Neutrophil migrasomes in Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is an autoimmune disease that causes harmful blood clots and leads to long-term damage in organs such as the brain, heart, and kidneys. It affects many people with lupus (roughly 25%) and can also be diagnosed in individuals without another autoimmune condition (primary APS). Altogether, APS is estimated to impact at least one of every 2,000 Americans. Even when patients are treated with blood thinners, about one in five still go on to have new clots, and current treatments do little to prevent the slow damage to small blood vessels that causes organs to fail over time. In 2015, our research group discovered that certain immune cells, known as neutrophils, can release web-like structures called NETs that facilitate clotting in APS. We have now turned our attention to another effector released by neutrophils — small, bubble-like particles called migrasomes, which carry sticky proteins on their surface that trigger clotting and inflammation. These migrasomes are larger than many other cell fragments in the blood and appear to come mostly from neutrophils. Our new data show that people with APS have more neutrophil migrasomes in their blood and that those migrasomes are coated with the same antibodies that drive the disease. We also find that neutrophil migrasomes can strongly activate platelets — the cells that start the clotting process — and that this effect is even more substantial when the migrasomes are coated with APS antibodies. This suggests that neutrophil migrasomes may be a key component in understanding how APS causes clots and organ damage. In this study, we will examine how these migrasomes form, their relationship to symptoms and disease patterns in APS and lupus, and whether they play a direct role in triggering blood clots in relevant mouse models. Our ultimate goal is to gain a deeper understanding of the biology of APS and discover new approaches to treat or prevent its most severe complications.

Antiphospholipid syndrome (APS) is an incurable immunothrombotic disorder that complicates one-quarter of cases of systemic lupus erythematosus (SLE), where it portends the acquisition of more organ damage over time. APS can also be diagnosed in a standalone form (primary APS), and altogether, APS affects at least one in 2000 Americans. Despite the use of anticoagulation, 20% of patients with APS will still experience a breakthrough thrombotic event. Anticoagulants also fail to treat the small-vessel vasculopathy that leads to organ deterioration over time. In 2015, our group discovered that neutrophil extracellular traps contribute to APS-associated thrombosis; however, another recently described thrombo-inflammatory neutrophil function—the formation of coagulation factor- and adhesion molecule-rich vesicles called migrasomes—has yet to be characterized in APS or other rheumatic diseases. Larger than microparticles at 1-3 µm, migrasomes emerge in integrin- and tetraspanin-dependent fashion from trailing retraction fibers before detaching from the cell’s body when it migrates away.Neutrophil migrasomes represent over 80% of circulating migrasomes in blood, with roughly one neutrophil migrasome detected for every 100 similarly sized platelets. Furthermore, neutrophil migrasomes have been shown to avidly adsorb and enrich coagulation factors on their surface. Our preliminary data now demonstrate (i) elevated levels of IgG-decorated neutrophil migrasomes in the blood of patients with APS; (ii) accelerated formation of migrasomes in vitro when neutrophils are cultured with patient-derived antiphospholipid antibodies; and (iii) potent platelet activation by neutrophil migrasomes, which is further enhanced when the migrasomes become decorated with APS patient IgG. Neutrophil migrasomes may, therefore, represent a previously unknown therapeutic target to combat the inflammatory aspects of APS and beyond. Aim 1 will characterize the properties of antiphospholipid antibody-triggered neutrophil migrasomes in vitro. Aim 2 will determine the extent to which neutrophil migrasomes are associated with APS and SLE clinical manifestations and disease endotypes. Aim 3 will understand the potential role of neutrophil migrasomes in antiphospholipid antibody-accelerated venous thrombosis.