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Title: Role of meningeal inflammation in cortical pathology and disease progression of multiple sclerosis
Author: Carassiti, Daniele
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that affects primarily young adults. The initial relapsing-remitting phase, characterized by transitory attacks of inflammatory demyelination, is treatable with immunomodulatory interventions while the later progressive stage of the disease is as yet untreatable. During disease progression the slow accumulation of cortical grey matter (GM) demyelination seems to reflect the nature of neurological symptoms and has been strongly associated with the presence of a compartmentalized immune response within the meninges. We hypothesized that a secluded chronic interaction of immune cells within the meningeal compartment is the mechanism underlying the accumulation of cortical damage during this phase. Our aims were to: characterize the phenotypes of immune cells contributing to meningeal inflammation; to describe their possible interactions; and to verify their association with GM pathology. This analysis, also performed in white matter, was aimed at comparing the inflammation in the two compartments. In parallel we correlated the pathological findings with clinical milestones to test the hypothesis of cortical pathology as a substrate for clinical progression. We performed a detailed quantitative immunohistochemical analysis on a cohort of 21 post-mortem progressive MS cases by sampling 483 brain tissue blocks provided by UK MS Tissue Bank. The proportion of demyelinated tissue in the GM was approximately four times greater than in WM and positively correlated with the presence in the subarachnoid space of a pro-inflammatory lymphocyte subset identified by the expression of CD8+ and CD161+ and with the density of MHCII+ microglia in the cortex. We showed that the most frequent lymphocytic subsets quantified in the MS brain were, in decreasing order, CD8+ T cells, CD20+ B cells, CD4+ T and CD8+CD161+ T cells. Furthermore, we identified the presence of mucosal associated invariant T (MAIT) cells, a novel IL-17 secreting subset of CD161+ lymphocytes expressing CCR6 and invariant TCRVα7.2, within the subarachnoid space and in WM perivascular infiltrates. In addition we reported that a higher density of meningeal inflammation correlates with a younger age at death These findings showed the presence of a pro-inflammatory response compartmentalized within the meninges of the MS brain, which was associated with an exacerbated cortical pathology and a more severe disease course, in particular affecting its late progressive phase. These observations support our hypothesis of a role of meningeal inflammation in the accumulation of cortical pathology during progressive MS. This detrimental immune activation within the meninges is a potential target for localized therapeutic interventions aiming to prevent or arrest its development during the progressive phase of the disease.
Supervisor: Reynolds, Richard ; Muraro, Paolo Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available