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Proinflammatory cytokines, microRNAs and schizophrenia
62
Abstracts
lymphoid organs and the intestine for T- and B-cell subsets. Our preliminary findings of an altered distribution and cell fate of T cells in the gut suggest that T cell Smad7 modulates the immune response during OSE and reconfirm the role of Smad7 in T cell differentiation. We intend to further examine how dysregulation of immune cells in the gut contributes to EAE initiation to facilitate therapeutic modulation in the future. doi:10.1016/j.jneuroim.2014.08.162
530 Latent gammaherpesvirus infection facilitates multiple sclerosis through immune regulation Marc Horwitza, Citlali Marquez Hernandezb, Costanza Casiraghib, Iryna Shaninab a
Microbiology and Immunology — Life Sciences Institute, University of British Columbia, Vancouver, Canada; bMicrobiology and Immunology — Life Sciences Institute, UBC, Vancouver, Canada Epstein–Barr virus (EBV) has been identified as a putative trigger of multiple sclerosis (MS). We hypothesized that latent EBV infection alters the immune response to a second stimulus thereby exacerbating autoimmunity. Previously, we reported that mice latently infected with murine gamma herpesvirus 68 (gammaHV-68), the murine homolog to EBV, were induced for experimental autoimmune encephalomyelitis (EAE), they developed an enhanced neuroinflammatory disease more reminiscent of MS with lesions developing in the brain with both CNS infiltrating CD4 and CD8 T cells as well as focal demyelination. In this report, we demonstrate that when gammaHV-68 establishes latency a persistent upregulation of CD40 on dendritic cells is observed. We show that this upregulation of CD40 on DCs from latently infected mice is required to drive the priming of the strong TH1 response as well as the significant drop in Treg frequencies observed in latently infected mice before and during EAE. Further, virus latency is established in memory B cells and not dendritic cells and importantly, virus reactivation and/or replication is not observed post EAE induction. In addition, upregulation of CD40 on DCs accompanies and persists with viral latency for over 5 months post infection retaining the ability to enhance autoimmunity. We demonstrate that latent virus infection of memory B cells indirectly facilitates DC regulation of the immune response and most likely does this through changes in the balance of type I interferons. Clearly, latent gammaherpesvirus infection leaves a long-lasting immune impact that enhances subsequent immune responses leading to enhanced neuroinflammation and CNS pathology. This represents a novel mechanism by which EBV acts to influence MS.
doi:10.1016/j.jneuroim.2014.08.163
565 Proinflammatory cytokines, microRNAs and schizophrenia Sehba Husain-krauttera, Juan Gallegob, Anil Malhotrab, Thomas Rothsteina a
Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, United States; bZucker Hillside Hospital, North Shore-Long Island Jewish Health System, Glen Oaks, United States
Schizophrenia is a mental disorder associated with a poor quality of life and a high risk of mortality. The biological basis of schizophrenia is complex and reflects dysfunction in various systems that are closely interlinked such as gene expression, cellular signaling, neurotransmitter function, and immune regulation. The involvement of some facets of the immune system in the mechanisms that underlie psychiatric disorders is not unexpected as the immune system is an integral part of the biological network. Cytokines are soluble peptides made by cells of the immune system as well as certain non-immune cells and several studies have shown that patients with schizophrenia have an increase in proinflammatory cytokines in plasma and cerebrospinal fluid (CSF). Our own pilot study comprising of ten patients with schizophrenia-spectrum disorders and ten healthy volunteers matched with patients in age, sex, and race shows a significant increase in the levels of cytokines IL-1beta, IL-6 and IL-8 in the CSF of patients compared to healthy controls. MicroRNAs (miRNAs) are small molecules involved in gene regulation and known to regulate cellular processes including development, differentiation, proliferation and death. miRNAs also play a prominent role in disease and many studies have linked alterations in miRNA expression to schizophrenia and other psychiatric disorders. Preliminary work by our group in the same sample group as the cytokine analysis also shows a different microRNA expression profile in CSF of patients with schizophrenia-spectrum disorders compared to healthy volunteers. Since we observed an alteration in cytokine levels as well as miRNA expression in patients with schizophrenia-spectrum disorders we examined the association between these two parameters. Through initial correlation analysis we found that levels of IL-6 in the CSF negatively correlate with expression levels of at least two miRNAs capable of down regulating the IL-6 encoding gene. Understanding this association will help us elucidate events that regulate neuropsychiatric disorders. We believe that this could lead to new potential therapeutic targets to treat schizophrenia through the discovery of new molecules and pathways involved in the disease process. doi:10.1016/j.jneuroim.2014.08.164
396 Anti-murine CD52 antibody treatment does not adversely affect the migratory ability of immune cells Evis Havaria, Michael J. Turnera, James C. Dodgeb, Christopher Treleavenb, Lamya S. Shihabuddinb, Bruce L. Robertsa, Johanne M. Kaplana, William M. Sidersa a
Neuroimmunology Research, Genzyme, a Sanofi company, Framingham, MA, United States; bNeuroscience, Genzyme, a Sanofi company, Framingham, MA, United States Objective: To evaluate the migratory properties of various immune cell populations following anti-muCD52 treatment in murine models of inflammation. Background: Alemtuzumab, an anti-CD52 humanized monoclonal antibody, is approved in over 30 countries for active relapsing– remitting multiple sclerosis (RRMS). Alemtuzumab causes depletion of circulating lymphocytes followed by a distinctive pattern of repopulation. Alemtuzumab showed superior efficacy vs. subcutaneous interferon beta-1a in phase 3 trials in active RRMS patients who were treatment-naive (CARE-MS I; NCT00530348) or had relapsed on prior therapy (CARE-MS II; NCT00548405). An anti-muCD52 antibody was used to expand our understanding of anti-CD52 therapy in mouse models of immune cell migration.
Abstracts
lymphoid organs and the intestine for T- and B-cell subsets. Our preliminary findings of an altered distribution and cell fate of T cells in the gut suggest that T cell Smad7 modulates the immune response during OSE and reconfirm the role of Smad7 in T cell differentiation. We intend to further examine how dysregulation of immune cells in the gut contributes to EAE initiation to facilitate therapeutic modulation in the future. doi:10.1016/j.jneuroim.2014.08.162
530 Latent gammaherpesvirus infection facilitates multiple sclerosis through immune regulation Marc Horwitza, Citlali Marquez Hernandezb, Costanza Casiraghib, Iryna Shaninab a
Microbiology and Immunology — Life Sciences Institute, University of British Columbia, Vancouver, Canada; bMicrobiology and Immunology — Life Sciences Institute, UBC, Vancouver, Canada Epstein–Barr virus (EBV) has been identified as a putative trigger of multiple sclerosis (MS). We hypothesized that latent EBV infection alters the immune response to a second stimulus thereby exacerbating autoimmunity. Previously, we reported that mice latently infected with murine gamma herpesvirus 68 (gammaHV-68), the murine homolog to EBV, were induced for experimental autoimmune encephalomyelitis (EAE), they developed an enhanced neuroinflammatory disease more reminiscent of MS with lesions developing in the brain with both CNS infiltrating CD4 and CD8 T cells as well as focal demyelination. In this report, we demonstrate that when gammaHV-68 establishes latency a persistent upregulation of CD40 on dendritic cells is observed. We show that this upregulation of CD40 on DCs from latently infected mice is required to drive the priming of the strong TH1 response as well as the significant drop in Treg frequencies observed in latently infected mice before and during EAE. Further, virus latency is established in memory B cells and not dendritic cells and importantly, virus reactivation and/or replication is not observed post EAE induction. In addition, upregulation of CD40 on DCs accompanies and persists with viral latency for over 5 months post infection retaining the ability to enhance autoimmunity. We demonstrate that latent virus infection of memory B cells indirectly facilitates DC regulation of the immune response and most likely does this through changes in the balance of type I interferons. Clearly, latent gammaherpesvirus infection leaves a long-lasting immune impact that enhances subsequent immune responses leading to enhanced neuroinflammation and CNS pathology. This represents a novel mechanism by which EBV acts to influence MS.
doi:10.1016/j.jneuroim.2014.08.163
565 Proinflammatory cytokines, microRNAs and schizophrenia Sehba Husain-krauttera, Juan Gallegob, Anil Malhotrab, Thomas Rothsteina a
Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, United States; bZucker Hillside Hospital, North Shore-Long Island Jewish Health System, Glen Oaks, United States
Schizophrenia is a mental disorder associated with a poor quality of life and a high risk of mortality. The biological basis of schizophrenia is complex and reflects dysfunction in various systems that are closely interlinked such as gene expression, cellular signaling, neurotransmitter function, and immune regulation. The involvement of some facets of the immune system in the mechanisms that underlie psychiatric disorders is not unexpected as the immune system is an integral part of the biological network. Cytokines are soluble peptides made by cells of the immune system as well as certain non-immune cells and several studies have shown that patients with schizophrenia have an increase in proinflammatory cytokines in plasma and cerebrospinal fluid (CSF). Our own pilot study comprising of ten patients with schizophrenia-spectrum disorders and ten healthy volunteers matched with patients in age, sex, and race shows a significant increase in the levels of cytokines IL-1beta, IL-6 and IL-8 in the CSF of patients compared to healthy controls. MicroRNAs (miRNAs) are small molecules involved in gene regulation and known to regulate cellular processes including development, differentiation, proliferation and death. miRNAs also play a prominent role in disease and many studies have linked alterations in miRNA expression to schizophrenia and other psychiatric disorders. Preliminary work by our group in the same sample group as the cytokine analysis also shows a different microRNA expression profile in CSF of patients with schizophrenia-spectrum disorders compared to healthy volunteers. Since we observed an alteration in cytokine levels as well as miRNA expression in patients with schizophrenia-spectrum disorders we examined the association between these two parameters. Through initial correlation analysis we found that levels of IL-6 in the CSF negatively correlate with expression levels of at least two miRNAs capable of down regulating the IL-6 encoding gene. Understanding this association will help us elucidate events that regulate neuropsychiatric disorders. We believe that this could lead to new potential therapeutic targets to treat schizophrenia through the discovery of new molecules and pathways involved in the disease process. doi:10.1016/j.jneuroim.2014.08.164
396 Anti-murine CD52 antibody treatment does not adversely affect the migratory ability of immune cells Evis Havaria, Michael J. Turnera, James C. Dodgeb, Christopher Treleavenb, Lamya S. Shihabuddinb, Bruce L. Robertsa, Johanne M. Kaplana, William M. Sidersa a
Neuroimmunology Research, Genzyme, a Sanofi company, Framingham, MA, United States; bNeuroscience, Genzyme, a Sanofi company, Framingham, MA, United States Objective: To evaluate the migratory properties of various immune cell populations following anti-muCD52 treatment in murine models of inflammation. Background: Alemtuzumab, an anti-CD52 humanized monoclonal antibody, is approved in over 30 countries for active relapsing– remitting multiple sclerosis (RRMS). Alemtuzumab causes depletion of circulating lymphocytes followed by a distinctive pattern of repopulation. Alemtuzumab showed superior efficacy vs. subcutaneous interferon beta-1a in phase 3 trials in active RRMS patients who were treatment-naive (CARE-MS I; NCT00530348) or had relapsed on prior therapy (CARE-MS II; NCT00548405). An anti-muCD52 antibody was used to expand our understanding of anti-CD52 therapy in mouse models of immune cell migration.