Year: 2015
Type: dissertation
Abstract: Multiple Sclerosis (MS) is a chronic, demyelinating disease which affects the central nervous system (CNS) resulting in progressive cognitive decline and physical disability. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS used to understand the cellular and molecular mechanisms underlying the disease. A greater understanding of disease pathogenesis can aid in the discovery of novel disease targets and more effective therapies for MS. Infection with viral or bacterial pathogens has been linked with the development of MS, while infection with helminth parasites has been associated with protection against the symptoms of MS and other autoimmune diseases. Here, the murine model of MS, EAE was used to examine the effect of infection with the respiratory pathogen Bordetella pertussis on development of CNS inflammation. The data demonstrate that infection of mice with B. pertussis significantly attenuates the clinical course of EAE induced by active immunization or cell transfer. This was reflected in a significant reduction in VLA-4 and LFA-1 expression on T cells and infiltration of IL-17+, IFN-?+ and IFN-?+IL-17+ CD4 T cells into the CNS. Infection with B. pertussis induced IL-10 production from dendritic cells and enhanced the frequency of IL-10-producing CD25-Foxp3+/-CD4+ T cells in vivo. Furthermore, the suppressive effects of B. pertussis infection on EAE were lost in IL-10-/- mice. The findings of the present study demonstrate that a bacterial infection of the respiratory tract can attenuate EAE by promoting production of the anti-inflammatory cytokine IL-10 that may suppress licensing of autoaggressive T cells in the lungs, thereby preventing their migration into the CNS. IL-17-producing T cells play a key pathogenic role in many autoimmune disorders, including MS and psoriasis, and are now major drug targets for these diseases. ?? T cells and CD4 T cells are the main sources of IL-17 during inflammation and host immunity. The current study and others have shown that IL-17-secreting V?4+ ?? T cells are found at a high frequency in the CNS of mice with EAE. This thesis describes a novel subtype of T cells distinct from conventional ?? or ?? T cells that co-express V?4, TCR? and TCR?, but not TCR?, and play a critical pathogenic role in CNS autoimmunity. TCR?-expressing V?4+ cells co-express CD4 and CD8 and constitute around 8-10% of V?4+ cells in the spleen, lymph nodes, lungs and liver. These cells are present in WT and TCR?-/- mice but not in TCR?-/- or TCR?-/- mice. Co- expression of ?, ? and ? chains was confirmed at the molecular level, revealing a restricted V?\nrepertoire with more heterogeneous V? and V? usage. ??V?4 T cells express IL-1R1, IL-23R, CD4, CD73, ICOS, CD44, CCR6 and ?4?1. Furthermore, these cells secrete IL-17A and IL- 22, following stimulation with IL-1? and IL-23 and respond to autoantigens when purified from mice with EAE. Depletion of V?4+ cells from either WT or TCR?-/- mice dramatically attenuated EAE, and this effect was associated with a significant reduction in MOG-specific IL-17, IFN-?, GM-CSF and IL-22 and CNS-infiltrating conventional Th17 cells. The data demonstrate that ??V?4 T cells infiltrate the CNS as early as day 3 during EAE. These findings identify a novel population of T cells that express V?4 and ?? TCRs which play a critical role in autoimmunity through the activation of Th17 cells.\nMultiple Sclerosis (MS) is a chronic, demyelinating disease which affects the central nervous system (CNS) resulting in progressive cognitive decline and physical disability. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS used to understand the cellular and molecular mechanisms underlying the disease. A greater understanding of disease pathogenesis can aid in the discovery of novel disease targets and more effective therapies for MS. Infection with viral or bacterial pathogens has been linked with the development of MS, while infection with helminth parasites has been associated with protection against the symptoms of MS and other autoimmune diseases. Here, the murine model of MS, EAE was used to examine the effect of infection with the respiratory pathogen Bordetella pertussis on development of CNS inflammation. The data demonstrate that infection of mice with B. pertussis significantly attenuates the clinical course of EAE induced by active immunization or cell transfer. This was reflected in a significant reduction in VLA-4 and LFA-1 expression on T cells and infiltration of IL-17+, IFN-?+ and IFN-?+IL-17+ CD4 T cells into the CNS. Infection with B. pertussis induced IL-10 production from dendritic cells and enhanced the frequency of IL-10-producing CD25-Foxp3+/-CD4+ T cells in vivo. Furthermore, the suppressive effects of B. pertussis infection on EAE were lost in IL-10-/- mice. The findings of the present study demonstrate that a bacterial infection of the respiratory tract can attenuate EAE by promoting production of the anti-inflammatory cytokine IL-10 that may suppress licensing of autoaggressive T cells in the lungs, thereby preventing their migration into the CNS. IL-17-producing T cells play a key pathogenic role in many autoimmune disorders, including MS and psoriasis, and are now major drug targets for these diseases. ?? T cells and CD4 T cells are the main sources of IL-17 during inflammation and host immunity. The current study and others have shown that IL-17-secreting V?4+ ?? T cells are found at a high frequency in the CNS of mice with EAE. This thesis describes a novel subtype of T cells distinct from conventional ?? or ?? T cells that co-express V?4, TCR? and TCR?, but not TCR?, and play a critical pathogenic role in CNS autoimmunity. TCR?-expressing V?4+ cells co-express CD4 and CD8 and constitute around 8-10% of V?4+ cells in the spleen, lymph nodes, lungs and liver. These cells are present in WT and TCR?-/- mice but not in TCR?-/- or TCR?-/- mice. Co- expression of ?, ? and ? chains was confirmed at the molecular level, revealing a restricted V?\nrepertoire with more heterogeneous V? and V? usage. ??V?4 T cells express IL-1R1, IL-23R, CD4, CD73, ICOS, CD44, CCR6 and ?4?1. Furthermore, these cells secrete IL-17A and IL- 22, following stimulation with IL-1? and IL-23 and respond to autoantigens when purified from mice with EAE. Depletion of V?4+ cells from either WT or TCR?-/- mice dramatically attenuated EAE, and this effect was associated with a significant reduction in MOG-specific IL-17, IFN-?, GM-CSF and IL-22 and CNS-infiltrating conventional Th17 cells. The data demonstrate that ??V?4 T cells infiltrate the CNS as early as day 3 during EAE. These findings identify a novel population of T cells that express V?4 and ?? TCRs which play a critical role in autoimmunity through the activation of Th17 cells.\nMultiple Sclerosis (MS) is a chronic, demyelinating disease which affects the central nervous system (CNS) resulting in progressive cognitive decline and physical disability. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS used to understand the cellular and molecular mechanisms underlying the disease. A greater understanding of disease pathogenesis can aid in the discovery of novel disease targets and more effective therapies for MS. Infection with viral or bacterial pathogens has been linked with the development of MS, while infection with helminth parasites has been associated with protection against the symptoms of MS and other autoimmune diseases. Here, the murine model of MS, EAE was used to examine the effect of infection with the respiratory pathogen Bordetella pertussis on development of CNS inflammation. The data demonstrate that infection of mice with B. pertussis significantly attenuates the clinical course of EAE induced by active immunization or cell transfer. This was reflected in a significant reduction in VLA-4 and LFA-1 expression on T cells and infiltration of IL-17+, IFN-?+ and IFN-?+IL-17+ CD4 T cells into the CNS. Infection with B. pertussis induced IL-10 production from dendritic cells and enhanced the frequency of IL-10-producing CD25-Foxp3+/-CD4+ T cells in vivo. Furthermore, the suppressive effects of B. pertussis infection on EAE were lost in IL-10-/- mice. The findings of the present study demonstrate that a bacterial infection of the respiratory tract can attenuate EAE by promoting production of the anti-inflammatory cytokine IL-10 that may suppress licensing of autoaggressive T cells in the lungs, thereby preventing their migration into the CNS. IL-17-producing T cells play a key pathogenic role in many autoimmune disorders, including MS and psoriasis, and are now major drug targets for these diseases. ?? T cells and CD4 T cells are the main sources of IL-17 during inflammation and host immunity. The current study and others have shown that IL-17-secreting V?4+ ?? T cells are found at a high frequency in the CNS of mice with EAE. This thesis describes a novel subtype of T cells distinct from conventional ?? or ?? T cells that co-express V?4, TCR? and TCR?, but not TCR?, and play a critical pathogenic role in CNS autoimmunity. TCR?-expressing V?4+ cells co-express CD4 and CD8 and constitute around 8-10% of V?4+ cells in the spleen, lymph nodes, lungs and liver. These cells are present in WT and TCR?-/- mice but not in TCR?-/- or TCR?-/- mice. Co- expression of ?, ? and ? chains was confirmed at the molecular level, revealing a restricted V?\nrepertoire with more heterogeneous V? and V? usage. ??V?4 T cells express IL-1R1, IL-23R, CD4, CD73, ICOS, CD44, CCR6 and ?4?1. Furthermore, these cells secrete IL-17A and IL- 22, following stimulation with IL-1? and IL-23 and respond to autoantigens when purified from mice with EAE. Depletion of V?4+ cells from either WT or TCR?-/- mice dramatically attenuated EAE, and this effect was associated with a significant reduction in MOG-specific IL-17, IFN-?, GM-CSF and IL-22 and CNS-infiltrating conventional Th17 cells.
Author: Sarah C. Edwards
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2898302739