Anticardiolipin IgG subclasses: association of IgG2 with arterial and/or venous thrombosis

Abstract

Objective: To determine whether the presence of anticardiolipin antibodies (aCL) of a specific IgG subclass is associated with clinical complications of the antiphospholipid antibody syndrome (APS) and whether polymorphisms of Fc receptors for IgG (FcgammaR) with differential binding preferences contribute to an increased risk of thrombotic complications.

Methods: In 60 patients with IgG aCL, we assessed clinical complications of the APS, measured the level of antibody activity, and determined the IgG subclass distribution of aCL by a modified enzyme-linked immunosorbent assay (ELISA) with murine anti-human IgG subclass monoclonal antibodies. Selective IgG subclass adsorption studies were performed to determine the relative contribution of specific IgG subclasses to overall aCL activity. Fcgamma receptor IIA (FcgammaRIIA) genotypes of aCL patients with thrombosis and of non-systemic lupus erythematosus controls were determined by polymerase chain reaction amplification of genomic DNA and allele-specific probes.

Results: IgG2 aCL, detected in 75% of the patients, was the major subclass of aCL. Selective adsorption studies demonstrated that IgG2, in contrast to IgG1, was the predominant subclass responsible for aCL reactivity. IgG2 aCL was the only subclass associated with clinical complications, specifically, arterial and/or venous thrombosis (P < 0.04). The presence of FcgammaRIIA-H131, a receptor expressed on platelets, monocytes, and endothelial cells and the only human FcgammaR which efficiently recognizes IgG2, was associated with thrombosis in aCL patients. Among 45 high-titer (>40 GPL [IgG phospholipid] units) aCL patients with thrombosis, 40% were homozygous for FcgammaRIIA-H131, compared with 25% of disease-free controls (P = 0.042).

Conclusion: While all 4 IgG subclasses are found in autoimmune aCL, only the presence of IgG2 is significantly associated with thrombotic complications. Reactivity in aCL ELISA is largely due to the presence of IgG2 in high-titer patients. The presence of IgG2 aCL, particularly in association with FcgammaRIIA-H131, may be a useful clinical predictor of increased thrombotic risk in patients with autoimmune IgG aCL. Allelic variants of FcgammaRIIA with distinct capacities to interact with IgG subclasses provide a mechanism for genetic susceptibility to an autoantibody-induced prothrombotic state.