Antiphospholipid syndrome: 30 years and our contribution.

In 1983, Graham Hughes first described the concept of antiphospholipid syndrome (APS). In 1984, we described the enzyme-linked immunosorbent assay (ELISA) system which directly detected circulating aCL in patients with systemic lupus erythematosus (SLE) who revealed biological false positive serological test for syphilis. In 1990, three groups, including our group, independently reported the necessity of a cofactor for the binding of autoimmune anticardiolipin antibodies (aCL) to the solid phase phospholipids. β2-glycoprotein I (β2GPI) was identified as this cofactor. In 1994,the epitope for aCL was shown to develop when β2GPI is adsorbed on polyoxygenated polystyrene plates. In 2000, we described antiprothrombin antibodies bind to prothrombin exposed to immobilized phosphatidylserine and established a phosphatidylserine dependent monoclonal antiprothrombin antibody. In 2004, a novel role of nicked β2GPI was identified in the negative feedback pathway of extrinsic fibrinolysis. Nicked β2GPI was found to bind angiostatin 4.5 and to attenuate its antiangiogenic property. In 2004, we demonstrated that the p38 MAPK pathway mediates induction of the TF gene in stimulated with human monoclonal anti- β2GPI antibodies. Very recently, β2GPI was identified as a complement regulator. The cross-link between complement activation and prothrombotic status in patients with APS has been drawn much attention. Genetic factors are hypothesized to play a role in the susceptibility to APS based on several family studies in patients with antiphospholipid antibodies (aPL) and/or clinical manifestations of APS. The genetics of β2GPI has been extensively studied. 247 Val/Leu polymorphism can affect the conformational change of β2-GPI and the exposure of the epitopes for aCL. We found that 247 Val was correlated with anti-β2-GPI production in patients with primary APS, and 247 Val may be important for β2-GPI antigenicity. STAT4 SNP in Japanese patients with SLE and/or APS. T allele frequencies in SLE and APS were significantly elevated compared with that in healthy controls. When analyzed only in primary APS patients, T allele frequency was further higher. BANK1, BLK and SNP in 1q25.1 region were associated with not only SLE but also APS in Japanese population. These results suggest that APS and SLE, in part, share a common genetic background.