The infectious origin of the antiphospholipid syndrome: induction by passive transfer of anti-β2GPI antibodies induced by common bacteria

The antiphospholipid syndrome (APS) is characterized by the presence of pathogenic autoantibodies against β₂-glycoprotein I (β₂GPI). The factors causing production of anti-β2GPI remain unidentified, but an association with infectious agents has been reported. We recently identified a hexapeptide (TLRVYK) that is recognized specifically by a pathogenic anti-β₂GPI monoclonal antibody. In the present study we evaluated the APS-related pathogenic potential of microbial pathogens, which share structural homology with the this hexapeptide. Mice were immunized with a panel of TLRVYK-related microbial particles and were studied for the development of mouse anti-β2GPI autoantibodies. Mouse IgG specific to the TLRVYK peptide were affinity purified from the immunized mice and passively infused i.v. into naive mice at day 0 of pregnancy. APS parameters were evaluated in the infused mice on day 15 of pregnancy. Following immunization, high titers of anti-peptide, anti-β₂GPI antibodies were observed in mice immunized with Haemophilus influenzae, Neisseria gonorrhoeae or tetanus toxoid. Naive mice infused with the affinity-purified anti-peptide antibodies had a significant thrombocytopenia, prolonged aPTT and elevated percentage of fetal loss, similar to the findings in a control group of mice immunized with a pathogenic anti-β2GPI monoclonal antibody. Our study establishes a mechanism of molecular mimicry in experimental APS, demonstrating that bacteria homologous with β2GPI structure are able to induce the generation of pathogenic anti-β2GPI antibodies along with APS manifestations.