Inflammatory demyelinating diseases are a broad group of disorders characterized by immune-mediated myelin damage of suspected autoimmune aetiology. Clinical and experimental evidences support the general concept that environmental microbial and non-microbial triggers may lead in genetic susceptible individuals to disruption of self-tolerance, including activation of self-reactive lymphocytes and generation of autoantibodies. However, the environmental triggers remain in most cases elusive, there is no easy way to assess the polygenic susceptibility trait in affected individuals, and we often fail to demonstrate the presence of circulating antibodies or other markers of an auto-immune signature. These limits ultimately result in diagnostic uncertainty and possible misdiagnosis. Finally, many of these disorders show a chronic progressive phase, which is clinically paralleled by increasing disability and resistance to treatment, and for which the ultimate cause is still unknown. This work tried to address some of these issues in the field of immune-mediated inflammatory disorders of the central and peripheral nervous system. In the first part of this work, we investigated the role of air pollution as novel environmental factor impacting on Multiple Sclerosis disease course. We found an association between respiratory exposure to particulate matter and occurrence of contrast-enhancing lesions on brain Magnetic Resonance Imaging in MS patients and we identified a candidate mechanism underlying this association involving up-regulation on peripheral blood lymphocytes of adhesion molecules and chemokine receptors and amplification of Th17 cells response. Secondly, we investigated the clinical and serological features of patients with contemporary demyelination of the central and peripheral nervous system (CCPD). The data suggested that CCPD manifests with heterogeneous features, frequent post-infectious onset, primary PNS or CNS involvement, monophasic or chronic disease course, unsatisfactory response to treatments, and generally poor outcome. As opposed to a previous report in a Japanese cohort, antibodies to Neurofascin-155, a transmembrane protein expressed on both CNS and PNS does not seem to represent a marker of the disease in Caucasian patients. The hypothesis of a distinctive genetic susceptibility profile in patients with CCPD, as well as in patients with other acute demyelinating syndromes of CNS, is currently under investigation. Contrarily, antibodies to NF155, as well as to other proteins involved in axo-glial coupling at the paranodal regions flanking the node of Ranvier, were found in 5.5% of a large multi-centre cohort of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and are associated with particular clinical features, a more aggressive disease course and a poor response to immunoglobulins. Moreover we identified that up to 40% of CIDP patients show reactivity to axonal of myelin nerve components, and sera are currently being investigated for identification of novel targets. Despite their low prevalence, the identification of these novel antibodies as reliable hallmark of the immune-mediated process of CIDP is highly valuable in terms of both advancement in the understanding of the disease-causing mechanisms as well as a tool to assist clinician in its diagnosis. In fact, the diagnosis of this CIDP is challenging and even in highly specialized centres half of the patients are misdiagnosed. Finally, we addressed the topic of the relationship between inflammatory and degenerative pathologic processes in sporadic inclusion body myositis (IBM), the most common muscle disease in adults aged older than 50 years, and found that TDP43-dependent splicing is altered in IBM suggesting that more widespread changes of RNA metabolism due TDP43 loss-of-function may bear pathogenic relevance to immunotherapy-resistant muscle and nerve degeneration.

Inflammatory demyelinating diseases are a broad group of disorders characterized by immune-mediated myelin damage of suspected autoimmune aetiology. Clinical and experimental evidences support the general concept that environmental microbial and non-microbial triggers may lead in genetic susceptible individuals to disruption of self-tolerance, including activation of self-reactive lymphocytes and generation of autoantibodies. However, the environmental triggers remain in most cases elusive, there is no easy way to assess the polygenic susceptibility trait in affected individuals, and we often fail to demonstrate the presence of circulating antibodies or other markers of an auto-immune signature. These limits ultimately result in diagnostic uncertainty and possible misdiagnosis. Finally, many of these disorders show a chronic progressive phase, which is clinically paralleled by increasing disability and resistance to treatment, and for which the ultimate cause is still unknown. This work tried to address some of these issues in the field of immune-mediated inflammatory disorders of the central and peripheral nervous system. In the first part of this work, we investigated the role of air pollution as novel environmental factor impacting on Multiple Sclerosis disease course. We found an association between respiratory exposure to particulate matter and occurrence of contrast-enhancing lesions on brain Magnetic Resonance Imaging in MS patients and we identified a candidate mechanism underlying this association involving up-regulation on peripheral blood lymphocytes of adhesion molecules and chemokine receptors and amplification of Th17 cells response. Secondly, we investigated the clinical and serological features of patients with contemporary demyelination of the central and peripheral nervous system (CCPD). The data suggested that CCPD manifests with heterogeneous features, frequent post-infectious onset, primary PNS or CNS involvement, monophasic or chronic disease course, unsatisfactory response to treatments, and generally poor outcome. As opposed to a previous report in a Japanese cohort, antibodies to Neurofascin-155, a transmembrane protein expressed on both CNS and PNS does not seem to represent a marker of the disease in Caucasian patients. The hypothesis of a distinctive genetic susceptibility profile in patients with CCPD, as well as in patients with other acute demyelinating syndromes of CNS, is currently under investigation. Contrarily, antibodies to NF155, as well as to other proteins involved in axo-glial coupling at the paranodal regions flanking the node of Ranvier, were found in 5.5% of a large multi-centre cohort of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and are associated with particular clinical features, a more aggressive disease course and a poor response to immunoglobulins. Moreover we identified that up to 40% of CIDP patients show reactivity to axonal of myelin nerve components, and sera are currently being investigated for identification of novel targets. Despite their low prevalence, the identification of these novel antibodies as reliable hallmark of the immune-mediated process of CIDP is highly valuable in terms of both advancement in the understanding of the disease-causing mechanisms as well as a tool to assist clinician in its diagnosis. In fact, the diagnosis of this CIDP is challenging and even in highly specialized centres half of the patients are misdiagnosed. Finally, we addressed the topic of the relationship between inflammatory and degenerative pathologic processes in sporadic inclusion body myositis (IBM), the most common muscle disease in adults aged older than 50 years, and found that TDP43-dependent splicing is altered in IBM suggesting that more widespread changes of RNA metabolism due TDP43 loss-of-function may bear pathogenic relevance to immunotherapy-resistant muscle and nerve degeneration.

AUTOIMMUNITY, ENVIRONMENT AND GENETICS IN INFLAMMATORY DISORDERS OF CENTRAL AND PERIPHERAL NERVOUS SYSTEM

CORTESE, ANDREA
2017-02-28

Abstract

Inflammatory demyelinating diseases are a broad group of disorders characterized by immune-mediated myelin damage of suspected autoimmune aetiology. Clinical and experimental evidences support the general concept that environmental microbial and non-microbial triggers may lead in genetic susceptible individuals to disruption of self-tolerance, including activation of self-reactive lymphocytes and generation of autoantibodies. However, the environmental triggers remain in most cases elusive, there is no easy way to assess the polygenic susceptibility trait in affected individuals, and we often fail to demonstrate the presence of circulating antibodies or other markers of an auto-immune signature. These limits ultimately result in diagnostic uncertainty and possible misdiagnosis. Finally, many of these disorders show a chronic progressive phase, which is clinically paralleled by increasing disability and resistance to treatment, and for which the ultimate cause is still unknown. This work tried to address some of these issues in the field of immune-mediated inflammatory disorders of the central and peripheral nervous system. In the first part of this work, we investigated the role of air pollution as novel environmental factor impacting on Multiple Sclerosis disease course. We found an association between respiratory exposure to particulate matter and occurrence of contrast-enhancing lesions on brain Magnetic Resonance Imaging in MS patients and we identified a candidate mechanism underlying this association involving up-regulation on peripheral blood lymphocytes of adhesion molecules and chemokine receptors and amplification of Th17 cells response. Secondly, we investigated the clinical and serological features of patients with contemporary demyelination of the central and peripheral nervous system (CCPD). The data suggested that CCPD manifests with heterogeneous features, frequent post-infectious onset, primary PNS or CNS involvement, monophasic or chronic disease course, unsatisfactory response to treatments, and generally poor outcome. As opposed to a previous report in a Japanese cohort, antibodies to Neurofascin-155, a transmembrane protein expressed on both CNS and PNS does not seem to represent a marker of the disease in Caucasian patients. The hypothesis of a distinctive genetic susceptibility profile in patients with CCPD, as well as in patients with other acute demyelinating syndromes of CNS, is currently under investigation. Contrarily, antibodies to NF155, as well as to other proteins involved in axo-glial coupling at the paranodal regions flanking the node of Ranvier, were found in 5.5% of a large multi-centre cohort of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and are associated with particular clinical features, a more aggressive disease course and a poor response to immunoglobulins. Moreover we identified that up to 40% of CIDP patients show reactivity to axonal of myelin nerve components, and sera are currently being investigated for identification of novel targets. Despite their low prevalence, the identification of these novel antibodies as reliable hallmark of the immune-mediated process of CIDP is highly valuable in terms of both advancement in the understanding of the disease-causing mechanisms as well as a tool to assist clinician in its diagnosis. In fact, the diagnosis of this CIDP is challenging and even in highly specialized centres half of the patients are misdiagnosed. Finally, we addressed the topic of the relationship between inflammatory and degenerative pathologic processes in sporadic inclusion body myositis (IBM), the most common muscle disease in adults aged older than 50 years, and found that TDP43-dependent splicing is altered in IBM suggesting that more widespread changes of RNA metabolism due TDP43 loss-of-function may bear pathogenic relevance to immunotherapy-resistant muscle and nerve degeneration.
28-feb-2017
Inflammatory demyelinating diseases are a broad group of disorders characterized by immune-mediated myelin damage of suspected autoimmune aetiology. Clinical and experimental evidences support the general concept that environmental microbial and non-microbial triggers may lead in genetic susceptible individuals to disruption of self-tolerance, including activation of self-reactive lymphocytes and generation of autoantibodies. However, the environmental triggers remain in most cases elusive, there is no easy way to assess the polygenic susceptibility trait in affected individuals, and we often fail to demonstrate the presence of circulating antibodies or other markers of an auto-immune signature. These limits ultimately result in diagnostic uncertainty and possible misdiagnosis. Finally, many of these disorders show a chronic progressive phase, which is clinically paralleled by increasing disability and resistance to treatment, and for which the ultimate cause is still unknown. This work tried to address some of these issues in the field of immune-mediated inflammatory disorders of the central and peripheral nervous system. In the first part of this work, we investigated the role of air pollution as novel environmental factor impacting on Multiple Sclerosis disease course. We found an association between respiratory exposure to particulate matter and occurrence of contrast-enhancing lesions on brain Magnetic Resonance Imaging in MS patients and we identified a candidate mechanism underlying this association involving up-regulation on peripheral blood lymphocytes of adhesion molecules and chemokine receptors and amplification of Th17 cells response. Secondly, we investigated the clinical and serological features of patients with contemporary demyelination of the central and peripheral nervous system (CCPD). The data suggested that CCPD manifests with heterogeneous features, frequent post-infectious onset, primary PNS or CNS involvement, monophasic or chronic disease course, unsatisfactory response to treatments, and generally poor outcome. As opposed to a previous report in a Japanese cohort, antibodies to Neurofascin-155, a transmembrane protein expressed on both CNS and PNS does not seem to represent a marker of the disease in Caucasian patients. The hypothesis of a distinctive genetic susceptibility profile in patients with CCPD, as well as in patients with other acute demyelinating syndromes of CNS, is currently under investigation. Contrarily, antibodies to NF155, as well as to other proteins involved in axo-glial coupling at the paranodal regions flanking the node of Ranvier, were found in 5.5% of a large multi-centre cohort of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and are associated with particular clinical features, a more aggressive disease course and a poor response to immunoglobulins. Moreover we identified that up to 40% of CIDP patients show reactivity to axonal of myelin nerve components, and sera are currently being investigated for identification of novel targets. Despite their low prevalence, the identification of these novel antibodies as reliable hallmark of the immune-mediated process of CIDP is highly valuable in terms of both advancement in the understanding of the disease-causing mechanisms as well as a tool to assist clinician in its diagnosis. In fact, the diagnosis of this CIDP is challenging and even in highly specialized centres half of the patients are misdiagnosed. Finally, we addressed the topic of the relationship between inflammatory and degenerative pathologic processes in sporadic inclusion body myositis (IBM), the most common muscle disease in adults aged older than 50 years, and found that TDP43-dependent splicing is altered in IBM suggesting that more widespread changes of RNA metabolism due TDP43 loss-of-function may bear pathogenic relevance to immunotherapy-resistant muscle and nerve degeneration.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11571/1218161
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