Cortical and Subcortical Dysmetabolism Are Dynamic Markers of Clinical Disability and Course in Anti-LGI1 Encephalitis.

BACKGROUND AND OBJECTIVES: This [18F]fluorodeoxyglucose (FDG) PET study evaluates the accuracy of semiquantitative measurement of putaminal hypermetabolism in identifying anti-leucine-rich, glioma-inactivated-1 (LGI1) protein autoimmune encephalitis (AE). In addition, the extent of brain dysmetabolism, their association with clinical outcomes, and longitudinal metabolic changes after immunotherapy in LGI1-AE are examined. METHODS: FDG-PET scans from 49 age-matched and sex-matched subjects (13 in LGI1-AE group, 15 in non-LGI1-AE group, 11 with Alzheimer disease [AD], and 10 negative controls [NCs]) and follow-up scans from 8 patients with LGI1 AE on a median 6 months after immunotherapy were analyzed. Putaminal standardized uptake value ratios (SUVRs) normalized to global brain (P-SUVRg), thalamus (P/Th), and midbrain (P/Mi) were evaluated for diagnostic accuracy. SUVRg was applied for all other analyses. RESULTS: P-SUVRg, P/Th, and P/Mi were higher in LGI1-AE group than in non-LGI1-AE group, AD group, and NCs (all p < 0.05). P/Mi and P-SUVRg differentiated LGI1-AE group robustly from other groups (areas under the curve 0.84-0.99). Mediotemporal lobe (MTL) SUVRg was increased in both LGI1-AE and non-LGI1-AE groups when compared with NCs (both p < 0.05). SUVRg was decreased in several frontoparietal regions and increased in pallidum, caudate, pons, olfactory, and inferior occipital gyrus in LGI1-AE group when compared with that in NCs (all p < 0.05). In LGI1-AE group, both MTL and putaminal hypermetabolism were reduced after immunotherapy. Normalization of regional cortical dysmetabolism associated with clinical improvement at the 6- and 20-month follow-up. DISCUSSION: Semiquantitative measurement of putaminal hypermetabolism with FDG-PET may be used to distinguish LGI1-AE from other pathologies. Metabolic abnormalities in LGI1-AE extend beyond putamen and MTL into other subcortical and cortical regions. FDG-PET may be used in evaluating disease evolution in LGI1-AE. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that semiquantitative measures of putaminal metabolism on PET can differentiate patients with LGI1-AE from patients without LGI1-AE, patients with AD, or NCs.

Evidence for and against subclinical disease activity and progressive disease in MOG antibody disease and neuromyelitis optica spectrum disorder.

Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) and aquaporin-4 IgG seropositive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD) are generally considered to be relapsing disorders, without clinical progression or subclinical disease activity outside of clinical relapses, in contrast to multiple sclerosis (MS). With advances in the diagnosis and treatment of these conditions, prolonged periods of remission without relapses can be achieved, and the question of whether progressive disease courses can occur has re-emerged. In this review, we focus on studies exploring evidence for and against relapse-independent clinical progression and/or subclinical disease activity in patients with MOGAD and AQP4-IgG+ NMOSD.

High-salt diet suppresses autoimmune demyelination by regulating the blood-brain barrier permeability.

Sodium chloride, "salt," is an essential component of daily food and vitally contributes to the body's homeostasis. However, excessive salt intake has often been held responsible for numerous health risks associated with the cardiovascular system and kidney. Recent reports linked a high-salt diet (HSD) to the exacerbation of artificially induced central nervous system (CNS) autoimmune pathology through changes in microbiota and enhanced TH17 cell differentiation [M. Kleinewietfeld et al., Nature 496, 518-522 (2013); C. Wu et al., Nature 496, 513-517 (2013); N. Wilck et al., Nature 551, 585-589 (2017)]. However, there is no evidence that dietary salt promotes or worsens a spontaneous autoimmune disease. Here we show that HSD suppresses autoimmune disease development in a mouse model of spontaneous CNS autoimmunity. We found that HSD consumption increased the circulating serum levels of the glucocorticoid hormone corticosterone. Corticosterone enhanced the expression of tight junction molecules on the brain endothelial cells and promoted the tightening of the blood-brain barrier (BBB) thereby controlling the entry of inflammatory T cells into the CNS. Our results demonstrate the multifaceted and potentially beneficial effects of moderately increased salt consumption in CNS autoimmunity.

Heparanome-Mediated Rescue of Oligodendrocyte Progenitor Quiescence following Inflammatory Demyelination.

The proinflammatory cytokine IFN-γ, which is chronically elevated in multiple sclerosis, induces pathologic quiescence in human oligodendrocyte progenitor cells (OPCs) via upregulation of the transcription factor PRRX1. In this study using animals of both sexes, we investigated the role of heparan sulfate proteoglycans in the modulation of IFN-γ signaling following demyelination. We found that IFN-γ profoundly impaired OPC proliferation and recruitment following adult spinal cord demyelination. IFN-γ-induced quiescence was mediated by direct signaling in OPCs as conditional genetic ablation of IFNγR1 (Ifngr1) in adult NG2+ OPCs completely abrogated these inhibitory effects. Intriguingly, OPC-specific IFN-γ signaling contributed to failed oligodendrocyte differentiation, which was associated with hyperactive Wnt/Bmp target gene expression in OPCs. We found that PI-88, a heparan sulfate mimetic, directly antagonized IFN-γ to rescue human OPC proliferation and differentiation in vitro and blocked the IFN-γ-mediated inhibitory effects on OPC recruitment in vivo Importantly, heparanase modulation by PI-88 or OGT2155 in demyelinated lesions rescued IFN-γ-mediated axonal damage and demyelination. In addition to OPC-specific effects, IFN-γ-augmented lesions were characterized by increased size, reactive astrogliosis, and proinflammatory microglial/macrophage activation along with exacerbated axonal injury and cell death. Heparanase inhibitor treatment rescued many of the negative IFN-γ-induced sequelae suggesting a profound modulation of the lesion environment. Together, these results suggest that the modulation of the heparanome represents a rational approach to mitigate the negative effects of proinflammatory signaling and rescuing pathologic quiescence in the inflamed and demyelinated human brain.SIGNIFICANCE STATEMENT The failure of remyelination in multiple sclerosis contributes to neurologic dysfunction and neurodegeneration. The activation and proliferation of oligodendrocyte progenitor cells (OPCs) is a necessary step in the recruitment phase of remyelination. Here, we show that the proinflammatory cytokine interferon-γ directly acts on OPCs to induce pathologic quiescence and thereby limit recruitment following demyelination. Heparan sulfate is a highly structured sulfated carbohydrate polymer that is present on the cell surface and regulates several aspects of the signaling microenvironment. We find that pathologic interferon-γ can be blocked by modulation of the heparanome following demyelination using either a heparan mimetic or by treatment with heparanase inhibitor. These studies establish the potential for modulation of heparanome as a regenerative approach in demyelinating disease.

Qki is an essential regulator of microglial phagocytosis in demyelination.

The mechanism underpinning the regulation of microglial phagocytosis in demyelinating diseases is unclear. Here, we showed that the Quaking protein (Qki) in microglia was greatly induced by demyelination in the brains of both mice and humans. Deletion of the Quaking gene (Qk) in microglia severely impaired the clearance of myelin debris. Transcriptomic profiling indicated that depletion of Qki impaired total RNA levels and splicing of the genes involved in phagosome formation and maturation. RNA immunoprecipitation (RIP) confirmed the physical interactions between the Qki protein and the mRNAs of Qki targets that are involved in phagocytosis, indicating that Qki regulates their RNA stability. Both Qki depletion and inhibition of Qki target Cd36 greatly reduced the phagocytic activity of microglia and macrophages. The defective uptake and degradation of myelin debris caused by Qki depletion in microglia resulted in unresolved myelin debris that impaired axon integrity, oligodendrocyte maturation, and subsequent remyelination. Thus, our results demonstrate that Qki is an essential regulator of microglia's phagocytic activity under demyelinating conditions.

Anti-inflammatory and immune-modulatory impacts of berberine on activation of autoreactive T cells in autoimmune inflammation.

Autoreactive inflammatory CD4+ T cells, such as T helper (Th)1 and Th17 subtypes, have been found to associate with the pathogenesis of autoimmune disorders. On the other hand, CD4+ Foxp3+ T regulatory (Treg) cells are crucial for the immune tolerance and have a critical role in the suppression of the excessive immune and inflammatory response promoted by these Th cells. In contrast, dendritic cells (DCs) and macrophages are immune cells that through their inflammatory functions promote autoreactive T-cell responses in autoimmune conditions. In recent years, there has been increasing attention to exploring effective immunomodulatory or anti-inflammatory agents from the herbal collection of traditional medicine. Berberine, an isoquinoline alkaloid, is one of the main active ingredients extracted from medicinal herbs and has been shown to exert various biological and pharmacological effects that are suggested to be mainly attributed to its anti-inflammatory and immunomodulatory properties. Several lines of experimental study have recently investigated the therapeutic potential of berberine for treating autoimmune conditions in animal models of human autoimmune diseases. Here, we aimed to seek mechanisms underlying immunomodulatory and anti-inflammatory effects of berberine on autoreactive inflammatory responses in autoimmune conditions. Reported data reveal that berberine can directly suppress functions and differentiation of pro-inflammatory Th1 and Th17 cells, and indirectly decrease Th cell-mediated inflammation through modulating or suppressing other cells assisting autoreactive inflammation, such as Tregs, DCs and macrophages.

Biomarkers in Rare Demyelinating Disease of the Central Nervous System.

Rare neurological diseases are a heterogeneous group corresponding approximately to 50% of all rare diseases. Neurologists are among the main specialists involved in their diagnostic investigation. At the moment, a consensus guideline on which neurologists may base clinical suspicion is not available. Moreover, neurologists need guidance with respect to screening investigations that may be performed. In this respect, biomarker research has emerged as a particularly active field due to its potential applications in clinical practice. With respect to autoimmune demyelinating diseases of the Central Nervous System (CNS), although these diseases occur in the frame of organ-specific autoimmunity, pathology of the disease itself is orchestrated among several anatomical and functional compartments. The differential diagnosis is broad and includes, but is not limited to, rare neurological diseases. Multiple Sclerosis (MS) needs to be differentially diagnosed from rare MS variants, Acute Disseminated Encephalomyelitis (ADEM), the range of Neuromyelitis Optica Spectrum Disorders (NMOSDs), Myelin Oligodendrocyte Glycoprotein (MOG) antibody disease and other systemic inflammatory diseases. Diagnostic biomarkers may facilitate timely diagnosis and proper disease management, preventing disease exacerbation due to misdiagnosis and false treatment. In this review, we will describe advances in biomarker research with respect to rare neuroinflammatory disease of the CNS.

Regulatory B Cells and Its Role in Central Nervous System Inflammatory Demyelinating Diseases.

Regulatory B (Breg) cells represent a population of suppressor B cells that participate in immunomodulatory processes and inhibition of excessive inflammation. The regulatory function of Breg cells have been demonstrated in mice and human with inflammatory diseases, cancer, after transplantation, and particularly in autoinflammatory disorders. In order to suppress inflammation, Breg cells produce anti-inflammatory mediators, induce death ligand-mediated apoptosis, and regulate many kinds of immune cells such as suppressing the proliferation and differentiation of effector T cell and increasing the number of regulatory T cells. Central nervous system Inflammatory demyelinating diseases (CNS IDDs) are a heterogeneous group of disorders, which occur against the background of an acute or chronic inflammatory process. With the advent of monoclonal antibodies directed against B cells, breakthroughs have been made in the treatment of CNS IDDs. Therefore, the number and function of B cells in IDDs have attracted attention. Meanwhile, increasing number of studies have confirmed that Breg cells play a role in alleviating autoimmune diseases, and treatment with Breg cells has also been proposed as a new therapeutic direction. In this review, we focus on the understanding of the development and function of Breg cells and on the diversification of Breg cells in CNS IDDs.

Voluntary running wheel attenuates motor deterioration and brain damage in cuprizone-induced demyelination.

Growing data from human and animal studies indicate the beneficial effects of exercise on several clinical outcomes in patients with multiple sclerosis (MS), an autoimmune, demyelinating disease, suggesting that it may slow down the disease progression, by reducing brain damage. However, the mechanisms involved are still elusive. Aim of this study was to address the effects of voluntary running wheel in a toxic-demyelinating model of MS, in which demyelination and brain inflammation occur in response to cuprizone (CPZ) treatment. Mice were housed in standard or wheel-equipped cages starting from the day of CPZ or normal chow feeding for three or six weeks and evaluated for weight changes, locomotor skills and neuromuscular functions over the course of the experimental design. Biochemical, molecular biology and immunohistochemical analyses were performed. Exercise prevented early weight loss caused by CPZ, indicating improved wellness in these mice. Both neuromuscular function and motor coordination were significantly enhanced by exercise in CPZ-treated mice. Moreover, exercise induced an early protection against axonal damage and the loss of the myelin associated proteins, myelin basic protein (MBP) and 2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNPase), in the striatum and the corpus callosum, in coincidence of a strongly attenuated microglia activation in both brain areas. Further, during the late phase of the treatment, exercise in CPZ mice reduced the recruitment of new OLs compared to sedentary CPZ mice, likely due to the precocious protection against myelin damage. Overall, these results suggest that life-style interventions can be effective against the demyelinating-inflammatory processes occurring in the brains of MS patients.

Early IFNγ-Mediated and Late Perforin-Mediated Suppression of Pathogenic CD4 T Cell Responses Are Both Required for Inhibition of Demyelinating Disease by CNS-Specific Autoregulatory CD8 T Cells.

Pathogenesis of immune-mediated demyelinating diseases like multiple sclerosis (MS) is thought to be governed by a complex cellular interplay between immunopathogenic and immunoregulatory responses. We have previously shown that central nervous system (CNS)-specific CD8 T cells have an unexpected protective role in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). In this study, we interrogated the suppressive potential of PLP178-191-specific CD8 T cells (PLP-CD8). Here, we show that PLP-CD8, when administered post-disease onset, rapidly ameliorated EAE progression, and suppressed PLP178-191-specific CD4 T cell responses as measured by delayed-type hypersensitivity (DTH). To accomplish DTH suppression, PLP-CD8 required differential production of perforin and IFNγ. Perforin was not required for the rapid suppressive action of these cells, but was critical for maintenance of optimal longer term DTH suppression. Conversely, IFNγ production by PLP-CD8 was necessary for swift DTH suppression, but was less significant for maintenance of longer term suppression. These data indicate that CNS-specific CD8 T cells employ an ordered regulatory mechanism program over a number of days in vivo during demyelinating disease and have mechanistic implications for this immunotherapeutic approach.

Anti-MAG neuropathy: Role of IgM antibodies, the paranodal junction and juxtaparanodal potassium channels.

OBJECTIVE: To improve understanding of disease pathophysiology in anti-myelin-associated glycoprotein (anti-MAG) neuropathy to guide further treatment approaches. METHODS: Anti-MAG neuropathy patients underwent clinical assessments, nerve conduction and excitability studies, and ultrasound assessment. RESULTS: Patients demonstrated a distinctive axonal excitability profile characterised by a reduction in superexcitability [MAG: -14.2 ±â€¯1.6% vs healthy controls (HC): -21.8 ±â€¯1.2%; p < 0.01] without alterations in most other excitability parameters. Mathematical modelling of nerve excitability recordings suggested that changes in axonal function could be explained by a 72.5% increase in juxtaparanodal fast potassium channel activation and an accompanying hyperpolarization of resting membrane potential (by 0.3 mV) resulting in a 94.2% reduction in discrepancy between anti-MAG data and the healthy control model. Superexcitability changes correlated strongly with clinical and neurophysiological parameters. Furthermore, structural assessments demonstrated a proximal pattern of nerve enlargement (C6 nerve root cross-sectional area: 15.9 ±â€¯8.1 mm2 vs HC: 9.1 ±â€¯2.3 mm2; p < 0.05). CONCLUSIONS: The imaging and neurophysiological results support the pathogenicity of anti-MAG IgM. Widening between adjacent loops of paranodal myelin due to antibodies would expand the pathway from the node to the juxtaparanode, increasing activation of juxtaparanodal fast potassium channels, thereby impairing saltatory conduction. SIGNIFICANCE: Potassium channel blockers may prove beneficial in restoring conduction closer to its normal state and improving nerve function in anti-MAG neuropathy.

Neuroimmune disorders of the central nervous system in children in the molecular era.

Immune-mediated disorders of the CNS in children are a complex group of demyelinating, inflammatory, parainfectious and postinfectious disorders with heterogeneous pathobiological mechanisms and clinical manifestations, often associated with fundamental derangement in immune regulation. In this Review, we aim to provide an update on our knowledge of neuroimmune disorders and highlight areas of research that are priorities for improving clinical management. We outline the clinical features of neuroimmune disorders, the current approaches to their treatment and new approaches in development. We then consider the pathological features, including biomarkers, pathological mechanisms and genetics, and discuss the value of immune assays in clinical investigation and basic research. On the basis of current knowledge and techniques, we propose four research priorities: rigorous and consistent collection of core clinical data, cooperative investigation of treatments, development of biological assays and genetic studies. These priorities should help us to achieve the shared goal of precision medicine for neuroimmune disorders. However, multicentre research and the creation of clinical consortia for these rare disorders will be necessary, and we hope that this Review serves as a call to action that is timely given current exciting advances in neuroimmune therapeutics.

New clinical implications of anti-myelin oligodendrocyte glycoprotein antibodies in children with CNS demyelinating diseases.

Acquired demyelinating CNS syndromes include a broad spectrum of clinical phenotypes and different entities can overlap. Therefore, differential diagnosis is still challenging. A humoral immune reaction against myelin oligodendrocyte glycoprotein (MOG) is present in a subgroup of these patients, particularly in children. Anti-MOG antibodies indicate a non-multiple sclerosis disease course. Indeed, early publications have suggested that anti-MOG antibodies argue for a monophasic course; recently an association with a high risk for recurrent non-MS disease has been shown. According new data, antibody analysis was included in a diagnostic algorithm for the diagnosis of acquired demyelinating CNS syndromes in children. Here, recent data from the implementation of anti-MOG antibodies in daily clinical practice are reviewed.

GAD65 neurological autoimmunity.

The glutamic acid decarboxylase 65-kilodalton isoform (GAD65) antibody is a biomarker of autoimmune central nervous system (CNS) disorders and, more commonly, nonneurological autoimmune diseases. Type 1 diabetes, autoimmune thyroid disease, and pernicious anemia are the most frequent GAD65 autoimmune associations. One or more of these disorders coexists in approximately 70% of patients with GAD65 neurological autoimmunity. Neurological phenotypes have CNS localization and include limbic encephalitis, epilepsy, cerebellar ataxia, and stiff-person syndrome (SPS), among others. Classic SPS is a disorder on the spectrum of CNS hyperexcitability which also includes phenotypes that are either more restricted (stiff-limb syndrome) or more widespread (progressive encephalomyelitis with rigidity and myoclonus). GAD65 antibody is not highly predictive of a paraneoplastic cause for neurological disorders, but diverse cancer types have been occasionally reported. For all phenotypes, responses to immunotherapy are variable (approximately 50% improve). GAD65 autoimmunity is important to recognize for both coexisting nonneurological autoimmune associations and potential immunotherapy-response. Muscle Nerve 56: 15-27, 2017.

The crucial role of Erk2 in demyelinating inflammation in the central nervous system.

BACKGROUND: Brain inflammation is a crucial component of demyelinating diseases such as multiple sclerosis. Although the initiation of inflammatory processes by the production of cytokines and chemokines by immune cells is well characterized, the processes of inflammatory aggravation of demyelinating diseases remain obscure. Here, we examined the contribution of Erk2, one of the isoforms of the extracellular signal-regulated kinase, to demyelinating inflammation. METHODS: We used the cuprizone-induced demyelinating mouse model. To examine the role of Erk2, we used Nestin-cre-driven Erk2-deficient mice. We also established primary culture of microglia or astrocytes in order to reveal the crosstalk between two cell types and to determine the downstream cascades of Erk2 in astrocytes. RESULTS: First, we found that Erk is especially activated in astrocytes within the corpus callosum before the peak of demyelination (at 4 weeks after the start of cuprizone feeding). Then, we found that in our model, genetic ablation of Erk2 from neural cells markedly preserved myelin structure and motor function as measured by the rota-rod test. While the initial activation of microglia was not altered in Erk2-deficient mice, these mice showed reduced expression of inflammatory mediators at 3-4 model weeks. Furthermore, the subsequent inflammatory glial responses, characterized by accumulation of microglia and reactive astrocytes, were significantly attenuated in Erk2-deficient mice. These data indicate that Erk2 in astrocytes is involved in augmentation of inflammation and gliosis. We also found that activated, cultured microglia could induce Erk2 activation in cultured astrocytes and subsequent production of inflammatory mediators such as Ccl-2. CONCLUSIONS: Our results suggest that Erk2 activation in astrocytes plays a crucial role in aggravating demyelinating inflammation by inducing inflammatory mediators and gliosis. Thus, therapies targeting Erk2 function in glial cells may be a promising approach to the treatment of distinct demyelinating diseases.

Neurology--the next 10 years.

Since the launch of our journal as Nature Clinical Practice Neurology in 2005, we have seen remarkable progress in many areas of neurology research, but what does the future hold? Will advances in basic research be translated into effective disease-modifying therapies, and will personalized medicine finally become a reality? For this special Viewpoint article, we invited a panel of Advisory Board members and other journal contributors to outline their research priorities and predictions in neurology for the next 10 years.

Progression of relapsing-remitting demyelinating disease does not require increased TCR affinity or epitope spread.

In this study, we investigate the basis of T cell recognition of myelin that governs the progression from acute symptoms into disease remission, relapse, and chronic progression in a secondary progressive model of demyelinating disease. Until now, the frequency and affinity of myelin-reactive CD4 T cells that elicit relapsing-remitting disease have not been quantified. The micropipette adhesion frequency assay was used to obtain a sensitive and physiologically relevant two-dimensional measurement of frequency and TCR affinity for myelin, as the inherent low affinity does not allow the use of specific peptide:MHC-II tetramers for this purpose. We found the highest affinity and frequency of polyclonal myelin oligodendrocyte glycoprotein-reactive cells infiltrate the CNS during acute disease, whereas affinities during remission, relapse, and chronic disease are not significantly different from each other. Frequency analysis revealed that the vast majority of CNS-infiltrating CD4 T cells are myelin oligodendrocyte glycoprotein reactive at all time points, demonstrating epitope spread is not a predominant factor for disease progression. Furthermore, time points at which mice were symptomatic were characterized by an infiltration of Th17 cells in the CNS, whereas symptom remission showed an enrichment of cells producing IFN-γ. Also, the ratio of regulatory T cells to Foxp3(-) CD4 T cells was significantly higher in the CNS at remission than during acute disease. The results of this study indicate that a high frequency of T cells specific for a single myelin Ag, rather than increased TCR affinity or epitope spread, governs the transition from acute symptoms through remission, relapse, and chronic disease states.

How type I interferons shape myeloid cell function in CNS autoimmunity.

The precise mechanisms underlying the effects of IFN-I in CNS autoimmunity remain poorly understood despite the long-standing use of these cytokines as first-line disease-modifying drugs in the treatment of RRMS, a chronic demyelinating CNS autoimmune disease. Systemic use of IFN-I results in pleiotropic immunomodulation linking the innate and adaptive immune responses. Recent research has demonstrated that in the setting of CNS autoimmunity, IFNs-I have multiple effects on myeloid cell subsets, such as circulating monocytes, granulocytes, DCs, and tissue macrophages, such as microglia. These diverse effects include changes in cell activation, maturation, antigen presentation, and cytokine production, thus influencing T cell differentiation and expansion, as well as the regulation of executive functions, such as apoptosis and phagocytosis. Moreover, current data suggest that the engagement of the IFNAR on myeloid cells changes the activation status of the inflammasome in a cell type-specific manner. Whereas most reports support primarily immune-suppressive effects of IFN-I on myeloid cells, endogenously produced, exogenously induced, and peripherally administered IFNs-I exert complex differential spatial effects during CNS autoimmune inflammation. Clearly characterizing the molecular and cellular basis of these effects promises to yield viable targets for a more directed, localized, cell type-specific IFN-I-based therapeutic approach. This kind of approach would allow for replacing the current treatment strategy in MS of broadly and unselectively altering all immune responses, regardless of their beneficial or detrimental nature.

Role of glial cells in innate immunity and their role in CNS demyelination.

The adaptive and innate arms of the immune system are the two pillars of host defense against environmental pathogens. Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS which is considered to be autoimmune and is thought to result from breakdown in the usual checks and balances of the adaptive immune response. The major pathological outcome of the disease is "the MS plaque" a unique feature of CNS demyelination characterized by the destruction of oligodendrocytes with loss of myelin and underlying axons. The MS plaque is not seen in other inflammatory disorders of the CNS. The prevailing opinion suggests that MS is mediated by the activation of an adaptive immune response which targets neural antigens. Currently, the role of an innate immune in the development of the lesions in MS has remained unclear. We explore the potential cellular elements of the innate immune system and in particular glial cells, which are likely candidates in inducing the specific pathological picture that is evident in MS. Activated microglia and the release of molecules which are detrimental to oligodendrocyte have been suggested as mechanisms by which innate immunity causes demyelination in MS. However a microglia/macrophage centric model does not explain the specificity of lesion development in MS. We propose that activation pathways of receptors of the innate immune system present on oligodendrocytes and astrocytes rather than microglia are central to the pathogenesis of demyelination seen in MS.

Microglial cystatin F expression is a sensitive indicator for ongoing demyelination with concurrent remyelination.

Demyelination coincides with numerous changes of gene expression in the central nervous system (CNS). Cystatin F, which is a papain-like lysosomal cysteine proteinase inhibitor that is normally expressed by immune cells and not in the brain, is massively induced in the CNS during acute demyelination. We found that microglia, which are monocyte/macrophage-lineage cells in the CNS, express cystatin F only during demyelination. By using several demyelinating animal models and the spinal cord tissues from multiple sclerosis (MS) patients, we examined spatiotemporal expression pattern of cystatin F by in situ hybridization and immunohistochemistry. We found that the timing of cystatin F induction matches with ongoing demyelination, and the places with cystatin F expression overlapped with the remyelinating area. Most interestingly, cystatin F induction ceased in chronic demyelination, in which remyelinating ability was lost. These findings demonstrate that the expression of cystatin F indicates the occurrence of ongoing demyelination/remyelination and the absence of cystatin F expression indicates the cessation of remyelination in the demyelinating area.