Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), affecting 2.3 million people worldwide, of which approximately 122,000 are in Italy. MS represents a multifactorial disease, typical of in young adulthood, whose cause is still unknown. An important role in the MS pathogenesis, seems to be played by inflammatory processes affecting the CNS associated with neurodegenerative phenomena with consequent alteration or loss of sensory, motor and cognitive functions. The characteristics of the inflammation and axonal damage that occur in MS, determined different disease forms: a relapsing-remitting form and a progressive form. The two forms of MS are distinguished according to the course of the disease. The first is characterized by an alternation of acute episodes of disease, alternating with periods without symptoms; the second, consists in a persistent and progressive disability. To date, there are no prognostic clinical and neuroradiological tools for MS. Consequently, it is not not being able to identify, since from the time of diagnosis, patients with a high risk of presenting a more severe disease course, makes the therapeutic choice difficult for the clinician and risky for the patient. In this scenario, identifying new diagnostic, prognostic and predictive markers of disease, through the use of advanced molecular technologies, is of fundamental importance. The aim of this thesis was to identify new biomarkers associated with a high risk of disease activity, through an exploratory analysis of the CSF levels of specific cytokines and pro-inflammatory chemokines associated with the activation of lymphocyte and microglial cells, underly the pathogenesis mechanisms of MS, and investigate the prognostic role of several biomarkers recognized in MS, whose validity is still debated (CXCL13, IgM, Nf-L, PVALB), evaluating the association between intrathecal (meningeal and CSF) and peripheral inflammation. The results obtained allowed to identify a CSF profile associated with a high risk of disease activity, characterized by high molecules levels released by activated T (IFNγ and TNFα), B (LIGHT, APRIL, CXCL13, CXCL12, LIGHT) and microglial cells (sCD163). Furthermore, biomarkers analysis, in combination with clinical and radiological evaluation, confirming an early compartmentalized intrathecal inflammation at the level, in MS patients at high risk of disease activity, already at the time of diagnosis. Finally, given the recent COVID-19 pandemic, a specific study on the antibody and cell-mediated response by MS patients treated with different immunosuppressive therapies (cladribin, fingolimod and ocrelizumab) was included in this thesis. The study demonstrated a different vaccine effect in patients treated with different treatments: patients receiving ocrelizumab showed an impaired antibody production and, on the contrary, a preserved cell-mediated response, associated with an inflammatory mediators production.

Exploring promising biomarkers in multiple sclerosis

Valentina Mazziotti
2023-01-01

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), affecting 2.3 million people worldwide, of which approximately 122,000 are in Italy. MS represents a multifactorial disease, typical of in young adulthood, whose cause is still unknown. An important role in the MS pathogenesis, seems to be played by inflammatory processes affecting the CNS associated with neurodegenerative phenomena with consequent alteration or loss of sensory, motor and cognitive functions. The characteristics of the inflammation and axonal damage that occur in MS, determined different disease forms: a relapsing-remitting form and a progressive form. The two forms of MS are distinguished according to the course of the disease. The first is characterized by an alternation of acute episodes of disease, alternating with periods without symptoms; the second, consists in a persistent and progressive disability. To date, there are no prognostic clinical and neuroradiological tools for MS. Consequently, it is not not being able to identify, since from the time of diagnosis, patients with a high risk of presenting a more severe disease course, makes the therapeutic choice difficult for the clinician and risky for the patient. In this scenario, identifying new diagnostic, prognostic and predictive markers of disease, through the use of advanced molecular technologies, is of fundamental importance. The aim of this thesis was to identify new biomarkers associated with a high risk of disease activity, through an exploratory analysis of the CSF levels of specific cytokines and pro-inflammatory chemokines associated with the activation of lymphocyte and microglial cells, underly the pathogenesis mechanisms of MS, and investigate the prognostic role of several biomarkers recognized in MS, whose validity is still debated (CXCL13, IgM, Nf-L, PVALB), evaluating the association between intrathecal (meningeal and CSF) and peripheral inflammation. The results obtained allowed to identify a CSF profile associated with a high risk of disease activity, characterized by high molecules levels released by activated T (IFNγ and TNFα), B (LIGHT, APRIL, CXCL13, CXCL12, LIGHT) and microglial cells (sCD163). Furthermore, biomarkers analysis, in combination with clinical and radiological evaluation, confirming an early compartmentalized intrathecal inflammation at the level, in MS patients at high risk of disease activity, already at the time of diagnosis. Finally, given the recent COVID-19 pandemic, a specific study on the antibody and cell-mediated response by MS patients treated with different immunosuppressive therapies (cladribin, fingolimod and ocrelizumab) was included in this thesis. The study demonstrated a different vaccine effect in patients treated with different treatments: patients receiving ocrelizumab showed an impaired antibody production and, on the contrary, a preserved cell-mediated response, associated with an inflammatory mediators production.
Multiple Sclerosis, Biomarkers, Immune response
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/1082370
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