REVISTA ESPAÑ OLA DE. Patología. Cyclical partial remyelination provokes demyelination in multiple sclerosis - PDF

Rev Esp Patol. 2011;44(2): Patología REVISTA ESPAÑ OLA DE REVIEW Cyclical partial remyelination provokes demyelination in multiple sclerosis Lawrence M. Agius Department

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Rev Esp Patol. 2011;44(2): Patología REVISTA ESPAÑ OLA DE REVIEW Cyclical partial remyelination provokes demyelination in multiple sclerosis Lawrence M. Agius Department of Pathology, Mater Dei Hospital, Tal-Qroqq, University Of Malta Medical School, Msida, Malta Received 13 November 2010; accepted 13 February 2011 Available online 26 March 2011 KEYWORDS Multiple sclerosis; Remyelination; Axon; Oligodendrocytes; Myelin Abstract Multiple sclerosis appears to be a self-programmed demyelination that alternates with repeated episodes of often partial remyelination of the axon within a milieu of an expanding plaque primarily located in the white matter. Degeneration of neurons is an additional feature of the disease that provokes abnormal axonal-myelin interactivity. A putative autoantigen in the central nervous system is believed to play a central role in the pathogenesis of the disease process that terminates only with permanent, complete elimination of the myelin sheath from the plaque region. In addition, axonal transaction sometimes occurs at an early stage of the disease. The occurrence of integral cyclical reactivity of partially regenerated myelin sheaths provokes an inflammatory response in its own right that injures both the myelin sheath and axonal processes of parent neurons. Further insight into the pathogenesis of multiple sclerosis depends on the recognition of substrate tissue susceptibility and the dynamics of oligodendrocytedepletion, which are characterized by complete permanent demyelination of the endstage plaque, often after several years of clinical relapses and remissions SEAP y SEC. Published by Elsevier España, S.L. All rights reserved. PALABRAS CLAVE Esclerosis múltiple; Remielinización; Axón; Oligodendrocitos; Mielina La remielinización parcial cíclica provoca la desmielinización en la esclerosis múltiple Resumen La esclerosis múltiple aparenta ser una desmielinización autoprogramada que alterna con múltiples episodios de remielinización frecuentemente parcial de los axones en una situación de expansión de placas situadas principalmente en la sustancia blanca. Una característica adicional de la enfermedad es la degeneración de las neuronas, que provoca una interactividad anómala entre los axones y la mielina. Se cree que un autoantígeno putativo del sistema nervioso central juega un papel importante en la patogénesis del proceso de la enfermedad que termina sólo con la eliminación completa y permanente de la capa de mielina de la región de la placa. Además, ocasionalmente, la transección axonal ocurre durante una etapa temprana de la enfermedad. Cuando las capas mielínicas parcialmente regeneradas experimentan una actividad cíclica, pueden provocar una respuesta inflamatoria propia que dañe tanto addresses: /$ see front matter 2010 SEAP y SEC. Published by Elsevier España, S.L. All rights reserved. doi: /j.patol 118 L.M. Agius la capa mielínica como los procesos axonales de las neuronas parentales. Una comprensión más profunda de la patogénesis de la esclerosis múltiple precisa el reconocimiento de la susceptibilidad del sustrato tisular y de la dinámica de la depleción de los oligodendrocitos, que se manifiestan con la desmielinización completa y permanente de la placa de la etapa final, frecuentemente después de varios años de recaídas y de remisiones de la enfermedad SEAP y SEC. Publicado por Elsevier España, S.L. Todos los derechos reservados. Introduction Table 2 Immunologic abnormalities in multiple sclerosis. Evolving pathogenesis of injury to the myelin sheath comprises a highly heterogeneous array of agonist events comprising onset dynamics and subsequent progression of plaques in multiple sclerosis (MS). Currently approved therapies for MS do not directly target neural processes 1. The definition of injury comprises a primary demyelination that is, however, dependent on axonal lack of integrity in further redefinition of cyclical attempts at remyelination. Oligodendrogliopathy leading to demyelination may only secondarily induce an immune response in MS 2. The clinical severity of the disease varies widely and corresponds to the heterogeneity in pathogenetic pathways in subsequently implicating not only immune response to a putative autoantigen but also a systemically operative inflammatory state of the central nervous system often accompanied by significant edema of the involved white matter (Table 1). As shown in Table 1, various features of neurodegeneration are integrally admixed with neuroinflammation and dynamics of an immune response primarily targeted to the enveloping myelin sheath. Ischemia, cell lysis, complement fixation and a persistent influx of mononuclear inflammatory cells compound a disease evolution that transforms white matter to gliotic foci of demyelination with relative axonal disruption and neurodegeneration. Primary concepts Resynthesis of primary concepts exclusively directed towards the potentially persistent or repeated relapsingremitting disease activity indicate a selectivity that promotes even further focal vulnerability of targeted lesions. It is within the sphere of such target selectivity promoted by a prominent incremental degree of edema, primarily of the white matter, that MS includes alternate resolution or persistence of disease pathology. Enhanced oligodendrocyte progenitor cell differentiation and remyelination promote neural repair in conjunction with immunomodulation, immunosuppression and neuroprotection 3 (Table 2). Table 1 Pathogenesis of multiple sclerosis lesions. Inflammation, acute axonal injury, demyelination Chronic neurodegeneration Unproven autoimmunity Source: Prineas JW 21. Associated class II major histocompatibility complex alleles DR15 and DQ6 Serum viral associations especially Herpes virus 6 and measles virus Restricted T-cell receptor genes in affected monozygotic twin Aberrant T-cell responses to alphab-crystallin, myelin basic protein, and myelin oligodendrocyte glycoprotein Source:Herndon RM 22. Figure 1 Axonal damage in multiple sclerosis. Biopsy of an active plaque, containing numerous foamy cells. Source 24. One would emphasize the correlative evidence of mononuclear inflammatory cell activity as a number of ongoing unresolved outcomes that subsequently transform to demyelination of successive myelin sheath lamellae of concentric distribution. Table 2 demonstrates accompanying dynamics of abnormal immune response more indicative of progression of MS lesions rather than pathogenetic factors in evolution. The central theme in the pathogenesis is the nonresolution of the injury in a manner that provokes further progression within the context of repeated loss of myelin of the axon. There is evidence for impaired differentiation, migration and activation of oligodendrocytes in later stages of MS 4. The recycling of the injurious event encompasses a continual or episodic worsening of the degree of viability of the parent neuron within the confined contextual setting, particularly, of edema of the myelin sheaths. Astrocytic hypertrophy promotes blood brain barrier integrity and possible intercellular communication independently of neurons 5. Interface phenomena and stromal matrix remodelling, as exemplified by the range of activity of matrix metalloproteinases within plaques, go beyond remodelling and promotes a continual reactivity that provokes injury further to loss of myelin (Figures 1 and 2). Cyclical partial remyelination provokes demyelination in multiple sclerosis 119 Table 4 Differential diagnosis of multiple sclerosis. Vacuolar myelopathy of AIDS Marchiafava-Bignami disease Radiation injury Leber s hereditary optic neuropathy 5-Fluorouracil treatment Adrenoleukodystrophy Subacute combined degeneration of the spinal cord Vasculitis, neoplasms, Lyme disease Figure 2 Axonal damage in multiple sclerosis. Immunohistochemistry for neurofilament protein reveals scattered axonal swellings. Source 24. Source 21. Figure 4 Remyelination in multiple sclerosis. Well-defined shadow plaque. The fibers stain for myelin albeit less intensely than in the adjacent subcortical white matter. Source 24 Figure 3 Axonal damage in multiple sclerosis. Some of the axonal swellings contain accumulations of beta-amyloid precursor protein. Source 24. Table 3 Chronic loss of oligodendrocytes. Lack of trophic support can cause: Wallerian degeneration Axonal transection Retrograde neuronal cell death Source: Sobel RA, et al 23. Vascularity of plaques constitutes a real source for ongoing reactivity within schematic reconstructive phenomena of possible substitutive events, as possible injurious transformations inflicting the axon-myelin ensheathment. Unitary reconstitution is a possible reappraisal of the range of possible such injury to both axon and myelin sheath (Figure 3). In particular, neuroinflammation may exert both beneficial and injurious effects on remyelination 6. The autoantigenicity, loss of tolerance, and the phenomenon of epitope spread, emerge as a set profile reactivity that incorporates inflammation. Inflammatory mononuclear cells transgress the parenchymal confines of the MS plaque in a specific predilected manner and in modes of encompassing potential extension of the lesions (Table 3). The specifics of the mode of initiation of such inflammatory reactivities are to some extent significant in terms of the progressive axonal demyelination. Slowly expanding demyelination may irreversibly damage normal and repaired myelin 7. The resulting profiles of the injurious events themselves are incremental reactivities of the inflammatory state that may derive from a multitude of sources culminating in a relative shedding of myelin sheaths. Table 3 demonstrates a central role for oligodendrogliopathy in axonal and neuronal pathology. Mechanisms underlying remyelination in MS remain elusive. CXCR2 promotes demyelination and inhibits remyelination 8. Myelin edema is a circumscribed form of such reactivity in its own right, and directly implicates a vulnerability that is inherently self-progressive. Inciting agents as sources for the persistence and relapsing-remitting nature of the disease activity are inherently inflammatory and are further reflected in immunologic and ischemic vascular phenomena (Table 4). Diagnosis of MS necessitates the exclusion of several primary alternate causes of myelin loss, as shown in Table 4, Figure 4. Shadow plaques in MS are currently interpreted as largely remyelinated axonal processes with only partial recovery of their myelin sheath complement. Electron microscopic studies have been instrumental in demonstrating the thin myelin sheaths of remyelinated fibers subsequent to relapse of MS. An important aspect of MS plaques is the heterogeneity of thinly myelinated and demyelinated fibers with progression of the disease, as shown in Figures 5 7. Inflammatory microenvironment The involvement of a background inflammatory microenvironment would account for a reactivity that immunologically amplifies such response and also activates the complement cascade. 120 L.M. Agius Cycles of responsive reparation of the myelin sheath constitutively reattempt a further modification of microenvironmental conditioning. Mesenchymal stem cells offer potential for tissue repair and for modulated immune response in MS 9. Indeed, myelin edema is itself a potentially recycling processing of the events that are prone to repeatedly expose the injured related axon and parent neuron to progressive attempts at reconstitution of the myelin. A scale of such magnitude encompasses the range of potential injury as modification of the microenvironment, as seen in the chronic MS plaque. The inflammatory conditioning and the general milieu leading to persistent reactivity account for a failed resolution of the injury that incrementally compounds the immunologic response in modes which transgress transformation and remodelling attempts of plaques in general. CXCR4 enhances differentiation of oligodendrocyte precursor cells and remyelination in MS 10. Cyclical dynamics Figure 5 Remyelination in multiple sclerosis. Semithin resinembedded section through the edge of the plaque shows that it contains many nerve fibers with relatively thin myelin sheaths (arrows). Source 24. Figure 6 Remyelination in multiple sclerosis. Electron microscopy shows an admixture of demyelinated and thinly remyelinated fibers. Source 24. Figure 7 Concurrent demyelination and remyelination. Sections through a shadow plaque (S) with central active demyelination. Source 24. Contextual cyclical dynamics of disease activity relates to an inflammatory state that autonomously governs vulnerability to further attacks of demyelinaiton and edema susceptibility. Remyelination depends especially on a degree of myelin plasticity and also controlling role of micrornas 11. The development of variability in parametric setting and in plaque dimensional expression indicates a complexity formulated on integration of various pathogenetic roles determining such inflammatory reactivity. Consequential issues as profiles of reactivity help outline a degree of compromise in the viability of neurons and axonal processes; there are permissive expressions of both onset dynamics and persistence profiles of clinical relapses of the disease. Estrogens and progestins in particular improve neuronal viability and myelin formation 12. Within such framework, a given formulation of injury dynamics may summate as persistent susceptibility patterns in cyclically demyelinating disease affecting both occurrence and reformulated reconstitution. A system disease pattern may be set up in pre-determined outline, and as susceptibility profile. Incompletely explained neuroinflammatory events, neuronal dysfunction of repair and chronicity of inflammation appear to account for progression in MS 13. The light and electron microscopic features of the actively demyelinating plaque lay particular stress on proximity of the inflammatory mononuclear cell infiltrate and macrophage response to the ongoing myelin breakdown process, and especially to the concurrent presence of lipidladen macrophages in the active plaques. A system biologic response corresponds to the evolution of an injury per se in inducing an active cellular stripping of the myelin sheath in the presence of a relatively preserved axonal process. Such an integral phenomenon allows for the deceptively simple process of recurrent waves of axonal demyelination as a constitutive response in its own right, and therefore provides a basis for a working pathogenesis for primary demyelination. Failure of remyelination accounts for sustained neurologic symptoms in MS; hyaluronan deposits inhibit oligodendroglial maturation 14. It is significant, however, that integral interactivity between axon and its myelin sheath, particularly with the added contextual reference to the supplying oligodendrocyte, is a basis for dynamics of an axonal involvement in the system biology of the parent neuron traversing its processes through the active plaque. Reciprocal communication between neurons and oligodendrocytes is crucial for myelin biogenesis and repair 15. The Virchow-Robin perivascular spaces, that are the source for both mononuclear inflammatory cells and many macrophages, incorporate potential plaque generation and delineation. Cyclical partial remyelination provokes demyelination in multiple sclerosis 121 Table 5 Spontaneous viral models of human demyelination 24. HIV encephalopathy HTLV-1 Acute disseminated encephalomyelitis Progressive multifocal leukoencephalopathy Source 21. Disease reactivity Disease reactivity is an expression of primal agonist action both in terms of inflammatory conditioning with edema formation of the myelin and also a reactivity that self-amplifies the relapse nature of attacks of demyelination and adds to axonal and parent neuronal injury. A viral etiology (Table 5) has long been suspected in MS, particularly in the light of epidemiologic data (Table 5). IgMs bind to CNS cells and reorganize the membrane, with subsequent oligodendrocyte proliferation and neuroprotection with enhanced myelinogenesis 16. Cyclical reactivity per se is distributional in the form of active plaques that evolve eventually to fully demyelinated regions of primarily white matter. The terms of reference of such lesions are conclusively exhibited by a depletion not only of myelin sheaths and further axonal transection but especially by the widespread depletion within the plaques of the oligodendrocyte cell population. Different subsets of patients with different forms of underlying pathogenesis allow for optimized treatment in MS 17. Distinctive recombinant manifestations of such disease activity are reflected particularly in oligodendrocyte susceptibility that evolves as end-stage or burnt-out MS plaques. Accumulation of injury is due particularly to axonal damage in MS 18. The microglia and macrophages, together with lymphocytes and especially parenchymal plasma cells, orchestrate a responsive cyclical phenomenon to induce reactive injury to both myelin and plaque stroma, as denoted by immunological targeting of a putative autoantigen within the central nervous system. Multiplying agent Considerations implicating the operative half-life dynamics of a multiplying agent would account for a distributional factor in lesion infliction. In addition, a balance of physical forces would account for myelination and repair by affecting extracellular forces and intracellular contractions with shape changes 19. Tissue injury is a paramount factor in inducing such cyclical progression of relapse and remission that alternates in provoking regenerative efforts of remyelination. A critical time window operates for possible remyelination 20. This involves remyelination in empowering further spread and extension of the plaques. It is the actual process of myelin breakdown subsequent to edema formation, primarily of the white matter, that precipitates a stereotyped chain of lesions created in the wake of partially resolving attempts at remyelination of axonal processes. Within frameworks of further demyelination, it is the active breakdown of thinly remyelinated axons that provokes cyclical breakdown at a significant rate of myelin lipid catabolism and turnover. In partial remyelination, progression of the lesions terminates disease activity only with the creation of a fully demyelinated end-stage plaque. Dimensions of injury Dimensions of injury would implicate the disappearance of a provocative agent that operatively induces demyelination and tissue injury through exposure of the axonal process, as indicated by dynamics of a plaque demyelination alternating with partial remyelination. Oligodendrocyte cell populations are the source of an instability of cytologic turnover within schemes of ongoing remyelination that lead to potential end-stage lesions incapable of further future myelin deposition around axons. Oligodendrocytes are predetermined agonists in cyclical remyelination that provoke in predetermined-like manner cyclical turnover of myelin breakdown products, and to divest axons and promote neurodegenerative atrophy. Concluding remarks Precipitating events in MS are the presence of partially remyelinated axons within plaques distributed largely in edematous white matter. The consequences of disease activity revolve principally around the dynamics of interactivity of axons with partial myelin sheaths and in a manner that provokes the evolving lesion to an endstage plaque, often after several years of disease course comprising remissions and relapses of myelin breakdown as main source of inflammatory reactivity. Within such frameworks of induced injury to myelin sheaths, the depletion of the resident oligodendrocyte cell population is an index of a reactivity that may include lysis of the cells and as cyclical exposure to an agonist event. Thi
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