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.

Influenza vaccination can induce new-onset anticardiolipins but not β2-glycoprotein-I antibodies among patients with systemic lupus erythematosus

“…Autoantibody production against phospholipid binding proteins has been documented as a consequence of exposure to infectious agents 24, 25 but conflicting reports still exist about the appearance of these aPL after vaccine administration. In healthy subjects given the Hepatitis B recombinant vaccine who exhibited changes in aPL values, a significant increase was observed in β2GPI values but not in aCL values 26 .…”

The Role of the Gut Microbiota in the Pathogenesis of Antiphospholipid Syndrome

“…Transient anti-β 2 GPI antibody production was induced experimentally in vivo by injection of pathogen proteins or peptides [26, 76]. Molecular mimicry has been best studied using antibodies that target the TLRVYK sequence in domain III [26, 25].…”

“…Transient anti-β 2 GPI antibody production was induced experimentally in vivo by injection of pathogen proteins or peptides [26, 76]. Molecular mimicry has been best studied using antibodies that target the TLRVYK sequence in domain III [26, 25]. Notably, the Shoenfeld group showed that mice immunized with proteins from Haemophilus influenzae , Neisseria gonorrhoeae , or tetanus toxoid, which all share sequence homology to the core region TLRVYK.…”

Final Diagnosis of Pediatric Patients with Prolonged in Activated Partial Thromboplastin Time Preoperative Study

“…There are also other acquired causes as the presence of heparin in the sample, being from treatment or contamination and the lupus anticoagulant (LA). This last one is caused by the presence of antiphospholipid antibodies, IgG and/or IgA immunoglobulins, which are present in almost 23% of apparently healthy children [2]- [4], most of all in the younger population [5] in which they are usually transitory in association with infections [4] [6] [7]. Duration in circulation of the lupus anticoagulant is not yet exactly known, but to be considered transitory, not related with autoimmune diseases as the antiphospholipid syndrome, it must be less than 12 weeks [6] [8]- [10].…”