The blood-clotting cells called platelets are usually good guys, stanching wounds so that we don't bleed to death. But for people with lupus, the cells are villains that exacerbate the disease, according to a new study. The work also suggests that an anticlotting drug commonly prescribed for heart disease patients might soothe lupus symptoms.
In lupus, the immune system produces antibodies that target the patient's own cells, causing painful joints, skin lesions, fatigue, and other symptoms. The blood of people with lupus often is prone to clotting, and they are more susceptible to heart attack and stroke. These symptoms suggest that platelets play a role in the disease.
Immunologist Patrick Blanco of the University of Bordeaux in France and colleagues wondered whether another platelet link could stem from a rare kind of immune system warrior known as a plasmacytoid dendritic cell (pDC). In the bloodstream, pDCs release chemical messengers called type I interferons that rev up the immune system. Lupus patients make too much type I interferon, which boosts production of the self-attacking antibodies that cause symptoms. Platelets, meanwhile, manufacture a protein called CD154 that turns on pDCs—and thus they might indirectly increase type I interferon output.
To determine if platelets exacerbate lupus by triggering pDCs to overactivate the immune system, Blanco and colleagues mixed platelets from healthy people with blood from lupus patients. Globs of antibodies present in the lupus blood glommed on to the platelets and turned them on. Activated platelets make CD154, the researchers found, and switch on pDCs, causing them to pump out four times the normal amount of one type I interferon. In a lupus patient, this could cause the immune system to ramp up its attacks on the body's cells. The team reports its findings online today in Science Translational Medicine.
If switched-on platelets worsen lupus, shutting down the cells might ease the disease's symptoms. So the researchers dosed lupus-mimicking mice with clopidogrel (Plavix), a drug that stymies clotting by preventing platelets from activating. In one strain of the mice, clopidogrel curbed the amount of kidney damage, a common and sometimes lethal consequence of the disease. The compound also boosted survival in this strain and another variety of lupus-mimicking mice. Blanco says that platelets are doubly destructive in lupus, ramping up autoimmune attacks and producing potentially fatal clots. So clopidogrel could be doubly beneficial, he says. His group is planning to launch a trial of the drug, which has been approved for use in people for more than a decade, in lupus patients.
Mary Crow, an immunologist and rheumatologist at the Hospital for Special Surgery in New York City, accepts the results. "I believe overall that platelets are playing a role" in promoting lupus symptoms, she says. But the work doesn't convince rheumatologist Lars Rönnblom of Uppsala University in Sweden. He notes, for instance, that clopidogrel helped one kind of lupus-mimicking mice even though the animals don't show high levels of type I interferons. This suggests that platelets don't necessarily make lupus worse by prodding pDCs, he says, though it doesn't exonerate them.