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Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination
Abstract
Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course, neuroradiological appearance of the lesions, involvement of susceptibility gene loci, and response to therapy. These features are supported by experimental evidence, which demonstrates that fundamentally different processes, such as autoimmunity or virus infection, may induce MS-like inflammatory demyelinating plaques and suggest that MS may be a disease with heterogeneous pathogenetic mechanisms. From a large pathology sample of MS, collected in three international centers, we selected 51 biopsies and 32 autopsies that contained actively demyelinating lesions defined by stringent criteria. The pathology of the lesions was analyzed using a broad spectrum of immunological and neurobiological markers. Four fundamentally different patterns of demyelination were found, defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction, and the immunopathological evidence of complement activation. Two patterns (I and II) showed close similarities to T-cell–mediated or T-cell plus antibody–mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. At a given time point of the disease—as reflected in autopsy cases—the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient. This pathogenetic heterogeneity of plaques from different MS patients may have fundamental implications for the diagnosis and therapy of this disease. Ann Neurol 2000;47:707–717
... Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by focal demyelination and axonal damage throughout the brain and spinal cord 1,2 . Microglia are innate phagocytic glia cells of the central nervous system (CNS) that play an essential role in brain homeostasis 3,4 . ...
... Microglia are innate phagocytic glia cells of the central nervous system (CNS) that play an essential role in brain homeostasis 3,4 . In MS pathology, they contribute to the HLA-DR + cell fraction phagocytosing myelin fragments in active and mixed active/ inactive (mixed) lesions 1,5 . Despite many studies focusing on the role of microglia in MS, their particular role in lesion initiation is not defined yet. ...
... Microglia nodules compared to non-nodular NAWM in MS had a significantly higher expression of a multitude of genes previously associated with MS pathology (CXCL16, IL18, MX1, LPL, CD14, CD83, IL1B, CDKN1A, GPNMB, HLA-DRB5, C1QA, C1qB, SPP1, TLR6, CHI3L1, after correction CXCL16, IL18, C1QA, C1qB remained significant) 1,10,27,28,[31][32][33][34][35][36][37] . C1qB was also upregulated by microglia nodules in stroke compared to stroke non-nodular WM, also after correction. ...
Microglia nodules (HLA-DR⁺ cell clusters) are associated with brain pathology. In this post-mortem study, we investigated whether they represent the first stage of multiple sclerosis (MS) lesion formation. We show that microglia nodules are associated with more severe MS pathology. Compared to microglia nodules in stroke, those in MS show enhanced expression of genes previously found upregulated in MS lesions. Furthermore, genes associated with lipid metabolism, presence of T and B cells, production of immunoglobulins and cytokines, activation of the complement cascade, and metabolic stress are upregulated in microglia nodules in MS. Compared to stroke, they more frequently phagocytose oxidized phospholipids and possess a more tubular mitochondrial network. Strikingly, in MS, some microglia nodules encapsulate partially demyelinated axons. Taken together, we propose that activation of microglia nodules in MS by cytokines and immunoglobulins, together with phagocytosis of oxidized phospholipids, may lead to a microglia phenotype prone to MS lesion formation.
... Autoreactive antibodies recognizing aquaporin-4 or MOG have a well described pathognic role in the MS-related diseases neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein (MOG) associated disease (reviewed in ref. 5). Although no definite autoantigen could be identified in MS so far, antibodies and complement are often deposited in active MS lesions, and some pwMS benefit from plasmapheresis suggesting that production of (auto) reactive antibodies can contribute to pathology in MS (6,7). However, the efficacy of the anti-CD20 B cell-depleting therapies rituximab and ocrelizumab in relapsing-remitting MS, which spare antibody-secreting cells (ASCs) and leave antibody titers mostly stable (8)(9)(10), suggests that other B cell effector functions also play a role in disease development. ...
... GFP levels of IL-6-overexpressing WT or IgH MOG iGB 6 cells or IgH MOG iGB cells transduced with an empty vector (iGB GFP ) remained stable in vivo upon adoptive cotransfer with 2D2 CD4 + T cells into Rag1-KO recipients (SI Appendix, Fig. S3B). Furthermore, iGB 6 in vivo, as measured in the serum of both IgH MOG iGB 6 and WT iGB 6 recipients whereas only very low levels of IL-6 were detectable in the serum of IgH MOG iGB GFP recipients (Fig. 4D). Importantly, IgH MOG iGB 6 recipients developed EAE with comparable severity but approximately 1 wk earlier than mice that received IgH MOG iGB GFP cells ( Fig. 4E and SI Appendix, Fig. S3C). ...
... GFP levels of IL-6-overexpressing WT or IgH MOG iGB 6 cells or IgH MOG iGB cells transduced with an empty vector (iGB GFP ) remained stable in vivo upon adoptive cotransfer with 2D2 CD4 + T cells into Rag1-KO recipients (SI Appendix, Fig. S3B). Furthermore, iGB 6 in vivo, as measured in the serum of both IgH MOG iGB 6 and WT iGB 6 recipients whereas only very low levels of IL-6 were detectable in the serum of IgH MOG iGB GFP recipients (Fig. 4D). Importantly, IgH MOG iGB 6 recipients developed EAE with comparable severity but approximately 1 wk earlier than mice that received IgH MOG iGB GFP cells ( Fig. 4E and SI Appendix, Fig. S3C). ...
In multiple sclerosis (MS), pathogenic T cell responses are known to be important drivers of autoimmune inflammation. However, increasing evidence suggests an additional role for B cells, which may contribute to pathogenesis via antigen presentation and production of proinflammatory cytokines. However, these B cell effector functions are not featured well in classical experimental autoimmune encephalomyelitis (EAE) mouse models. Here, we compared properties of myelin oligodendrocyte glycoprotein (MOG)-specific and polyclonal B cells and developed an adjuvant-free cotransfer EAE mouse model, where highly activated, MOG-specific induced germinal center B cells provide the critical stimulus for disease development. We could show that high levels of MOG-specific immunoglobulin G (IgGs) are not required for EAE development, suggesting that antigen presentation and activation of cognate T cells by B cells may be important for pathogenesis. As our model allows for B cell manipulation prior to transfer, we found that overexpression of the proinflammatory cytokine interleukin (IL)-6 by MOG-specific B cells leads to an accelerated EAE onset accompanied by activation/expansion of the myeloid compartment rather than a changed T cell response. Accordingly, knocking out IL-6 or tumor necrosis factor α in MOG-specific B cells via CRISPR-Cas9 did not affect activation of pathogenic T cells. In summary, we generated a tool to dissect pathogenic B cell effector function in EAE development, which should improve our understanding of pathogenic processes in MS.
... Regenerative medicine is one of the fields of medicine that focuses on functional repair or regeneration of cells, tissues, and even organs. This reparative technology is promising, [29,30]. In MS, the inflammatory process in the CNS leads to demyelination. ...
... Attempts to regenerate myelin can be recognized pathologically in the brains of MS patients by the existence of shadow plaques, which are partially remyelinated lesions. Analysis of brain tissue from MS patients suggests several different pathological patterns of demyelination [30][31][32]. ...
... Growth factor therapy involves the administration of molecules that stimulate the growth and differentiation of brain and nervous system cells. Recent research advances in regenerative therapies for neurological diseases have resulted in a great deal of research in the field of regenerative medicine [29,30]. Stem cells are unspecialized cells in the body that retains the ability to generate cells of an undifferentiated state identical to themselves or differentiate into other types of body cells with specialized functions. ...
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation and demyelination, leading to substantial disability and socioeconomic burden. With the absence of a definitive cure for MS, there is a critical need to explore neuroprotective strategies that can preserve neuronal function and impede disease progression. This article comprehensively reviews current knowledge and emerging therapeutic approaches to preserve neuronal function and promote repair in individuals with MS. The review highlights neuroprotective strategies, including immunomodulatory therapies, neuroreparative agents, and lifestyle modifications, that have shown promise in clinical studies. Additionally, the article discusses the potential of personalized treatment approaches based on individual MS profiles and the use of emerging neuroregenerative therapies to improve patients’ quality of life and prevent relapses. By enhancing our understanding of these neuroprotective strategies, it is hoped that more effective management of MS can be achieved, reducing the disease’s impact on patient’s lives.
... Based on ongoing demyelination, active lesions can be further divided into active and demyelinating (early or late) and active and post-demyelinating lesions [9]. Furthermore, evidence from pathology samples of MS patients reveals that the earliest stages of active lesions are heterogeneous and have shown four different patterns (I, II, III, IV) ( Fig. 1) [11]. Immune-mediated demyelination is a hallmark of pattern I/II, except that antibody/ complement deposition is the specific feature of pattern II active lesions. ...
... In pattern III, primary oligodendrocyte damage is proposed. In addition, pattern IV is T cell-associated demyelination with extensive non-apoptotic oligodendrocyte degeneration [11]. In order to identify blood biomarkers and potential pathogenic mechanisms of different patterns of active lesions, recently, Stork and colleagues have used microarray with more than 700 peptides representing both human and viral antigens. ...
... Active lesion Early demyelinating lesion* Pattern I Demyelination associated with activated macrophages/ microglia and T cells [9,11,12] Pattern II T cell and antibody mediated demyelination Pattern III Oligodendrocyte with nuclear condensation and apoptotic cell bodies Pattern IV Non-apoptotic oligodendrocyte death Late demyelinating lesion* Macrophages/microglia throughout the lesion area Myelin degradation products (MBP, PLP) within macrophages/microglia Post-demyelinating lesion** Destruction of myelin has ceased, but macrophages/ microglia are still present throughout the lesion Mixed active/inactive Demyelinating lesion Hypo-cellular lesion center with macrophages/microglia limited to the lesion border Myelin degradation products within macrophages/ microglia Post-demyelinating lesion Hypo-cellular lesion center with macrophages/microglia limited to the lesion border Absence of remaining myelin degradation products in macrophages/microglia Smoldering/slowly expanding lesion*** Narrow rim of macrophages/microglia containing myelin degradation products such as MBP/PLP reflecting ongoing demyelination Inactive lesion -Hypo-cellular lesion area Lack of macrophages/microglia within the lesion and border homeostasis in MS. In addition, they can be [24] detrimental by barring myelin repair and neural regeneration. ...
Multiple sclerosis (MS) is a chronic autoimmune and demyelinating disease of the central nervous system (CNS) which leads to focal demyelinated lesions in the brain and spinal cord. Failure of remyelination contributes to chronic disability in young adults. Characterization of events occurring during the demyelination and remyelination processes and those of which subsequently limit remyelination or contribute to demyelination can provide the possibility of new therapies development for MS. Most of the currently available therapies and investigations modulate immune responses and mediators. Since most therapeutic strategies have unsatisfied outcomes, developing new therapies that enhance brain lesion repair is a priority. A close look at cellular and chemical components of MS lesions will pave the way to a better understanding of lesions pathology and will provide possible opportunities for repair strategies and targeted pharmacotherapy. This review summarizes the lesion components and features, particularly the detrimental elements, and discusses the possibility of suggesting new potential targets as therapies for demyelinating diseases like MS.
... These pathological hallmarks reported during initial stages of the disease are often accompanied by the clinical manifestation of functional relapses followed by remission, also known as relapsing-remitting multiple sclerosis (RRMS). Hence, the heterogeneity of this disease governs the course and severity of the neurological outcomes in patients with MS [2,3]. Although the exact cause is unknown, the infiltration of peripheral inflammatory lymphocytes and myeloid cells degenerate the myelin sheath along axons [4][5][6][7]. ...
... Classically, myelin antigen-activated immune cells such as circulating T lymphocytes, B lymphocytes and activated monocytic cells, traverse the disrupted BBB and infiltrate into the CNS to target putative myelin epitopes [For review see 38]. Although this hypothesis highlights the prominent role of immune cells promulgating inflammation and demyelination in MS, it fails to explain an underlying cause that initiates the autoimmune response [2]. Investigational inference may be derived from a recent genome-wide analysis mapping the X chromosome from 47,429 MS patients, which demonstrated that MS variants were enriched in human microglia, along with peripheral immune cells [39]. ...
... The infiltration of immune cells and activated phagocytic cells is often associated with the formation of active lesions. The activated microglial cells are commonly found at the edge of demyelinating lesions, periplaque white matter and NAWM whereas, macrophages are found in the center of active lesions [2,124]. This type of lesion is more common in patients suffering from acute or RRMS [125]. ...
Multiple sclerosis (MS) is a heterogeneous disease of the central nervous system that is governed by neural tissue loss and dystrophy during its progressive phase, with complex reactive pathological cellular changes. The immune-mediated mechanisms that promulgate the demyelinating lesions during the relapses of acute episodes are not characteristic of chronic lesions during progressive MS. This has limited our capacity to target the disease effectively as it evolves within the central nervous system white and gray matter, thereby leaving neurologists without effective options to manage individuals as they transition to a secondary progressive phase. The current review highlights the molecular and cellular sequelae that have been identified to cooperate and/or contribute to neurodegeneration that identifies individuals with progressive forms of MS. We emphasize the need for appropriate monitoring via known and novel molecular and imaging biomarkers that can accurately detect and predict progression for the purposes of newly designed clinical trials that may demonstrate efficacy of neuroprotection and potentially neurorepair. To achieve neurorepair, we focus on the modifications required in the reactive cellular and extracellular milieu, in order to enable endogenous cell growth as well as transplanted cells that can integrate and/or renew the degenerative MS plaque.
... Age, disease duration, clinical phenotype, as well as disease-modifying treatment all contribute to the dynamic nature of focal WM pathology (Frischer et al., 2015;Lucchinetti et al., 2000). This accounts for the large inter-and intraindividual heterogeneity of MS, which conventional MRI is largely unable to capture. ...
... Second, plaque microstructure is altered in plaque periphery before any observable change in conventional MRI signals. This finding suggests, in keeping with neuropathological observations (Frischer et al., 2015;Kuhlmann et al., 2017;Lassmann et al., 2007;Lucchinetti et al., 2000), that subclinical ongoing inflammation and/or demyelination takes place in the periphery of an active plaque, well before it is detectable on FLAIR or T1 postgadolinium sequences. If confirmed on larger population samples, this finding might significantly modify treatment management in MS patients. ...
... Indeed, it is composed of only 17 patients, with a rather broad range of characteristics such as age, disease duration, disease phenotype, disease-modifying treatment, etc., which are known to influence the disability state of the patient and thus their ability to put together repair mechanisms within cerebral tissues (Bodini et al., 2016;Frischer et al., 2015;Lassmann, 2013;Lassmann et al., 2001;Lucchinetti et al., 2000;Patrikios et al., 2006). In addition, the time interval between two scanning sessions varied rather widely across patients (between 14 and 61 months), although it was brought back to an annual rate where possible. ...
Introduction
Quantitative MRI quantifies tissue microstructural properties and supports the characterization of cerebral tissue damages. With an MPM protocol, 4 parameter maps are constructed: MTsat, PD, R1 and R2*, reflecting tissue physical properties associated with iron and myelin contents. Thus, qMRI is a good candidate for in vivo monitoring of cerebral damage and repair mechanisms related to MS. Here, we used qMRI to investigate the longitudinal microstructural changes in MS brain.
Methods
Seventeen MS patients (age 25–65, 11 RRMS) were scanned on a 3T MRI, in two sessions separated with a median of 30 months, and the parameters evolution was evaluated within several tissue classes: NAWM, NACGM and NADGM, as well as focal WM lesions. An individual annual rate of change for each qMRI parameter was computed, and its correlation to clinical status was evaluated. For WM plaques, three areas were defined, and a GLMM tested the effect of area, time points, and their interaction on each median qMRI parameter value.
Results
Patients with a better clinical evolution, that is, clinically stable or improving state, showed positive annual rate of change in MTsat and R2* within NAWM and NACGM, suggesting repair mechanisms in terms of increased myelin content and/or axonal density as well as edema/inflammation resorption. When examining WM lesions, qMRI parameters within surrounding NAWM showed microstructural modifications, even before any focal lesion is visible on conventional FLAIR MRI.
Conclusion
The results illustrate the benefit of multiple qMRI data in monitoring subtle changes within normal appearing brain tissues and plaque dynamics in relation with tissue repair or disease progression.
... Interestingly, while all active MS lesions were characterized by a chronic inflammatory demyelinating process mediated by T lymphocytes and macrophages, the immunological and cell-specific structural components varied significantly between different patients. By careful analysis, four basic patterns were described (Lucchinetti et al., 1996;Lucchinetti et al., 1999Lucchinetti et al., , 2000. In the first (pattern I), the demyelinating lesion included inflammatory T cells and macrophages wrapped around blood vessels but showed relative preservation of myelin-producing cells (oligodendrocytes) and no antibody involvement (Brück et al., 1995;Lucchinetti et al., 1996;Gay et al., 1997;Babbe et al., 2000). ...
... Pattern IV was unique in showing oligodendrocyte death within the focus of the demyelinating lesion, but no antibody deposition, suggesting that this type of lesion is caused by a defect in oligodendrocytes, i.e., is a primary oligodendrogliopathy (Lucchinetti et al., 1996). Pattern III was also highly distinct in that it showed little to no inflammation but was described as a "dying back" oligodendrogliopathy, whereby oligodendroglial proteins located at the distal end of oligodendrocyte processes, such as myelin associated glycoprotein (MAG) and cyclic nucleotide phosphodiesterase (CNPase) were completely absent, while myelin proteins concentrated at a more central position on oligodendrocytes (in the compact myelin), such as myelin basic protein (MBP) and proteolipid protein (PLP), remained intact (Itoyama et al., 1980;Ludwin and Johnson, 1981;Lucchinetti et al., 2000). With progression of this type of lesion, the destruction appeared to spread more centrally, leading ultimately to oligodendroglial apoptosis. ...
... Over the last thirty years, a growing number of studies have provided evidence supporting the idea that hypoxia may be an etiological factor in MS, either as the initial trigger or in maintaining the ongoing inflammatory attack. This was first suggested by the similarity between the dying back oligodendrogliopathy common to type III MS lesions and acute white matter stroke, suggesting that a hypoxia-driven pathogenic mechanism may underlie this type of MS lesion (Lucchinetti et al., 1999(Lucchinetti et al., , 2000. This concept was supported by the finding that HIF-1α expression was found in oligodendrocytes and other cell types in type III lesions but not in other patterns of MS lesions (Aboul-Enein et al., 2003). ...
Multiple sclerosis (MS) is the most common neurological disease affecting the young-middle age population in the Western hemisphere. Pathologically, it is a chronic inflammatory disease in which autoreactive T lymphocytes cross the blood-brain barrier to destroy the myelin insulating sheaths around axons. While accumulating evidence suggests a potential role for hypoxia in disease pathogenesis, interestingly, recent studies in the mouse MS model experimental autoimmune encephalomyelitis (EAE) have demonstrated the protective effect of hypoxic conditioning, both in the form of pre-conditioning and more importantly, when used to treat pre-existing disease. In this review we summarize the findings of these studies with a focus on: (i) the molecular mechanisms underlying the protective effect of hypoxic conditioning, and (ii) the potential clinical implications of these findings.
... Demyelinating activity is the hallmark of active MS lesions, which demonstrate patient-dependent immunopathological heterogeneity that persists over the time when lesions are active. [1][2][3][4] Four distinct immunopatterns (IPs) of early active MS lesions have been described, 1,5,6 reflecting differences in immune effector mechanisms of lesion formation. Patterns I and II are both associated with T lymphocyte and macrophage infiltration, with additional antibody and complement deposition seen exclusively in pattern II lesions. ...
... Demyelinating activity is the hallmark of active MS lesions, which demonstrate patient-dependent immunopathological heterogeneity that persists over the time when lesions are active. [1][2][3][4] Four distinct immunopatterns (IPs) of early active MS lesions have been described, 1,5,6 reflecting differences in immune effector mechanisms of lesion formation. Patterns I and II are both associated with T lymphocyte and macrophage infiltration, with additional antibody and complement deposition seen exclusively in pattern II lesions. ...
... Pattern IV, which has thus far only been described in three cases of progressive MS, is characterized by oligodendrocyte degeneration in the periplaque white matter. 1 Immunopathological heterogeneity of lesions may harbor fundamental implications for individualizing MS patients' therapy and prognosis. While pathological data are rarely acquired for MS patients, typically through biopsy for a tumefactive lesion 7 or at autopsy, they are crucial for understanding mechanisms of the disease. ...
Objective:
In this observational study on a cohort of biopsy-proven central nervous system demyelinating disease consistent with MS, we examined the relationship between early-active demyelinating lesion immunopattern (IP) with subsequent clinical course, radiographic progression, and cognitive function.
Methods:
Seventy-five patients had at least one early-active lesion on biopsy and were pathologically classified into three immunopatterns based on published criteria. The median time from biopsy at follow-up was 11 years, median age at biopsy - 41, EDSS - 4.0. At last follow-up, the median age was 50, EDSS - 3.0. Clinical examination, cognitive assessment (CogState battery), and 3-Tesla-MRI (MPRAGE/FLAIR/T2/DIR/PSIR/DTI) were obtained.
Results:
IP-I was identified in 14/75 (19%), IP-II was identified in 41/75 (56%), and IP-III was identified in 18/75 (25%) patients. Patients did not differ significantly by immunopattern in clinical measures at onset or last follow-up. The proportions of disease courses after a median of 11 years were similar across immunopatterns, relapsing-remitting being most common (63%), followed by monophasic (32%). No differences in volumetric or DTI measures were found. CogState performance was similar for most tasks. A slight yet statistically significant difference was identified for episodic memory scores, with IP-III patients recalling one word less on average.
Interpretation:
In this study, immunopathological heterogeneity of early-active MS lesions identified at biopsy does not correlate with different long-term clinical, neuroimaging or cognitive outcomes. This could be explained by the fact that while active white matter lesions are pathological substrates for relapses, MS progression is driven by mechanisms converging across immunopatterns, regardless of pathogenic mechanisms driving the acute demyelinated plaque.
... Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disease of the central nervous system (CNS). Multiple molecular mechanisms have been posited to drive lesion pathology (1)(2)(3), but the failure to identify relevant CNS immune targets has significantly hampered a comprehensive understanding of disease pathogenesis and the development of targeted therapies. ...
... Although myelin-specific MS rAbs represent a smaller subset of observed specificities, they caused rapid oligodendrocyte cell death and myelin loss when applied to mouse spinal cord or cerebellar explant cultures in the presence of human complement (14,15). Complement-mediated demyelination induced by myelin-specific MS antibodies could promote the deposition of IgG and terminal complement products found in approximately 50% of active MS lesions (1) implying that intrathecal IgGs may play a direct role in CNS injury. ...
B cell clonal expansion and cerebrospinal fluid (CSF) oligoclonal IgG bands are established features of the immune response in multiple sclerosis (MS). Clone-specific IgG1 monoclonal recombinant antibodies (rAbs) derived from MS patient CSF plasmablasts bound to conformational proteolipid protein 1 (PLP1) membrane complexes and, when injected into mouse brain with human complement, recapitulated histologic features of MS pathology: oligodendrocyte cell loss, complement deposition, and CD68+ phagocyte infiltration. Conformational PLP1 membrane epitopes were complex and governed by the local cholesterol and glycolipid microenvironment. Antibodies against conformational PLP1 membrane complexes targeted multiple surface epitopes, were enriched within the CSF compartment, and were detected in most MS patients but not in inflammatory and non-inflammatory neurologic controls. CSF PLP1 complex antibodies provide a pathogenic autoantibody biomarker specific for MS.
... Demyelination in multiple sclerosis (MS) patients is a heterogeneous process that gives rise to various clinical variants. In the classical study [33], four different types of lesions (Type I -IV) were identified, each corresponding to a different clinical variant. The presence of different lesion types reflects the stage-dependent nature of the pathology, with the evolution of lesional pathology contributing to the heterogeneity. ...
... We recall that assumption (8) of Lemma 2.1 is satisfied for = 2, 3. Then we can compute and the last inequality holds because of Lemma 3.1. Note that the previous definition for the constant , together with (33) and the smallness of ensure that ...
We investigated existence of global weak solutions for a system of chemotaxis-hapotaxis type with nonlinear degenerate diffusion, arising in modelling Multiple Sclerosis disease. The model consists of three equations describing the evolution of macrophages ($m$), cytokine ($c$) and apoptotic oligodendrocytes ($d$). The main novelty in our work is the presence of a nonlinear diffusivity $D(m)$, which results to be more appropriate from the modelling point of view. Under suitable assumptions and for sufficiently regular initial data, adapting the strategy in [30,44], we show the existence of global bounded solutions for the model analysed.
... Например, патологоанатомические исследования показали, что Т-клетки, Вклетки и макрофаги обычно обнаруживаются при гистопатологическом исследовании поражений РС либо при биопсии, либо при вскрытии. Исследования магнитно-резонансной томографии (МРТ) также продемонстрировали нарушение гематоэнцефалического барьера, определяемое утечкой контрастных веществ на основе гадолиния, на ранних этапах развития рассеянного склероза у пациентов с рецидивирующе-ремиттирующим заболеванием [5][6][7][8][9]. ...
... Последующие углубленные исследования, включая серологические, позволили идентифицировать ВЭБ в качестве нового представителя семейства герпесвирусов. В 1979 году научное название изменили на Human herpesvirus 4, в 2016 году -ещѐ раз, для указания подсемейства, к которому вид относится, на Human gammaherpesvirus 4 [7,8,9]. ...
Вирус Эпштейна-Барр – один из наиболее распространенных вирусов человека. Хроническая или рецидивирующая ВЭБ-инфекция способна индуцировать развитие лимфомы, рассеянного склероза (РС) и других заболеваний [3]. В статье рассмотрена связь ВЭБ с различными видами лимфом, патогенез ВЭБ-индуцированной трансформации иммунных клеток. Также приведены доказательства роли ВЭБ в развитии РС.
... The neurologists define MS lesions attack as a neurological defect that persists more than one day and can be correlated with an anatomical localization with no evidence of any infection or fever. The neurological defect always evolves from 2 -4 weeks, and it entirely or partially recovers between 6 and 8 weeks, either spontaneously or with corticosteroid medication 26,27 . However, patients with presenting an attack, MRI is the most accurate and vital diagnostic modality to confirm the diagnosis, especially with intravenous contrast agent given. ...
... This can serve to monitor the characteristics of lesion (demyelinating and inflammatory) as well as distribution and localization of the lesions within CNS 28 . Moreover, on the MR imaging, one anatomical region is presented by monofocal attack or more than one anatomical CNS region concurrently, such seen by multifocal attacks 26,27 . ...
Multiple sclerosis (MS) is a demyelinating disease that mainly impacts the central nervous system (CNS) and spinal cord. Several factors may affect the risk of MS lesions. Hence, this study was carried out to determine factors associated with brain MS lesions detected by Magnetic Resonance Imaging (MRI). A prospective cross-sectional survey was carried out in this study. An unenhanced T1, T2, Fluid Attenuated Inversion Recovery (FLAIR) with axial, sagittal, and coronal sections were performed. The respondents who had exposed to radiotherapy or chemotherapy had previous brain pathology or surgery, and brain congenital anomalies were excluded from this survey. A P-value of ˂ 0.05 was considered significant. A total of 71 subjects underwent MRI and included in the statistical analysis. The mean age of the subjects was 31.5 ± 11.5 years, with predominance for females (59.2%) among this study population. Moreover, the findings reported that the family history of MS was highly significantly associated with MS (P = 0.001). Besides, there was no significant association found between gender (P = 0.682), smoking (P = 0.272), alcohol intake (P = 0.986), hypertension (P = 0.792), diabetes mellitus (DM) (P = 0.198), and body mass index (BMI) (P = 0.650). From this study, the family history of MS is found to develop the risk of MS.
... Analyses of MS CNS tissue 13,14 and cerebrospinal fluid (CSF) biomarkers from MS patients identified compartmentalized inflammation in CNS tissue 15,16 insufficiently targeted by current DMTs 17 and varied neurodegenerative processes [18][19][20] . These candidate mechanisms evolve with MS duration 21 and, analogous to the heterogeneity of the formation of acute MS lesions 22 , are not uniformly detected in all MS patients. This observed heterogeneity of MS disease mechanisms implies that similarly to other chronic diseases with complex pathophysiology such as cardiovascular diseases, patient-specific "custom combination treatments" may be required to inhibit disability progression in MS. ...
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS). Clemastine fumarate, the over-the-counter antihistamine and muscarinic receptor blocker, has remyelinating potential in MS. A clemastine arm was added to an ongoing platform clinical trial TRAP-MS ( NCT03109288 ) to identify a cerebrospinal fluid (CSF) remyelination signature and to collect safety data on clemastine in patients progressing independently of relapse activity (PIRA). The clemastine arm was stopped per protocol-defined criteria when 3/9 patients triggered individual safety stopping criteria (χ ² p=0.00015 compared to remaining TRAP-MS treatments). Clemastine treated patients had significantly higher treatment-induced disability progression slopes compared to remaining TRAP-MS participants (p=0.0075). Quantification of ∼7000 proteins in CSF samples collected before and after clemastine treatment showed significant increase in purinergic/ATP signaling and pyroptosis cell death. Mechanistic studies showed that clemastine with sub-lytic doses of extracellular ATP activates inflammasome and induces pyroptotic cell death in macrophages. Clemastine with ATP also caused pyroptosis of induced pluripotent stem cell-derived human oligodendrocytes. Antagonist of the purinergic channel P2RX7 that is strongly expressed in oligodendrocytes and myeloid cells, blocked these toxic effects of clemastine. Finally, re-analyses of published snRNAseq studies revealed increased P2RX7 expression and pyroptosis transcriptional signature in microglia and oligodendrocytes in MS brain, especially in chronic active lesions. CSF proteomic pyroptosis score was increased in untreated MS patients, was higher in patients with progressive than relapsing-remitting disease and correlated significantly with rates of MS progression. Thus, pyroptosis is likely first well-characterized mechanism of CNS injury underlying PIRA even outside of clemastine toxicity.
One Sentence Summary
Clemastine enhanced disability accumulation in patients progressing by non-lesional MS activity by potentiating intrathecal P2RX7 signaling and pyroptosis.
... Up to this time, microstructural investigation of MS-associated brain tissue damage remains challenging, primarily because of the lack of accurate methods able to depict the heterogeneous nature of MS pathology in vivo. MS lesions are indeed heterogeneous in terms of inflammatory response, myelin and axonal damage (Lucchinetti et al., 2000). In their initial stage, they are usually characterized by opening of the blood-brain barrier, causing perivascular and parenchymal acute inflammation (Reich et al., 2018). ...
In multiple sclerosis (MS), accurate in vivo characterization of the heterogeneous lesional and extra-lesional tissue pathology remains challenging. Marshalling several advanced imaging techniques — quantitative relaxation time (T1) mapping, a model-free average diffusion signal approach and four multi-shell diffusion models — this study investigates the performance of multi-shell diffusion models and characterizes the microstructural damage within (i) different MS lesion types — active, chronic active, and chronic inactive — (ii) their respective periplaque white matter (WM), and (iii) the surrounding normal-appearing white matter (NAWM). In 83 MS participants (56 relapsing-remitting, 27 progressive) and 23 age and sex-matched healthy controls (HC), we analysed a total of 317 paramagnetic rim lesions (PRL+), 232 non-paramagnetic rim lesions (PRL-), 38 contrast-enhancing lesions (CEL). Consistent with previous findings and histology, our analysis revealed the ability of advanced multi-shell diffusion models to characterize the unique microstructural patterns of CEL, and to elucidate their possible evolution into a resolving (chronic inactive) vs smoldering (chronic active) inflammatory stage. In addition, we showed that the microstructural damage extends well beyond the MRI-visible lesion edge, gradually fading out while moving outward from the lesion edge into the immediate WM periplaque and the NAWM, the latter still characterized by diffuse microstructural damage in MS vs HC. This study also emphasizes the critical role of selecting appropriate diffusion models to elucidate the complex pathological architecture of MS lesions and their periplaque. More specifically, multi-compartment diffusion models based on biophysically interpretable metrics such as neurite orientation dispersion and density (NODDI; mean auc=0.8002) emerge as the preferred choice for MS applications, while simpler models based on a representation of the diffusion signal, like diffusion tensor imaging (DTI; mean auc=0.6942), consistently underperformed, also when compared to T1 mapping (mean auc=0.73375).
... The heterogeneous histopathology in different phenotypes and lesion stages/types (early active, remyelinated, chronic active, and chronic inactive and lesions) may also explain these differences. 21 The studies discussed so far have averaged the T1-w/T2-w ratio from the entire lesion mask rather than assessing lesion masks individually. A recent study showed that T1-w/T2-w values of brain lesions with paramagnetic rim were significantly lower compared to non-paramagnetic rim lesions, supporting its previous histopathological association with a pronounced tissue matrix damage. ...
T1/T2-weighted ratio is a novel magnetic resonance imaging (MRI) biomarker based on conventional sequences, related to microstructural integrity and with increasing use in multiple sclerosis (MS) research. Different from other advanced MRI techniques, this method has the advantage of being based on routinely acquired MRI sequences, a feature that enables analysis of retrospective cohorts with considerable clinical value. This article provides an overview of this method, describing the previous cross-sectional and longitudinal findings in the main MS clinical phenotypes and in different brain tissues: focal white matter (WM) lesions, normal-appearing white matter (NAWM), cortical gray matter (GM), and deep normal-appearing gray matter (NAGM). We also discuss the clinical associations, possible reasons for conflicting results, correlations with other MRI-based measures, and histopathological associations. We highlight the limitations of the biomarker itself and the methodology of each study. Finally, we update the reader on its potential use as an imaging biomarker in research.
... B cells have been found in multiple regions of the CNS in MS patients, including the meninges, lesioned and normal white matter, the cortex, and CSF [119]. Although the distribution of B-cell clones in different brain compartments provides evidence that B cells can cross different CNS barriers, the mechanisms underlying how and where B cells cross these barriers have not been fully elucidated [47]. ...
Abnormal inflammatory states in the brain are associated with a variety of brain diseases. The dynamic changes in the number and function of immune cells in cerebrospinal fluid (CSF) are advantageous for the early prediction and diagnosis of immune diseases affecting the brain. The aggregated factors and cells in inflamed CSF may represent candidate targets for therapy. The physiological barriers in the brain, such as the blood‒brain barrier (BBB), establish a stable environment for the distribution of resident immune cells. However, the underlying mechanism by which peripheral immune cells migrate into the brain and their role in maintaining immune homeostasis in CSF are still unclear. To advance our understanding of the causal link between brain diseases and immune cell status, we investigated the characteristics of immune cell changes in CSF and the molecular mechanisms involved in common brain diseases. Furthermore, we summarized the diagnostic and treatment methods for brain diseases in which immune cells and related cytokines in CSF are used as targets. Further investigations of the new immune cell subtypes and their contributions to the development of brain diseases are needed to improve diagnostic specificity and therapy.
... Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) that is characterized mainly by immune cell infiltration, inflammation, and demyelination (Lucchinetti et al., 2000). The disease can occur in younger adults between the ages of 20 and 50 years. ...
Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease of the central nervous system (CNS) in young adults and results in progressive neurological defects. The relapsing-remitting phenotype (RRMS) is the most common disease course in MS and may progress to the progressive form (PPMS). There is a gap in knowledge regarding whether the relapsing form can be distinguished from the progressive course or healthy subjects (HS) based on an altered serum metabolite profile. In this study, we performed global untargeted metabolomics with the 2D GCxGC-MS platform to identify altered metabolites between RRMS, PPMS, and HS. We profiled 235 metabolites in the serum of patients with RRMS (n=41), PPMS (n=31), and HS (n=91). A comparison of RRMS and HS patients revealed 22 significantly altered metabolites at p<0.05 (false discovery rate [FDR]=0.3). The PPMS and HS comparisons revealed 28 altered metabolites at p<0.05 (FDR=0.2). Pathway analysis using MetaboAnalyst revealed enrichment of four metabolic pathways in both RRMS and PPMS (hypergeometric test p<0.05): 1) galactose metabolism; 2) amino sugar and nucleotide sugar metabolism; 3) phenylalanine, tyrosine, and tryptophan biosynthesis; and 4) aminoacyl-tRNA biosynthesis. The Qiagen IPA enrichment test identified the sulfatase 2 (SULF2) (p=0.0033) and integrin subunit beta 1 binding protein 1 (ITGB1BP1) (p=0.0067) genes as upstream regulators of altered metabolites in the RRMS vs. HS groups. However, in the PPMS vs. HS comparison, valine was enriched in the neurodegeneration of brain cells (p=0.05), and heptadecanoic acid, alpha-ketoisocaproic acid, and glycerol participated in inflammation in the CNS (p=0.03). Overall, our study suggested that RRMS and PPMS may contribute metabolic fingerprints in the form of unique altered metabolites for discriminating MS disease from HS, with the potential for the construction of a metabolite panel for progressive autoimmune diseases such as MS.
... Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) that is characterized mainly by immune cell in ltration, in ammation, and demyelination (Lucchinetti et al., 2000). The disease can occur in younger adults between the ages of 20 and 50 years. ...
Introduction
Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease of the central nervous system (CNS) in young adults and results in progressive neurological defects. The relapsing-remitting phenotype (RRMS) is the most common disease course in MS and may progress to the progressive form (PPMS).
Objectives
There is a gap in knowledge regarding whether the relapsing form can be distinguished from the progressive course or healthy subjects (HS) based on an altered serum metabolite profile. In this study, we performed global untargeted metabolomics with the 2D GCxGC-MS platform to identify altered metabolites between RRMS, PPMS, and HS.
Methods
We profiled 235 metabolites in the serum of patients with RRMS (n = 41), PPMS (n = 31), and HS (n = 91). A comparison of RRMS and HS patients revealed 22 significantly altered metabolites at p < 0.05 (false discovery rate [FDR] = 0.3). The PPMS and HS comparisons revealed 28 altered metabolites at p < 0.05 (FDR = 0.2).
Results
Pathway analysis using MetaboAnalyst revealed enrichment of four metabolic pathways in both RRMS and PPMS (hypergeometric test p < 0.05): 1) galactose metabolism; 2) amino sugar and nucleotide sugar metabolism; 3) phenylalanine, tyrosine, and tryptophan biosynthesis; and 4) aminoacyl-tRNA biosynthesis. The Qiagen IPA enrichment test identified the sulfatase 2 (SULF2) (p = 0.0033) and integrin subunit beta 1 binding protein 1 (ITGB1BP1) (p = 0.0067) genes as upstream regulators of altered metabolites in the RRMS vs. HS groups. However, in the PPMS vs. HS comparison, valine was enriched in the neurodegeneration of brain cells (p = 0.05), and heptadecanoic acid, alpha-ketoisocaproic acid, and glycerol participated in inflammation in the CNS (p = 0.03).
Conclusion
Overall, our study suggested that RRMS and PPMS may contribute metabolic fingerprints in the form of unique altered metabolites for discriminating MS disease from HS, with the potential for the construction of a metabolite panel for progressive autoimmune diseases such as MS.
... Experts interested in this topic should read these articles first. Quantitative studies comparing myelin water imaging and histopathology were cited many times, confirming that multiecho T2-relaxation myelin water imaging can effectively marker myelin content in the CNS (26). MS often presents alternating relapses and remissions, accompanied by varying degrees of glial cell activation and proliferation, demyelination and remyelination, and a dynamic cascade of axonal loss (27), posing a challenge for myelin water imaging. ...
Background
Multiple sclerosis (MS) is a condition that can impact the central nervous system (CNS) and cause damage to the myelin, which is responsible for facilitating the normal transmission of electrical impulses along the nerves. We performed a bibliometric analysis of the scientific publications on myelin imaging in MS to reveal the development trends in this field and to evaluate research trends in myelin imaging in MS.
Methods
The Web of Science Core Collection was searched for articles related to myelin imaging in MS published between January 2000 and December 2022. CiteSpace, VOSviewer, and R language were used to evaluate and visualize contributions by and co-occurrence relationships among countries and institutions, authors, journals, citations, keywords, and so on.
Results
A total of 1,639 articles addressed the topic of myelin imaging in MS. The United States had the largest number of annual publications. The University of London was the institution with the highest number of publications (n=118) and citations (n=9,885). The top 3 productive authors were all from the University of British Columbia in Canada. An article published by Mackay et al. in 1994 had the most citations (n=272). Neuroimage [impact factor (IF) =7.40, Journal Citation Reports quartile 1 (Q1)] was the most productive journal in terms of the number of articles relating to myelin imaging in MS (n=149). In recent years, myelin water imaging, synthetic magnetic resonance imaging (SyMRI), inhomogeneous magnetization, positron emission tomography (PET) imaging, and aquaporin-4 (AQP4) have been researched hotspots of myelin imaging in MS.
Conclusions
With advancements in the pathophysiological research on myelin changes in MS, myelin imaging is playing an important role in the diagnosis and treatment of MS. In addition, the use of new sequences of myelin imaging to distinguish MS from other inflammatory demyelinating diseases is a future development trend in this field.
... There is evidence that demyelination is driven by different mechanisms involving the adaptive and innate immune system (Lucchinetti et al., 2000). Remyelination of demyelinated lesions occurs spontaneously but is often structurally and functionally incomplete. ...
In central nervous system (CNS), demyelination is a pathological process featured with a loss of myelin sheaths around axons, which is responsible for the diseases of multiple sclerosis, neuromyelitis optica, and so on. Transforming growth factor‐beta1 (TGF‐β1) is a multifunctional cytokine participating in abundant physiological and pathological processes in CNS. However, the effects of TGF‐β1 on CNS demyelinating disease and its underlying mechanisms are controversial and not well understood. Herein, we evaluated the protective potential of TGF‐β1 in a rodent demyelinating model established by lysophosphatidylcholine (LPC) injection. It was identified that supplement of TGF‐β1 evidently rescued the cognitive deficit and motor dysfunction in LPC modeling mice assessed by novel object recognition and balance beam behavioral tests. Besides, quantified by luxol fast blue staining, immunofluorescence, and western blot, administration of TGF‐β1 was found to significantly ameliorate the demyelinating lesion and reactive astrogliosis by suppressing p38 MAPK pathway. Mechanistically, the results of in vitro experiments indicated that treatment of TGF‐β1 could directly promote the differentiation and migration of cultured oligodendrocytes. Our study revealed that modulating TGF‐β1 activity might serve as a promising and innovative therapeutic strategy in CNS demyelinating diseases.
... Given that progressive subtypes are associated with more extensive spinal cord involvement and the poor response to diseasemodifying therapies in these patients, this raises the question if it is possible that the limited effect of therapy in the progressive subtypes might be due to the intrathecal persistence of pathogenic B and T cell clones driving parenchymal inflammation and which are poorly accessible for peripherally delivered therapies [46]. While complement and immunoglobulin depositions can be found in lesions in brain and spinal cord, whether there is in fact antibody-mediated demyelination (direct, or indirect via the activation of autoreactive T cells) or as a result of complement-based mechanisms (independent or dependent of antibodies), is still uncertain [79][80][81]. ...
A disparity exists between spinal cord and brain involvement in multiple sclerosis (MS), each independently contributing to disability. Underlying differences between brain and cord are not just anatomical in nature (volume, white/grey matter organization, vascularization), but also in barrier functions (differences in function and composition of the blood-spinal cord barrier compared to blood-brain barrier) and possibly in repair mechanisms. Also, immunological phenotypes seem to influence localization of inflammatory activity. Whereas the brain has gained a lot of attention in MS research, the spinal cord lags behind. Advanced imaging techniques and biomarkers are improving and providing us with tools to uncover the mechanisms of spinal cord pathology in MS. In the present review, we elaborate on the underlying anatomical and physiological factors driving differences between brain and cord involvement in MS and review current literature on pathophysiology of spinal cord involvement in MS and the observed differences to brain involvement.
... Die 4 klassischen pathologischen Läsionstypen, von Typ I bis Typ IV, beruhen auf unterschiedlichen Eigenschaften des Immunsystems. Von beson derer Bedeutung sind TypIILäsionen, die durch Antikörperab lagerungen gekennzeichnet sind und somit das humorale Im munsystem direkt in die Entwicklung von MSLäsionen einbezie hen [66]. Das humorale Immunsystem ist sowohl bei AAwMS als auch bei HwMS sehr aktiv, da in peripheren Blutproben erhöhte Mengen an Antikörper sezernierenden Zellen vorhanden sind [67]. ...
Multiple Sklerose (MS) ist die häufigste nichttraumatische Ursache für Behinderungen bei jungen Menschen, wobei der Verlust des Sehvermögens bei dieser Krankheit den zweitgrößten Anteil an der Behinderung ausmacht. Insbesondere afroamerikanische MS-Patienten haben ein schlechteres Sehvermögen als die Vergleichsgruppe der Kaukasier. In dieser Übersichtsarbeit untersuchen wir die Unterschiede bei Augenkrankheiten in der MS-Population unter Berücksichtigung der vorhandenen Wissenslücken und diskutieren die zugrunde liegende Natur der pathologischen Diskrepanzen.
... Cuprizone (bis-cyclohexanone oxalydihydrazone, CPZ) administration is regarded as a useful model to replicate pattern-III lesions [18] characteristic of progressive forms of MS. Our group pioneered the histological and biochemical characterization of CPZ-induced demyelination in rats [19] and produced evidence of Notch and TGF-β involvement in cell fate decisions of adult brain SVZ NSC cultures and their implications in OPC proliferation and maturation [20]. ...
Multiple sclerosis (MS) is an immune-mediated central nervous system (CNS) disease characterized by demyelination resulting from oligodendrocyte loss and inflammation. Cuprizone (CPZ) administration experimentally replicates MS pattern-III lesions, generating an inflammatory response through microgliosis and astrogliosis. Potentially remyelinating agents include oligodeoxynucleotides (ODN) with a specific immunomodulatory sequence consisting of the active motif PyNTTTTGT. In this work, the remyelinating effects of ODN IMT504 were evaluated through immunohistochemistry and qPCR analyses in a rat CPZ-induced demyelination model. Subcutaneous IMT504 administration exacerbated the pro-inflammatory response to demyelination and accelerated the transition to an anti-inflammatory state. IMT504 reduced microgliosis in general and the number of phagocytic microglia in particular and expanded the population of oligodendroglial progenitor cells (OPCs), later reflected in an increase in mature oligodendrocytes. The intracranial injection of IMT504 and intravenous inoculation of IMT504-treated B lymphocytes rendered comparable results. Altogether, these findings unveil potentially beneficial properties of IMT504 in the regulation of neuroinflammation and oligodendrogenesis, which may aid the development of therapies for demyelinating diseases such as MS.
... Moreover, changes in cerebrovascular function, including a widespread reduction in CBF, may contribute to the pathophysiology of MS (D'haeseleer et al., 2011;Zlokovic, 2011). Metabolic impairment may contribute to hypoxia, demyelination, neuronal loss, brain atrophy and disability progression (Lucchinetti et al., 2000;Lassmann, 2003;Wuerfel et al., 2004;Ge et al., 2005;Trapp and Stys, 2009;Marrie et al., 2010;Holland et al., 2012;Juurlink, 2013;Debernard et al., 2014;Kappus et al., 2016). Previous studies have reported that when the structural brain damage becomes detectable (in terms of GM atrophy and network disruptions), the cognitive impairment in MS is also present (Fleischer et al., 2019;Nauta et al., 2021), suggesting that structural changes may be a subsequent outcome of the cerebrovascular impairment and CBF may thus offer an earlier marker of neuroplasticity. ...
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. A better understanding of the mechanisms supporting brain plasticity in MS would help to develop targeted interventions to promote recovery. A total of 29 MS patients and 19 healthy volunteers underwent clinical assessment and multi-modal MRI acquisition [fMRI during serial reaction time task (SRT), DWI, T1w structural scans and ASL of resting perfusion] at baseline and after 4-weeks of SRT training. Reduction of functional hyperactivation was observed in MS patients following the training, shown by the stronger reduction of the BOLD response during task execution compared to healthy volunteers. The functional reorganization was accompanied by a positive correlation between improvements in task accuracy and the change in resting perfusion after 4 weeks’ training in right angular and supramarginal gyri in MS patients. No longitudinal changes in WM and GM measures and no correlation between task performance improvements and brain structure were observed in MS patients. Our results highlight a potential role for CBF as an early marker of plasticity, in terms of functional (cortical reorganization) and behavioral (performance improvement) changes in MS patients that may help to guide future interventions that exploit preserved plasticity mechanisms.
... Colocalization analysis revealed that PD-1 expression was specific to Iba1 + cells within the lesion rim and was largely excluded from both NAWMand lesion-associated GFAP + astrocytes (Fig. 5I). Although all types of described active lesions contain a significant number of T cells, classically they are not as abundant in areas of active demyelination, such as that seen in the chronic active lesion core and rim [53,54]. Nevertheless, T cells are key players in MS pathogenesis, so we sought to determine the T cell contribution to PD-1 expression in chronic active lesions; however, the T cells found did not appear to express appreciable levels of PD-1 (Additional file 1: Figure S6), consistent with previous reports [40]. ...
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS). Infiltrating inflammatory immune cells perpetuate demyelination and axonal damage in the CNS and significantly contribute to pathology and clinical deficits. While the cytokine interferon (IFN)γ is classically described as deleterious in acute CNS autoimmunity, we and others have shown astrocytic IFNγ signaling also has a neuroprotective role. Here, we performed RNA sequencing and ingenuity pathway analysis on IFNγ-treated astrocytes and found that PD-L1 was prominently expressed. Interestingly, PD-1/PD-L1 antagonism reduced apoptosis in leukocytes exposed to IFNγ-treated astrocytes in vitro. To further elucidate the role of astrocytic IFNγ signaling on the PD-1/PD-L1 axis in vivo, we induced the experimental autoimmune encephalomyelitis (EAE) model of MS in Aldh1l1-CreERT2, Ifngr1fl/fl mice. Mice with conditional astrocytic deletion of IFNγ receptor exhibited a reduction in PD-L1 expression which corresponded to increased infiltrating leukocytes, particularly from the myeloid lineage, and exacerbated clinical disease. PD-1 agonism reduced EAE severity and CNS-infiltrating leukocytes. Importantly, PD-1 is expressed by myeloid cells surrounding MS lesions. These data support that IFNγ signaling in astrocytes diminishes inflammation during chronic autoimmunity via upregulation of PD-L1, suggesting potential therapeutic benefit for MS patients.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12974-023-02917-4.
... Active white matter demyelinating lesions are represented by the existence of macrophages which contain cytoplasmic early myelin degeneration materials both during the lesion and at the lesion edge (Brück et al., 1995). All these lesions are highly uncommon in chronic MS and frequently present in the active form of MS (secondary progressive MS [SPMS] and relapsingremitting MS (RRMS) with relapses), which is a potentially pathological substrate for the attacks (Lucchinetti et al., 2000). In brain lesions, perivascular inflammation is commonly described as containing granulocytes, plasma cells, fewer B lymphocytes, as well as T lymphocytes, are typical characters to MS retina, where the vessels running via the RNFL are known as indicating a perivascular inflammation involving mononuclear cells, lymphocytes, and phagocytic (Popescu & Lucchinetti, 2012). ...
... Of specific relevance are type II lesions, which are characterized by antibody deposition, and thus directly implicating the humoral immune system in the development of MS lesions. 66 The humoral immune system is highly active in both AAwMS and HwMS, as there are increased levels of antibody-secreting cells in peripheral blood samples. 67 Furthermore, it is now known that AAwMS have higher levels of intrathecal humoral inflammatory changes based on higher levels of IgG synthesis rate and IgG index. ...
Multiple sclerosis (MS) is the most common non-traumatic cause of disability in young people, with vision loss in the disease representing the second largest contributor to disability. In particular, African-American patients with MS are noted to have lower vision than their Caucasian counterparts. In this review, we examine the disparities in eye diseases in the MS population with our gaps in knowledge and discuss the underlying nature of pathological disparities.
... Since from the first studies on MS [4], it was clear that its characteristic feature was the inflammatory process leading to myelin injury. The heterogeneity of demyelination patterns between different patients, but homogeneous for the same patient, at early stage of the disease [34], suggest a wide range of immune mechanism underlying the formation of plaques. ...
We present a mathematical study for the development of Multiple Sclerosis in which a spatio-temporal kinetic model describes, at mesoscopic level, the dynamics of a high number of interacting agents. We consider both interactions among different populations of human cells and motion of immune cells, stimulated by cytokines. Moreover, we reproduce the consumption of myelin sheath due to anomalously activated lymphocytes and its restoration by oligodendrocytes. Successively, we fix a small time parameter and assume that the considered processes occur at different scales. This allows to perform a formal limit, obtaining macroscopic reaction-diffusion equations for the number densities with a chemotaxis term. A natural step is then to study the system, inquiring about the formation of spatial patterns through a Turing instability analysis of the problem and basing the discussion on microscopic parameters of the model. In particular, we get spatial patterns oscillating in time that may reproduce brain lesions characteristic of different phases of the pathology.
... White matter lesions, although small, might lead to remote effects via disconnection of white matter tracts(C. Lucchinetti et al., 2000), thereby disrupting efficient communication in brain networks and resulting in cognitive or mood dysfunctions (Ter Telgte et al., 2018). Currently, accumulating evidence suggests that this structural disconnection can address the clinical progression of demyelinating diseases, such as multiple sclerosis (Ravano et al., 2021;Schoonheim et al., 2022). ...
Objectives
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system. Accumulating evidence suggests there is a distinct pattern of brain lesions characteristic of NMOSD, and brain MRI has potential prognostic implications. However, the question of how the brain lesions in NMOSD are associated with its distinct clinical course remains incompletely understood. Here, we aimed to investigate the association between neurological impairment and brain lesions via brain structural disconnection.
Methods
Twenty patients were diagnosed with NMOSD according to the 2015 International Panel for NMO Diagnosis criteria. The white matter lesions were manually drawn section by section. Whole-brain structural disconnection was estimated, and connectome-based predictive modeling (CPM) was used to estimate the patient’s Expanded Disability Status Scale score (EDSS) from their disconnection severity matrix. Furthermore, correlational tractography was performed to assess the fractional anisotropy (FA) and axial diffusivity (AD) of white matter fibers, which negatively correlated with the EDSS score.
Results
CPM successfully predicted the EDSS using the disconnection severity matrix (r = 0.506, p = 0.028; q² = 0.274). Among the important edges in the prediction process, the majority of edges connected the motor to the frontoparietal network. Correlational tractography identified a decreased FA and AD value according to EDSS scores in periependymal white matter tracts.
Discussion
Structural disconnection-based predictive modeling and local connectome analysis showed that frontoparietal and periependymal white matter disconnection is predictive and associated with the EDSS score of NMOSD patients.
... The presence of oligoclonal bands in the cerebrospinal fluid is also a great marker for multiple sclerosis, as it evidences previous activity of the disease and thus can be used as evidence of DIT (THOMPSON et al., 2018;HARTUNG et al., 2019;ARRAMBIDE et al., 2019). In patients with multiple sclerosis, an increase in antibodies, especially immunoglobulin G (IgG), antibodies against oligodendrocyte and myelin glycoproteins, and activated complement components was evidenced in the cerebrospinal fluid (LALIVE et al., 2006;LUCCHINETTI et al., 2000;LUTTEROTTI;BERGER;REINDL, 2007). ...
Multiple sclerosis is a chronic inflammatory autoimmune disease of the central nervous system, characterized by mononuclear cell infiltration, axon demyelination and gliosis in the myelin sheath, with formation of multiple plaques. It affects individuals aged between 25 and 50 years old, female and residents of higher latitudes. The etiology of multiple sclerosis is multifactorial and not fully understood; however, the influence of genetic predisposition and environmental factors on immune dysregulation is recognized. The pathophysiology of the disease is mediated by self-reactive T lymphocytes that respond to autoantigens from the central nervous system. The emergence of multifocal regions of demyelination, axonal loss, loss of oligodendrocytes and astroglial scarring result in impaired neurological function, leading to neurodegeneration. Although there is still no cure for multiple sclerosis, scientific research has provided great advances in therapeutic strategies. Currently there are approaches to attenuate specific signs and symptoms, drugs to control disease relapses and treatments designed to modify or delay the course of multiple sclerosis. Although these drugs show promising effects, they are ineffective in curing the patient. In addition, they present a fundamental problem, which is the non-selective action on the cells of the immune system, which triggers serious side effects. Considering the limitations of studies in humans due to the difficulty of accessing the affected tissues, the use of experimental models that simulate the singularities of multiple sclerosis is a key element for the study of the pathogenesis of inflammation and therapeutic alternatives. Experimental autoimmune encephalomyelitis, an animal model that presents several similarities with pathophysiological, histological and clinical aspects of multiple sclerosis, is the most used model for these studies. Therefore, in this chapter, the aim was to review the historical context, definition, etiology, pathophysiology, clinical manifestations, diagnosis and treatment of multiple sclerosis and, at the same time, address aspects of the timeline, induction, the evolutionary course and the immunopathogenesis of the most studied model for the investigation of the nuances of multiple sclerosis, correlating the similarities and differences between both.
... Some studies have demonstrated a signal increase in diffusion-weighted imaging (DWI) associated with a reduction of the apparent diffusion coefficient (ADC) values in the very early phase of acute MS lesions [70][71][72][73]. The possible mechanisms of reduced diffusivity include infiltration of inflammatory cells as well as cytotoxic cell swelling and disturbances of energy metabolism, leading to reduced extracellular space [70,72,[74][75][76][77]. The reduced ADC signal is transient and may appear not only in the early development stage of demyelinating lesions, but also before the stage of enhancement, and normalizes before the disappearance of enhancement [70,73,74,76,78]. ...
Magnetic resonance imaging (MRI) is the most sensitive technique for detecting inflammatory demyelinating lesions in multiple sclerosis (MS) and plays a crucial role in diagnosis and monitoring treatment effectiveness, and for predicting the disease course. In clinical practice, detection of MS lesions is mainly based on T2-weighted and contrast-enhanced T1-weighted sequences. Contrast-enhancing lesions (CEL) on T1-weighted sequences are related to (sub)acute inflammation, while new or enlarging T2 lesions reflect the permanent footprint from a previous acute inflammatory demyelinating event. These two types of MRI features provide redundant information, at least in regular monitoring of the disease. Due to the concern of gadolinium deposition after repetitive injections of gadolinium-based contrast agents (GBCAs), scientific organizations and regulatory agencies in Europe and North America have proposed that these contrast agents should be administered only if clinically necessary. In this article, we provide data on the mode of action of GBCAs in MS, the indications of the use of these agents in clinical practice, their value in MS for diagnostic, prognostic, and monitoring purposes, and their use in specific populations (children, pregnant women, and breast-feeders). We discuss imaging strategies that achieve the highest sensitivity for detecting CELs in compliance with the safety regulations established by different regulatory agencies. Finally, we will briefly discuss some alternatives to the use of GBCA for detecting blood-brain barrier disruption in MS lesions. CLINICAL RELEVANCE STATEMENT: Although use of GBCA at diagnostic workup of suspected MS is highly valuable for diagnostic and prognostic purposes, their use in routine monitoring is not mandatory and must be reduced, as detection of disease activity can be based on the identification of new or enlarging lesions on T2-weighted images. KEY POINTS: • Both the EMA and the FDA state that the use of GBCA in medicine should be restricted to clinical scenarios in which the additional information offered by the contrast agent is required. • The use of GBCA is generally recommended in the diagnostic workup in subjects with suspected MS and is generally not necessary for routine monitoring in clinical practice. • Alternative MRI-based approaches for detecting acute focal inflammatory MS lesions are not yet ready to be used in clinical practice.
... [3][4][5] The ethology is unknow, 6 and it is hypothesized that autoreactive lymphocytes migrate to the central nervous and would be the responsible of the demyelinating plaques. 7 The lesions can affect all the areas of the central nervous system, the histopathology is different among patients, [8][9][10][11] and for these reasons, the clinical manifestations and the evolution of the patients are very variable. 12,13 Consequently, the diagnosis is complex, and it is based on criteria diagnosis which include the assertion of symptoms related with demyelination and laboratory test. ...
Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system. It affects young people, and a considerable percentage of patients need the help of a wheelchair in 15 years of evolution. Currently, there is not a specific technique for the diagnosis of MS. The detection of oligoclonal IgG bands (OIgGBs) is the most sensitive assay for it, but it is not standardizable, only reference laboratories develop it, and uses cerebrospinal fluid. To obtain this sample, a lumbar puncture is necessary, an invasive proceeding with important side effects. It is important to develop and implement standard assays to obtain a rapid diagnosis because the earlier the treatment, the better the evolution of the disease. There are numerous modifying disease therapies, which delay the progression of the disease, but they have important side effects, and a considerable percentage of patients give up the treatment. In addition, around 40% of MS patients do not respond to the therapy and the disease progresses. Numerous researches have been focused on the characterization of predictive biomarkers of response to treatment, in order to help physicians to decide when to change to a second-line treatment, and then the best therapeutic option. Here, we review the new biomarkers for the diagnosis and response to treatment in MS. We draw attention in a new assay, the detection of serum IgM to phosphatidylcholine, that showed a similar sensitivity as OIgGBs and predicts the response to disease modifying treatments.
... As mentioned earlier, these cells can adopt an anti-inflammatory phenotype to promote remyelination or become effector cells for myelin destruction and clearance through their pro-inflammatory function. Microglial activation may ultimately lead to the development of focal primary demyelinated areas of the acute inflammatory process with varying degrees of axonal injury [92]. ...
Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS). Immune cell infiltration can lead to permanent activation of macrophages and microglia in the parenchyma, resulting in demyelination and neurodegeneration. Thus, neurodegeneration that begins with acute lymphocytic inflammation may progress to chronic inflammation. This chronic inflammation is thought to underlie the development of so-called smouldering lesions. These lesions evolve from acute inflammatory lesions and are associated with continuous low-grade demyelination and neurodegeneration over many years. Their presence is associated with poor disease prognosis and promotes the transition to progressive MS, which may later manifest clinically as progressive MS when neurodegeneration exceeds the upper limit of functional compensation. In smouldering lesions, in the presence of only moderate inflammatory activity, a toxic environment is clearly identifiable and contributes to the progressive degeneration of neurons, axons, and oligodendrocytes and, thus, to clinical disease progression. In addition to the cells of the immune system, the development of oxidative stress in MS lesions, mitochondrial damage, and hypoxia caused by the resulting energy deficit and iron accumulation are thought to play a role in this process. In addition to classical immune mediators, this chronic toxic environment contains high concentrations of oxidants and iron ions, as well as the excitatory neurotransmitter glutamate. In this review, we will discuss how these pathobiochemical markers and mechanisms, alone or in combination, lead to neuronal, axonal, and glial cell death and ultimately to the process of neuroinflammation and neurodegeneration, and then discuss the concepts and conclusions that emerge from these findings. Understanding the role of these pathobiochemical markers would be important to gain a better insight into the relationship between the clinical classification and the pathomechanism of MS.
... More specifically, it is characterized by inflammation and demyelination, resulting in the formation of focal areas of myelin loss in the white matter of the brain, called plaques or lesions [1]. Different histological patterns of plaques have been identified [2], but it is commonly believed that the onset of any typical new lesion is characterized by the same pathological changes [3]. ...
In this paper, we study a modification of the mathematical model describing inflammation and demyelination patterns in the brain caused by Multiple Sclerosis proposed in Lombardo et al. (J Math Biol 75:373–417, 2017). In particular, we hypothesize a minimal amount of macrophages to be able to start and sustain the inflammatory response. Thus, the model function for macrophage activation includes an Allee effect. We investigate the emergence of Turing patterns by combining linearised and weakly nonlinear analysis, bifurcation diagrams and numerical simulations, focusing on the comparison with the previous model.
... Evidence reveals that microglia influence both demyelination and remyelination processes in MS [30]. In early RRMS, microglia are present in acute MS lesions along with the B cells, macrophages, and T cells [31,32]. ...
Multiple sclerosis (MS) is a persistent inflammatory disease affecting the central nervous system. Bruton's tyrosine kinase (BTK) is an enzyme crucial in the communication process of B cells, which have a significant impact on the development of MS. Recently, BTK inhibitors have emerged as a promising treatment strategy for MS due to their ability to modulate the immune system. In this study, an extensive literature search was performed utilizing multiple databases, such as PubMed, Embase, and Scopus to examine the potential use of BTK inhibitors in managing cognitive disorders experienced by individuals with MS. We found that BTK inhibitors targeting microglia offer potential advantages for managing neurodegeneration associated with cognitive impairments in MS patients by slowing down degeneration processes effectively. Their ability to impact microglial function and penetrate the CNS positions them as promising candidates for improving cognitive function. This study suggests that BTK inhibitors provide new possibilities for managing inflammatory and neurodegenerative phases of MS through their effects on microglia activation pathways. Further research and clinical trials are necessary to fully explore their efficacy in treating MS while addressing barriers related to cognitive impairment.
... The aim is to provide data that can help to conduct specific rehabilitation programs, considering the heterogeneity of the demyelinating lesions and their different and unique patterns in each patient. [23] ...
Background:
Multiple sclerosis (MS) is a progressive and neurodegenerative disease of the central nervous system. Its symptoms vary greatly, which makes its diagnosis complex, expensive, and time-consuming. One of its most prevalent symptoms is muscle fatigue. It occurs in about 92% of patients with MS (PwMS) and is defined as a decrease in maximal strength or energy production in response to contractile activity. This article aims to compare the behavior of a healthy control (HC) with that of a patient with MS before and after muscle fatigue.
Methods:
For this purpose, a static baropodometric test and a dynamic electromyographic analysis are performed to calculate the area of the stabilometric ellipse, the remitting MS (RMS) value, and the sample entropy (SampEn) of the signals, as a proof of concept to explore the feasibility of this test in the muscle fatigue quantitative analysis; in addition, the statistical analysis was realized to verify the results.
Results:
According to the results, the ellipse area increased in the presence of muscle fatigue, indicating a decrease in postural stability. Likewise, the RMS value increased in the MS patient and decreased in the HC subject and the opposite behavior in the SampEn was observed in the presence of muscle fatigue.
Conclusion:
Thus, this study demonstrates that SampEn is a viable parameter to estimate muscle fatigue in PwMS and other neuromuscular diseases.
... Thus, the disease is characterized by the migration of activated antigen-specific T and B cells into the nervous system, local reactivation by antigen-presenting cells, activation of local glial and microglial cells, secretion of chemokines, cytokines, and specific inflammatory mediators, such as complement and nitric oxide (NO), and possibly lead to demyelination of neuronal axons. 3 Myelin antigens, including myelin basic protein (MBP), proteolipid protein (PLP), and/or spinal cord homogenate can induce EAE with H2R, S, or B gene in susceptible mouse strains. A highly immunogenic myelin protein is myelin oligodendrocyte glycoprotein (MOG), which can cause chronic EAE in susceptible animals by eliciting humoral and cellular immune responses. ...
Experimental autoimmune encephalomyelitis (EAE) is a mouse model that can be used to investigate aetiology, pathogenesis, and treatment approaches for multiple sclerosis (MS). A novel integrated bioinformatics approach was used to understand the involvement of differentially expressed genes (DEGs) in the spleen of EAE mice through data mining of existing microarray and RNA-seq datasets. We screened differentially expressed mRNAs using mRNA expression profile data of EAE spleens taken from Gene Expression Omnibus (GEO). Functional and pathway enrichment analyses of DEGs were performed by Database for Annotation, Visualization, and Integrated Discovery (DAVID). Subsequently, the DEGs-encoded protein-protein interaction (PPI) network was constructed. The 784 DEGs in GSE99300 A.SW PP-EAE mice spleen mRNA profiles, 859 DEGs in GSE151701 EAE mice spleen mRNA profiles, and 646 DEGs in GSE99300 SJL/J PP-EAE mice spleen mRNA profiles were explored. Functional enrichment of 55 common DEGs among 3 sub-datasets revealed several immune-related terms, such as neutrophil extravasation, leucocyte migration, antimicrobial humoral immune response mediated by an antimicrobial peptide, toll-like receptor 4 bindings, IL-17 signalling pathway, and TGF-beta signalling pathway. In the screening of 10 hub genes, including MPO, ELANE, CTSG, LTF, LCN2, SELP, CAMP, S100A9, ITGA2B, and PRTN3, and in choosing and validating the 5 DEGs, including ANK1, MBOAT2, SLC25A21, SLC43A1, and SOX6, the results showed that SLC43A1 and SOX6 were significantly decreased in EAE mice spleen. Thus this study offers a list of genes expressed in the spleen that might play a key role in the pathogenesis of EAE.
... Multiple sclerosis, a chronic inflammatory disease, is characterized by the attack of immune cells towards myelin sheath leading to remitting-relapsing demyelination and axon loss in central nervous system [19]. Gliomas, the most common form of aggressive brain malignancies exhibit many hallmarks of NDs, including altered vasculature, seizures, and excitotoxicity, often caused by genetic mutation. ...
Despite ongoing advancements in research, the inability of therapeutics to cross the blood–brain barrier (BBB) makes the treatment of neurological disorders (NDs) a challenging task, offering only partial symptomatic relief. Various adverse effects associated with existing approaches are another significant barrier that prompts the usage of structurally diverse phytochemicals as preventive/therapeutic lead against NDs in preclinical and clinical settings. Despite numerous beneficial properties, phytochemicals suffer from poor pharmacokinetic profile which limits their pharmacological activity and necessitates the utility of nanotechnology for efficient drug delivery. Nanocarriers have been shown to be proficient carriers that can enhance drug delivery, bioavailability, biocompatibility, and stability of phytochemicals. We, thus, conducted a meticulous literature survey using several electronic databases to gather relevant studies in order to provide a comprehensive summary about the use of nanocarriers in delivering phytochemicals as a treatment approach for NDs. Additionally, the review highlights the mechanisms of drug transport of nanocarriers across the BBB and explores their potential future applications in this emerging field.
... The incidence of MS has been estimated 2 million people worldwide, and 20 per 100,000 in the Asia Pacific region, with women being at higher risk than men (3:1). Several symptoms may appear during the disease progression such as ataxia, dysarthria, fatigue, spasticity, pain, seizure, and cognitive dysfunction (Barnett and Prineas, 2004;Lucchinetti et al., 2000). The most common symptoms of oro-facial include facial palsy (Bell's palsy), trigeminal neuralgia, and sensory neuropathy. ...
Introduction: Multiple sclerosis (MS) is an autoimmune disease, which is characterized by multifocal demyelination of axons in the CNS. Complications due to the disease, as well as the use of immunosuppressive drugs, antidepressants, etc., lead to some abnormalities. These drugs predispose to oral bleeding and are particularly susceptible to infection. The main side effects of drugs in the oral cavity are stomatitis, ulcers, gingivitis, candidiasis, and some opportunistic infections (such as herpes simplex). Dentists should also be aware of the importance of the disease in the diagnosis, treatment, and prognosis of some lesions as well as its specific conditions. Hence, in this study, the histopathological changes of the oral mucosa and salivary glands were studied on C57BL/6 demyelination mice (multiple sclerosis model).
... Some studies have demonstrated a signal increase in diffusion-weighted imaging (DWI) associated with a reduction of the apparent diffusion coefficient (ADC) values in the very early phase of acute MS lesions [70][71][72][73]. The possible mechanisms of reduced diffusivity include infiltration of inflammatory cells as well as cytotoxic cell swelling and disturbances of energy metabolism, leading to reduced extracellular space [70,72,[74][75][76][77]. The reduced ADC signal is transient and may appear not only in the early development stage of demyelinating lesions, but also before the stage of enhancement, and normalizes before the disappearance of enhancement [70,73,74,76,78]. ...
Objectives:
To evaluate compliance with the available recommendations, we assessed the current clinical practice of imaging in the evaluation of multiple sclerosis (MS).
Methods:
An online questionnaire was emailed to all members and affiliates. Information was gathered on applied MR imaging protocols, gadolinium-based contrast agents (GBCA) use and image analysis. We compared the survey results with the Magnetic Resonance Imaging in MS (MAGNIMS) recommendations considered as the reference standard.
Results:
A total of 428 entries were received from 44 countries. Of these, 82% of responders were neuroradiologists. 55% performed more than ten scans per week for MS imaging. The systematic use of 3 T is rare (18%). Over 90% follow specific protocol recommendations with 3D FLAIR, T2-weighted and DWI being the most frequently used sequences. Over 50% use SWI at initial diagnosis and 3D gradient-echo T1-weighted imaging is the most used MRI sequence for pre- and post-contrast imaging. Mismatches with recommendations were identified including the use of only one sagittal T2-weighted sequence for spinal cord imaging, the systematic use of GBCA at follow-up (over 30% of institutions), a delay time shorter than 5 min after GBCA administration (25%) and an inadequate follow-up duration in pediatric acute disseminated encephalomyelitis (80%). There is scarce use of automated software to compare images or to assess atrophy (13% and 7%). The proportions do not differ significantly between academic and non-academic institutions.
Conclusions:
While current practice in MS imaging is rather homogeneous across Europe, our survey suggests that recommendations are only partially followed.
Clinical relevance statement:
Hurdles were identified, mainly in the areas of GBCA use, spinal cord imaging, underuse of specific MRI sequences and monitoring strategies. This work will help radiologists to identify the mismatches between their own practices and the recommendations and act upon them.
Key points:
• While current practice in MS imaging is rather homogeneous across Europe, our survey suggests that available recommendations are only partially followed. • Several hurdles have been identified through the survey that mainly lies in the areas of GBCA use, spinal cord imaging, underuse of specific MRI sequences and monitoring strategies.
... MS develops in genetically predisposed individuals as a result of a combination of environmental factors, viral or bacterial pathogens, cytokines secreted in inflammatory and autoimmune response, and other yet unidentified etiological agents. Various lesions can be seen in patients with MS, such as CNS inflammatory infiltrates, astrogliosis, demyelination, and early axonal damage [70][71][72]. ...
Chlamydia infections are common infections that are transmitted through sexual C. pneumonia is a pathogen that causes different acute and chronic infections. Due to the increase in biological knowledge and the use of more sensitive and specific techniques in the detection of the pathogen in recent years, it is thought that C. pneumonia has a role in various cardiovascular and central nervous system (CNS) diseases. There is increasing evidence that C. pneumonia may have a role in various chronic neurologic diseases, especially Alzheimer’s disease (AD) and multiple sclerosis (MS). C. pneumonia crosses the blood-brain barrier via monocytes and triggers neuroinflammation in the central nervous system. Various diagnostic methods (molecular, histopathologic, and culture) have shown the presence of C. pneumonia in patients with late-onset AD dementia. It is thought that C. pneumonia may be a cofactor in the development of MS disease by causing chronic permanent brain infection in MS patients. There are also reports of C. pneumonia causing other CNS diseases such as Guillaine Barre syndrome, encephalitis/meningoencephalitis, and cerebellar ataxia. In this section, the relationship between Chlamydia infections and neurological diseases will be discussed based on scientific research.
... Over 20 times more immunoglobulin G (IgG) can be extracted from MS plaques than those from the control brain [10]. The common features of acute demyelinating plaques are marked deposition of IgG and activated complement [11][12][13] which are consistently present in active lesions and cortical grey matter lesions [14,15]. Demyelination and axonal damage occur in the presence of antibodies and require activation of the entire complement cascade [3]. ...
Grey matter pathology is central to the progression of multiple sclerosis (MS). We discovered that MS plasma immunoglobulin G (IgG) antibodies, mainly IgG1, form large aggregates (>100 nm) which are retained in the flow-through after binding to Protein A. Utilizing an annexin V live-cell apoptosis detection assay, we demonstrated six times higher levels of neuronal apoptosis induced by MS plasma IgG aggregates (n = 190, from two cohorts) compared to other neurological disorders (n = 116) and healthy donors (n = 44). MS IgG aggregate-mediated, complement-dependent neuronal apoptosis was evaluated in multiple model systems including primary human neurons, primary human astrocytes, neuroblastoma SH-SY5Y cells, and newborn mouse brain slices. Immunocytochemistry revealed the co-deposition of IgG, early and late complement activation products (C1q, C3b, and membrane attack complex C5b9), as well as active caspase 3 in treated neuronal cells. Furthermore, we found that MS plasma cytotoxic antibodies are not present in Protein G flow-through, nor in the paired plasma. The neuronal apoptosis can be inhibited by IgG depletion, disruption of IgG aggregates, pan-caspase inhibitor, and is completely abolished by digestion with IgG-cleaving enzyme IdeS. Transmission electron microscopy and nanoparticle tracking analysis revealed the sizes of MS IgG aggregates are greater than 100 nm. Our data support the pathological role of MS IgG antibodies and corroborate their connection to complement activation and axonal damage, suggesting that apoptosis may be a mechanism of neurodegeneration in MS.
... More specifically, it is characterized by inflammation and demyelination, resulting in the formation of focal areas of myelin loss in the white matter of the brain, called plaques or lesions [20]. Different histological patterns of plaques have been identified [22], but it is commonly believed that the onset of any typical new lesion is characterized by the same pathological changes [2]. Some mathematical models able to reproduce many of the typical pathological features of Multiple Sclerosis have been proposed and investigated; they are usually constituted by proper systems of PDEs [16,10,3,21], but also systems of ODEs [14] or stochastic models [6] are able to describe the relapse-remittance dynamics in patients affected by Multiple Sclerosis. ...
In this paper, we study a modification of the mathematical model describing inflammation and demyelination patterns in the brain caused by Multiple Sclerosis proposed in [Lombardo et al. (2017), Journal of Mathematical Biology, 75, 373--417]. In particular, we hypothesize a minimal amount of macrophages to be able to start and sustain the inflammatory response. Thus, the model function for macrophage activation includes an Allee effect. We investigate the emergence of Turing patterns by combining linearised and weakly nonlinear analysis, bifurcation diagrams and numerical simulations, focusing on the comparison with the previous model.
... The pathology of not only advanced but also most of early MS biopsies and autopsies are characterized by IgG and complement deposition, identified as pattern II lesions. 54,55 Supporting the participation of antibodies, MS patients with a pattern II pathology show favourable clinical outcomes upon therapeutic plasma exchange. 56,57 Furthermore, antibodies in pattern II patients were found to have an increased reactivity to Nogo-A peptides, which are present on neurons and oligodendrocytes. ...
Background
Although distinct brain-homing B cells have been identified in multiple sclerosis (MS), it is unknown how these further evolve to contribute to local pathology. We explored B-cell maturation in the central nervous system (CNS) of MS patients and determined their association with immunoglobulin (Ig) production, T-cell presence, and lesion formation.
Methods
Ex vivo flow cytometry was performed on post-mortem blood, cerebrospinal fluid (CSF), meninges and white matter from 28 MS and 10 control brain donors to characterize B cells and antibody-secreting cells (ASCs). MS brain tissue sections were analysed with immunostainings and microarrays. IgG index and CSF oligoclonal bands were measured with nephelometry, isoelectric focusing, and immunoblotting. Blood-derived B cells were cocultured under T follicular helper-like conditions to evaluate their ASC-differentiating capacity in vitro.
Findings
ASC versus B-cell ratios were increased in post-mortem CNS compartments of MS but not control donors. Local presence of ASCs associated with a mature CD45low phenotype, focal MS lesional activity, lesional Ig gene expression, and CSF IgG levels as well as clonality. In vitro B-cell maturation into ASCs did not differ between MS and control donors. Notably, lesional CD4+ memory T cells positively correlated with ASC presence, reflected by local interplay with T cells.
Interpretation
These findings provide evidence that local B cells at least in late-stage MS preferentially mature into ASCs, which are largely responsible for intrathecal and local Ig production. This is especially seen in active MS white matter lesions and likely depends on the interaction with CD4+ memory T cells.
Funding
Stichting MS Research (19-1057 MS; 20-490f MS), National MS Fonds (OZ2018-003).
... anti-CD20 therapy | ocrelizumab | CD20-expressing T cells | CD20 dim T cells | CD20 dim CD8 + T cells While anti-CD20 (aCD20) therapy has proven highly successful in the treatment of multiple sclerosis (MS) and is approved for use in patients with both relapsing-remitting MS (RRMS) and primary progressive MS (PPMS) (1)(2)(3)(4)(5)(6)(7)(8), concepts surrounding its therapeutic mode of action in MS have continued to evolve. The original studies of aCD20 in patients with MS were pursued with the view that depletion of CD20-expressing B cells may be beneficial given the long-standing recognition of abnormally elevated cerebrospinal fluid (CSF) immunoglobulins and demonstration of antibodies bound to myelin within phagocytic cells of MS lesions, as well as the presence of oligoclonal bands and the clonal persistence of intrathecal B cells (9,10). However, studies showing no major treatment effects of aCD20 on the abnormal CSF antibody profiles of patients (11)(12)(13) at the same time that they benefit from much-reduced new disease activity, shifted attention to antibody-independent contributions of B cells to the development of new MS relapses. ...
A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20 dim CD8 ⁺ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20 dim CD8 ⁺ T cells had a greater contribution to treatment-associated changes in the CD8 ⁺ T cell pool than was the case for CD4 ⁺ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20 dim CD8 ⁺ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19 ⁺ CD24 high CD38 high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20 dim CD8 ⁺ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8 ⁺ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.
Written by a neurologist with 20 years of experience working in a general hospital, this engaging and informative book brings together 55 example cases from a general hospital setting with differential diagnoses. The case report format facilitates up to date management including modern neuroimaging, but also allows the reader to consider the potential diagnoses before turning the page to determine the correct diagnosis and treatment. The history, epidemiology as well as diagnostic criteria and management of specific neurological disorders are provided in an accompanying comment section. Unusual for a book of neurology, patients have had an opportunity to explain how neurological illness impacted their physical, psychological and social activities (provided by a relative/carer when the patient could not contribute). The themes provide a personal and truthful testament of the immediate and longer-term real-life impact of neurological illness, giving readers an insight into the effects of neurological diagnoses on their patients.
Clusters of ramified HLA-DR + cells, known as microglia nodules, are associated with brain pathology. Here we investigated if microglia nodules in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) are different from microglia nodules in white matter (WM) in stroke and whether they may relate to the start of demyelinating MS lesions. We studied the relation between microglia nodules and pathological severity in an MS autopsy cohort (n=167), and we compared frequency, size, and gene expression of microglia nodules in MS (n=7) and stroke (n=7). MS donors with microglia nodules (64%) had a higher lesion load and a higher proportion of active lesions compared to donors without microglia nodules (36%). We found altered expression of genes in microglia nodules in MS compared to stroke, including genes previously shown to be upregulated in MS lesions. Genes associated with lipid metabolism, presence and proliferation of T and B cells, production of and response to immunoglobulins and cytokines (specifically TNF and IFN), activation of the complement cascade, and metabolic stress were upregulated. Using immunohistochemistry, we confirmed that in MS, more than in stroke, microglia nodules are associated with membrane attack complexes, have phagocytosed oxidized phospholipids, and have a tubular mitochondrial network reflecting increased metabolic activity. Furthermore, in MS, some nodules encapsulated partially demyelinated axons. Taken together, we propose that activation of some microglia nodules in MS by pro-inflammatory cytokines and immunoglobulins in combination with phagocytosis of oxidized phospholipids may lead to a volatile phenotype prone to form MS lesions. 3
Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is challenging. Using experimental autoimmune encephalomyelitis (EAE) in common marmosets, a model of MS that recapitulates focal cerebral inflammatory demyelinating lesions, we investigated whether MRI is sensitive to, and can characterize, remyelination. In 6 animals followed with multisequence 7-tesla MRI, 31 focal lesions, predicted to be demyelinated or remyelinated based on signal intensity on proton density-weighted images, were subsequently assessed with histopathology. Remyelination occurred in 4 of 6 marmosets and 45% of lesions. Radiological-pathological comparison showed that MRI had high statistical sensitivity (100%) and specificity (90%) for detecting remyelination. This study demonstrates the prevalence of spontaneous remyelination in marmoset EAE and the ability of in vivo MRI to detect it, with implications for preclinical testing of pro-remyelinating agents.
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Multiple Sclerosis (MS) is the most common demyelinating disease with inflammatory demyelination in central nerve system (CNS). Beside the defect in myelin repair process, the balance change in inflammatory and anti- inflammatory cytokines is one of the most significant factors in MS pathogenesis. This study aimed at evaluating the effects of co-overexpressing beta interferon (IFN-β) and Leukemia inhibitory factor (LIF) in human adipose derived stem cells (IFN-β/LIF-hADSCs) on the experimental autoimmune encephalomyelitis (EAE).
12 days after the induction of EAE on female mice C57Bl/6 with MOG35-55 and the emergence of primary clinical signs, the IFN-β/LIF-hADSCs were injected though the mice tail vein of the EAE mice. The mice were sacrificed after 32 days and the spinal cords of the experimental groups were dissected out for the histopathologic and real time RT-PCR studies.
Here, we showed that the clinical scores and infiltration of mononuclear cells of treated mice with IFN-β/LIF-hADSCs were decreased significantly. Remyelination and oligodendrogenesis were significantly increased in the test (IFN-β/LIF-hADSCs) group. The findings revealed that the pattern of inflammatory and anti- inflammatory cytokines gene expression in the IFN-β/LIF-hADSCs group was reversed comparing to control group.
Overexpression of LIF as a neurotrophic and IFN-β as an anti-inflammatory cytokine in hADSCs increases the immunomodulatory effect of hADSCs and improves remyelination and oligodendrogenesis in EAE model. This, besides hADSCs capacity for proliferation and differentiation might enhance the treatment efficacy and provide a promising candidate for stem cell-based gene therapy of MS therapy in future.
A method for in situ hybridization of digoxigenin-labeled cDNA and cRNA probes to myelin protein mRNA is described. This technique has dual advantages of high structural resolution and high sensitivity and avoids problems associated with handling of radioactive materials. Furthermore, it can be readily combined in double labeling with immunocytochemical protein detection. We have used this technique to detect and locate mRNA for myelin basic protein (MBP), proteolipid protein (PLP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and myelin-associated glycoprotein (MAG) in oligodendrocytes of 7-day-old and adult rat brains. PLP and MAG mRNA were restricted to the perinuclear cytoplasm, whereas MBP and CNPase mRNA was additionally present in peripheral oligodendrocyte processes.
Multiple sclerosis (MS) brain tissue, spleen, and PBMC were studied using immunocytochemistry and FACS for immunoreactivity for lymphotoxin (LT) and TNF. Both cytokines were identified in acute and chronic active MS lesions but were absent from chronic silent lesions. LT was associated with CD3+ lymphocytes and Leu-M5+ microglia cells at the lesion edge and to a lesser extent, in adjacent white matter. TNF was associated with astrocytes in all areas of the lesion, and with foamy macrophages in the center of the active lesion. In acute lesions, immunoreactivity for TNF in endothelial cells was noted at the lesion edge. No LT or TNF reactivity was detected in Alzheimer's or Parkinson's disease brain tissues but was present at lower levels in central nervous system (CNS) tissue from other inflammatory conditions, except for adrenoleucodystrophy which displayed high levels of LT in microglia. No increase in LT and TNF reactivity was detected in spleen and PBMC of MS patients suggesting specific reactivity within the CNS. These results indicate that LT and TNF may be involved in the immunopathogenesis of MS, and can be detected in both inflammatory cells and cells endogenous to the CNS.
In this study the authors have developed a model with which can be studied directly the influence of circulating anti-myelin antibody on the clinical and pathologic course of inflammatory T-cell-mediated experimental allergic encephalomyelitis (EAE) in the rat. EAE was induced by passive transfer of either myelin basic protein (MBP)-activated spleen cells derived from sensitized donors or long-term-cultured MBP-specific T-cell lines. At the onset of the disease, monoclonal antibodies against a myelin/oligodendrocyte glycoprotein (MOG) were injected intravenously. This antigen is exposed on the surface of central nervous system myelin and oligodendrocytes. Intravenous injection of the antibody in the course of T-cell-mediated transfer EAE augmented the severity and duration of clinical signs and resulted in the formation of large, confluent demyelinated plaques.
Frozen brain specimens from patients with multiple sclerosis (MS) and other neurologic diseases were analyzed using immunocytochemical techniques for the presence of TNF. In brain lesions in MS, and subacute sclerosing panencephalitis, TNF+ cells were demonstrated. At the lesion site in MS, TNF+ staining is associated with both astrocytes and macrophages. These observations were not made in Alzheimer's disease or normal brain tissue. The presence of TNF in MS lesions suggests a significant role for cytokines and the immune response in disease progression.
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Tissues from 13 exceptionally early cases of multiple sclerosis were studied to identify and characterize the primary demyelinating lesion, using a variety of histological and immunocytochemical methods. Multifactorial cluster analysis identified five significantly distinct lesion groups, which showed histological progression from simple microglial lesions, predominating in tissues from the earliest cases, to complex hypercellular fully demyelinated plaques, chiefly associated with cases of intermediate duration. Quiescent lesions showing evidence of remyelination were found at all stages of the disease studied, but hypocellular inactive plaques, were associated with older cases. Evidence is presented that initial demyelination is effected by activated resident microglia. Undegraded myelin is initially enveloped by membranes bearing fixed complexes of immunoglobulin and complement. In contrast with perivenous encephalomyelitis, in which demyelination was dominated by T-cell infiltration, multiple sclerosis lesions of comparable duration and maturity exhibited humoral immune reactions. Parenchymal CD4+ T-cell infiltration developed in association with subsequent plaque maturation. These results emphasize the need for lesion staging when multiple sclerosis tissues are being used in the investigation of pathogenic mechanisms, and suggest that further analysis of the oligoclonal B-cell response may be productive in the search for primary provoking antigens.
Multiple sclerosis is a chronic inflammatory disease characterized by perivenous inflammation and focal destruction of myelin. Many attempts have been undertaken previously to create animal models of chronic inflammatory demyelinating diseases through autoimmunity or virus infection. Recently, however, a new model of myelin oligodendrocyte glycoprotein (MOG) induced autoimmune encephalomyelitis became available, which, in a very standardized and predictable way, leads to chronic (relapsing or progressive) disease and widespread CNS demyelination.
In the present study we actively induced MOG‐experimental autoimmune encephalomyelitis (EAE) in different inbred rat strains using different immunization protocols. The pathology found in our models closely reflects the spectrum of multiple sclerosis (MS) pathology: Classical MS as well as variants such as optic neuritis, Devic's disease and Marburg's type of acute MS are mimicked in rats immunized with MOG antigen. Furthermore we demonstrate, that by using the proper strain/sensitization regime, subforms of MS such as for instance neuromyelitis optica can be reproducibly induced. Our study further supports the notion, that incidence and expression of the disease in this model, alike the situation in multiple sclerosis, is determined by genetic and environmental factors.
It is generally believed that most T2-weighted (T2) lesions in the central white matter of patients with multiple sclerosis begin with a variable period of T1-weighted (T1) gadolinium (Gd) enhancement and that T1 Gd-enhancing and T2 lesions represent stages of a single pathological process. Lesion probability maps can be used to test this hypothesis by providing a quantitative description of the spatial distribution of these two types of lesions across a patient population. The simplest prediction of this hypothesis would be that the spatial distributions of T1 Gd-enhancing and T2 lesions are identical. We generated T1 Gd-enhancing and T2 lesion probability maps from 19 patients with relapsing-remitting multiple sclerosis. There was a significantly higher probability (P = 0.001) for T2 lesions to be found in the central relative to the peripheral white matter (risk ratio 4.5), although the relative distribution of T1 Gd-enhancing lesions was not significantly different (P = 0.7) between central and peripheral white matter regions (risk ratio 0.6). Longitudinal data on the same population were used to demonstrate a similar distribution asymmetry between new T1 Gd-enhancing and new T2 lesions that developed over the course of 1 year. Alternative hypotheses to explain this observation were tested. We found no spatial difference in the likelihood of development of persistent T2 lesions following T1 Gd enhancement. The relative distribution of T1 Gd-enhancing lesions was shown to be independent of the dose of Gd contrast agent and the frequency of scanning. Our findings suggest that a proportion of the periventricular T2 lesion volume may arise from mechanisms other than those associated with early breakdown of the blood-brain barrier leading to T1 Gd enhancement.
Since 1955, this landmark masterwork has been revered for its authoritative presentation of the entire state of scientific and clinical knowledge about multiple sclerosis. The state-of-the-art 4th Edition presents the most recent information on the genetics and epidemiology, clinical neurology, pathogenesis, and management of this common neurological disease. Amply illustrated and referenced and beautifully written, McAlpines Multiple Sclerosis has been described as "A standard reference for multiple sclerosis researchers, embryonic 'MS-ologists' and hard-pressed clinical neurologists alike" (Brain, review of the last edition). Reviews the earliest clinical and pathological descriptions of multiple sclerosis. Offers a very strong section on pathogenesis. Includes more than 550 high-quality illustrations clarifying important scientific and clinical concepts. Uses a remarkably clear presentation to make complicated data as easy as possible to understand. Presents the most recent information on genetics and epidemiology, with an emphasis on clinical relevance. Covers all of the latest approaches to diagnosis and management. Offers new chapters on treatment of the acute relapse, treatment of symptoms, and disease-modifying treatments. Includes contributions from four new world-renowned authors to reflect more international perspectives. Features a new, more user-friendly page design for enhanced ease of reference.
Nitric oxide (NO) generated by the inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study mice genetically deficient for iNOS are shown to be susceptible to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG). In iNOS (–/–) mice the course of disease was earlier in onset and more aggressive compared to control animals. A disease-relevant compensatory up-regulation of neuronal (n)NOS and endothelial (e)NOS with increased production of NO in iNOS (–/–) mice is excluded by 1) the failure to detect increased nNOS and eNOS mRNA, 2) the absence of detection of nitrosylated tyrosine residues in EAE tissue indicating absence of NO-derived peroxynitrite, and 3) the lack of disease-preventing effects of NG-nitro-L-arginine methylester. In conclusion, these results do not support the hypothesis that NO is crucial for the development of EAE.
A new monoclonal antibody Ki-M1P that is raised against supernatants of detergent solubilized human lymph node tissue is described. Ki-M1P recognizes in particular monocytes and their macrophage derivatives as tested by light- and electron-microscopic immunohistochemistry. Granulocytes, dendritic cells as the accessory cells of humoral and cellular immune response, and epithelial, endothelial, neural, and mesenchymal cells do not react with Ki-M1P. In extensive application Ki-M1P has proven to be a useful marker for distinguishing monocytic leukemias within FAB groups M4 and M5. The recognized antigen is composed of five proteins with molecular masses of about 60, 92, 98, 124, and 150 kDa in blood monocytes, whereas tissue macrophages tested so far expressed only the 60-kDa protein. Because the Ki-M1P antigen is not destroyed or masked during routine fixation and paraffin embedding of biopsy tissue samples, Ki-M1P represents a useful diagnostic reagent for the identification of physiological functional and pathologic reaction forms as well as neoplastic variants of the human monocyte/macrophage system even in retrospective studies.
The myelin/oligodendrocyte glycoprotein (MOG) is identified by monoclonal antibody 8-18C5. MOG is localized on the surface of myelin and oligodendrocyte processes. Recently, several studies have shown that MOG plays an important role as a target for antibody-induced demyelination. In the present study, we investigated MOG expression in the brains of normal and myelin-deficient (mld) mutant mice during development. By gel electrophoresis and immunoblotting, we observed the developmental pattern of two closely migrating bands, with apparent molecular masses of 26 and 28 kilodaltons. Their concentrations increased coordinately during the most active phase of myelin and myelin basic protein (MBP) synthesis. Between 20 and 25 days of age, the MOG developmental pattern superimposed that of MBP as well as myelin yields. In mld mutant mice, which are affected by a severe deficit of MBP synthesis, MOG was present at reduced levels (40% of controls at 60 days of age). At 85 days of age, mld mice exhibited increased concentrations of MBP, and myelin was better compacted. At this age, MOG concentrations increased and reached 70% of controls. These results suggest that MOG could play a role in the maintenance or completion of the myelin sheath. Its expression level may be modulated by the presence of compact myelin and/or MBP in the myelin sheath.
The loss of myelin-associated glycoprotein (MAG) and myelin basic protein (MBP) was compared by quantitative immunocytochemistry in demyelinating lesions of measles encephalomyelitis (ME), multiple sclerosis (MS), and progressive multifocal leukoencephalopathy (PML). Serial sections from paraffin-embedded tissue were reacted with antisera for MAG and MBP, and areas of staining loss were compared morphometrically. Lesions in ME showed MAG loss equal to that of MBP, lesions of PML showed MAG loss greater than that of MBP, and MS lesions showed a mixture of patterns. These data demonstrate distinctive patterns of MAG and MBP loss in these three diseases.
A panel of mouse monoclonal antibodies to rat and human myelin-associated glycoprotein (MAG) was developed. Normal mice were unresponsive to rat MAG, and successful immunization with rat MAG was only achieved in autoimmune NZB mice. By contrast, all strains of mice were responsive to human MAG. The monoclonal antibodies developed differ with respect to immunoglobulin type, their specificity for human and/or rat MAG, and their recognition of protein or carbohydrate epitopes in MAG. In general, the antibodies that react with the protein backbone recognize both rat and human MAG, whereas a large number of the monoclonal antibodies recognize a carbohydrate determinant in human MAG that is not in rat MAG. Immunocytochemical staining of adult human spinal cord with the monoclonal antibodies resulted in periaxonal staining of myelin sheaths similar to that produced by well-defined, rabbit, polyclonal anti-MAG serum. In addition, the antibodies recognizing carbohydrate determinants in human MAG strongly stained oligodendrocyte cytoplasm. These monoclonal antibodies will be of value for the further chemical and biological characterization of MAG.
Ia antigen, encoded within the major histocompatibility complex, plays an important role in the activation of T lymphocytes. Since experimental allergic encephalitis is an essentially T cell-mediated disease, Ia antigen in the central nervous system (CNS) may be pathogenetically relevant. The occurrence of Ia antigen in the CNS of normal rats and of rats with experimental allergic encephalitis was studied by light and electron microscope immunocytochemistry using the monoclonal anti-Ia antibodies Ox 4 and Ox 6. In normal, unsensitized animals a district population of stellate cells in the meninges and some perivascular mononuclear cells in the nervous tissue carried Ia antigen. In rats with experimental allergic encephalitis a dramatic increase of Ia-positive cells was found. In addition to the positive cells found in normal animals, monocytes, macrophages and many lymphocytes in the meningeal perivascular and parenchymal inflammatory infiltrates as well as "activated microglia" stained for Ia antigen. We did not find evidence for Ia expression on endothelial cells, astrocytes or other components of the CNS in either normal or diseased rats.
Demyelination was produced in mice by intracerebral inoculation of Theiler's murine encephalomyelitis virus. The earliest ultrastructural changes occurred in the inner cytoplasmic tongues of oligodendrocytes, the most distal extension of these cells. Viral antigen was localized to glial loops that connect with myelin lamellae. This study indicates that a "dying-back" process may occur in virus-infected oligodendrocytes, which then results in demyelination.
To study the distribution of myelin-associated glycoprotein (MAG) in human nervous tissue and in multiple sclerosis (MS) lesions, we used paraffin sections and our modification of the peroxidase-antiperoxidase technique. Sections of MS lesions also were treated with antiserum to basic protein (BP) and with histological stains for axons and myelin sheaths. In tissue from normal developing central nervous system, oligodendroglia, their processes, and wwly formed myelin sheaths were intensely stained by MAG antiserum. In adults, MAG was found in periaxonal regions of myelinated fibers of the central and peripheral nervous system. The most striking finding in MS lesions was the extension of decreased MAG immunostaining into white matter that appeared normal when treated with BP antiserum or luxol fast blue. In acute early MS lesions the decrease in MAG immunostaining extended far beyond the margin of acute demyelination, where the BP staining of degenerating sheaths often was increased. In chronic inactive plaques, this decrease in periaxonal MAG immunostaining was limited to relatively few fibers in a thin rim around each lesion. These observations suggest that in MS, immunoreactivity of periaxonal MAG is altered before myelin breakdown begins. Early in degeneration, myelin sheaths and their fragments often were more intensely stained by BP antiserum than normal sheaths; later the staining intensity decreased. In shadow plaques, BP antiserum stained some oligodendroglia. Their appearance and location among thinly myelinated axons suggested that these oligondendroglia were forming new sheaths around previously demyelinated axons.
To compare distributions of oligodendroglial myelin-associated glycoprotein (MAG) and myelin basic protein (BP) during demyelination in acute experimental allergic encephalomyelitis (EAE). Lewis rats were sensitized with an emulsion containing guinea pig spinal cord and complete Freund's adjuvant. The rats were examined clinically and groups were perfused with fixative before symptoms appeared (7d), within 48 h of symptom onset (10d) and during more severe illness (14d, 21d). Paraffin sections of cerebrum, brainstem, and spinal cord were immunostained with antisera to MAG and BP. Other sections in each serially mounted series were stained with luxol fast blue, hematoxylin and eosin or with the Bodian method to correlate MAG and BP results with histological changes. No abnormalities were detected 7d after sensitization. After 10d, small perivenular inflammatory cell infiltrates were present in white matter, displaced myelinated fibers, but their MAG stained periaxonal regions and BP-stained myelin sheaths appeared normal. In pontine grey matter lesions, there were focal abnormalities in a few myelin sheaths. After 21d, demyelinating lesions were present that were largest in pontine grey matter. Decreased MAG staining was present in areas of myelin sheath loss. MAG-stained fragments were found in zones of active myelin breakdown but no decrease or other change in MAG staining extended beyond the margins of demyelinating lesions into areas with normally stained myelin sheaths. Thus, in contrast to multiple sclerosis (Itoyama et al. 1980), changes in periaxonal oligodendroglial MAG are not present in acute EAE before inflammatory cell infiltrates or myelin sheath changes appear. Our findings suggest that myelin sheaths are the primary targets in EAE-induced demyelination. Oligodendroglia appear to be relatively unaffected and are available to remyelinate axons.
Active plaques from 4 patients with multiple sclerosis were examined for myelin-associated glycoprotein (MAG) and myelin basic protein (MBP) using the peroxidase-antiperoxidase (PAP) immunocytochemical procedure applied to paraffin sections. MBP loss was intimately related to the presence of infiltrating macrophages which appeared to remove MBP-positive fragments directly off intact myelin sheaths. Phagocytosis of MAG-positive myelin sheaths was also observed. These findings support previous morphological studies that suggest that phagocytosis by macrophages of myelin attached to axons is an important mechanism of demyelination in multiple sclerosis.
Immune staining for the myelin-associated glycoprotein (MAG) by the peroxidase-antiperoxidase technique in vibratome, paraffin and Epon sections of peripheral nerve resulted in a periaxonal ring of immune reaction product and an absence of staining over compact myelin. The thickness of the periaxonal rings of staining in Epon sections were similar when axons were surrounded by single Schwann cell processes and when they were surrounded by compact myelin sheaths. Thicker rings of periaxonal staining were present when axons were surrounded by multiple layers of uncompacted Schwann cell membranes. When swelling of the Schwann cell periaxonal cytoplasm separated the periaxonal Schwann cell membrane from compact myelin by distances that could be readily resolved in the light microscope, immune staining for MAG was found over the periaxonal Schwann cell membrane but not over compact myelin. Biochemical experiments in which myelin or MAG was treated with sodium ethoxide and hydrogen peroxide, under conditions similar to those used for etching Epon sections prior to immune staining, showed that the immune reactivity of MAG was stable to these treatments. Finally, a pre-embedding technique for immune staining at the electron-microscopic level showed MAG reaction product on the cytoplasmic side of Schwann cell periaxonal membranes and the membranes of Schmidt-Lanterman incisures and paranodal loops. These results confirm and strengthen the evidence from previous reports indicating that MAG is confined to periaxonal membranes, Schmidt-Lanterman incisures, paranodal loops, and the outer mesaxon of myelinating Schwann cells and is absent from compact myelin. These results are discussed in reference to a recent report apparently showing the presence of MAG in compact CNS myelin. Based on the data presented and discussed in this paper, it is concluded that MAG is located in specific non-compact regions of central and peripheral myelin sheaths and not in compact myelin lamellae.
Macrophages were examined for immunoglobulin G (IgG) and albumin in actively demyelinating lesions in two patients with multiple sclerosis (MS) using the peroxidase-antiperoxidase immunocytochemical technique. In both cases, macrophages were present that stained for cytoplasmic or surface IgG or both. In one case, in which the tissue was rapidly fixed in chilled fixative, macrophages located among myelinated nerve fibers at plaque margins, but not elsewhere in the plaque, revealed surface IgG in the form of caps restricted to one or both poles of the cell. These caps were absent in sections stained for albumin. Because capping implies the presence of a multivalent ligand close to the cell surface and because cap formation was observed only in macrophages contacting myelin sheaths, we suggest that antimyelin antibody cytophilic for macrophages may be present in the central nervous system in MS, and that immune ligand-mediated phagocytosis may play a role in myelin breakdown in the disease. This study provides the first direct evidence that IgG participates locally in myelin breakdown in MS.
Recurrent demyelination was produced in mice by Cuprizone administration. During the second course of Cuprizone, the animals showed greater resistance to the toxin and demyelination occurred slowly and was complete only after prolonged periods. The earliest changes in oligodendrocytes occurred in the most distal processes, the inner cytoplasmic tongues, which showed degenerative changes 3 to 4 weeks before degeneration of the oligodendrocyte cell bodies or demyelination occurred. The results show for the first time that in demyelinating disease, a "dying-back" process similar to that described in axonal disease can affect the oligodendrocyte.
Monocyte/macrophage differentiation was studied in biopsy samples of multiple sclerosis (MS) lesions obtained in the early course of the disease. Macrophages were identified by immunocytochemistry using a panel of antibodies recognizing different macrophage-activation antigens. The number of cells stained with each antibody was related to the demyelinating activity of the lesions as detected by the presence of myelin degradation products. The pan-macrophage marker Ki-M1P revealed the highest numbers of macrophages in early and late active lesions. Lower numbers were encountered in inactive, demyelinated, or remyelinated lesions. The acute stage inflammatory macrophage markers MRP14 and 27E10 were expressed in either only early active (MRP14) or early and late active (27E10) lesions, thus allowing the identification of actively demyelinating lesions. The chronic stage inflammatory macrophage marker 25F9, in contrast, showed increasing expression with decreasing lesional activity. These findings indicate a differentiated pattern of macrophage activation in MS lesions and allow the staging of demyelinating lesions in routinely fixed and paraffin-embedded tissue.
Patterns of inflammation, demyelination and oligodendrocyte pathology were studied in acute multiple sclerosis and during early and late exacerbations of chronic multiple sclerosis. Cells within lesions were identified by immunocytochemistry with markers for T lymphocytes, macrophages, oligodendrocytes and astrocytes. In addition, in situ hybridization for proteolipid protein mRNA was used to identify myelinating and myelin supporting oligodendrocytes. Degenerating cells in the lesions were detected by DNA fragmentation in cell nuclei. The inflammatory reaction in all three types of multiple sclerosis lesions was shown to be dominated by T lymphocytes and macrophages. In late chronic multiple sclerosis lesions, a significant increase in the number of immunoglobulin producing plasma cells was found in infiltrates as compared with acute and early multiple sclerosis lesions. In all three types of multiple sclerosis, confluent plaques of demyelination were found to be present. In acute multiple sclerosis, demyelination was found to be associated with extensive destruction of other tissue elements, including oligodendrocytes, astrocytes and axons, but even in these destructive lesions a considerable number of oligodendrocytes was preserved and at disposal therefore, for rapid remyelination. During early exacerbations of chronic multiple sclerosis, selective demyelination was associated with almost complete preservation of oligodendrocytes in the majority of cases. Correspondingly, a high number of remyelinating lesions was present at that stage of disease. In lesions developing late after onset of multiple sclerosis, demyelination generally accompanied extensive destruction and loss of oligodendrocytes. In these lesions, remyelination was sparse and restricted to lesional borders. The observed patterns of cell death suggest that in some cases oligodendrocytes, in others myelin sheaths are the primary target of the destructive process. Our data indicate that the type and amount of inflammation, de- and remyelination, and of tissue damage vary between different forms of multiple sclerosis and between different stages of the disease, possibly reflecting different pathogenic mechanisms in a disease spectrum.
Receptors for the Fc part of IgG, FcRI (CD64), FcRII (CD32), and FcRIII (CD16) were studied by indirect immunoperoxidase staining of cryostat sections from normal and multiple sclerosis (MS) brains. Microglia in the parenchyma of normal white matter had a dendritic morphology, and were weakly stained by monoclonal antibodies (mAbs) to FcRI, FcRII, and FcRIII. In active MS lesions reactive microglia were strongly stained by the mAbs 32.2 (FcRI), IV-3 (FcRII), and 3G8 (FcRIII). Perivascular macrophages were stained by all anti-FcR mAbs in both normal white matter and in MS lesions, whereas endothelial cells were stained by the anti-FcRIII mAb only. The FcR on microglia and perivascular macrophages may be of functional importance in antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, and local immunoregulation. FcR on endothelium may be of importance in binding and transportation of immune complexes into the CNS. FcR mediated functions may consequently be highly relevant to the pathogenesis of MS.
Nitric oxide (NO) has been implicated as a pathogenic mediator in a variety of central nervous system (CNS) disease states, including the animal model of multiple sclerosis (MS) and experimental allergic encephalomyelitis. We have examined post-mortem brain tissues collected from patients previously diagnosed with MS, as well as tissues collected from the brains of patients dying without neuropathies. Both Northern blot analysis and reverse transcriptase (RT)-driven in situ PCR (RT-in situ PCR) studies demonstrated that inducible NO synthase (iNOS) mRNA was present in the brain tissues from MS patients but was absent in equivalent tissues from normal controls. We have also performed experiments identifying the cell type responsible for iNOS expression by RT-in situ PCR in combination with immunohistochemistry. Concomitantly, we analyzed the tissues for the presence of the NO reaction product nitrotyrosine to demonstrate the presence of a protein nitrosylation adduct. We report here that iNOS mRNA was detectable in the brains of 100% of the CNS tissues from seven MS patients examined but in none of the three normal brains. RT-in situ PCR experiments also demonstrated the presence of iNOS mRNA in the cytoplasm of cells that also expressed the ligand recognized by the Ricinus communis agglutinin 1 (RCA-1), a monocyte/macrophage lineage marker. Additionally, specific labeling of cells was observed when brain tissues from MS patients were exposed to antisera reactive with nitrotyrosine residues but was significantly less plentiful in brain tissue from patients without CNS disease. These results demonstrate that iNOS, one of the enzymes responsible for the production of NO, is expressed at significant levels in the brains of patients with MS and may contribute to the pathology associated with the disease.
The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.
Multiple sclerosis (MS), an inflammatory autoimmune demyelinating disorder of the central nervous system, is the most common cause of acquired neurological dysfunction arising in the second to fourth decades of life. A genetic component to MS is indicated by an increased relative risk of 20-40 to siblings compared to the general population (lambda s), and an increased concordance rate in monozygotic compared to dizygotic twins. Association and/or linkage studies to candidate genes have produced many reports of significant genetic effects including those for the major histocompatability complex (MHC; particularly the HLA-DR2 allele), immunoglobulin heavy chain (IgH), T-cell receptor (TCR) and myelin basic protein (MBP) loci. With the exception of the MHC, however, these results have been difficult to replicate and/or apply beyond isolated populations. We have therefore conducted a two-stage, multi-analytical genomic screen to identify genomic regions potentially harbouring MS susceptibility genes. We genotyped 443 markers and 19 such regions were identified. These included the MHC region on 6p, the only region with a consistently reported genetic effect. However, no single locus generated overwhelming evidence of linkage. Our results suggest that a multifactorial aetiology, including both environmental and multiple genetic factors of moderate effect, is more likely than an aetiology consisting of simple mendelian disease gene(s).
The population prevalence of multiple sclerosis is 0.1%; however, the risk of the disease in the siblings of affected individuals is very much higher at 3-5%. The importance of genetic factors in accounting for this increased risk is confirmed by the results of twin and adoption studies. Despite the evidence for a strong genetic effect, a weak major histocompatibility complex (MHC) association is the only consistently observed feature in the genetics of multiple sclerosis. Other candidates have been proposed, including genes encoding the immunoglobulin heavy chain, T cell receptor beta chain and APOC2, but none has yet been confirmed. Evidence for linkage and association to the myelin basic protein gene has been reported in a genetically isolated Finnish population, but it has not been possible to reproduce these results in other populations. We used a two-stage approach to search the human genome for the genes causing susceptibility to multiple sclerosis. Two principal regions of linkage are identified, chromosomes 17q22 and 6p21 (MHC). Our results are compatible with genetic models involving epistatic interaction between these and several additional genes.
Ultrastructural analysis of myelin from 8-month-old mice deficient in the myelin-associated glycoprotein revealed pronounced and characteristic alterations of the periaxonal oligodendrocyte processes, consisting of intracytoplasmic deposition of vesicular material, multivesicular bodies, mitochondria, and lipofuscin granules, as well as granular or paracrystalline inclusions. These alterations are similar to those described before as "dying-back oligodendrogliopathy" in diseases of toxic or immune-mediated demyelination including multiple sclerosis.
To investigate whether apoptosis is involved in the fate of oligodendrocytes in chronic multiple sclerosis lesions, the pro-apoptotic molecules fas and tumor necrosis factor receptors and the anti-apoptotic molecule bcl-2 were examined by immunohistochemistry, and DNA fragmentation was assessed by an end labeling technique. Fas and both tumor necrosis factor receptors were preferentially expressed on oligodendrocytes in multiple sclerosis lesions, this phenotype being more evident at the lesion edge. The ligand for fasL, was constitutively present at high levels on microglia. The anti-apoptotic molecule bcl-2 was selectively expressed on oligodendrocytes in silent lesions and on astrocytes in active lesions. These molecules were also detected in control material, albeit at lower levels. In chronic active lesions, a few inflammatory cells displayed fas reactivity, whereas the majority expressed bcl-2. DNA fragmentation was found in a number of infiltrating cells and some microglia, whereas, with one possible exception, oligodendrocytes showed no evidence of apoptosis. Thus, while apoptosis is involved in the elimination of infiltrating cells, it plays little or no role in oligodendrocyte depletion in multiple sclerosis, a process that may be related to a lytic pathway. In addition, microglia constitutively displayed the ligand for fas, and appeared to be the major effector cell population in the central nervous system.
We describe a case of multiple sclerosis characterized by deposition of immunoglobulin and complement in the areas of active demyelination. This was particularly evident for the C9neo antigen, which is a marker for the activated lytic complement complex and was exclusively deposited in the areas of active myelin destruction. In addition, macrophages in the lesions contained degradation products that were immunoreactive for myelin antigens, immunoglobulins, and C9neo antigen. Destruction of myelin sheaths was associated with incomplete loss of oligodendrocytes in the active areas and reappearance of oligodendrocytes with remyelination in the inactive plaque center.
Autoantibodies to MOG mediate myelin damage in MS
- Genain CP
- Cannella B
- Hauser SL
- Raine CS
Differentiation between cellular apoptosis and necrosis by combined use of in situ tailing and nick translation techniques
- Gold R
- Schmied M
- Giegerich G
The demyelinating potential of antibodies to myelin oligodendroglia glycoprotein is related to their ability to fix complement
- Piddlesden S
- Lassmann H
- Zimprich F
Distinct patterns of multiple sclerosis pathology indicates heterogeneity in pathogenesis
- Lucchinetti CL
- Bruck WB
- Rodriguez M
- Lassmann H