**5. Autoantibodies targeting β2GPI/HLA-DR complex are involved in the pathogenesis of APS**

Immunofluorescence staining and *in situ* proximity-ligation assay (PLA), which detect close proximity (less than 40 nm) between two molecules [13], showed that β2GPI and HLA-DR were co-localized in endothelial cells of the placental decidua vessels from APS patients with spontaneous abortion. In contrast, no co-localization of β2GPI and HLA-DR was observed in placental tissues obtained from patients without APS [4].

In addition, we found that monoclonal antibody EY2C9 exhibited complementmediated cytotoxicity against 293 T cells expressing β2GPI together with the APS susceptibility allele HLA-DR7, however the cytotoxicity was not detected against 293 T cells expressing HLA-DR7 alone or against those transfected with β2GPI alone [4].

HLA class II expression on endothelial cells is known to be induced after exposure to cytokines, such as IFN-γ and TNF-α [14]. Therefore, inflammatory stimuli can induce HLA class II expression on vascular endothelial cells, and HLA class II molecules transport structurally altered β2GPI, which has high affinity for the peptide-binding grooves of the alleles of HLA class II. Autoantibodies against β2GPI/HLA class II complexes may damage vascular endothelial cells expressing β2GPI/HLA class II complexes in a complement-dependent manner and cause clinical manifestations of APS, including vascular thrombosis and pregnancy

complications. In this way, β2GPI/HLA class II complexes and autoantibodies against the complexes may be involved in the pathogenesis of APS.
