 354;9Pathogenesis of Multiple SclerosisLesions RevisitedIn the light of the current consensus that thepathogenesis of the lesions of multiple sclerosisis heterogeneous, it is not surprising that no single predominant mechanism for this disease hasemerged. Indeed, with a condition that includesfulminant as well as chronic forms with such awide-ranging phenotype, multiple pathogeneticmechanisms have been proposed.43 In fact, thepattern of the lesions appears to be totally unpredictable; both acute and chronic cases have oldas well as new lesions, illustrating the dynamicnature of the disease process. Regardless of thisinnate variability, the end-point chronic silent lesion (without active inflammation) is a constantand pathognomonic feature of multiple sclerosis.NeuropathologyThe histologic features of lesions of acute multiple sclerosis (Fig. 2A, 2B, and 2C) include an indistinct margin, hypercellularity, intense perivascular infiltration by small lymphocytes (Fig.2D and 2E), parenchymal edema, loss of myelinand oligodendrocytes, widespread axonal damage (Fig. 2F and 2G), plasma cells, myelin-ladenmacrophages, hypertrophic astrocytes, and littleor no astroglial scarring. Demyelination in acutelesions may be due to an antimyelin antibody–mediated phenomenon in which normal lamellarmyelin is transformed into vesicular networks(Fig. 2H and 2I), coated with antimyelin oligodendrocyte glycoprotein or antimyelin basic protein immu

review article The new england journal of medicine 942 n engl j med 354;9 www.nejm.org march 2, 2006 Medical Progress Multiple Sclerosis — The Plaque and Its Pathogenesis Elliot M. Frohman, M.D., Ph.