Bacterial induction of autoantibodies to β2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome

Abstract

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. Recently, we identified a hexapeptide (TLRVYK) that is recognized specifically by a pathogenic anti-β2GPI mAb. In the present study we evaluated the APS-related pathogenic potential of microbial pathogens carrying sequences related to this hexapeptide. Mice immunized with a panel of microbial preparations were studied for the development of anti-β2GPI autoantibodies. IgG specific to the TLRVYK peptide were affinity purified from the immunized mice and passively infused intravenously 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 antipeptide [TLRVYK] anti-β2GPI Ab's were observed in mice immunized with Haemophilus influenzae, Neisseria gonorrhoeae, or tetanus toxoid. The specificity of binding to the corresponding target molecules was confirmed by competition and immunoblot assays. Naive mice infused with the affinity-purified antipeptide Ab's had significant thrombocytopenia, prolonged activated partial thromboplastin time and elevated percentage of fetal loss, similar to a control group of mice immunized with a pathogenic anti-β2GPI mAb. Our study establishes a mechanism of molecular mimicry in experimental APS, demonstrating that bacterial peptides homologous with β2GPI induce pathogenic anti-β2GPI Ab's along with APS manifestations.

The Roll of Toll-like Receptors in the Antiphospholipid Syndrome

“…Romay-Penabad et al [31] showed in agreement with previous observations that β 2 GPI binds to annexin A2 on target cells recognized by aPL antibodies [20,32]. The lack of annexin A2 or addition of anti-A2 antibodies seemed to produce a significant but incomplete inhibition of some pathogenic effects induced by aPL antibodies.…”

Molecular mimicry in neurological disease: what is the evidence?

“…In addition, there are preliminary data showing cross-reactivity between gliadin and neuronal synapsin I in patients with celiac disease (which can be complicated by neurological syndromes such as neuropathy, seizures and behavioral changes) [157,162]. Finally, molecular mimicry may contribute to the pathogenesis of patients with APS that develop chorea [6,163]. APS is characterized by recurrent fetal loss, thrombocytopenia and thromboembolic disease [6,163].…”

“…Finally, molecular mimicry may contribute to the pathogenesis of patients with APS that develop chorea [6,163]. APS is characterized by recurrent fetal loss, thrombocytopenia and thromboembolic disease [6,163]. These patients develop autoantibodies to b-2-glycoprotein-I (b2GPI), which may be induced by molecular mimicry [6,163].…”

“…APS is characterized by recurrent fetal loss, thrombocytopenia and thromboembolic disease [6,163]. These patients develop autoantibodies to b-2-glycoprotein-I (b2GPI), which may be induced by molecular mimicry [6,163]. In a subset of patients with APS and chorea, serum reacted with streptococcal GlcNAc, and the interaction was inhibited with b2GPI, suggesting molecular mimicry between two antigens [164].…”

The role of endothelial cell biology in endocarditis

“…Libman-Sacks valvular lesions are sterile fibrofibrinous vegetation that may develop anywhere on the endocardial surface of the heart but most commonly on left-sided valves, particularly the ventricular surface of the mitral valve. Studies have demonstrated a linear subendothelial deposition of anti-cardiolipin/beta2 glycoprotein I antibodies in valve specimens derived from patients with antiphospholipid syndrome (Ziporen et al 1996;Afek et al 1999;Blank et al 2002). Several lines of evidence suggest that, similar to infective endocarditis, the involvement of tissue factor plays a critical role in endocarditis occurring in patients with antiphospholipid syndrome.…”