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Publication Detail
The role of glycosphingolipids in SLE T cell dysfunction
  • Publication Type:
    Thesis/Dissertation
  • Authors:
    McDonald GL
  • Date awarded:
    15/01/2015
  • Supervisors:
    Jury EC
  • Awarding institution:
    University College London
  • Date Submitted:
    08/04/2015
  • Translators:
    Jury EC
Abstract
Patients with the autoimmune rheumatic disease SLE are characterized by multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes including abnormal control of lipid biosynthesis pathways. Here I reveal that CD4+T cells from SLE patients displayed an altered profile of lipid raft-associated glycosphingolipids (GSLs), in particular lactosylceramide, globotriaosyl (Gb3) and ganglioside GM1, compared to healthy controls. Elevated GSLs in patients were associated with increased expression of liver- X-receptor-beta (LXRβ) a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Raised GSL expression was recapitulated in healthy CD4+T cells by in vitro stimulation with synthetic and endogenous LXR agonists, an effect that was blocked by an LXR antagonist. Increased GSL expression in CD4+T cells was associated with intracellular accumulation and accelerated GSL trafficking, reminiscent of cells from patients with glycolipid storage diseases. Inhibiting GSL biosynthesis in vitro using a clinically approved inhibitor (N- butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+T cell signaling and functional defects and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Thus I demonstrate a role for defects in lipid metabolism in SLE pathogenesis that could be normalized by targeting GSL biosynthesis. Finally, preliminary findings show that functional T cell subsets have a distinct plasma membrane lipid profile, which is associated with altered expression of molecules associated with lipid metabolism. Furthermore, stimulation of cells with oxysterols has a direct effect on the plasma membrane lipid profile and T cell subset function.
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