
Contributions
Abstract: P445
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Immunology
Autoreactive CD4+ T-cells, abnormal regulatory T-cells (Tregs) and defects in lipid metabolism that influence T-cell responses are crucial in the pathogenesis of multiple sclerosis (MS). Liver-X-receptors (LXRs) are key transcriptional regulators of cholesterol metabolism with anti-inflammatory effects in immune cells. We hypothesise that LXR activation influences immune cell behavior by altering the lipid content of plasma membrane (PM) microdomains, enriched for cholesterol and glycosphingolipids (GSLs) that regulate immune-cell signaling and that this transcriptional regulatory network is defective in patients with MS.T-cell subsets from healthy donors had distinct PM lipid profiles with Tregs having increased GSL (p=< 0.001) and reduced cholesterol compared to Tresp resulting in reduced Treg membrane fluidity. These changes were mirrored by increased Treg expression of GSL biosynthesis enzyme (UDP-Glucose Ceramide Glucosyltransferase, UGCG, p=0.0001), the cholesterol metabolism regulator LXRβ, and LXR-target genes (ATP binding cassette sterol transporter, ABCG1 (p=0.001); the fatty acid regulator, fatty acid synthase, FASN; and lipid trafficking enzyme, Niemann Pick type C1-NPC1, (p=0.0001)) thus supporting a role for lipid metabolism in maintaining Treg/Tresp homeostasis and function. Stimulation of LXR by LXR-ligands (both endogenous, 24,25-epoxycholesterol and synthetic, GW3965) modulated PM cholesterol and GSL levels by regulating the expression of GSL biosynthesis enzyme (UGCG) and sterol transporter (ABCG1). This resulted in reduced membrane fluidity and was associated with reduced Tresp proliferation and increased production of interleukin-2.Interestingly, PM-lipids and lipid metabolism genes were dysregulated in ex vivo Tresp and Tregs from people with MS. PM cholesterol and GSL were increased in Tregs and Tresp (p=< 0.05) compared to healthy donors. Furthermore, CD4+ T-cells isolated from people with MS had reduced LXRβ expression and significantly reduced expression of LXR target genes including ABCG1 (regulating cholesterol efflux), FASN (regulating fatty acid biosynthesis) and NPC1 (cholesterol trafficking) compared to healthy donors (p=< 0.001) suggesting lipid metabolism is altered in MS CD4+ T cells. Initial genome-wide gene expression analysis identified that some of these pathways were significantly modulated by 12 month interferon-β therapy in T-cells from people with MS.Thus altered lipid metabolism could influence MS pathogenesis.
Disclosure: This study is funded by UK MS Society (grant no.76)
Kirsty Waddington: Nothing to disclose.
Marsilio Adriani: Nothing to disclose.
Petra Nytrova: Nothing to disclose.
Ines Pineda-Torra: Nothing to disclose.
Elizabeth Jury: Nothing to disclose.
Eva Havrdova: Honoraria and consulting fees (Bayer, GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi-Aventis, Merck Serono, Roche, Teva, and Novartis); consulting services, speaking and serving on scientific advisory boards and research support (Czech Ministry of Education); funding from ABIRISK
Rachel Farrell: Honoraria and consulting fees from Biogen Idec, Merck, Teva, GW Pharma, Canbex pharmaceuticals, Allergan PLC. Research support from NIHR Biomedical Research Centre
Abstract: P445
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Immunology
Autoreactive CD4+ T-cells, abnormal regulatory T-cells (Tregs) and defects in lipid metabolism that influence T-cell responses are crucial in the pathogenesis of multiple sclerosis (MS). Liver-X-receptors (LXRs) are key transcriptional regulators of cholesterol metabolism with anti-inflammatory effects in immune cells. We hypothesise that LXR activation influences immune cell behavior by altering the lipid content of plasma membrane (PM) microdomains, enriched for cholesterol and glycosphingolipids (GSLs) that regulate immune-cell signaling and that this transcriptional regulatory network is defective in patients with MS.T-cell subsets from healthy donors had distinct PM lipid profiles with Tregs having increased GSL (p=< 0.001) and reduced cholesterol compared to Tresp resulting in reduced Treg membrane fluidity. These changes were mirrored by increased Treg expression of GSL biosynthesis enzyme (UDP-Glucose Ceramide Glucosyltransferase, UGCG, p=0.0001), the cholesterol metabolism regulator LXRβ, and LXR-target genes (ATP binding cassette sterol transporter, ABCG1 (p=0.001); the fatty acid regulator, fatty acid synthase, FASN; and lipid trafficking enzyme, Niemann Pick type C1-NPC1, (p=0.0001)) thus supporting a role for lipid metabolism in maintaining Treg/Tresp homeostasis and function. Stimulation of LXR by LXR-ligands (both endogenous, 24,25-epoxycholesterol and synthetic, GW3965) modulated PM cholesterol and GSL levels by regulating the expression of GSL biosynthesis enzyme (UGCG) and sterol transporter (ABCG1). This resulted in reduced membrane fluidity and was associated with reduced Tresp proliferation and increased production of interleukin-2.Interestingly, PM-lipids and lipid metabolism genes were dysregulated in ex vivo Tresp and Tregs from people with MS. PM cholesterol and GSL were increased in Tregs and Tresp (p=< 0.05) compared to healthy donors. Furthermore, CD4+ T-cells isolated from people with MS had reduced LXRβ expression and significantly reduced expression of LXR target genes including ABCG1 (regulating cholesterol efflux), FASN (regulating fatty acid biosynthesis) and NPC1 (cholesterol trafficking) compared to healthy donors (p=< 0.001) suggesting lipid metabolism is altered in MS CD4+ T cells. Initial genome-wide gene expression analysis identified that some of these pathways were significantly modulated by 12 month interferon-β therapy in T-cells from people with MS.Thus altered lipid metabolism could influence MS pathogenesis.
Disclosure: This study is funded by UK MS Society (grant no.76)
Kirsty Waddington: Nothing to disclose.
Marsilio Adriani: Nothing to disclose.
Petra Nytrova: Nothing to disclose.
Ines Pineda-Torra: Nothing to disclose.
Elizabeth Jury: Nothing to disclose.
Eva Havrdova: Honoraria and consulting fees (Bayer, GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi-Aventis, Merck Serono, Roche, Teva, and Novartis); consulting services, speaking and serving on scientific advisory boards and research support (Czech Ministry of Education); funding from ABIRISK
Rachel Farrell: Honoraria and consulting fees from Biogen Idec, Merck, Teva, GW Pharma, Canbex pharmaceuticals, Allergan PLC. Research support from NIHR Biomedical Research Centre