Puberty is a dynamic period marked by changing levels of sex hormones, the development of seconda... more Puberty is a dynamic period marked by changing levels of sex hormones, the development of secondary sexual characteristics and reproductive maturity. This period has profound effects on various organ systems, including the immune system. The critical changes that occur in the immune system during pubertal onset have been shown to have implications for autoimmune conditions, including Multiple Sclerosis (MS). MS is rare prior to puberty but can manifest in children after puberty. This disease also has a clear female preponderance that only arises following pubertal onset, highlighting a potential role for sex hormones in autoimmunity. Early onset of puberty has also been shown to be a risk factor for MS. The purpose of this review is to overview the evidence that puberty regulates MS susceptibility and disease activity. Given that there is a paucity of studies that directly evaluate the effects of puberty on the immune system, we also discuss how the immune system is different in chi...
Peroxisome proliferator-activated receptors (PPARs; PPAR-, PPAR-, and PPAR-) comprise a family... more Peroxisome proliferator-activated receptors (PPARs; PPAR-, PPAR-, and PPAR-) comprise a family of nuclear receptors that sense fatty acid levels and translate this information into altered gene transcription. Previously, it was reported that treatment of mice with a synthetic ligand activator of PPAR-, GW0742, ameliorates experimental autoimmune encephalomyelitis (EAE), indicating a possible role for this nuclear receptor in the control of central nervous system (CNS) autoimmune inflammation. We show that mice deficient in PPAR- (PPAR- /) develop a severe inflammatory response during EAE characterized by a striking accumulation of IFN- + IL-17A and IFN- + IL-17A + CD4 + cells in the spinal cord. The preferential expansion of these T helper subsets in the CNS of PPAR- / mice occurred as a result of a constellation of immune system aberrations that included higher CD4 + cell proliferation, cytokine production, and T-bet expression and enhanced expression of IL-12 family cytokines by myeloid cells. We also show that the effect of PPAR- in inhibiting the production of IFN- and IL-12 family cytokines is ligand dependent and is observed in both mouse and human immune cells. Collectively, these findings suggest that PPAR- serves as an important molecular brake for the control of autoimmune inflammation.
To investigate acute graft-versus-host disease (GVHD) protection in the murine regimen of total l... more To investigate acute graft-versus-host disease (GVHD) protection in the murine regimen of total lymphoid irradiation and anti-thymocyte serum (TLI/ATS), we performed transplants of 50 × 10 6 bone marrow cells and 60 × 10 6 splenocytes (BMT) from wild-type (WT) C57BL/6 donors into WT BALB/c hosts treated with TLI/ATS or control BALB/c hosts given 800 cGy total body irradiation (TBI) and ATS. TLI/ATS-conditioned WT hosts given BMT from WT donors all survived 100 days without GVHD. BMT from WT donors into TBI/ATS treated WT hosts resulted in lethal GVHD. TLI/ATS-treated natural killer (NK) Tcell deficient Jα18−/− hosts also died of GVHD. TLI/ATS conditioned WT hosts receiving WT BMT demonstrated a significant (pb 0.01) increase in the absolute number of donor CD4+CD25+Foxp3+ cells (CD4+ Tregs) in the spleen at day 6 after BMT relative to TBI/ATS controls or TLI/ATS-treated Jα18−/− hosts. All BMT groups developing GVHD demonstrated dramatic donor CD8+ T cell accumulation in the mesenteric lymph nodes (MLN) and colon at day 6 after BMT. Adoptive transfer of sorted BALB/c NK T cells protected TLI/ATS-treated Jα18−/− hosts from donor CD8+ T cell accumulation, with a significant (pb 0.001) increase in the absolute number of donor CD4+ Tregs in the host spleen at day 6. Depletion of CD25+ T cells before BMT into TLI/ATS-treated WT hosts resulted in loss of donor CD4+ Tregs in the host spleen and lethal GVHD. The present studies show that both host NK Tcells and donor CD4+CD25+Foxp3+ Tregs are required to protect against GVHD after TLI/ATS conditioning and allogeneic BMT.
3-Hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, 'statins' are widely used or... more 3-Hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, 'statins' are widely used oral cholesterol-lowering drugs. Statins competitively inhibit HMG-CoA reductase, the enzyme that catalyzes conversion of HMG-CoA to L-mevalonate, a key intermediate in cholesterol synthesis. Certain metabolites of mevalonate are also involved in posttranslational modification of specific proteins involved in cell proliferation and differentiation. Thus, statins have important biologic effects that may be independent of their choles-
Background: Being obese is associated with both increased risk of developing multiple sclerosis (... more Background: Being obese is associated with both increased risk of developing multiple sclerosis (MS) and greater MS disease activity. Objectives: The objective of this study is to investigate levels and potential pathophysiologic contribution of serum adipose-hormones (adipokines) in pediatric-onset MS. Methods: Following a Luminex adipokine screen, adiponectin (APN) and its isoforms were quantified by enzyme-linked immunosorbent assay (ELISA) in 169 children with incident acquired demyelinating syndromes (ADS), prospectively ascertained as having either MS or other forms of inflammatory central nervous system (CNS) demyelination. The effect of recombinant APN and APN-containing sera was assessed on functional responses of normal human peripheral blood myeloid and T cells and on human CNS-derived microglia. Results: Compared to other cohorts, children with MS harbored higher serum APN levels, principally driven by higher levels of the low-molecular-weight isoform. Recombinant APN an...
Peptidyl arginine deiminases have been shown to be hyperactive in neurodegenerative diseases incl... more Peptidyl arginine deiminases have been shown to be hyperactive in neurodegenerative diseases including multiple sclerosis. An -amino acid based core structure, derived from a hydantoin core, with unique heterocycles on the side chains were synthesized as potential non-covalent inhibitors of PAD enzymes. Amongst the various heterocycles investigated, compound 23 carrying an imidazole moiety, exhibited the highest potency in this series with some selectivity for PAD2, and was further investigated in vivo. Pharmacokinetics in mice suggested the Cmax to be 12.0 ± 2.5 μg/mL and 170 ± 10 ng/mL in the serum and brain, respectively, when compound 23 was administered at 50 mg/kg via single dose i.p. At the same dose, compound 23 also reversed physical disability and cleared the brain of T-cell infiltration in an EAE mouse model of multiple sclerosis (MS). This novel series of compounds show promise for further development as disease modifying agents for the potential treatment of MS.
Journal of immunology (Baltimore, Md. : 1950), Jan 21, 2015
Females exhibit more robust Th1 responses than males. Our previous work suggested that this sex d... more Females exhibit more robust Th1 responses than males. Our previous work suggested that this sex disparity is a consequence of higher activity of the androgen-induced gene peroxisome proliferator-activated receptor α (PPARα) in male CD4(+) T cells. The objective of this study was to elucidate the cellular and molecular mechanism of how PPARα inhibits Th1 responses in male mice. In this study, we found that PPARα functions within CD4(+) and CD8(+) T lymphocytes and NKT cells to negatively regulate IFN-γ responses in male mice and identified Ifng as the gene target of PPARα repression. Treatment of male CD4(+) T cells with the PPARα agonist fenofibrate induced the recruitment of PPARα and the nuclear receptor-interacting protein, nuclear receptor corepressor 1, to specific cis-regulatory elements in the Ifng locus. This recruitment associated with reduced histone acetylation at these sites. Knockdown of nuclear receptor corepressor 1 in primary male T cells abolished the effect of feno...
Peroxisome proliferator-activated receptors (PPARs; PPAR-alpha, PPAR-delta, and PPAR-gamma) compr... more Peroxisome proliferator-activated receptors (PPARs; PPAR-alpha, PPAR-delta, and PPAR-gamma) comprise a family of nuclear receptors that sense fatty acid levels and translate this information into altered gene transcription. Previously, it was reported that treatment of mice with a synthetic ligand activator of PPAR-delta, GW0742, ameliorates experimental autoimmune encephalomyelitis (EAE), indicating a possible role for this nuclear receptor in the control of central nervous system (CNS) autoimmune inflammation. We show that mice deficient in PPAR-delta (PPAR-delta(-/-)) develop a severe inflammatory response during EAE characterized by a striking accumulation of IFN-gamma(+)IL-17A(-) and IFN-gamma(+)IL-17A(+) CD4(+) cells in the spinal cord. The preferential expansion of these T helper subsets in the CNS of PPAR-delta(-/-) mice occurred as a result of a constellation of immune system aberrations that included higher CD4(+) cell proliferation, cytokine production, and T-bet expressi...
Proceedings of the National Academy of Sciences, 2012
Women develop certain autoimmune diseases more often than men. It has been hypothesized that this... more Women develop certain autoimmune diseases more often than men. It has been hypothesized that this may relate to the development of more robust T-helper (Th)1 responses in women. To test whether women exhibit a Th1 bias, we isolated naïve cluster of differentiation (CD)4+ T cells from peripheral blood of healthy women and men and measured the proliferation and cytokine production by these cells in response to submaximal amounts of anti-CD3 and anti-CD28. We observed that CD4+ T cells from women produced higher levels of IFNγ as well as tended to proliferate more than male CD4+ T cells. Intriguingly, male CD4+ T cells instead had a predilection toward IL-17A production. This sex dichotomy in Th cytokine production was found to be even more striking in the Swiss/Jackson Laboratory (SJL) mouse. Studies in mice and humans indicated that the sexual dimorphism in Th1 and Th17 cytokine production was dependent on the androgen status and the T-cell expression of peroxisome proliferator activ...
Proceedings of the National Academy of Sciences, 2019
Significance EAE typically presents with hind-limb paralysis and is associated with severe T cell... more Significance EAE typically presents with hind-limb paralysis and is associated with severe T cell-mediated inflammation and axon injury throughout the spinal cord and parts of the brain. Because axon loss is so rapid in this model, it is difficult to intervene for the purpose of evaluating neuroprotective therapies. Here we describe a mild form of EAE that does not even meet the threshold for scoring on traditional EAE scales, yet with age results in devastating neurodegenerative changes in the spinal cord, including grey matter atrophy, neuron loss, and synapse degradation. These observations underscore the utility of T cell receptor transgenic mice to study the effect of natural aging on CNS autoimmunity and neurodegeneration.
Multiple sclerosis (MS) is a CNS-demyelinating disease characterised by relapsing and chronic neu... more Multiple sclerosis (MS) is a CNS-demyelinating disease characterised by relapsing and chronic neurological impairment. While traditionally CNS autoantigen-specific CD4 + T cells have been considered the culprits in the initial phase of the disease, recent observations have altered this concept. It is now recognised that other T lymphocyte subclasses can initiate CNS demyelination. In addition, other cell types and molecules may play an important role in MS pathogenesis. There is overwhelming evidence that MS is a dynamic process, in which recurrent episodes of blood-brain barrier disruption and CNS inflammation play a crucial role in early disease stages, leading eventually to the largely irreversible changes of demyelination, gliosis and axonal degeneration. These observations may have important therapeutic implications. Within the last ten years, several medications have been approved for MS treatment. These agents, all of which are given parenterally, are only partially effective and are often associated with adverse effects and potential toxicities. The number and different types of medications used for MS are likely to increase in the near future, as several novel therapies are currently tested in clinical trials. 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors, 'statins', are cholesterol-lowering drugs that are given orally, are safe and have biological effects independent of their cholesterol-reducing properties. Recent reports have shown that statins have anti-inflammatory and neuroprotective properties that may be beneficial in the treatment of MS. This article will outline experimental evidence that suggests potential clinical benefits of statins for MS patients.
Ovarian cancer G protein-coupled receptor 1 (OGR1) is a proton-sensing molecule that can detect d... more Ovarian cancer G protein-coupled receptor 1 (OGR1) is a proton-sensing molecule that can detect decreases in extracellular pH that occur during inflammation. Although OGR1 has been shown to have pro-inflammatory functions in various diseases, its role in autoimmunity has not been examined. We therefore sought to determine whether OGR1 has a role in the development of T cell autoimmunity by contrasting the development of experimental autoimmune encephalomyelitis between wild type and OGR1-knockout mice. OGR1-knockout mice showed a drastically attenuated clinical course of disease that was associated with a profound reduction in the expansion of myelin oligodendrocyte glycoprotein 35-55-reactive T helper 1 (Th1) and Th17 cells in the periphery and a reduced accumulation of Th1 and Th17 effectors in the central nervous system. We determined that these impaired T cell responses in OGR1-knockout mice associated with a reduced frequency and number of dendritic cells in draining lymph node...
Multiple Sclerosis (MS) is an inflammatory, neurodegenerative autoimmune disease associated with ... more Multiple Sclerosis (MS) is an inflammatory, neurodegenerative autoimmune disease associated with sensory and motor dysfunction. Although estimates vary, ∼50% of patients with MS experience pain during their disease. The mechanisms underlying the development of pain are not fully understood and no effective treatment for MS related pain is available. Previous work from our laboratory demonstrated that voluntary exercise (wheel running) can reduce nociceptive behaviours at disease onset in female mice with experimental autoimmune encephalomyelitis (EAE), an animal model used to study the immunopathogenesis of MS. However, given the established sex differences in the underlying mechanisms of chronic pain and MS, we wanted to investigate whether wheel running would also be effective at preventing nociceptive behaviours in male mice with EAE. C57BL/6 mice of both sexes were given access to running wheels for 1h/day until disease onset, when nociceptive behaviour was assessed using von Frey hairs. Daily running effectively reduced nociceptive behaviour in female mice, but not in males. We explored the potential biological mechanisms for these effects and found the reduction in nociceptive behaviour in females was associated with reduced levels of inflammatory cytokines from myelin-reactive T cells as well as reduced DRG excitability as seen by decreased calcium responses. These changes were not seen in male mice. Instead, running increased the levels of inflammatory cytokines and potentiated Ca responses in DRG cells. Our results show that voluntary wheel running has sex dependent effects on nociceptive behaviour and inflammatory responses in male and female mice with EAE.
Puberty is a dynamic period marked by changing levels of sex hormones, the development of seconda... more Puberty is a dynamic period marked by changing levels of sex hormones, the development of secondary sexual characteristics and reproductive maturity. This period has profound effects on various organ systems, including the immune system. The critical changes that occur in the immune system during pubertal onset have been shown to have implications for autoimmune conditions, including Multiple Sclerosis (MS). MS is rare prior to puberty but can manifest in children after puberty. This disease also has a clear female preponderance that only arises following pubertal onset, highlighting a potential role for sex hormones in autoimmunity. Early onset of puberty has also been shown to be a risk factor for MS. The purpose of this review is to overview the evidence that puberty regulates MS susceptibility and disease activity. Given that there is a paucity of studies that directly evaluate the effects of puberty on the immune system, we also discuss how the immune system is different in chi...
Peroxisome proliferator-activated receptors (PPARs; PPAR-, PPAR-, and PPAR-) comprise a family... more Peroxisome proliferator-activated receptors (PPARs; PPAR-, PPAR-, and PPAR-) comprise a family of nuclear receptors that sense fatty acid levels and translate this information into altered gene transcription. Previously, it was reported that treatment of mice with a synthetic ligand activator of PPAR-, GW0742, ameliorates experimental autoimmune encephalomyelitis (EAE), indicating a possible role for this nuclear receptor in the control of central nervous system (CNS) autoimmune inflammation. We show that mice deficient in PPAR- (PPAR- /) develop a severe inflammatory response during EAE characterized by a striking accumulation of IFN- + IL-17A and IFN- + IL-17A + CD4 + cells in the spinal cord. The preferential expansion of these T helper subsets in the CNS of PPAR- / mice occurred as a result of a constellation of immune system aberrations that included higher CD4 + cell proliferation, cytokine production, and T-bet expression and enhanced expression of IL-12 family cytokines by myeloid cells. We also show that the effect of PPAR- in inhibiting the production of IFN- and IL-12 family cytokines is ligand dependent and is observed in both mouse and human immune cells. Collectively, these findings suggest that PPAR- serves as an important molecular brake for the control of autoimmune inflammation.
To investigate acute graft-versus-host disease (GVHD) protection in the murine regimen of total l... more To investigate acute graft-versus-host disease (GVHD) protection in the murine regimen of total lymphoid irradiation and anti-thymocyte serum (TLI/ATS), we performed transplants of 50 × 10 6 bone marrow cells and 60 × 10 6 splenocytes (BMT) from wild-type (WT) C57BL/6 donors into WT BALB/c hosts treated with TLI/ATS or control BALB/c hosts given 800 cGy total body irradiation (TBI) and ATS. TLI/ATS-conditioned WT hosts given BMT from WT donors all survived 100 days without GVHD. BMT from WT donors into TBI/ATS treated WT hosts resulted in lethal GVHD. TLI/ATS-treated natural killer (NK) Tcell deficient Jα18−/− hosts also died of GVHD. TLI/ATS conditioned WT hosts receiving WT BMT demonstrated a significant (pb 0.01) increase in the absolute number of donor CD4+CD25+Foxp3+ cells (CD4+ Tregs) in the spleen at day 6 after BMT relative to TBI/ATS controls or TLI/ATS-treated Jα18−/− hosts. All BMT groups developing GVHD demonstrated dramatic donor CD8+ T cell accumulation in the mesenteric lymph nodes (MLN) and colon at day 6 after BMT. Adoptive transfer of sorted BALB/c NK T cells protected TLI/ATS-treated Jα18−/− hosts from donor CD8+ T cell accumulation, with a significant (pb 0.001) increase in the absolute number of donor CD4+ Tregs in the host spleen at day 6. Depletion of CD25+ T cells before BMT into TLI/ATS-treated WT hosts resulted in loss of donor CD4+ Tregs in the host spleen and lethal GVHD. The present studies show that both host NK Tcells and donor CD4+CD25+Foxp3+ Tregs are required to protect against GVHD after TLI/ATS conditioning and allogeneic BMT.
3-Hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, 'statins' are widely used or... more 3-Hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, 'statins' are widely used oral cholesterol-lowering drugs. Statins competitively inhibit HMG-CoA reductase, the enzyme that catalyzes conversion of HMG-CoA to L-mevalonate, a key intermediate in cholesterol synthesis. Certain metabolites of mevalonate are also involved in posttranslational modification of specific proteins involved in cell proliferation and differentiation. Thus, statins have important biologic effects that may be independent of their choles-
Background: Being obese is associated with both increased risk of developing multiple sclerosis (... more Background: Being obese is associated with both increased risk of developing multiple sclerosis (MS) and greater MS disease activity. Objectives: The objective of this study is to investigate levels and potential pathophysiologic contribution of serum adipose-hormones (adipokines) in pediatric-onset MS. Methods: Following a Luminex adipokine screen, adiponectin (APN) and its isoforms were quantified by enzyme-linked immunosorbent assay (ELISA) in 169 children with incident acquired demyelinating syndromes (ADS), prospectively ascertained as having either MS or other forms of inflammatory central nervous system (CNS) demyelination. The effect of recombinant APN and APN-containing sera was assessed on functional responses of normal human peripheral blood myeloid and T cells and on human CNS-derived microglia. Results: Compared to other cohorts, children with MS harbored higher serum APN levels, principally driven by higher levels of the low-molecular-weight isoform. Recombinant APN an...
Peptidyl arginine deiminases have been shown to be hyperactive in neurodegenerative diseases incl... more Peptidyl arginine deiminases have been shown to be hyperactive in neurodegenerative diseases including multiple sclerosis. An -amino acid based core structure, derived from a hydantoin core, with unique heterocycles on the side chains were synthesized as potential non-covalent inhibitors of PAD enzymes. Amongst the various heterocycles investigated, compound 23 carrying an imidazole moiety, exhibited the highest potency in this series with some selectivity for PAD2, and was further investigated in vivo. Pharmacokinetics in mice suggested the Cmax to be 12.0 ± 2.5 μg/mL and 170 ± 10 ng/mL in the serum and brain, respectively, when compound 23 was administered at 50 mg/kg via single dose i.p. At the same dose, compound 23 also reversed physical disability and cleared the brain of T-cell infiltration in an EAE mouse model of multiple sclerosis (MS). This novel series of compounds show promise for further development as disease modifying agents for the potential treatment of MS.
Journal of immunology (Baltimore, Md. : 1950), Jan 21, 2015
Females exhibit more robust Th1 responses than males. Our previous work suggested that this sex d... more Females exhibit more robust Th1 responses than males. Our previous work suggested that this sex disparity is a consequence of higher activity of the androgen-induced gene peroxisome proliferator-activated receptor α (PPARα) in male CD4(+) T cells. The objective of this study was to elucidate the cellular and molecular mechanism of how PPARα inhibits Th1 responses in male mice. In this study, we found that PPARα functions within CD4(+) and CD8(+) T lymphocytes and NKT cells to negatively regulate IFN-γ responses in male mice and identified Ifng as the gene target of PPARα repression. Treatment of male CD4(+) T cells with the PPARα agonist fenofibrate induced the recruitment of PPARα and the nuclear receptor-interacting protein, nuclear receptor corepressor 1, to specific cis-regulatory elements in the Ifng locus. This recruitment associated with reduced histone acetylation at these sites. Knockdown of nuclear receptor corepressor 1 in primary male T cells abolished the effect of feno...
Peroxisome proliferator-activated receptors (PPARs; PPAR-alpha, PPAR-delta, and PPAR-gamma) compr... more Peroxisome proliferator-activated receptors (PPARs; PPAR-alpha, PPAR-delta, and PPAR-gamma) comprise a family of nuclear receptors that sense fatty acid levels and translate this information into altered gene transcription. Previously, it was reported that treatment of mice with a synthetic ligand activator of PPAR-delta, GW0742, ameliorates experimental autoimmune encephalomyelitis (EAE), indicating a possible role for this nuclear receptor in the control of central nervous system (CNS) autoimmune inflammation. We show that mice deficient in PPAR-delta (PPAR-delta(-/-)) develop a severe inflammatory response during EAE characterized by a striking accumulation of IFN-gamma(+)IL-17A(-) and IFN-gamma(+)IL-17A(+) CD4(+) cells in the spinal cord. The preferential expansion of these T helper subsets in the CNS of PPAR-delta(-/-) mice occurred as a result of a constellation of immune system aberrations that included higher CD4(+) cell proliferation, cytokine production, and T-bet expressi...
Proceedings of the National Academy of Sciences, 2012
Women develop certain autoimmune diseases more often than men. It has been hypothesized that this... more Women develop certain autoimmune diseases more often than men. It has been hypothesized that this may relate to the development of more robust T-helper (Th)1 responses in women. To test whether women exhibit a Th1 bias, we isolated naïve cluster of differentiation (CD)4+ T cells from peripheral blood of healthy women and men and measured the proliferation and cytokine production by these cells in response to submaximal amounts of anti-CD3 and anti-CD28. We observed that CD4+ T cells from women produced higher levels of IFNγ as well as tended to proliferate more than male CD4+ T cells. Intriguingly, male CD4+ T cells instead had a predilection toward IL-17A production. This sex dichotomy in Th cytokine production was found to be even more striking in the Swiss/Jackson Laboratory (SJL) mouse. Studies in mice and humans indicated that the sexual dimorphism in Th1 and Th17 cytokine production was dependent on the androgen status and the T-cell expression of peroxisome proliferator activ...
Proceedings of the National Academy of Sciences, 2019
Significance EAE typically presents with hind-limb paralysis and is associated with severe T cell... more Significance EAE typically presents with hind-limb paralysis and is associated with severe T cell-mediated inflammation and axon injury throughout the spinal cord and parts of the brain. Because axon loss is so rapid in this model, it is difficult to intervene for the purpose of evaluating neuroprotective therapies. Here we describe a mild form of EAE that does not even meet the threshold for scoring on traditional EAE scales, yet with age results in devastating neurodegenerative changes in the spinal cord, including grey matter atrophy, neuron loss, and synapse degradation. These observations underscore the utility of T cell receptor transgenic mice to study the effect of natural aging on CNS autoimmunity and neurodegeneration.
Multiple sclerosis (MS) is a CNS-demyelinating disease characterised by relapsing and chronic neu... more Multiple sclerosis (MS) is a CNS-demyelinating disease characterised by relapsing and chronic neurological impairment. While traditionally CNS autoantigen-specific CD4 + T cells have been considered the culprits in the initial phase of the disease, recent observations have altered this concept. It is now recognised that other T lymphocyte subclasses can initiate CNS demyelination. In addition, other cell types and molecules may play an important role in MS pathogenesis. There is overwhelming evidence that MS is a dynamic process, in which recurrent episodes of blood-brain barrier disruption and CNS inflammation play a crucial role in early disease stages, leading eventually to the largely irreversible changes of demyelination, gliosis and axonal degeneration. These observations may have important therapeutic implications. Within the last ten years, several medications have been approved for MS treatment. These agents, all of which are given parenterally, are only partially effective and are often associated with adverse effects and potential toxicities. The number and different types of medications used for MS are likely to increase in the near future, as several novel therapies are currently tested in clinical trials. 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors, 'statins', are cholesterol-lowering drugs that are given orally, are safe and have biological effects independent of their cholesterol-reducing properties. Recent reports have shown that statins have anti-inflammatory and neuroprotective properties that may be beneficial in the treatment of MS. This article will outline experimental evidence that suggests potential clinical benefits of statins for MS patients.
Ovarian cancer G protein-coupled receptor 1 (OGR1) is a proton-sensing molecule that can detect d... more Ovarian cancer G protein-coupled receptor 1 (OGR1) is a proton-sensing molecule that can detect decreases in extracellular pH that occur during inflammation. Although OGR1 has been shown to have pro-inflammatory functions in various diseases, its role in autoimmunity has not been examined. We therefore sought to determine whether OGR1 has a role in the development of T cell autoimmunity by contrasting the development of experimental autoimmune encephalomyelitis between wild type and OGR1-knockout mice. OGR1-knockout mice showed a drastically attenuated clinical course of disease that was associated with a profound reduction in the expansion of myelin oligodendrocyte glycoprotein 35-55-reactive T helper 1 (Th1) and Th17 cells in the periphery and a reduced accumulation of Th1 and Th17 effectors in the central nervous system. We determined that these impaired T cell responses in OGR1-knockout mice associated with a reduced frequency and number of dendritic cells in draining lymph node...
Multiple Sclerosis (MS) is an inflammatory, neurodegenerative autoimmune disease associated with ... more Multiple Sclerosis (MS) is an inflammatory, neurodegenerative autoimmune disease associated with sensory and motor dysfunction. Although estimates vary, ∼50% of patients with MS experience pain during their disease. The mechanisms underlying the development of pain are not fully understood and no effective treatment for MS related pain is available. Previous work from our laboratory demonstrated that voluntary exercise (wheel running) can reduce nociceptive behaviours at disease onset in female mice with experimental autoimmune encephalomyelitis (EAE), an animal model used to study the immunopathogenesis of MS. However, given the established sex differences in the underlying mechanisms of chronic pain and MS, we wanted to investigate whether wheel running would also be effective at preventing nociceptive behaviours in male mice with EAE. C57BL/6 mice of both sexes were given access to running wheels for 1h/day until disease onset, when nociceptive behaviour was assessed using von Frey hairs. Daily running effectively reduced nociceptive behaviour in female mice, but not in males. We explored the potential biological mechanisms for these effects and found the reduction in nociceptive behaviour in females was associated with reduced levels of inflammatory cytokines from myelin-reactive T cells as well as reduced DRG excitability as seen by decreased calcium responses. These changes were not seen in male mice. Instead, running increased the levels of inflammatory cytokines and potentiated Ca responses in DRG cells. Our results show that voluntary wheel running has sex dependent effects on nociceptive behaviour and inflammatory responses in male and female mice with EAE.
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