Grant: Operating Grant

Anti-phospholipid syndrome (APS) is an autoimmune disease that occurs in approximately 50-70% of patients with systemic lupus erythematosus (SLE) who possess anti-phospholipid antibodies (aPL), but it can also occur in individuals without SLE. APS is defined as the presence of aPL plus a clinical event associated with aPL (such as "thrombosis" [blood clot], heart attack, or stroke). Currently, while it is clear that aPL are associated with adverse clinical events in SLE and APS, little is known about the mechanisms that lead to their occurrence. It is also not clear why some patients with aPL develop symptoms, while others do not. We hypothesize that a minimum of two factors are needed to produce APS: (1) persistent and high levels of aPL in the blood; and (2) exposure of the individual to a factor (e.g., infection, inflammation, or injury) that initiates a process called "innate immune activation". "Innate immune activation" can cause localized changes in the blood vessels that make them more prone to blood clots. Together, aPL and "innate immune activation" can predispose patients to blood clots, especially if other risk factors (e.g., smoking) are present. We propose to directly test this hypothesis in a mouse model by creating an environment in which both factors (aPL and "innate immune activation") are present. The findings from this proposal have the potential to improve the quality of life for individuals living with APS. Thrombosis is a devastating clinical manifestation of APS that can be life-threatening or result in long-term disability and life-long anticoagulation. If we find that activation of the innate system plays a role in APS, this will provide a new approach to monitoring and treating patients with APS. Thus, findings from our studies have the potential not only to improve the quality of life of these individuals, but also to significantly reduce the cost of medical care for patients with APS.