Novel Antibody And Innate Immune Pathways In The Pathogenesis Of Anti-phospholipid Syndrome

The antiphospholipid syndrome(APS)is a thrombophilic disorder characterized by clinical manifestations of vascular thrombosis and obstetric complications associated with the presence of specific antiphospholipid antibodies(a PLs).APLs are a heterogeneous group of immunoglobulins directed against phospholipids or specific phospholipid-binding plasma proteins such as 2GPI,prothrombin(PT),thrombomodulin and protein C.The conventional a PLs typically evaluated include anticardiolipin(a CL)antibody(Ig G and Ig M),anti-2-glycoprotein I(anti-2GPI)antibodies(Ig G and Ig M),and lupus anticoagulant(LAC).A multitude of additional biomarkers for APS have been investigated,but most have been proved to add little additional diagnostic value.Then screening for new biomarkers to accurately identify APS patients for the diagnosis and evaluation of the disease will be more important.In addition to antibody-mediated pathogenesis in APS,innate immune cells,including monocytes,neutrophils,platelets and endothelial cells also play important roles in the pathogenesis of APS.The neutrophils are involved in the formation of thrombus through the release of neutrophil extracellular traps(NETs),and their researches in APS have also received some attention.On the other hand,the native immune factor type I interferon and its pathways have been reported to be abnormally expressed in APS.However,it is unclear how the type I interferon pathway is involved in the pathogenesis of APS and whether it can promote prothrombus status by acting on innate immune cells.The study is of great scientific significance and application value to clear the pathogenesis of innate immunity in APS,and it may represent a new potent strategy in APS treatment..In this paper,at first,we analyzed the clinical manifestations and immunological characteristics of our single-center APS database(APS-SH)in Shanghai,and then we used high-throughput protein chip technology to screen the serum of APS patients from our APSSH database.We found that the level of antibody against myosin Va expressed by MYO5 A gene in APS group was significantly increased,and it was significantly higher in the primary APS than in the secondary APS group.Next,we studied the role of type I interferon in the formation of thrombosis by activating innate immune cells.We found that type I interferon pathway was abnormally overexpressed in peripheral blood mononuclear cells of APS patients,and neutrophils can produce more NETs in APS patients.In vitro studies,we have found that interferon-a can synergize a PL purified from APS sera to promote the release of NETs.The expression of thrombosis-associated protein Axl/Gas6 were increased in human monocyte cell line and human umbilical vein endothelial cell line after stimulated by interferon-a.Therefore,our study reveals the mechanism of APS through two aspects including antibody and innate immune mediated mechanisms,suggesting that anti-myosin Va antibody may be new marker of APS.And for type I interferon and its downstream Axl/Gas6 pathway may be potential target for the clinical treatment and mechanism research of APS.