β2-glycoprotein I complexed with MHC class II molecules are involved in the pathogenesis of antiphospholipid syndrome

Abstract

Antiphospholipid syndrome (APS) is characterized by thrombosis and pregnancy complications, which is associated with antiphospholipid (aPL) antibodies. It has been known that several MHC class II (HLA-II) gene polymorphisms are associated with APS, although mechanisms how HLA-II gene polymorphisms regulate APS still have remained unclear. β2-glycoprotein I (β2GPI) is the main phospholipid-binding molecule recognized by aPL antibodies. It is also unclear how β2GPI is recognized by aPL antibodies. On the other hand, Arase et al. has recently found that IgG heavy chain/HLA-II complexes were specific targets for autoantibodies in rheumatoid arthritis. Here, we found that intracellular β2GPI is transported to the cell surface by HLA-II molecules. Furthermore, human anti-cardiolipin monoclonal antibody (EY2C9) as well as autoantibodies in APS patient’s sera specifically recognized β2GPI complexed with HLA-II molecules of APS-susceptible alleles (HLA-DR7). In addition, 100 of the 120 APS patients (83.3%) analyzed, including those whose antiphospholipid antibody titers were within normal range, possessed autoantibodies that recognize β2GPI/HLA-DR7 complexes in the absence of phospholipids. Indeed, β2GPI / HLA-II complexes were detected in endothelial cells of vessels in uterine decidual tissues obtained from APS patients with spontaneous abortion. Furthermore, EY2C9 mediated complement-dependent cytotoxicity against cells expressing β2GPI / HLA-DR7 complex.

These data suggest that β2GPI / HLA-II complexes are involved in pathologies of APS and detection of autoantibodies against β2GPI / HLA-DR7 complex could contribute for better recognition of patients with APS.