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Beneficial effects of short chain fatty acids on the course of experimental autoimmune encephalomyelitis
Abstracts
143 Beneficial effects of short chain fatty acids on the course of experimental autoimmune encephalomyelitis Alexander Duscha, Johannes Berg, Jan Thöne, Seray Demir, Ralf Gold, Aiden Haghikia Department of Neurology, Ruhr-Universität, Bochum, Germany Despite there are new insights into the genetics and epigenetics of multiple sclerosis (MS) its etiology, in particular the role of the environment is still widely unknown. Lately, the role of the environment within the human organism, the gut microbiome as a potential cause for complex disorders has gained attention. The microbiomic theory has, however, raised new questions, i.e. which factors fundamentally influence the composition of the gut microbiome in individuals and whether nutrition may beneficially influence the microbiome and course of disease. Recent findings suggest that fatty acids may influence the immune response, and hence, alter the natural course of immune related disorders. We investigated the role of short chain fatty acids (SCFA), in particular propionic acid (PA) on the course of experimental autoimmune encephalomyelitis (EAE). MOG-immunized C57/Bl6-mice were either treated with PA from the day of immunization (prophylactic group; n = 15), or the solvent (water control group; n = 29), or with PA after onset of first EAE symptoms (therapeutic group; n = 25) via oral gavage. We then quantified the extent of spinal cord demyelination and neuronal damage and assessed possible changes in immune cell subsets in the peripheral and gut compartments. We observed a significantly ameliorated course of EAE in the prophylactic group as compared to the water control group. However, the therapeutic group did not reveal any significant differences to the water control group. Within the spinal cord we observed considerably less demyelination and axonal damage in the prophylactic group. So far, our results point to shift towards increased regulatory elements (FOXP3 + CD25+) within the gut compartment. Our findings suggest that SCFA as shown for PA may influence the course of EAE. The first data point to a direct effect of SCFA on regulatory immune cells within the lamina propria of gut. However, since SCFA are produced by resident gut bacteria from indigestible carbohydrates, e.g. vegetables, the question remains whether the effect seen in our setup may be partially due to the induction/ proliferation of a certain phylum or class of bacteria that preferably produce SCFA. If so, change in diet may become an integral part of MS therapy in addition to immunomodulatory drugs.
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migraine-like headaches. Anti-neuronal antibodies directed against intracellular or membrane antigens have previously been identified in HaNDL patients' serum and/or CSF samples supporting the presence of an immune response against the central nervous system. Materials and Methods: Sera of 5 HaNDL patients and 10 each age/ gender matched multiple sclerosis (MS), migraine patients and healthy controls were included. Pooled sera of five HaNDL patients and 30 controls were screened by protein macroarray. All sera were also individually subjected to immunoprecipitation with neuroblastoma cells and the bound antigens were identified by using an HPLC system and an ion trap mass spectrometer. Results: Protein macroarray analysis identified 73 clones reactive with only HaNDL patients' pooled sera. Mass spectrometry analysis of immunoprecipitated bands that were only obtained by HaNDL patients' sera yielded 5 proteins above the cutoff score. Notably, three of them were DNA repair proteins (DRPs) which were also identified by protein macroarray. Mitogen activated protein kinase-4 (MAPK-4) and DNAdependent protein kinase catalytic subunit (DPKCU) antibodies were detected in 3 patients, whereas DNA excision repair protein-6 (ERCC-6) antibody was found in one patient. Discussion: In this study, antibodies directed against same DRPs were identified in HaNDL patients' sera by two independent methods. MAPK4 and ERCC-6 antibodies have not been previously reported, whereas antibodies to DPKCU have been commonly associated with autoimmune connective tissue disorders. Inflammation-induced DNA damage and apoptosis might induce formation of nucleoprotein complexes and also increase cleavage of DRP leading to presentation of novel epitopes capable of activating autoreactive T cells. Alternatively, DRP antibodies might also cause increased DNA damage and apoptosis thereby triggering autoimmunity. Thus presence of DRP antibodies indicates DNA damage and emphasizes inflammation as a contributor of HaNDL pathogenesis. Keywords: HaNDL; DNA repair; antibody; protein macroarray; immunoprecipitation doi:10.1016/j.jneuroim.2014.08.155
192 Affinity-dependent effects of Teriflunomide and impact on T cell metabolism Melanie Eschborna, Maren Lindnera, Vilmos Posevitza, Dietmar Zehnb, Heinz Wiendla, Luisa Klotza a
Department of Neurology, University Hospital Münster, Münster, Germany; bSwiss Vaccine Research Institute, University Hospital Lausanne, Lausanne, Switzerland
doi:10.1016/j.jneuroim.2014.08.154
134 Antibodies to DNA repair proteins in HaNDL patients Ece Erdaga, Erdem Tuzuna, Murat Kurtuncub, Burcak Vurala a
Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey; bFaculty of Medicine, Istanbul University, Istanbul, Turkey
Introduction: Syndrome of transient headache and neurological deficits with cerebrospinal fluid (CSF) lymphocytosis (HaNDL) is characterized by episodes of temporary neurological symptoms and
Teriflunomide (TF) is a novel oral agent that has been shown to reduce disease activity in relapsing–remitting multiple sclerosis (MS) and has already been approved as the first-line therapy for MS. TF reduces the de novo pyrimidine synthesis pathway by inhibiting dihydroorotate dehydrogenase (DHODH) activity thereby limiting lymphocyte expansion. It is known that a DHODH independent alternative pyrimidine supply pathway also exists (salvage pathway) which is used by resting lymphocytes, however the pyrimidine demand of activated cells can be fueled only by the de novo pathway. Therefore, TF has been so far regarded as a mild but global suppressor of proliferation of activated lymphocytes. We wanted to investigate whether the extent of TF-mediated effects might depend on the quality of T cell activation. Therefore, we took advantage of the model antigen system ovalbumin (OVA) and performed in vitro stimulation of OVA-specific CD8+ T cells (OT-I
143 Beneficial effects of short chain fatty acids on the course of experimental autoimmune encephalomyelitis Alexander Duscha, Johannes Berg, Jan Thöne, Seray Demir, Ralf Gold, Aiden Haghikia Department of Neurology, Ruhr-Universität, Bochum, Germany Despite there are new insights into the genetics and epigenetics of multiple sclerosis (MS) its etiology, in particular the role of the environment is still widely unknown. Lately, the role of the environment within the human organism, the gut microbiome as a potential cause for complex disorders has gained attention. The microbiomic theory has, however, raised new questions, i.e. which factors fundamentally influence the composition of the gut microbiome in individuals and whether nutrition may beneficially influence the microbiome and course of disease. Recent findings suggest that fatty acids may influence the immune response, and hence, alter the natural course of immune related disorders. We investigated the role of short chain fatty acids (SCFA), in particular propionic acid (PA) on the course of experimental autoimmune encephalomyelitis (EAE). MOG-immunized C57/Bl6-mice were either treated with PA from the day of immunization (prophylactic group; n = 15), or the solvent (water control group; n = 29), or with PA after onset of first EAE symptoms (therapeutic group; n = 25) via oral gavage. We then quantified the extent of spinal cord demyelination and neuronal damage and assessed possible changes in immune cell subsets in the peripheral and gut compartments. We observed a significantly ameliorated course of EAE in the prophylactic group as compared to the water control group. However, the therapeutic group did not reveal any significant differences to the water control group. Within the spinal cord we observed considerably less demyelination and axonal damage in the prophylactic group. So far, our results point to shift towards increased regulatory elements (FOXP3 + CD25+) within the gut compartment. Our findings suggest that SCFA as shown for PA may influence the course of EAE. The first data point to a direct effect of SCFA on regulatory immune cells within the lamina propria of gut. However, since SCFA are produced by resident gut bacteria from indigestible carbohydrates, e.g. vegetables, the question remains whether the effect seen in our setup may be partially due to the induction/ proliferation of a certain phylum or class of bacteria that preferably produce SCFA. If so, change in diet may become an integral part of MS therapy in addition to immunomodulatory drugs.
59
migraine-like headaches. Anti-neuronal antibodies directed against intracellular or membrane antigens have previously been identified in HaNDL patients' serum and/or CSF samples supporting the presence of an immune response against the central nervous system. Materials and Methods: Sera of 5 HaNDL patients and 10 each age/ gender matched multiple sclerosis (MS), migraine patients and healthy controls were included. Pooled sera of five HaNDL patients and 30 controls were screened by protein macroarray. All sera were also individually subjected to immunoprecipitation with neuroblastoma cells and the bound antigens were identified by using an HPLC system and an ion trap mass spectrometer. Results: Protein macroarray analysis identified 73 clones reactive with only HaNDL patients' pooled sera. Mass spectrometry analysis of immunoprecipitated bands that were only obtained by HaNDL patients' sera yielded 5 proteins above the cutoff score. Notably, three of them were DNA repair proteins (DRPs) which were also identified by protein macroarray. Mitogen activated protein kinase-4 (MAPK-4) and DNAdependent protein kinase catalytic subunit (DPKCU) antibodies were detected in 3 patients, whereas DNA excision repair protein-6 (ERCC-6) antibody was found in one patient. Discussion: In this study, antibodies directed against same DRPs were identified in HaNDL patients' sera by two independent methods. MAPK4 and ERCC-6 antibodies have not been previously reported, whereas antibodies to DPKCU have been commonly associated with autoimmune connective tissue disorders. Inflammation-induced DNA damage and apoptosis might induce formation of nucleoprotein complexes and also increase cleavage of DRP leading to presentation of novel epitopes capable of activating autoreactive T cells. Alternatively, DRP antibodies might also cause increased DNA damage and apoptosis thereby triggering autoimmunity. Thus presence of DRP antibodies indicates DNA damage and emphasizes inflammation as a contributor of HaNDL pathogenesis. Keywords: HaNDL; DNA repair; antibody; protein macroarray; immunoprecipitation doi:10.1016/j.jneuroim.2014.08.155
192 Affinity-dependent effects of Teriflunomide and impact on T cell metabolism Melanie Eschborna, Maren Lindnera, Vilmos Posevitza, Dietmar Zehnb, Heinz Wiendla, Luisa Klotza a
Department of Neurology, University Hospital Münster, Münster, Germany; bSwiss Vaccine Research Institute, University Hospital Lausanne, Lausanne, Switzerland
doi:10.1016/j.jneuroim.2014.08.154
134 Antibodies to DNA repair proteins in HaNDL patients Ece Erdaga, Erdem Tuzuna, Murat Kurtuncub, Burcak Vurala a
Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey; bFaculty of Medicine, Istanbul University, Istanbul, Turkey
Introduction: Syndrome of transient headache and neurological deficits with cerebrospinal fluid (CSF) lymphocytosis (HaNDL) is characterized by episodes of temporary neurological symptoms and
Teriflunomide (TF) is a novel oral agent that has been shown to reduce disease activity in relapsing–remitting multiple sclerosis (MS) and has already been approved as the first-line therapy for MS. TF reduces the de novo pyrimidine synthesis pathway by inhibiting dihydroorotate dehydrogenase (DHODH) activity thereby limiting lymphocyte expansion. It is known that a DHODH independent alternative pyrimidine supply pathway also exists (salvage pathway) which is used by resting lymphocytes, however the pyrimidine demand of activated cells can be fueled only by the de novo pathway. Therefore, TF has been so far regarded as a mild but global suppressor of proliferation of activated lymphocytes. We wanted to investigate whether the extent of TF-mediated effects might depend on the quality of T cell activation. Therefore, we took advantage of the model antigen system ovalbumin (OVA) and performed in vitro stimulation of OVA-specific CD8+ T cells (OT-I