New mechanisms for thrombosis and atherosclerosis in SLE and APS

Patients with lupus may develop atherosclerosis years earlier than people without the disease. They are also more susceptible to blood clots that can lead to strokes and other health problems. We plan to test whether an immune system protein known as C4a, whose levels are often high in patients with lupus, promotes blood clots and atherosclerosis. We will determine whether C4a stimulates the cell fragments in the blood called platelets that spur clots to form. We will also determine whether C4a alters the linings of blood vessels, which could lead to atherosclerosis. The findings could indicate whether C4a is a good target for new lupus treatments and help researchers develop drugs to block it.

What this study means for people with lupus

“Patients with lupus are vulnerable to blood clots and atherosclerosis, the buildup of fatty blockages in arteries. We will test whether an immune system protein stimulates these problems. Our results will indicate whether the protein is a good target for new drugs to treat lupus.”

Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are autoimmune diseases that predominantly affect women of reproductive age. Cardiovascular complications including thrombosis and accelerated atherosclerosis are common clinical features in these disorders, and are the leading causes of death for patients with SLE. In SLE and APS, immune complexes activate the complement system, culminating in the generation of activated complement products including C4a and the release of proinflammatory mediators, and cause tissue injuries. The function of C4a has been elusive. Recent studies demonstrated that the protease-activated receptors, PAR1 and PAR4, crucial signaling receptors for the activation of platelets and endothelia, are potentially the long-sought receptors for C4a. This finding offers a new and unexplored mechanism that engages processed complement proteins to mediate coagulation, and suggests that cardiovascular pathologies including platelet activation and endothelial dysfunction may be modulated in part by the interaction of C4a and its receptors. To test this hypothesis, we will 1) determine the functional relevance of C4a binding to PAR1 and PAR4 on human platelets and endothelial cells and 2) analyze the effects of C4a on activating platelets and endothelia in vivo using mouse models. Combining ex vivo analyses on human platelets, in vitro experiments on genetically engineered endothelial cells, human C4 genetics and in vivo analyses in animal models, these studies will provide new insight into the crosstalk between the complement system and the coagulation pathways and into the pathophysiologic roles of complement activation in cardiovascular diseases. Our long-term goal is to develop new therapeutics for treating/preventing the cardiovascular complications in immune-complex mediated diseases such as SLE and APS. This proposal will provide invaluable knowledge towards understanding the functions of C4a and its roles in these diseases.