Fcγ Receptor IIA H/R131 Polymorphism in Patients with Antiphospholipid Antibodies

Summary

A role for Fcγ receptor in the pathophysiology of thrombosis in APS has been hypothesized. The polymorphism of this receptor, FcγRIIA H/R131, is associated with the binding affinity for human IgG₂ (i.e. FcγRIIA-H131 isoform has a higher affinity than FcγRIIA-R131). Since anti-β₂ glycoprotein I antibodies (anti β₂GPI), which play a major pathogenic role in APS, show IgG₂ dominant distribution, we investigated the prevalence of receptor isoforms in patients with anti-phospholipid antibodies (aPL) by a PCR-RFLP method. We studied 100 Caucasian patients with aPL (57 primary APS, 32 secondary APS to SLE and 11 other diseases with aPL) and 41 healthy controls. H131/H131, H131/R131 and R131/R131 genotypes were found in 21 (21%), 50 (50%) and 29 (29%) in the patient group, and 9 (22%), 23 (56%) and 9 (22%) in control group, respectively. Thus there was no statistically significant difference in the prevalence of each genotype in these groups. None of the clinical manifestations of primary APS (arterial/venous thrombosis, recurrent pregnancy loss and thrombocytopenia) was significantly correlated with any FcγRIIA genotype. In conclusion, FcγRIIA polymorphism did not correlate with the manifestations of APS, and FcγRIIA genotype is not a genetic marker of APS.

• References

• 1 Hughes GRV. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-4.
• 2 Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van BredaVriesman PJC, Barbui T, Zwaal RFAZ, Bevers EM. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 952-3.
• 3 Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Koike T. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 1990; 336: 177-8.
• 4 McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that induces a lipid-binding inhibitor of coagulation: β₂-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990; 87: 4120-4.
• 5 Hunt JE, Krilis S. The fifth domain of β₂-glycoprotein I contains a phospholipid binding site (Cys281-Cys288) and a region recognized by anti-cardiolipin antibodies. J Immunol 1994; 152: 653-9.
• 6 Igarashi M, Matsuura E, Igarashi Y, Nagae H, Ichikawa K, Triplett DA, Koike T. Human β₂-glycoprotein I as an anticardiolipin cofactor determined using deleted mutants expressed by a Baculovirus system. Blood 1996; 87: 3262-70.
• 7 Matsuura E, Igarashi Y, Yasuda T, Triplett DA, Koike T. Anticardiolipin antibodies recognize β₂-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med 1994; 179: 457-62.
• 8 Roubey RAS, Eisenberg RA, Harper MF, Winfield JB. “Anticardiolipin” autoantibodies recognize β₂-glycoprotein I in the absence of phospholipid. J Immunol 1995; 154: 954-60.
• 9 Roubey RAS. Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other “antiphospholipid” antibodies. Blood 1994; 84: 2854-67.
• 10 Roubey RAS. Immunology of the antiphospholipid antibody syndrome. Arthritis Rheum 1996; 39: 1444-54.
• 11 Arnout J. The pathogenesis of the antiphospholipid syndrome: a hypothesis based on parallelisms with heparin-induced thrombocytopenia. Thromb Haemost 1996; 75: 536-41.
• 12 Chong BH, Pitney WR, Castaldi PA. Heparin-induced thrombocytopenia: association of thrombotic complications with heparin-dependent IgG antibody that induces thromboxane synthesis and platelet aggregation. Lancet 1982; 2: 1246-9.
• 13 Chong BH, Pilgrim RL, Cooley MA, Chesterman CN. Increased expression of platelet IgG Fc receptors in immune heparin-induced thrombocytopenia. Blood 1993; 81: 988-93.
• 14 Anderson GP. Insights into heparin-induced thrombocytopenia. Br J Haematol 1992; 80: 504-8.
• 15 Simantov R, LaSala JM, Lo SK, Gharavi AE, Sammaritano LR, Salmon JE, Silverstein RL. Activation of cultured vascular endothelial cells by anti-phospholipid antibodies. J Clin Invest 1995; 96: 2211-9.
• 16 Del PaPa N, Guidali L, Sala A, Buccellati C, Khamashta MA, Ichikawa K, Koike T, Balestrieri G, Tincani A, Hughes GRV, Meroni PL. Endothelial cells as target for antiphospholipid antibodies. Arthritis Rheum 1997; 40: 551-61.
• 17 Brooks DG, Qui WQ, Luster AD, Ravetch JV. Structure and expression of human IgG FcRII(CD32). J Exp Med 1989; 170: 1369-85.
• 18 van de Winkel JGJ, Capel PJA. Human IgG Fc receptor heterogeneity. Immunol Today 1993; 14: 215-21.
• 19 Warmerdam PAM, van de Winkel JGJ, Vlug A, Westerdaal NAC, Capel PJA. A single amino acid in the second Ig-like domain of the human Fcγ receptor II is critical for human IgG₂ binding. J Immunol 1991; 147: 1338-43.
• 20 Clark MR, Stuart SG, Kimberly RP, Ory PA, Goldstein IM. A single amino acid distinguishes the high-responder from the low-responder form of Fc receptor II on human monocytes. Eur J Immunol 1991; 21: 1911-6.
• 21 Kimberly RP, Salmon JE, Edberg JC. Receptors for immunoglobulin G: molecular diversity and implications for disease. Arthritis Rheum 1995; 38: 306-14.
• 22 Yee AMF, Ng SC, Sobel RE, Salmon JE. Fcγ RIIA polymorphism as a risk factor for invasive pneumococcal infection in systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1180-2.
• 23 Salmon JE, Millard S, Schachter LA, Arnett FC, Ginzler EM, Gourley MF, Ramsey-Goldman RE, Peterson MG, Kimberly RP. FcγRIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 1996; 97: 1348-54.
• 24 Arvieux J, Roussel B, Ponard D, Colomb MG. IgG₂ subclass restriction of anti-β₂ glycoprotein I antibodies in autoimmune patients. Clin Exp Immunol 1994; 95: 310-5.
• 25 Harris EN. Antiphospholipid antibodies. Br J Haematol 1990; 74: 1-9.
• 26 Jiang XM, Arepally G, Poncz M, McKenzie SE. Rapid detection of the FcγRIIA-H/R131 ligand-binding polymorphism using an allele-specific restriction enzyme digestion (ASRED). J Immunol Methods 1996; 199: 55-9.
• 27 Amengual O, Atsumi T, Khamashta M, Koike T, Hughes GRV. Specificity of ELISA for antibody to β₂-glycoprotein I in patients with antiphospholipid syndrome. Br J Rheumatol 1996; 35: 1239-43.
• 28 Harris EN, Gharavi AE, Patel BM, Hughes GRV. Evaluation of the anti-cardiolipin antibody test: report of an international workshop held 4 April 1986. Clin Exp Immunol 1987; 68: 215-22.
• 29 Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Suzuki T, Yoshida S, Koike T. Heterogeneity of anticardiolipin antibodies defined by the anticardiolipin cofactor. J Immunol 1992; 148: 3885-91.
• 30 Tannenbaum SH, Finko R, Cines DB. Antibody and immune complexes induce tissue factor production by human endothelial cells. J Immunol 1986; 137: 1532-7.
• 31 Atsumi T, Khamashta MA, Amengual O, Hughes GRV. Up-regulated tissue factor expression in antiphospholipid syndrome. Thromb Haemost 1997; 77: 222-3.
• 32 Jurado M, Paramo JA, Gutierrez-Pimentel M, Rocha E. Fibrinolytic potential and antiphospholipid antibodies in systemic lupus erythematosus and other connective tissue disorders. Thromb Haemost 1992; 68: 516-20.
• 33 Kelton JG, Sheridan D, Santos A, Smith J, Steeves K, Smith C, Brown C, Murphy WG. Heparin-induced thrombocytopenia: Laboratory studies. Blood 1988; 72: 925-30.
• 34 Brandt JT, Isenhart CE, Osborne JM, Ahmed A, Anderson CL. On the role of Fcγ-RIIa phenotype in heparin-induced thrombocytopenia. Thromb Haemost 1995; 74: 1564-72.
• 35 Burgess JK, Lindeman R, Chesterman CN, Chong BH. Single amino acid mutation of Fcγ receptor is associated with the development of heparin-induced thrombocytopenia. Br J Haematol 1995; 91: 761-6.
• 36 Arepally G, McKenzie SE, Jiang XM, Poncz M, Cines DB. FcγRIIA H/R131 polymorphism, subclass-specific IgG anti-heparin/platelet factor 4 antibodies and clinical course in patients with heparin-induced thrombocytopenia and thrombosis. Blood 1997; 89: 370-5.