2007 Cell Signaling, Human Lupus Biology
|Photo: Dean Forbes|
At some point in lupus, messages are sent among cells that lead the immune system to malfunction. With her LRI Novel Research Grant, Dr. Stevens is aiming to understand and interrupt this flawed communication.
When the immune system is healthy, she notes, it can prevent unwanted, damaging responses by turning itself off—thanks to ‘off switches’ on the surface of white blood cells.
Dr. Stevens has found that one of these critical switches, a molecule known as PD-L1, is missing on the cells of children with active lupus. Interestingly, the molecule re-appears when the lupus subsides and goes into remission.
With LRI support, Dr. Stevens will work to identify what controls the production of PD-L1 in these children.
So far, she and her team have made advances in understanding why people with lupus don’t express PD-L1 properly, citing in particular enzymes called “caspases.” These enzymes are involved in normal cell death and can control the expression of PD-L1.
People with lupus seem to have over-active caspases that destroy their PD-L1 proteins, thus blocking this normal regulation of inflammation. But when lupus cells are treated with inhibitors of caspases, they can express PD-L1 normally. Dr. Stevens sees promise here, in the potential for treating people with lupus with medicines that inhibit caspases.
Also a potential biomarker?
Dr. Stevens also notes that PD-L1 is a marker in the clinic for disease activity, and that a big problem in caring for people with lupus may be solved by measuring PD-L1 levels in the blood. The result might help in determine if infection or lupus flare is to blame in cases when people with lupus get sick, for example.
Her team is developing a practical PD-L1 test that could be used in clinical laboratories to examine its potential as a biomarker in adults and children with and without infections.
Active systemic lupus erythematosus is associated with failure of antigen-presenting cells to express programmed death ligand-1. N Mozaffarian, AE Wiedeman, AM Stevens (2008). Rheumatology, 47(9):1335-41.