1,721,043 research outputs found
Can CSF biomarkers predict future MS disease activity and severity?
No full textMultiple sclerosis (MS) is a heterogeneous disease. With several disease modifying treatments of different mechanisms of action in use now and in development, it is important to identify reliable biomarkers to identify those higher risk MS patients in whom stronger but riskier treatments might be used, as well as to identify those for whom safer treatments of lower efficacy would be sufficient. Here we review cerebrospinal fluid (CSF) and blood biomarkers that show promise for differentiating people with MS who are at risk for severe disease and disability from those with more benign disease. We reviewed published literature for studies reporting biomarkers with predictive value in MS. Most studies of MS CSF found the presence of oligoclonal bands (both IgG and IgM), high IgG index and high levels of kappa light chains to each be associated with worse prognosis. Neurofilament light chain (NfL) and two markers of glial activation, glial fibrillary acidic protein (GFAP) and YKL-40, were higher in CSF of people with subsequent clinical progression or imaging evidence for neurodegeneration. Few reports have been made yet on the prognostic significance of blood NfL, but in one early report baseline, serum NfL (sNfL) predicted subsequent brain volume loss
Editorial: B cells in inflammatory and neurodegenerative diseases of the central nervous system
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Editorial: Community series in reassessing the immune system contribution in multiple sclerosis: therapeutic target, biomarkers of disease and immune pathogenesis, volume II
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Cognitive impairment predicts disability progression and cortical thinning in MS: An 8-year study
No full textMultiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS). Although cognitive impairment (CI) affects a large proportion of MS patients, only few data are available about its prognostic value associated with advanced magnetic resonance imaging (MRI) metrics
The BAFF / APRIL system as therapeutic target in multiple sclerosis
No full textThe complex system of BAFF (B-cell-activating factor of the TNF family) and APRIL (A proliferation-inducing ligand) has been studied in animal models of autoimmune diseases such as those resembling human systemic lupus erythematosus and Sjogren's syndrome and multiple sclerosis (MS). Accumulating evidence suggests that BAFF and APRIL have a physiological role in B cell immunity regulation, however inappropriate production of these factors may represent a key event which disrupts immune tolerance which is associated with systemic autoimmune diseases. Areas covered: We provide an update on the latest studies of the BAFF/APRIL system in multiple sclerosis, as well as on related clinical trials. Expert Opinion: Experimental and clinical evidence suggests that increased BAFF levels may interfere directly and indirectly with B cell immunity; this can lead to breakdown of immune tolerance, the production of autoantibodies and continuous local intracerebral inflammation and brain tissue destruction. A more comprehensive understanding of the cell/molecular mechanism immune reactions specifically regulated by BAFF/APRIL in MS would better elucidate the specific cell phenotype targeted by actual anti-BAFF/APRIL therapies; this may enable the identification of either specific biomarkers of MS subgroups that would benefit of anti-BAFF/APRIL treatments or new targets of MS-specific anti-BAFF/APRIL therapies
Intrathecal inflammation in progressive multiple sclerosis
Full text linkProgressive forms of multiple sclerosis (MS) are associated with chronic demyelination, axonal loss, neurodegeneration, cortical and deep gray matter damage, and atrophy. These changes are strictly associated with compartmentalized sustained inflammation within the brain parenchyma, the leptomeninges, and the cerebrospinal fluid. In progressive MS, molecular mechanisms underlying active demyelination differ from processes that drive neurodegeneration at cortical and subcortical locations. The widespread pattern of neurodegeneration is consistent with mechanisms associated with the inflammatory molecular load of the cerebrospinal fluid. This is at variance with gray matter demyelination that typically occurs at focal subpial sites, in the proximity of ectopic meningeal lymphoid follicles. Accordingly, it is possible that variations in the extent and location of neurodegeneration may be accounted for by individual differences in CSF flow, and by the composition of soluble inflammatory factors and their clearance. In addition, "double hit" damage may occur at sites allowing a bidirectional exchange between interstitial fluid and CSF, such as the Virchow-Robin spaces and the periventricular ependymal barrier. An important aspect of CSF inflammation and deep gray matter damage in MS involves dysfunction of the blood-cerebrospinal fluid barrier and inflammation in the choroid plexus. Here, we provide a comprehensive review on the role of intrathecal inflammation compartmentalized to CNS and non-neural tissues in progressive MS
Potential neuroprotective effect of Fingolimod in multiple sclerosis and its association with clinical variables
No full textMultiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system affecting both white matter and grey matter in the earliest phases of its course. The crucial role of neurodegeneration in disability progression in MS, regardless of white matter damage, has been confirmed by several imaging and neuropathological studies. Fingolimod is an effective immunomodulator of the sphingosine 1-phosphate receptor, approved in relapsing remitting MS and able to cross the blood-brain barrier and to slow disability progression and brain volume loss. However, it remains unclear whether this neuroprotective action is due to a peripheral anti-inflammatory effect and/or to a direct effect on neuronal cells. Areas covered: In this review, the authors summarize the published preclinical and clinical studies on the effect of Fingolimod in limiting the focal and diffuse grey matter damage in MS. Expert opinion: Fingolimod might have a significant neuroprotective effect on relapsing remitting MS based on its modulatory effect on oligodendroglial cells and astrocytes, and on its direct effect on cortical neurons. Future clinical studies including measures of grey matter damage are required to confirm in vivo such neuroprotective effect
Meningeal inflammation as a driver of cortical grey matter pathology and clinical progression in multiple sclerosis
No full textGrowing evidence from cerebrospinal fluid samples and post-mortem brain tissue from individuals with multiple sclerosis (MS) and rodent models indicates that the meninges have a key role in the inflammatory and neurodegenerative mechanisms underlying progressive MS pathology. The subarachnoid space and associated perivascular spaces between the membranes of the meninges are the access points for entry of lymphocytes, monocytes and macrophages into the brain parenchyma, and the main route for diffusion of inflammatory and cytotoxic molecules from the cerebrospinal fluid into the brain tissue. In addition, the meningeal spaces act as an exit route for CNS-derived antigens, immune cells and metabolites. A number of studies have demonstrated an association between chronic meningeal inflammation and a more severe clinical course of MS, suggesting that the build-up of immune cell aggregates in the meninges represents a rational target for therapeutic intervention. Therefore, understanding the precise cell and molecular mechanisms, timing and anatomical features involved in the compartmentalization of inflammation within the meningeal spaces in MS is vital. Here, we present a detailed review and discussion of the cellular, molecular and radiological evidence for a role of meningeal inflammation in MS, alongside the clinical and therapeutic implications
B-cell enrichment and Epstein-Barr virus infection in inflammatory cortical lesions in secondary progressive multiple sclerosis
No full textGray matter lesions are thought to play a key role in the progression of disability and cognitive impairment in multiple sclerosis (MS) patients, but whether gray matter damage is caused by inflammation or secondary to axon loss in the white matter, or both, is not clear. In an analysis of postmortem brain samples from 44 cases of secondary progressive MS, 26 cases were characterized by meningeal inflammation with ectopic B-cell follicles and prominent gray matter pathology; subpial cortical lesions containing dense perivascular lymphocytic infiltrates were present in 11 of these cases. Because intracortical immune infiltrates were enriched in B-lineage cells and because we have shown previously that B cells accumulating in the MS brain support an active Epstein-Barr virus (EBV) infection, we investigated evidence of EBV in the infiltrated cortical lesions. Cells expressing EBV-encoded small RNA and plasma cells expressing EBV early lytic proteins (BZLF1, BFRF1) were present in all and most of the intracortical perivascular cuffs examined, respectively. Immunohistochemistry for CD8-positive cells, granzyme B, perforin, and CD107a indicated cytotoxic activity toward EBV-infected plasma cells that was consistently observed in infiltrated cortical lesions, suggesting active immune surveillance. These findings indicate that both meningeal and intraparenchymal inflammation may contribute to cortical damage during MS progression, and that intracortical inflammation may be sustained by an EBV-driven immunopathologic response, similar to findings in white matter lesions and meninges
Effects of the plasticiser DEHP on lung of newborn rats: catalase immunocytochemistry and morphometric analysis
No full textExperimental administration of di-(2-ethylexyl)-phthalate (DEHP), a plasticiser employed in the fabrication of polyvinyl chloride (PVC), causes increases in lipid metabolising enzymes along with marked peroxisomal proliferation. The effects are found in several mammalian tissues, of which the rodent liver is the most responsive target. Leakage of DEHP from PVC devices is favoured by high temperature and contact with lipid-containing biological fluids. Since preterm babies are currently ventilated through endotracheal PVC tubes, it seemed worthwhile to investigate DEHP effects on immature mammalian lung. In this research, female rats were fed with DEHP in the last week of pregnancy and after delivery, and lungs were excised from 2-day-old pups. At this age, in fact, rat lung histological features closely resemble those found in 24- to 36-week-old human fetuses. In treated animals, morphometric analysis of histological parameters revealed a dramatic decrease in the number of parenchymal airspaces, together with significant increases in their mean size. Moreover, cytochemical detection of the peroxisomal marker catalase revealed an increase in the number of type II pneumocytes. Our findings closely resemble abnormal histological features observed in autoptic lung specimens from children affected with chronic lung diseases
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