Induction of antiphospholipid antibodies by immunization with synthetic viral and bacterial peptides

Abstract

We previously induced pathogenic antibodies against anionic phospholipids (PL) in experimental animals by immunization with lipid-free purified human beta2glycoprotein I (beta2GPI). We hypothesized that antiphospholipid antibodies (aPL) are induced by in vivo binding of foreign beta2GPI to self-PL, thus forming an immunogenic complex against which aPL antibodies are produced. If this hypothesis is true, other PL-binding proteins that are products of ubiquitous viral/bacterial agents may also induce aPL. To test this hypothesis, groups of NIH/Swiss mice were immunized with synthetic peptides of viral and bacterial origin that share structural similarity with the putative PL-binding region of beta2GPI. Compared with the control groups, animals immunized with the peptides produced significantly higher levels of aPL and anti-beta2GPI antibodies. These findings demonstrate that some PL-binding viral and bacterial proteins function like beta2GPI in inducing aPL and anti-beta2GPI production, and are consistent with a role for such viral and bacterial proteins in inducing aPL antibody production in humans.

Antiphospholipid antibodies induced in mice by immunization with a cytomegalovirus‐derived peptide cause thrombosis and activation of endothelial cells in vivo

“…Our recent experiments with GDKV-induced aPL mAb suggest that the tertiary structure of these peptides is involved in their recognition by aPL. In summary, our results indicate that aPL can be generated in animals by active immunization with several phospholipid-binding peptides/proteins, suggesting a possible mechanism of induction of APS (17,20,21). These findings suggest that incidental immunization with these viral and bacterial proteins during a subclinical infection may trigger aPL production.…”

“…This peptide, like the PL binding site of ␤ 2 GP (GDKV), contains a lysine-rich region flanked by hydrophobic residues ( Table 1). Binding of this peptide to PL was determined in an assay in which the competition of the peptide with ␤ 2 GP was measured in PLcoated plates, as previously described (21).…”

“…To study the functional and binding characteristics and the pathogenic effects of TIFIinduced aPL, mAb were developed in PL/J mice (The Jackson Laboratory, Bar Harbor, ME) by immunizing them with TIFI conjugated to BSA (TIFI-BSA) in adjuvant, as previously described (21). Spleen cells from a TIFI-BSA-immunized aPL-producing mouse were fused with Sp2/0 (CRL-2016; American Type Culture Collection, Rockville, MD), a nonsecreting myeloma cell line, using polyethylene glycol (22).…”

“…Therefore, aPL were induced in mice by immunization with synthetic peptides of viral and bacterial origin that had sequence and functional similarity to the phospholipid-binding site of of TLPA-BACSU from Bacilus subtilis) (21). The next step was to determine whether these antibodies have functional and pathogenic properties similar to those found in aPL in patients with APS and/or SLE.…”

Anti-beta 2 glycoprotein I antibodies in centenarians

“…In the APS, the breakdown of the tolerance towards the self b2GPI has been suggested to be the result of a molecular mimicry between exogenous and self molecules, at least in part due to the wide aminoacid homology of b2GPI from different species (Matsuura et al, 1991;Tincani et al, 2002;Gharavi et al, 1999;Blank et al, 2002). Still debated is the initial trigger of the response against the b2GPI, although preliminary data suggest that bacterial and/ or viral peptides sharing common aminoacid sequences could be responsible Blank et al, 2002).…”