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Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients
Georgia McDonald, … , Terry Butters, Elizabeth C. Jury
Georgia McDonald, … , Terry Butters, Elizabeth C. Jury
Published January 27, 2014
Citation Information: J Clin Invest. 2014;124(2):712-724. https://doi.org/10.1172/JCI69571.
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Research Article

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients

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Abstract

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have 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, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft–associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor β (LXRβ), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with 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. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE.

Authors

Georgia McDonald, Shantal Deepak, Laura Miguel, Cleo J. Hall, David A. Isenberg, Anthony I. Magee, Terry Butters, Elizabeth C. Jury

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Figure 8

Proposed model for altered GSL expression and metabolism in CD4+ T cells from SLE patients.

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Proposed model for altered GSL expression and metabolism in CD4+ T cells...
We propose that several components of SLE pathology, including dyslipidemia and T cell hyperactivity (i), elicit upregulation of the nuclear receptor LXRβ, and hence its downstream target genes NPC1 and NPC2 (ii). Enhanced activation of LXRβ induces increased de novo GSL biosynthesis (iii). CD4+ T cells from SLE patients are characterized by accelerated GSL trafficking and accumulation of GSL in the plasma membrane (iv) and intracellular compartments (v), despite higher levels of functionally normal lysosomes (vi). Inhibition of GSL biosynthesis with NB-DNJ reduced cellular GSL levels and modified cell function in CD4+ T cells from SLE patients (vii). TGN, trans-Golgi network.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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