H Lassmann

..In this short review, possible paraclinical markers for tissue destruction on the basis of the main features of myelin destruction are discussed. Furthermore, the importance of early axonal damage in multiple sclerosis is highlighted...

..However, the patterns of inflammation differ between different disease stages. This may in part explain, why anti-inflammatory or immunosuppressive treatments fail in progressive multiple sclerosis...

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..1921; 2: 16-43 and del Río-Hortega P. Are the glia with very few processes homologous with Schwann cells? Clin Neuropathol. 2012; 31: 460-462, originally published in Bol de la Soc Esp de Biol. 1922; X: 25-28...

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..Our data suggest that the inflammation-associated oxidative burst in activated microglia and macrophages plays an important role in demyelination and free radical-mediated tissue injury in the pathogenesis of multiple sclerosis...

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..Similar structural abnormalities were also seen in a subset of active lesions in multiple sclerosis. Our studies suggest that astrocyte injury may be an important early step in the cascade of lesion formation in brain inflammation...

..All types of changes in the MS brain and spinal cord occur on the background of inflammation; the type of inflammation, however, differs between different stages and forms of the disease...

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..The relative contribution of the different immune reactions may in part explain the inter-individual and stage dependent heterogeneity of multiple sclerosis lesions...

..The purpose of this review is to discuss the relevance of different models for multiple sclerosis and new insights into pathophysiology of the disease obtained from experimental studies...

..In addition, proper selection of the best suited EAE model for a specific study is essential...

..This process seems to be driven by the aberrant formation of ectopic lymphatic tissue within the brain compartment...

..This heterogeneity is reflected by different clinical manifestations of the disease, such as relapsing or progressive MS, and also explains at least in part the relation of MS to other inflammatory demyelinating diseases...

..Anti-oxidant and mitochondria protective therapeutic strategies may be beneficial both in multiple sclerosis and Alzheimer's disease in particular in early stages of the disease...

..Finally, it is suggested that neuroprotective strategies, which target mitochondrial injury and its downstream effects on neurons and axons are promising future therapeutic options...

..It further highlights that unequivocal proof of Epstein-Barr virus infection in multiple sclerosis lesions is still lacking, due to issues related to the sensitivity and specificity of the detection methods...

..In addition, these data also imply that molecules, identified in these studies, must be confirmed and validated in the correct context of lesion initiation and/or progression...

..However, mitochondrial injury, resulting in energy failure, is a key element of neurodegeneration in MS and is apparently driven by radical production in activated microglia...

..The activation of the tethered cells may trigger the formation of inflammatory foci and could pave the way for inflammation in degenerative CNS disease...

..It further indicates that the disease processes of multiple sclerosis may die out in aged patients with long-standing disease...

..Future therapeutic interventions will have to target inflammation, which is compartmentalized in the central nervous system. In addition, however, neuroprotective therapies may be necessary...

..We found that the cholinergic anti-inflammatory pathway limits the site-directed influx of activated T cells into the lesioned facial motor nucleus, but cannot counteract CNS inflammation in EAE...

..MHC class II molecules were expressed on microglia and macrophages, but not on astrocytes. These data indicate that in MS lesions all cells of the central nervous system are potential targets for Class I MHC restricted cytotoxic T-cells...

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..Changes in the chemokine expression profile along with a leaky blood-brain barrier pave the ground for an accelerated development of CNS inflammation...

..These results suggest that the variable and patient-dependent extent of remyelination must be considered in the design of future clinical trials aimed at promoting CNS repair...

..Furthermore, the age at which this occurs precedes by far the onset of axonal degeneration in Abcd1-deficient mice, implying that oligodendrocyte/myelin disturbances may precede axonopathy in X-ALD...

..In light of this complex situation, it is concluded that clinical trials of stem- or progenitor cell transplantation in multiple sclerosis are currently premature...

..An in vitro study, however, suggested glutamate receptor 3 (GluR3) antibody-mediated astrocytic loss. Therefore, we investigated astrocytic apoptosis and loss in situ...

..Our studies suggest that nitric oxide and its metabolites contribute to axonal pathology and possibly also to subsequent neurological dysfunction in EAE...

..Finally, we will lay out the different pathways leading to oligodendrocyte and myelin loss in human CNS diseases, and we will reveal the different principles leading to the restoration of myelin sheaths or to a failure to do so...

..To what extent chronic inflammation in the cortex of MS patients influences the development of AD lesions is so far unresolved...

..Both, vascular pathology as well as metabolic disturbances induced by toxins of activated macrophages and microglia may be responsible for such lesions in multiple sclerosis...

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..This could indicate that CD4+ and CD8+ T cells might fulfill complementary roles in the intact and the diseased organ...

..Moreover, we also found these cells in both mesenteric lymph nodes and spleens. Hence, microglia- and bone marrow-derived DCs can leave the CNS via the blood stream...

..The findings indicate that mechanisms associated with innate immunity may play a role in the formation of hypoxia-like demyelinating lesions in MS...

..This pathology may be induced by a mismetabolism of the beta-amyloid precursor proteins or their interaction with cytoskeletal proteins related to neuronal degeneration...

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..Additionally, the presence of HCV RNA within the demyelinated lesion indicates a possible role in triggering or propagating disease...

..Our data suggest that calcium influx through voltage-dependent calcium channels is one possible candidate mechanism for axonal degeneration in inflammatory demyelinating disorders...

..This might, at least in part, explain the heterogeneity in genetic susceptibility, clinical presentation and response to treatment observed between individuals...

..Our data identify cortical demyelination as a potential substrate of cerebellar dysfunction in MS...

..Hence, dysferlin is not only a marker for leaky brain vessels, but also reveals dissociation of perivascular inflammatory infiltrates and blood-brain barrier disturbance in multiple sclerosis...

..With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyelination...

..Since the pathogenetic pathways of demyelination and tissue damage vary between different MS patients, their identification by paraclinical markers is of critical importance for diagnosis and therapeutic management...

..Due to their neuroprotective effects, the rim of periplaque tissue, where these proteins are expressed, may be resistant to further damage in an expanding lesion and may therefore remain as a layer of preserved myelinated tissue...

..Thus, the majority of tumour-infiltrating mononuclear phagocytes were found to possess a rather mature phenotype. The number of Mo/M phi with mature phenotype within the tumours correlated with T lymphocyte infiltration in the tissue...

..We conclude that D110 immunoreactivity in glioblastoma does not seem to be related to tissue hypoxia. D110 identifies immunocompetent cells, which positively influence survival of glioblastoma patients...

..Long-term results of future clinical work will have to decide whether the prevention of the neuroma through end-to-side coaptation will be an appropriate therapy for this difficult problem...

..A diagnostic hallmark of this disease is the presence of serum autoantibodies against the water channel aquaporin-4 (AQP-4) on astrocytes...

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..Specific attention is given to the recent recognition of cytotoxicity by CD8+/granzyme-B-positive T lymphocytes as a new pathogenic mechanism of neuronal damage...

..These data indicate that cortical lesions have to be considered as an additional pathological substrate for cognitive dysfunction in MS patients...

..In this review, we discuss the possibility that disease involvement of grey matter structures may significantly contribute to clinical disability in multiple sclerosis patients...

..We show that the pathology of mdf comprises cerebellar atrophy, Purkinje cell loss and optic nerve atrophy, and therefore defines a new animal model for neurodegenerative diseases with cerebellar involvement in humans...

..Our data suggest profound oxidative injury of oligodendrocytes and neurons to be associated with active demyelination and axonal or neuronal injury in multiple sclerosis...

..pneumoniae. Taken together, our data indicated a critical role for Tec in T cell-intrinsic signaling pathways that regulate the in vivo generation of CD44(high)CD62L(-) effector/memory Th17 populations...

..Aim of this short review is to discuss the main factors determining lesional topography in brain inflammation and to illustrate these patterns of tissue injury with clinical examples...

..Furthermore, we detected a locus-specific parent-of-origin effect with suggestive linkage in Eae17. Further genetic and functional dissection of these loci may disclose critical disease-regulating molecular mechanisms...

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..We interpret our findings such that in an ontogenic lack of CD4(+) T cells, EAE is mediated by CD8(+) and elevated levels of alphabetaCD4(-)CD8(-) cells, and that CNS damage is partly enacted by the activity of CD8(+) T cells...

..Thus, we demonstrate therapeutic targeting of CCR1-dependent leukocyte recruitment to the central nervous system in a multiple sclerosis (MS)-like rat model...

..These findings are relevant to some types of human demyelination, where abundant deposits of MAC are found in association with pathology...

..Thus, our studies document a genetic influence of the MHC-region on the relative contribution of macrophages versus microglia in the pathogenesis of EAE...

..These results indicate that gray matter oligodendrocyte differ from white matter oligodendrocytes in their capacity to stabilize metabolic disturbances by an unfolded protein response...

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..This study directly shows, for what we believe is the first time, that a cytotoxic T-cell mechanism contributes to loss of neurons in human brain disease...

..These data suggest a critical role for CXCL10 and CXCR3 in the accumulation of T cells in the CNS of MS patients...

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..Based on this study, future therapeutic strategies designed to limit the deleterious effects of complement activation, eosinophil degranulation and neutrophil/macrophage/microglial activation are worthy of further investigation...

..In MS, damage of axons is closely linked to the CD8(+) CTLs, and protection against CTL-mediated damage should be considered as a new therapeutic approach in MS and other neuroinflammatory diseases...

..The contribution of B cells to pathogenesis appears to be mainly through demyelination rather than through inflammation...

..The findings suggest that hypoxia-like tissue injury in Pattern III multiple sclerosis lesions may be due to mitochondrial impairment...

..Significant expression of HMGB1 and its receptors on accumulating activated macrophages and resident microglia may thus provide a positive feedback loop that amplifies the inflammatory response during MS and EAE pathogenesis...

..These results provide new insights with regard to CNS tissue damage mediated by CD8 T cells and for understanding the role of CD8 T cells in MS...

..We report a case of SREAT with biopsy proven (on two occasions) primary CNS demyelination and radiological evidence of steroid responsiveness, identifying primary CNS demyelination as a complication of autoimmune thyroid disease...

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..These findings strongly support a role for a complement activating AQP4-specific autoantibody as the initiator of the NMO lesion, and further distinguish NMO from MS...

..This specific blockage almost completely abrogated CNS inflammation and clinical disease. These findings highlight the speed and efficiency of antigen recognition in vivo and add to our understanding of T cell-mediated autoimmunity...

..Although stem cell therapy was introduced initially for cell replacement, we examine here whether NPCs possess immunomodulatory effects...

..In addition, in OSE mice, but not in single-transgenic parental mice, anti-MOG antibodies were switched from IgM to IgG1...

..We propose that combined Flt3L and HSV1-TK adenoviral-mediated gene therapy may provide an effective antiglioma treatment with increased efficacy in clinical trials of glioma...

..Furthermore it does not segregate with patterns of immunopathology in MS. We did not find an association between CCR5*Delta32 mutation and disease severity and age of onset in MS...

..Our results show that the constitutive overexpression of c-FLIP(L) in T cells is sufficient to drive Th2 polarization of effector T cell responses and indicate that it might function as a key regulator of Th cell differentiation...

..The combined observations point to differences, but also similarities in the relation of myelin, axon, and immunopathology with genotype, and to a common aggravation of the phenotype with age...

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..This has great relevance for the possibility of therapeutic intervention in demyelinating diseases such as multiple sclerosis, for example by targeting signaling events leading to monocyte recruitment...

..Low-level reactivation of weakly pathogenic T cells was not due to anergy because these cells could be activated by specific antigen in situ as well as after isolation ex vivo...

..Here, we summarize the histological hallmarks and most important neuropathological differential diagnoses of early MS, and provide practical guidelines for the diagnosis of inflammatory demyelinating diseases...

..As judged by mononuclear phagocyte chemokine receptor expression, there appear to be distinct tissue environments in pattern II and III MS lesions...

..Design of therapeutic strategies based on fibrin depletion could potentially benefit the clinical course of demyelinating diseases such as multiple sclerosis...

..The reactivity to MOBP15-36 detected in MS shown here and in another study further emphasizes the potential significance of this epitope for MS...