Collaborative work between the Glycobiology Institute and researchers at University College and Imperial College in London has identified a molecular defect in patients with systemic lupus erythematosus (SLE) that could have an impact on their treatment.
Dr Terry Butters at the Institute, together with Dr Liz Jury and Professors Anthony Magee and David Isenberg and colleagues, have published their findings in the Journal of Clinical Investigation (1). Their work demonstrates that the defect in cells from SLE patients can be alleviated using a drug already in use to treat a different disease.
SLE is a complex autoimmune disease affecting many parts of the body with symptoms ranging from mild to life-threatening. Current treatments include corticosteroids and immunosuppressants, and are based on trying to alleviate the symptoms.
A combination of genetic and environmental factors is likely to trigger the disease but the exact mechanisms underlying it are unclear. Abnormal T-cell receptor (TCR) signalling is a key feature, causing T cell hypersensitivity and influencing B cell generation of antibodies. The increase in antibodies raised against host proteins and lipids gives rise to some of the disease symptoms.
Suspicion has fallen on a defect in lipid metabolism as one possible contributor to disease pathogenesis. Researchers have detected abnormal lipid content in cells from SLE patients but few details are known.
Now the collaboration between glycobiologist Dr Butters, Dr Jury’s rheumatic disease group, lipid raft expert Professor Magee, and rheumatologist Professor Isenberg, has shed much more light on the defect.
The group looked directly at lipid levels in cells from SLE patient and healthy donors. They were interested in a particular type of lipid called glycosphingolipids (GSLs). GSLs can be found in lipid rafts – specialized membrane microdomains - and have been implicated in abnormal TCR signalling.
They found that T cells from SLE patients compared with healthy donors have an increased amount of GSLs in their plasma membrane and that they also display abnormal trafficking (recycling) of the lipids.
Confocal microscopy of T cells stained for lysosomes (LAMP1, magenta) and glycolipid-rich lipid regions (CTB, green), showing elevated expression and clustering in cells derived from SLE patients
This immediately suggested a possible mechanism by which signaling might be disrupted. ‘TCRs sit alongside GSLs in the membrane and their interaction could be responsible for the T cell hyperactivity,’ explains Dr Butters. ‘This could be via positive or negative interactions.’
Following on from this observation, the group looked at what would happen if they altered GSL levels pharmacologically.
‘We chose a pharmacological inhibitor of GSL production by cells, N-butyldeoxynojirimycin, which is used for Gaucher’s disease,’ says Dr Butters. ‘The drug was developed in the Glycobiology Institute and has been an approved therapy for over 10 years. It’s a systemic GSL depletion agent, blocking the first step in GSL biosynthesis, and slows down the burden of glycolipids being built up.’
When they treated T cells from SLE patients with the drug, they observed a dramatic change. Clinically relevant doses of the drug reduced the amount of GSL on the cell surface and damped down the abnormal responses of the cells, reducing T cell hyperactivity and the association between the T and B cells in provoking autoimmunity. The cells were restored to a virtually normal phenotype.
The group also went on to show one possible way in which the elevated GSL level in patient cells might arise. They found that increased GSL levels were associated with raised expression of the nuclear receptor LXRβ which is known to control cellular lipid metabolism and trafficking.
Together, the work provides an interesting and emerging picture of a possible underlying defect in SLE patients. Whilst further molecular studies will be important in understanding how the close connectivity of GSLs to proteins influences signaling, the findings suggest that targeting lipid biosynthesis pathways could be a novel therapeutic strategy for SLE patients.
The use of a clinically approved drug opens the way for a new approach to treating SLE patients, says Dr Butters. ‘It’s a safe therapeutic and is well tolerated. So there’s a great opportunity to get into the clinic with an approved drug. For me, the most exciting thing would be to go on to show in the clinic that this drug could have an impact on lupus patients.’
At the Glycobiology Institute, looking for new ways to improve existing drugs is a key goal – and that includes developing a range of GSL biosynthesis inhibitors with fewer side effects which can be delivered at lower concentrations.
Reference
- Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients. McDonald, G., Deepak, S., Miguel, L., Hall, C.J., Isenberg, D.A., Magee, A.I, Butters, T. and Jury, E.C. Journal of Clinical Investigation (2014). doi:10.1172/JCI69571. http://www.jci.org/articles/view/69571
Acknowledgements: This work was funded by the following charities that provide help and support for patients as well as funding research:
www.arthritisresearchuk.org
Arthritis Research UK is the leading UK funder of research into the cause, treatment and cure of arthritis and related conditions.
www.lupusuk.org.uk
LUPUS UK is the only national registered charity supporting people with systemic lupus and discoid lupus and assisting those approaching diagnosis.
Jane Itzhaki
No comments:
Post a Comment