Skip to main content
NCBI home page
Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 2004 Dec;63(12):1645–1648. doi: 10.1136/ard.2003.015552

Association of HLA-DM polymorphism with the production of antiphospholipid antibodies

M Sanchez 1, K Katsumata 1, T Atsumi 1, F Romero 1, M Bertolaccini 1, A Funke 1, O Amengual 1, E Kondeatis 1, R Vaughan 1, A Cox 1, G Hughes 1, M Khamashta 1
PMCID: PMC1754864  PMID: 15547089

Abstract

Objective: To investigate whether variation in the HLA-DM gene is important in producing a group of pathogenic autoantibodies—antiphospholipid antibodies (aPL)—on the basis that HLA class II restricted antigen presentation is involved in the production of aPL.

Methods: HLA-DMA and DMB polymorphisms were genotyped by polymerase chain reaction combined with restriction enzyme digestion in 51 white patients with primary antiphospholipid syndrome (APS), 82 with systemic lupus erythematosus (SLE) (42 with APS and 40 without APS), and 109 healthy white controls. The association with the aPL profile was examined.

Results: The distribution of DMA alleles in APS patients and in patients with APS associated with SLE was significantly different from that in controls by 4x2 χ2 test with 3 degrees of freedom (p = 0.035 and 0.011, respectively), but it was not different between SLE patients without APS and controls. The allelic distribution of DMA was also different between patients with IgG class anticardiolipin antibody or those with lupus anticoagulant (LA) and controls (p = 0.012 and 0.007, respectively) and between patients with and without LA among SLE patients (p = 0.035). All these differences included the increase in DMA*0102 in the former groups.

Conclusions: The results suggest that HLA-DMA*0102 or its linked gene(s) form one of the genetic risks for the production of aPL.

Full Text

The Full Text of this article is available as a PDF (68.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amengual O., Atsumi T., Khamashta M. A., Koike T., Hughes G. R. Specificity of ELISA for antibody to beta 2-glycoprotein I in patients with antiphospholipid syndrome. Br J Rheumatol. 1996 Dec;35(12):1239–1243. doi: 10.1093/rheumatology/35.12.1239. [DOI] [PubMed] [Google Scholar]
  2. Arnett F. C., Olsen M. L., Anderson K. L., Reveille J. D. Molecular analysis of major histocompatibility complex alleles associated with the lupus anticoagulant. J Clin Invest. 1991 May;87(5):1490–1495. doi: 10.1172/JCI115158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arnett F. C., Thiagarajan P., Ahn C., Reveille J. D. Associations of anti-beta2-glycoprotein I autoantibodies with HLA class II alleles in three ethnic groups. Arthritis Rheum. 1999 Feb;42(2):268–274. doi: 10.1002/1529-0131(199902)42:2<268::AID-ANR8>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
  4. Asherson R. A., Doherty D. G., Vergani D., Khamashta M. A., Hughes G. R. Major histocompatibility complex associations with primary antiphospholipid syndrome. Arthritis Rheum. 1992 Jan;35(1):124–125. doi: 10.1002/art.1780350119. [DOI] [PubMed] [Google Scholar]
  5. Bertolaccini M. L., Atsumi T., Caliz A. R., Amengual O., Khamashta M. A., Hughes G. R., Koike T. Association of antiphosphatidylserine/prothrombin autoantibodies with HLA class II genes. Arthritis Rheum. 2000 Mar;43(3):683–688. doi: 10.1002/1529-0131(200003)43:3<683::AID-ANR26>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  6. Bertolaccini M. L., Atsumi T., Khamashta M. A., Amengual O., Hughes G. R. Autoantibodies to human prothrombin and clinical manifestations in 207 patients with systemic lupus erythematosus. J Rheumatol. 1998 Jun;25(6):1104–1108. [PubMed] [Google Scholar]
  7. Brandt J. T., Triplett D. A., Alving B., Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost. 1995 Oct;74(4):1185–1190. [PubMed] [Google Scholar]
  8. Caliz R., Atsumi T., Kondeatis E., Amengual O., Khamashta M. A., Vaughan R. W., Lanchbury J. S., Hughes G. R. HLA class II gene polymorphisms in antiphospholipid syndrome: haplotype analysis in 83 Caucasoid patients. Rheumatology (Oxford) 2001 Jan;40(1):31–36. doi: 10.1093/rheumatology/40.1.31. [DOI] [PubMed] [Google Scholar]
  9. Carrington M., Harding A. Sequence analysis of two novel HLA-DMA alleles. Immunogenetics. 1994;40(2):165–165. doi: 10.1007/BF00188184. [DOI] [PubMed] [Google Scholar]
  10. Carrington M., Yeager M., Mann D. Characterization of HLA-DMB polymorphism. Immunogenetics. 1993;38(6):446–449. doi: 10.1007/BF00184526. [DOI] [PubMed] [Google Scholar]
  11. Demaison C., Ravirajan C. T., Isenberg D. A., Zouali M. Analysis of variable region genes encoding anti-Sm and anti-cardiolipin antibodies from a systemic lupus erythematosus patient. Immunology. 1995 Nov;86(3):487–494. [PMC free article] [PubMed] [Google Scholar]
  12. Djilali-Saiah I., Benini V., Daniel S., Assan R., Bach J. F., Caillat-Zucman S. Linkage disequilibrium between HLA class II (DR, DQ, DP) and antigen processing (LMP, TAP, DM) genes of the major histocompatibility complex. Tissue Antigens. 1996 Aug;48(2):87–92. doi: 10.1111/j.1399-0039.1996.tb02612.x. [DOI] [PubMed] [Google Scholar]
  13. Djilali-Saiah I., Benini V., Schmitz J., Timsit J., Assan R., Boitard C., Bach J. F., Caillat-Zucman S. Absence of primary association between DM gene polymorphism and insulin-dependent diabetes mellitus or celiac disease. Hum Immunol. 1996 Aug;49(1):22–27. doi: 10.1016/0198-8859(96)00041-9. [DOI] [PubMed] [Google Scholar]
  14. Esposito L., Lampasona V., Bonifacio E., Bosi E., Ferrari M. Lack of association of DMB polymorphism with insulin-dependent diabetes. J Autoimmun. 1997 Aug;10(4):395–400. doi: 10.1006/jaut.1997.0144. [DOI] [PubMed] [Google Scholar]
  15. Harris E. N., Gharavi A. E., Patel S. P., Hughes G. R. Evaluation of the anti-cardiolipin antibody test: report of an international workshop held 4 April 1986. Clin Exp Immunol. 1987 Apr;68(1):215–222. [PMC free article] [PubMed] [Google Scholar]
  16. Hartung K., Coldewey R., Corvetta A., Deicher H., Kalden J. R., Krapf F., Lang B., Lakomek H. J., Liedvogel B., Peter H. H. MHC gene products and anticardiolipin antibodies in systemic lupus erythematosus results of a multicenter study. SLE Study Group. Autoimmunity. 1992;13(2):95–99. doi: 10.3109/08916939209001909. [DOI] [PubMed] [Google Scholar]
  17. Ishihara M., Naruse T., Ohno S., Kawata H., Mizuki N., Yamagata N., Ishida T., Nose Y., Inoko H. Analysis of HLA-DM polymorphisms in sarcoidosis. Hum Immunol. 1996 Sep 1;49(2):144–146. doi: 10.1016/0198-8859(96)82496-7. [DOI] [PubMed] [Google Scholar]
  18. Kelly A. P., Monaco J. J., Cho S. G., Trowsdale J. A new human HLA class II-related locus, DM. Nature. 1991 Oct 10;353(6344):571–573. doi: 10.1038/353571a0. [DOI] [PubMed] [Google Scholar]
  19. Kuwata S., Yanagisawa M., Nakagawa H., Saeki H., Etoh T., Miyamoto M., Juji T. HLA-DM gene polymorphisms in atopic dermatitis. J Allergy Clin Immunol. 1996 Dec;98(6 Pt 2):S192–S200. doi: 10.1016/s0091-6749(96)70066-0. [DOI] [PubMed] [Google Scholar]
  20. Matsuura E., Igarashi Y., Yasuda T., Triplett D. A., Koike T. Anticardiolipin antibodies recognize beta 2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med. 1994 Feb 1;179(2):457–462. doi: 10.1084/jem.179.2.457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mellins E., Smith L., Arp B., Cotner T., Celis E., Pious D. Defective processing and presentation of exogenous antigens in mutants with normal HLA class II genes. Nature. 1990 Jan 4;343(6253):71–74. doi: 10.1038/343071a0. [DOI] [PubMed] [Google Scholar]
  22. Menon S., Rahman M. A., Ravirajan C. T., Kandiah D., Longhurst C. M., McNally T., Williams W. M., Latchman D. S., Isenberg D. A. The production, binding characteristics and sequence analysis of four human IgG monoclonal antiphospholipid antibodies. J Autoimmun. 1997 Feb;10(1):43–57. doi: 10.1006/jaut.1996.0106. [DOI] [PubMed] [Google Scholar]
  23. Naruse T. K., Kawata H., Ishihara M., Ando A., Kagiya M., Nose Y., Isshiki G., Inoko H. Analysis on allelic variation of the HLA-DMB gene in Japanese by PCR-RFLP as well as direct DNA sequencing and identification of a new DMB allele, DMB*0105. Tissue Antigens. 1996 Jun;47(6):530–537. doi: 10.1111/j.1399-0039.1996.tb02595.x. [DOI] [PubMed] [Google Scholar]
  24. Olerup O., Aldener A., Fogdell A. HLA-DQB1 and -DQA1 typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours. Tissue Antigens. 1993 Mar;41(3):119–134. doi: 10.1111/j.1399-0039.1993.tb01991.x. [DOI] [PubMed] [Google Scholar]
  25. Olerup O., Zetterquist H. HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens. 1992 May;39(5):225–235. doi: 10.1111/j.1399-0039.1992.tb01940.x. [DOI] [PubMed] [Google Scholar]
  26. Perdriger A., Guggenbuhl P., Chalès G., Yaouanq J., Quelvennec E., Bonnard M. N., Pawlotsky Y., Semana G. Positive association of the HLA DMB1*0101-0101 genotype with rheumatoid arthritis. Rheumatology (Oxford) 1999 May;38(5):448–452. doi: 10.1093/rheumatology/38.5.448. [DOI] [PubMed] [Google Scholar]
  27. Pinet V., Combe B., Avinens O., Caillat-Zucman S., Sany J., Clot J., Eliaou J. F. Polymorphism of the HLA-DMA and DMB genes in rheumatoid arthritis. Arthritis Rheum. 1997 May;40(5):854–858. doi: 10.1002/art.1780400512. [DOI] [PubMed] [Google Scholar]
  28. Ristori G., Carcassi C., Lai S., Fiori P., Cacciani A., Floris L., Montesperelli C., Di Giovanni S., Buttinelli C., Contu L. HLA-DM polymorphisms do not associate with multiple sclerosis: an association study with analysis of myelin basic protein T cell specificity. J Neuroimmunol. 1997 Aug;77(2):181–184. doi: 10.1016/s0165-5728(97)00069-6. [DOI] [PubMed] [Google Scholar]
  29. Rooney A. M., McNally T., Mackie I. J., Machin S. J. The Taipan snake venom time: a new test for lupus anticoagulant. J Clin Pathol. 1994 Jun;47(6):497–501. doi: 10.1136/jcp.47.6.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Singal D. P., Ye M. HLA-DM polymorphisms in patients with rheumatoid arthritis. J Rheumatol. 1998 Jul;25(7):1295–1298. [PubMed] [Google Scholar]
  31. Takeuchi F., Nabeta H., Hong G. H., Kuwata S., Tanimoto K., Ito K. Polymorphisms of DMA and DMB genes in Japanese systemic lupus erythematosus. Br J Rheumatol. 1998 Jan;37(1):95–97. doi: 10.1093/rheumatology/37.1.95. [DOI] [PubMed] [Google Scholar]
  32. Takeuchi F., Nabeta H., Kuwata S., Tanimoto K., Ito K. Association of DMA and DMB with RA in Japanese. Clin Exp Rheumatol. 1997 Mar-Apr;15(2):189–192. [PubMed] [Google Scholar]
  33. Tan E. M., Cohen A. S., Fries J. F., Masi A. T., McShane D. J., Rothfield N. F., Schaller J. G., Talal N., Winchester R. J. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 Nov;25(11):1271–1277. doi: 10.1002/art.1780251101. [DOI] [PubMed] [Google Scholar]
  34. Vogt A. B., Kropshofer H., Hämmerling G. J. How HLA-DM affects the peptide repertoire bound to HLA-DR molecules. Hum Immunol. 1997 May;54(2):170–179. doi: 10.1016/s0198-8859(97)00077-3. [DOI] [PubMed] [Google Scholar]
  35. West J. E., Reed A. M. Analysis of HLA-DM polymorphism in juvenile dermatomyositis (JDM) patients. Hum Immunol. 1999 Mar;60(3):255–258. doi: 10.1016/s0198-8859(98)00118-9. [DOI] [PubMed] [Google Scholar]
  36. Wilson W. A., Gharavi A. E., Koike T., Lockshin M. D., Branch D. W., Piette J. C., Brey R., Derksen R., Harris E. N., Hughes G. R. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999 Jul;42(7):1309–1311. doi: 10.1002/1529-0131(199907)42:7<1309::AID-ANR1>3.0.CO;2-F. [DOI] [PubMed] [Google Scholar]
  37. Wilson W. A. Histocompatibility genes in antiphospholipid antibody syndrome. Lupus. 1996 Aug;5(4):259–262. doi: 10.1177/096120339600500403. [DOI] [PubMed] [Google Scholar]
  38. Wilson W. A., Scopelitis E., Michalski J. P., Pierangeli S. S., Silveira L. H., Elston R. C., Harris E. N. Familial anticardiolipin antibodies and C4 deficiency genotypes that coexist with MHC DQB1 risk factors. J Rheumatol. 1995 Feb;22(2):227–235. [PubMed] [Google Scholar]
  39. Yen J. H., Chen C. J., Tsai W. C., Tsai J. J., Chang J. G., Liu H. W. HLA-DMA and DMB genotyping in patients with rheumatoid arthritis. J Rheumatol. 1997 Mar;24(3):442–444. [PubMed] [Google Scholar]

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Publishing Group

RESOURCES