Presence of Immune Complexes of IgG/IgM Bound to B2-glycoprotein I Is Associated With Non-criteria Clinical Manifestations in Patients With Antiphospholipid Syndrome

Abstract

Background: Antiphospholipid syndrome (APS) is an acquired autoimmune disorder defined by the presence of both clinical (thromboembolic events or pregnancy morbidity) and laboratory (antiphospholipid antibodies, aPL) manifestations. Despite their importance, several clinical manifestations strongly associated with APS such as livedo reticularis (LR), thrombocytopenia, sicca-ophthalmic(sicca), heart, or neurological manifestations are not included in the APS clinical classification criteria. Circulating immune complexes (CIC) formed by Beta-2-glycoprotein I (B2GPI) and aPL (B2-CIC) have been described and their presence has been related with thrombotic events.Methods: Cross-sectional and observational cohort study in APS patients with thrombotic symptomatology.Setting and Participants: Fifty-seven patients from the University Hospital Center Bezanijska Kosa (Belgrade, Serbia) who met the APS classification criteria (35 with primary APS and 22 with APS associated to systemic lupus erythematosus). This study aimed to determine the prevalence of B2-CIC in APS patients and to evaluate their association with clinical manifestations of APS not included in the classification criteria.Results: B2-CIC prevalence in APS patients was 19.3%. The presence of thrombocytopenia (OR:5.7), livedo reticularis (OR:5.6), sicca (OR:12.6), and leukopenia (OR:5.6) was significantly higher in patients with B2-CIC than in the rest of APS patients. C3 and C4 complement factor levels were significantly lower in B2-CIC positive patients, which suggests a greater consumption of complement. Patients with quadruple aPL positivity (triple aPL-positivity plus the presence of B2-CIC) showed a higher prevalence of thrombocytopenia, leucopenia and LR than those with single/double aPL-positivity. No significant differences were found in the frequencies observed in patients with triple-only vs. single/double aPL-positivity. There were no significant differences between patients with primary APS and lupus-associated APS regarding the prevalence of B2-CIC and outcomes.Conclusions: Presence of B2-CIC is strongly associated with several non-criteria clinical manifestations related to APS and to higher complement consumption. More studies are required to better understand the clinical significance of B2-CIC.

Blood Cell-Bound C4d as a Marker of Complement Activation in Patients With the Antiphospholipid Syndrome

“…In contrast, the mechanism(s) responsible for complement activation in APS has not been clarified yet. Although circulating anti-β 2 GPI/β 2 GPI complexes can be found in a limited proportion of patients (41, 42), they are undetectable in most of them suggesting that tissue bound complexes (e.g., on vessel walls) (16, 39) and/or additional mechanisms play a role in complement activation.…”

Immune Complexes of Beta-2-Glycoprotein I and IgA Antiphospholipid Antibodies Identify Patients With Elevated Risk of Thrombosis and Early Mortality After Heart Transplantation

“…Its study has allowed us to recognize that there is no simple mechanism by which obstetric complications are triggered in the pathogenesis of PHC but rather diverse pathologic pathways (TLR, NADPHox, LRP8) are being linked to aPL (39,40). In this way, a new pathophysiological pathway of APL is studied through the presence of immune complexes of B2GP1 and aPL (IgG, IgM, or IgA isotype) and its association with acute events (23) and with extra-criteria manifestations of APS (41).…”

IgG Immune Complexes Inhibit Naïve T Cell Proliferation and Suppress Effector Function in Cytotoxic T Cells

“…When antibodies bind to multivalent antigens, they form immune complexes (ICs) decorated with multiple antibody molecules that can bind with high avidity to Fc gamma receptors (FcgRs) expressed on a wide variety of immune cells, triggering a plethora of well-characterized phenotypes essential for immune homeostasis. IgG ICs are naturally found in sera of healthy subjects, but their presence is often more pronounced in disease states including autoimmunity and cancer (2)(3)(4)(5)(6)(7). IC-FcgR interactions can elicit inhibitory or stimulatory signals, contributing to the overall outcome of an immune response (8)(9)(10).…”