ANTICARDIOLIPIN IGG SUBCLASSES - ASSOCIATION OF IGG2 WITH ARTERIAL AND OR VENOUS THROMBOSIS/

Objective. To determine whether the presence of anticardiolipin antibo dies (aCL) of a specific IgG subclass is associated with clinical comp lications of the antiphospholipid antibody syndrome (APS) and whether polymorphisms of Fc receptors for IgG (Fc gamma R) with differential b inding preferences contribute to an increased risk of thrombotic compl ications. Methods. In 60 patients with IgG aCL, we assessed clinical c omplications of the APS, measured the level of antibody activity, and determined the IgG subclass distribution of aCL by a modified enzyme-l inked immunosorbent assay (ELISA) with murine antihuman IgG subclass m onoclonal antibodies, Selective IgG subclass adsorption studies were p erformed to determine the relative contribution of specific IgG subcla sses to overall aCL activity, Fc gamma receptor IIA (Fc gamma RIIA) ge notypes of aCL patients with thrombosis and of non-systemic lupus eryt hematosus controls were determined by polymerase chain reaction amplif ication of genomic DNA and allele-specific probes. Results. IgG2 aCL, detected in 75% of the patients, was the major subclass of aCL, Select ive adsorption studies demonstrated that IgG2, in contrast to IgG1, wa s the predominant subclass responsible for aCL reactivity, IgG2 aCL wa s the only subclass associated with clinical complications, specifical ly, arterial and/or venous thrombosis (P < 0.04). The presence of Fc g amma RIIA-H131, a receptor expressed on platelets, monocytes, and endo thelial cells and the only human Fc gamma R which efficiently recogniz es 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 Fc gamma RIIA-H131, compared with 25% of dis ease-free controls (P = 0.042). Conclusion. While all 4 IgG subclasses are found in autoimmune aCL, only the presence of IgG2 is significant ly associated with thrombotic complications, Reactivity in aCL ELISA i s largely due to the presence of IgG2 in high-titer patients, The pres ence of IgG2 aCL, particularly in association with Fc gamma RIIA-H131, may be a useful clinical predictor of increased thrombotic risk in pa tients,vith autoimmune IgG aCL. Allelic variants of Fc gamma RIIA with distinct capacities to interact with IgG subclasses provide a mechani sm for genetic susceptibility to an autoantibody-induced prothrombotic state.