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Abstract Number: 848

Targeting Glycosphingolipid Biosynthesis Normalises T Lymphocyte Function in Patients with Systemic Lupus Eyrthematosus

Georgia McDonald1, Laura Miguel1, Cleo Hall1, David A. Isenberg2, Anthony I. Magee3, Terry Butters4 and Elizabeth C. Jury5, 1Centre for Rheumatology Research, Division of Medicine, University College London, London, United Kingdom, 2Centre for Rheumatology Research, Rayne Building, 4th Floor, Centre for Rheumatology, Department of Medicine, University College London, London, United Kingdom, 3Section of Molecular Medicine, National Heart & Lung Institute, Imperial College London, London, United Kingdom, 4Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom, 5Division of Medicine, Centre for Rheumatology Research, University College London, London, United Kingdom

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: lipids and systemic lupus erythematosus (SLE), T cells

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Session Information

Title: Systemic Lupus Erythematosus - Human Etiology and Pathogenesis I

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Patients with systemic lupus erythematosus (SLE) are characterised by hyperactive T-cells that provide help to auto-reactive B-cells. Underlying this hyperactivity are alterations in the lipid and protein composition of membrane lipid microdomains (lipid rafts) that influence the nature, duration and outcome of immune synapse formation between T-cells and antigen presenting cells including B-cells. We examined the profile of lipid raft-associated glycosphingolipids (GSL) in T-cells, the mechanisms underlying their abnormal expression in patients with SLE and whether by normalising GSL expression, T-cell function could be restored in patients.

Methods:

High performance liquid chromatography and flow cytometry were used to assess the GSL profile and phenotype of T-cells from 98 patients with SLE compared with 82 healthy controls and 23 patients with other autoimmune rheumatic disease. Western blotting, quantitative PCR and confocal microscopy using fluorescently-labelled GSLs were used to assess levels of proteins controlling GSL expression and GSL location within T-cells. T-cell function was assessed by measuring phosphorylation of proximal and downstream signalling molecules, proliferation and cytokine production.

Results:

The expression levels of lipid raft-associated GSL lactosylceramide (LC), Gb3 and GM1 were significantly increased in T-cells from patients with SLE compared to healthy and disease controls.  In healthy donors LC+, GM1+ and Gb3+ T-cells had an activated phenotype, increased expression of proliferation marker Ki-67 and transcription factor RORgT, however, raised GSL expression was not associated with a specific T-cell phenotype in patients with SLE. Increased GSL expression in T-cells from SLE patients was not associated with altered levels of enzymes controlling GSL biosynthesis but was associated with increased GSL recycling from the plasma membrane to intracellular compartments. T-cells from patients with SLE incorporated fluorescently-labelled-LC into intracellular vesicles more rapidly compared to T-cells from healthy controls and this was accompanied by increased expression of the Niemann-Pick 1 and 2 genes that control GSL recycling. In vitro culture of T-cells from SLE patients with direct inhibitors of GSL biosynthesis normalised GSL membrane expression and restored their function in terms of lipid raft-associated T-cell signalling, proliferation and cytokine production.

Conclusion:

We show that targeting lipid biosynthesis pathways using clinically approved inhibitors can rectify hyperactivity in autoimmune T-cells and restore their function.


Disclosure:

G. McDonald,
None;

L. Miguel,
None;

C. Hall,
None;

D. A. Isenberg,
None;

A. I. Magee,
None;

T. Butters,
None;

E. C. Jury,
None.

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