The prevalence of a non-phospholipid-binding form of β2-Glycoprotein I in human plasma : Consequences for the development of Anti-β2-glycoprotein I antibodies

The presence of antiphospholipid antibodies (aPL) is strongly corre-lated with venous and arterial thrombosis, fetal loss and thrombocyto-penia. This relation is called the antiphospholipid syndrome (APS). It is well recognized that thrombosis related aPL are not directed against phospholipids alone, but to phospholipid bound plasma proteins like b 2 -glycoprotein I (b 2 GPI). aPL that need b 2 GPI for the binding to negatively charged phospholipids are called anti-b 2 GPI-antibodies. Recently, a mutation in the gene encoding b 2 GPI has been described, which results in an amino acid substitution Trp316 into Ser316. This Ser316-b 2 GPI did not bind to negatively charged phospholipids. Because only phospholipid bound b 2 GPI is recognized by human anti-b 2 GPI-antibodies, it might be argued that individuals carrying the Trp316Ser mutation are protected against the development of anti-b 2 GPI-antibodies. To investigate this hypothesis, the prevalence of the Trp316Ser mutation was measured in 170 systemic lupus erythematosus (SLE) pa-tients and in 18 patients with the primary antiphospholipid syndrome (PAPS) and the mutation was correlated with the presence of anti-b 2 GPI-antibodies. In the total patient group 1 homozygous patient and 21 heterozygous patients were found. The allele frequency of the mutation in SLE patients with anti-b 2 GPI-antibodies (0.063) was comparable to that found in SLE patients without anti-b 2-GPI-anti-bodies (0.062). These results indicate that the heterozygous presence of Trp316Ser mutation does not prevent an individual from developing anti-b 2 GPI-antibodies. We showed that this can be explained by the concentration of Trp316-b 2 GPI in heterozygous patients, which is far above the minimal b 2 GPI level necessary for optimal phospholipid binding. In our single patient homozygous for the Trp316Ser mutation no binding of b 2 GPI to the phospholipid surface was detected and no anti-b 2 GPI-antibodies were present in the plasma of this patient. In conclusion, heterozygous Trp316Ser b 2 GPI persons are not protected against the development of anti-b 2 GPI-antibodies. To confirm that homozygotes do not develop anti-b 2 GPI-antibodies a very large population is needed, due to the relatively low prevalence of the mutation.