The IgA Isotype of Anti-β2 Glycoprotein I Antibodies Recognizes Epitopes in Domains 3, 4, and 5 That Are Located in a Lateral Zone of the Molecule (L-Shaped)

Abstract

Background: Antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with presence of anti-phospholipid antibodies (aPL). The APS classification criteria only consider the aPL of IgG/IgM isotype, however testing of aPL of IgA isotype is recommended when APS is suspected and consensus aPL are negative. IgA anti-βeta-2 glycoprotein-I (B2GP1) has been clearly related with occurrence of thrombotic events. Antibodies anti-B2GP1 of IgG/M isotypes recognize an epitope in Domain 1 (R39-G43), the epitopes that recognize IgA anti-B2GP1 antibodies are not well-identified. Aim: To determine the zones of B2GP1 recognized by antibodies of IgA isotype from patients with APS symptomatology and positive for IgA anti-B2GP1. Methods: IgA antibodies to Domain-1(D1) and Domain-4/5(D4/5) of B2GP1 (ELISA) and epitope mapping on oligopeptide arrays of B2GP1 were evaluated in sera from a group of 93 patients with at least one thrombotic and with isolated positivity for IgA anti-B2GP1 antibodies (negative for other aPL). Results: A total of 47 patients (50.5%) were positive for anti-D4/5 and 23(25%) were positive for anti-D1. When peptide arrays were analyzed, three zones of B2GP1 reactivity were identified for more than 50% of patients. The center of these zones corresponds to amino acids 140(D3), 204(D4), and 264(D5). The peptides recognized on D3 and D4 contain amino acid sequences sharing high homology with proteins of microorganism that were previously related with a possible APS infectious etiology. In the three-dimensional structure of B2GP1, the three peptides, as the R39-G43 epitope, are located on the right side of the molecule (L-shape). The left side (J-shape) does not bind the antibodies. Conclusions: Patients with thrombotic APS clinical-criteria, and isolated IgA anti-B2GP1 positivity appear to preferentially bind, not to the D1 or D4/5 domains of B2GP1, but rather to three sites in D3, D4, and D5. The sites on D3 and D4 were previously described as the target identified by human monoclonal antibodies derived from patients that were capable of inducing APS in animal models. The localization of these epitopes opens a new route to explore to increase understanding of the patholophysiology of the APS and to propose new alternatives and therapeutic targets.

High IgA antiphospholipid autoantibodies in healthy Sudanese explain the increased prevalence among Sudanese compared to Swedish systemic lupus erythematosus patients

“… 40 In a recent study by Serrano et al., APS patients with thrombosis more often had IgA antibodies against β 2 GPI domains 3, 4 and 5 than they had IgA anti-D1. 41 These findings conformed to an earlier study by Blank et al., showing that three peptides interfering with binding of monoclonal antibodies against domains 1 and 2, 3 and 4 prevented the development of experimental APS. 42 In our study, neither IgA anti-β 2 GPI nor IgA anti-D1 associated with thrombotic or obstetric events among Sudanese patients.…”

Immunoglobulin A Isotype of Antiphospholipid Antibodies Does Not Provide Added Value for the Diagnosis of Antiphospholipid Syndrome in a Chinese Population

“…However, a recent study has revealed the opposite conclusion that IgA–aPL is associated with thrombosis and obstetric complications ( 10 ). Some other previous studies also have mentioned the robust association between IgA–aPL and thrombosis ( 13 , 39 – 42 ) and that even IgA–aβ 2 GPI can be used as an independent risk factor for the development of APS-related events ( 13 ) and should be included as a consensus criterion for the diagnosis of APS ( 43 ). These controversial conclusions can mainly be attributed to differences in the included criteria of the study population, ethnic distribution, or statistical methods of the study.…”

Elevated IgA antiphospholipid antibodies in healthy pregnant women in Sudan but not Sweden, without corresponding increase in IgA anti-β2 glycoprotein I domain 1 antibodies

“… 51 These data are corroborated by a recent report showing that IgA anti-β 2 GPI from patients with thrombotic APS do not mainly bind domain 1, but instead target three sites in domains 3, 4 and 5. 52 Monoclonal antibodies against these epitopes have previously been shown to produce APS in animal models. 53 Murthy et al.…”