Major histocompatibility complex associations with primary antiphospholipid syndrome.код для вставкиСкачать
124 CONCISE COMMUNICATION Major histocompatibility complex associations with primary antiphospholipid syndrome The antiphospholipid syndrome is characterized by venous and arterial thromboses, recurrent fetal loss, thrombocytopenia, and the presence of autoantibodies to cardiolipin (aCL) and other negatively charged phospholipids (1). While this syndrome is mainly seen in patients with systemic lupus erythematosus (SLE), it is also seen in a group of patients who do not manifest any of the major clinical or serologic features of SLE, a condition referred to as a primary antiphospholipid syndrome (PAPS) (2). Recent studies have shown an association between the presence of aCL and HLA-DR7 (3) as well as DR4 ( 4 3 , and a negative association with DR3, in different populations. Both HLADR4 and DR7, which are coded for by the DRBl gene, are in strong linkage disequilibrium with the DRw53 allele of the DRB4 gene (6), suggesting a predisposing role for DRw53 in aCL positivity. Two recent studies have documented an association between PAPS and DRw53 (7) and DQw7 (8). To investigate the relative contributions of the major histocompatibility complex (MHC) class I1 and class I11 genes to aCL positivity, we determined the DR and DQ genotypes and MHC class I11 gene polymorphisms in 13 English patients with PAPS and in 69 racially and geographically matched adult control subjects. Patients with PAPS conformed to the criteria we proposed in 1989 (1). They presented essentially with thromboses (venous/arterial), which often were recurrent, and/or with recurrent fetal loss. They did not have any of the typical clinical or serologic features of SLE. The lupus anticoagulant was measured according to the method of Exner et a1 (9) and the aCL according to our previously described method (10). Twelve of the 13 patients had both the lupus anticoagulant and aCL; the remaining patient had only the lupus anticoagulant. All patients with positive aCL had moderate to high elevations of IgG aCL, which in 2 of them, was accompanied by low levels of IgM aCL. HLA-DR and DQB alleles were identified by restriction fragment length polymorphism (RFLP) analysis, using Taq I-digested DNA with complementary DNA probes for the DRB and DQB genes, and sequence-specific oligonucleotide probing of DNA fragments amplified by the polymerase chain reaction, as described previously (11). MHC class 111 gene polymorphisms were identified by Taq I RFLP analysis using probes for the complement component C4 and steroid 21-hydroxylase genes (12). (The DRB, DQB, C4, and 21-hydroxylase gene probes were kindly donated by J. L. Bidwell, UK Transplant Service, Bristol, A. Jonsson, Swedish University of Agricultural Sciences, Uppsala, and R. D. Campbell, Oxford University.) Significant differences in genotype frequencies in patients and controls in this study were limited to the HLA class I1 region of the MHC. The frequencies of the DRB and DQB alleles in patients and controls are shown in Table 1. Using these techniques, DRl cannot be distinguished from DRBr, DRw52a cannot be distinguished from DRwSZc, and some DR7 polymorphisms cannot be distinguished from DR9; so, the frequencies of these alleles were combined. Two significant differences in HLA class I1 allele frequencies in these patients were noted. HLA-DR4 was present in 10 of 13 patients compared with 25 of 69 controls (2= 7.704; P < 0.01), and DRw53 was present in 12 of 13 patients compared with 44 of 69 controls (2= 4.115; P < 0.05). Due to the small number of patients tested, these comparisons d o not remain significant after correction for multiple testing. The one patient negative for DRw53 had only the lupus anticoagulant, but was aCL negative. HLADR3 was absent in all patients, and the frequencies of HLA-DRw52 a or c and DRw52 b were reduced; however, neither decrease was statistically significant. N o significant associations between any DQB alleles Table 1. HLA-DR and DQB allele frequencies (% positive) in 13 patients with primary antiphospholipid syndrome (PAPS) and in 69 healthy control subjects DRB allele PAPS patients Control subjects DQB allele PAPS patients Control subjects DRllDRBr DR2 (DRwlS) DR2 (DRwl6) DR3 (DRwl7) DR4 DR5 (DRw11) DR5 (DRw 12) DRw6 (DRw 13) DRw6 (DRw 14) DR7/DR9 DRw8 DRwlO DRw52 a/c DRw52 b DRw53 15.4 15.4 0 0 76.9* 0 7.7 23.1 1.7 38.5 1.7 0 23.1 15.4 92.3t 23.2 27.5 2.9 23.2 36.2 7.2 2.9 14.5 5.8 31.9 7.2 1.4 27.5 34.8 63.8 DQB I *050 I 0502 0503 0601 0602 0603 0401 15.4 0 7.7 0 15.4 15.4 1.7 15.4 53.8 46.2 23.1 0 0402 0 24.6 I .4 5.8 0 27.5 5.8 7.2 42.0 30.4 29.0 11.6 0 4.3 * P < 0.01. relative t P < 0.05, relative risk = 5.8, versus controls. risk = 6.8, versus controls. Arthritis and Rheumatism, Vol. 35, No. 1 (January 1992) 0604 020 1 0301 0302 0303 CONCISE COMMUNICATION 125 or C4 or 21-hydroxylase gene polymorphisms and PAPS were found. DR3, DRw52a, and deletion of the C4A gene, which are strongly associated with SLE in Caucasoid and black populations, were decreased in our patients, which is further evidence for a different immunogenetic predisposition as compared with definite SLE. DR4 is generally linked with DQB1*0301 (DQw7) or DQB1*0302 (DQw8) in Caucasoids (13). The frequencies of both these alleles are slightly raised in patients compared with controls, indicating that the high incidence of DR4 is not due to an increase in the frequency of one particular DR4 haplotype. Although the frequency of DQw7 is increased, confirming the report by Arnett et al @), our findings suggest that this increase is due to linkage disequilibrium between DR4-DRw53 and DQw7, and that the DR locus is more strongly associated with PAPS than is the DQB locus. Furthermore, the highest relative risk for PAPS is conferred by the DRw53 allele, which was present in all aCL-positive patients, suggesting that this allele may play a direct role in mediating an autoimmune response to phospholipids. These are preliminary data and must be interpreted with caution because of the small number of patients tested; however, the data are consistent with a role for the DRB4 gene in the expression of aCL. R. A. Asherson, MD, FACP, FCP(SA) The Rayne Institute, St. Thomas’ Hospital D. G. Doherty, MSc D. Vergani, MD, PhD King’s College Hospital M. A. Khamashta, MD, PhD G. R. V. Hughes, MD, FRCP The Rayne Institute, St. Thomas’ Hospital London, U K 1. Asherson RA, Khamashta MA, Ordi-Ros J, Derksen RHWM, Machin SJ, Barquinero J, Out HH, Harris EN, Vilardeu-Torres M, Hughes GRV: The “primary” antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore) 68:36&374, 1989 2. Asherson RA: A “primary” antiphospholipid syndrome. J Rheumatol 15: 1742-1746, 1988 3. Savi M, Ferraccioli GF, Neri TM, Zanelli P, Dall’Aglio PP, Tincani A, Balestrieri G, Carella G, Cattaneo R: HLA-DR antigens and anticardiolipin antibodies in northern Italian systemic lupus erythematosus patients. Arthritis Rheum 31: 15681570, 1988 4. McHugh NJ, Maddison PJ: HLA-DR antigens and anticardiolipin antibodies in patients with systemic lupus erythematosus (letter). Arthritis Rheum 32:162%1624, 1989 5. McNeil HP, Gavaghan TP, Krilis SA, Geczy AF, Chesterman CN: HLA-DR antigens and anticardiolipin antibodies. Clin Exp Rheumatol8:425-427, 1990 6. Bidwell JL: DNA-RFLP analysis and genotyping of HLA-DR and DQ antigens. Immunol Today 9:18-23, 1988 7. Goldstein B, Smith CD, Sengar DPS: MHC class I1 studies of primary antiphospholipid antibody syndrome and of serum antiphospholipid antibodies in systemic lupus erythematosus (abstract). Arthritis Rheum 33 (suppl9):S125, 1990 8. Arnett FC, Olsen ML, Anderson KL, Reveille JD: Molecular analysis of major histocompatibility complex alleles associated with the lupus anticoagulant. J Clin Invest 87:1490-1495, 1991 9. Exner T, Rickard KA, Kronenberg H: Studies on phospholipids in the action of a lupus coagulation inhibitor. Pathology 7:319328, 1975 10. Gharavi AE, Harris EN, Asherson RA, Hughes GRV: Anticardiolipin antibodies: isotype distribution and phospholipid specificity. Ann Rheum Dis 46:1-6,1987 11. Doherty Mi,Donaldson PT: HLA-DRB and DQB typing by a combination of serology, restriction fragment length polymorphism analysis and oligonucleotide probing. Eur J Immunogenetics 18: 1 11-124, 1991 12. Schneider PM, Carroll MC, Alper CA, Rittner C, Whitehead AS, Yunis EJ, Colten HR: Polymorphism of the human complement C4 and steroid 21-hydroxylase genes: restriction fragment length polymorphism revealing structural deletions, homoduplications, and size variants. J Clin Invest 78:650-657, 1986 13. Todd JA, Bell JI, McDevitt HO: HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329599404. 1987 Erratum In the article by Walz-LeBlanc et al in the October 1991 issue of Arthritis and Rheumatism (Walz-LeBlanc BAE, Reynolds WJ, MacFadden DK: Allopurinol sensitivity in a patient with chronic tophaceous gout: success of intravenous desensitization after failure of oral desensitization. Arthritis Rheum 34:1329-1331, 1991), Dr. LeBlanc’sdegrees and affiliations were listed incorrectly.The footnote listing this information should have read as follows: “Barbara A. E. Walz-LeBlanc, MD, FRCP(C): former Rheumatology Fellow, Toronto Western Hospital (currently Geoff Carr Lupus Fellow, Wellesley Hospital, Toronto).” We regret the error.