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

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The antiphospholipid syndrome is characterized by a wide variety of vaso-occlusive manifestations associated with autoantibodies directed against β2-glycoprotein-I. The pathogenicity of anti-β2GPI antibodies has been demonstrated in animal models. The factor(s) causing production of anti-β2GPI remain unidentified, but several indirect arguments support the idea that microbial agents might influence the course of antiphospholipid syndrome and an association with microbial pathogens has recently been documented. Microbes can contain chemical structures that mimic normal host self-proteins, a phenomenon termed molecular mimicry. Employing a peptide phage display library, we identified hexapeptides that react specifically with anti-β2GPI monoclonal antibodies. These peptides were found to modulate the experimental model for antiphospholipid syndrome. In the current study we found high homology between one of the hexapeptides- TLRVYK, and various bacteria and viruses. We therefore immunized naive mice with a panel of TLRVYK-corresponding microbial particles to find whether they posses a pathogenic potential for autoimmunity. We show that mice which were infused with antibodies derived from mice immunized with tetanus toxoid, haemophilus influenzae or with neisseria gonorrhoeae developed clinical manifestations of experimental antiphospholipid syndrome (e.g. mice infused with anti-β2GPI derived from tetanus immunized developed thrombocytopenia 497 ± 98 × 10-3 cells/dl compared to 1012 ± 214 × 10-3 cells/dl in control mice, high percentage of fetal resorption 48 ± 3% in comparison to 4 ± 2% and prolonged aPTT 69 ± 4 sec in comparison to 23 ± 3 sec in mice infused with IgG from Shigella disenteriae immunized mice). The pathogenetic mechanism for anti-β2GI generation seems to be an epitope mimicry with common bacterial molecules.