Skip to main content
NCBI home page
Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 1998 Jun;57(6):366–370. doi: 10.1136/ard.57.6.366

Immunoglobulin allotype gene polymorphisms in systemic sclerosis: interactive effect of MHC class II and KM genes on anticentromere antibody production

H Kameda 1, J Pandey 1, J Kaburaki 1, H Inoko 1, M Kuwana 1
PMCID: PMC1752620  PMID: 9771212

Abstract

OBJECTIVE—To examine potential interactions between immunoglobulin (Ig)allotype gene polymorphisms and susceptibility to systemic sclerosis (SSc) as well as serological expression in SSc patients.
METHODS—IgG heavy chain allotypes G1M(f, z), G2M(n+, n-), G3M(b, g) and Ig light chain allotype KM(1, (1, 2), 3) were genotyped in 105 Japanese SSc patients and 47 race matched normal controls using polymerase chain reaction (PCR) based methods. Associations of each Ig allotype with SSc related antinuclear antibodies were examined in combination with or without MHC class II alleles.
RESULTS—GM/KM genotypic and allelic frequencies were similar in SSc patients and in normal controls. Frequencies of G1M(f) and G2M(n+) were significantly decreased in anticentromere antibody (ACA) positive SSc patients compared with ACA negative SSc patients (p = 0.04 and 0.02, respectively). Conversely, the presence of DQB1*0501 and KM(1, 2) significantly increased the risk of ACA positivity.
CONCLUSION—Ig allotype gene polymorphisms were not associated with susceptibility to SSc. Instead, the results suggested that MHC class II and KM genes are associated with autoimmune responses by interactively promoting the production of ACA.

 Keywords: autoantibody; immunoglobulin allotype; major histocompatibility complex; scleroderma

Full Text

The Full Text of this article is available as a PDF (91.0 KB).

Selected References

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

  1. Balbín M., Grubb A., Abrahamson M., Grubb R. Determination of allotypes G1m(f) and G1m(z) at the genomic level by subclass-specific amplification of DNA and use of allele-specific probes. Exp Clin Immunogenet. 1991;8(2):88–95. [PubMed] [Google Scholar]
  2. Balbín M., Grubb A., de Lange G. G., Grubb R. DNA sequences specific for Caucasian G3m(b) and (g) allotypes: allotyping at the genomic level. Immunogenetics. 1994;39(3):187–193. doi: 10.1007/BF00241259. [DOI] [PubMed] [Google Scholar]
  3. Brusco A., de Lange G. G., Boccazzi C., Carbonara A. O. Molecular characterization of Gm(n+) and G2m(n-) allotypes. Immunogenetics. 1995;42(5):414–417. doi: 10.1007/BF00179404. [DOI] [PubMed] [Google Scholar]
  4. Chen Z. Y., Fedrick J. A., Pandey J. P., Silver R., Maricq H. R., Fudenberg H. H., Dobson R. L., Ainsworth S. K. Anticentromere antibody and immunoglobulin allotypes in scleroderma. Arch Dermatol. 1985 Mar;121(3):339–344. [PubMed] [Google Scholar]
  5. Dugoujon J. M., Cambon-Thomsen A. Immunoglobulin allotypes (GM and KM) and their interactions with HLA antigens in autoimmune diseases: a review. Autoimmunity. 1995;22(4):245–260. doi: 10.3109/08916939508995322. [DOI] [PubMed] [Google Scholar]
  6. Genth E., Zarnowski H., Mierau R., Wohltmann D., Hartl P. W. HLA-DR4 and Gm(1,3;5,21) are associated with U1-nRNP antibody positive connective tissue disease. Ann Rheum Dis. 1987 Mar;46(3):189–196. doi: 10.1136/ard.46.3.189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Grubb R. Advances in human immunoglobulin allotypes. Exp Clin Immunogenet. 1995;12(3):191–197. doi: 10.1159/000424871. [DOI] [PubMed] [Google Scholar]
  8. Hoffman R. W., Sharp G. C., Irvin W. S., Anderson S. K., Hewett J. E., Pandey J. P. Association of immunoglobulin Km and Gm allotypes with specific antinuclear antibodies and disease susceptibility among connective tissue disease patients. Arthritis Rheum. 1991 Apr;34(4):453–458. doi: 10.1002/art.1780340410. [DOI] [PubMed] [Google Scholar]
  9. Kuwana M., Kaburaki J., Okano Y., Inoko H., Tsuji K. The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma). J Clin Invest. 1993 Sep;92(3):1296–1301. doi: 10.1172/JCI116703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kuwana M., Kaburaki J., Okano Y., Tojo T., Homma M. Clinical and prognostic associations based on serum antinuclear antibodies in Japanese patients with systemic sclerosis. Arthritis Rheum. 1994 Jan;37(1):75–83. doi: 10.1002/art.1780370111. [DOI] [PubMed] [Google Scholar]
  11. Kuwana M., Medsger T. A., Jr, Wright T. M. T and B cell collaboration is essential for the autoantibody response to DNA topoisomerase I in systemic sclerosis. J Immunol. 1995 Sep 1;155(5):2703–2714. [PubMed] [Google Scholar]
  12. Kuwana M., Okano Y., Kaburaki J., Inoko H. HLA class II genes associated with anticentromere antibody in Japanese patients with systemic sclerosis (scleroderma). Ann Rheum Dis. 1995 Dec;54(12):983–987. doi: 10.1136/ard.54.12.983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kuwana M., Okano Y., Kaburaki J., Tojo T., Medsger T. A., Jr Racial differences in the distribution of systemic sclerosis-related serum antinuclear antibodies. Arthritis Rheum. 1994 Jun;37(6):902–906. doi: 10.1002/art.1780370619. [DOI] [PubMed] [Google Scholar]
  14. Kuwana M., Okano Y., Kaburaki J., Tsuji K., Inoko H. Major histocompatibility complex class II gene associations with anti-U1 small nuclear ribonucleoprotein antibody. Relationship to immunoreactivity with individual constituent proteins. Arthritis Rheum. 1995 Mar;38(3):396–405. doi: 10.1002/art.1780380317. [DOI] [PubMed] [Google Scholar]
  15. Mamula M. J., Fatenejad S., Craft J. B cells process and present lupus autoantigens that initiate autoimmune T cell responses. J Immunol. 1994 Feb 1;152(3):1453–1461. [PubMed] [Google Scholar]
  16. Matsumoto H. Characteristics of Mongoloid and neighboring populations based on the genetic markers of human immunoglobulins. Hum Genet. 1988 Nov;80(3):207–218. doi: 10.1007/BF01790088. [DOI] [PubMed] [Google Scholar]
  17. McGregor A. R., Watson A., Yunis E., Pandey J. P., Takehara K., Tidwell J. T., Ruggieri A., Silver R. M., LeRoy E. C., Maricq H. R. Familial clustering of scleroderma spectrum disease. Am J Med. 1988 Jun;84(6):1023–1032. doi: 10.1016/0002-9343(88)90307-5. [DOI] [PubMed] [Google Scholar]
  18. Moxley G., Gibbs R. S. Polymerase chain reaction-based genotyping for allotypic markers of immunoglobulin kappa shows allelic association of Km with kappa variable segment. Genomics. 1992 May;13(1):104–108. doi: 10.1016/0888-7543(92)90208-a. [DOI] [PubMed] [Google Scholar]
  19. Nakao Y., Matsumoto H., Miyazaki T., Nishitani H., Ota K., Fujita T., Tsuji K. Gm allotypes in myasthenia gravis. Lancet. 1980 Mar 29;1(8170):677–680. [PubMed] [Google Scholar]
  20. Pereira S., Black C., Welsh K., Ansell B., Jayson M., Maddison P., Rowell N. Autoantibodies and immunogenetics in 30 patients with systemic sclerosis and their families. J Rheumatol. 1987 Aug;14(4):760–765. [PubMed] [Google Scholar]
  21. Reveille J. D. Molecular genetics of systemic sclerosis. Curr Opin Rheumatol. 1995 Nov;7(6):522–528. doi: 10.1097/00002281-199511000-00010. [DOI] [PubMed] [Google Scholar]
  22. Schur P. H., Pandey J. P., Fedrick J. A. Gm allotypes in white patients with systemic lupus erythematosus. Arthritis Rheum. 1985 Jul;28(7):828–830. doi: 10.1002/art.1780280716. [DOI] [PubMed] [Google Scholar]
  23. Silman A. J., Newman J. Genetic and environmental factors in scleroderma. Curr Opin Rheumatol. 1994 Nov;6(6):607–611. doi: 10.1097/00002281-199411000-00010. [DOI] [PubMed] [Google Scholar]
  24. Sobel E. S., Kakkanaiah V. N., Kakkanaiah M., Cheek R. L., Cohen P. L., Eisenberg R. A. T-B collaboration for autoantibody production in lpr mice is cognate and MHC-restricted. J Immunol. 1994 Jun 15;152(12):6011–6016. [PubMed] [Google Scholar]
  25. Uno H., Sasazuki T., Tamai H., Matsumoto H. Two major genes, linked to HLA and Gm, control susceptibility to Graves' disease. Nature. 1981 Aug 20;292(5825):768–770. doi: 10.1038/292768a0. [DOI] [PubMed] [Google Scholar]
  26. Whittingham S., Mathews J. D., Schanfield M. S., Matthews J. V., Tait B. D., Morris P. J., Mackay I. R. Interactive effect of Gm allotypes and HLA-B locus antigens on the human antibody response to a bacterial antigen. Clin Exp Immunol. 1980 Apr;40(1):8–15. [PMC free article] [PubMed] [Google Scholar]
  27. Whittingham S., Mathews J. D., Schanfield M. S., Tait B. D., Mackay I. R. HLA and Gm genes in systemic lupus erythematosus. Tissue Antigens. 1983 Jan;21(1):50–57. doi: 10.1111/j.1399-0039.1983.tb00372.x. [DOI] [PubMed] [Google Scholar]
  28. Whittingham S., Mathews J. D., Schanfield M. S., Tait B. D., Mackay I. R. Interaction of HLA and Gm in autoimmune chronic active hepatitis. Clin Exp Immunol. 1981 Jan;43(1):80–86. [PMC free article] [PubMed] [Google Scholar]
  29. Whittingham S., Propert D. N., Mackay I. R. A strong association between the antinuclear antibody anti-La (SS-B) and the kappa chain allotype Km(1). Immunogenetics. 1984;19(4):295–299. doi: 10.1007/BF00345402. [DOI] [PubMed] [Google Scholar]

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

RESOURCES