Abstract
Several of the heterogeneous clinical manifestations of systemic lupus erythematosus have been associated with specific autoantibodies. Associations between HLA class II antigens and autoantibodies to the ribonucleoproteins Ro(SSA) and La(SSB) have been reported in these patients. Because HLA class II molecules present antigen to T cell receptors (TCRs), we have searched for a TCR gene associated with the production of anti-Ro(SSA) antibodies. A pair of restriction fragment length polymorphisms (RFLPs), one of which hybridizes to the TCR constant region C beta 1 and the other to the C beta 2 gene, has been identified, suggesting these may be genotypic markers for an extended region of the TCR beta locus. This RFLP pair occurs in 76% of patients with Ro(SSA) precipitins, 84% of anti-Ro(SSA)-positive patients lacking La(SSB) precipitins, but only 41% of the patients lacking both precipitins (P = 0.0004). This disproportionate occurrence in a subset of lupus patients indicates that these RFLPs are not disease susceptibility markers, but rather are important markers for TCR genes whose products are involved in the production of anti-Ro(SSA) antibodies. The majority of patients who have these RFLPs and HLA class II antigens previously associated with the anti-Ro(SSA) response make this antibody, suggesting that interactions between products of these loci occur in response to Ro(SSA).
Full text
PDFSelected References
These references are in PubMed. This may not be the complete list of references from this article.
- Acha-Orbea H., Mitchell D. J., Timmermann L., Wraith D. C., Tausch G. S., Waldor M. K., Zamvil S. S., McDevitt H. O., Steinman L. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell. 1988 Jul 15;54(2):263–273. doi: 10.1016/0092-8674(88)90558-2. [DOI] [PubMed] [Google Scholar]
- Acha-Orbea H., Steinman L., McDevitt H. O. T cell receptors in murine autoimmune diseases. Annu Rev Immunol. 1989;7:371–405. doi: 10.1146/annurev.iy.07.040189.002103. [DOI] [PubMed] [Google Scholar]
- Alexander E. L., Hirsch T. J., Arnett F. C., Provost T. T., Stevens M. B. Ro(SSA) and La(SSB) antibodies in the clinical spectrum of Sjögren's syndrome. J Rheumatol. 1982 Mar-Apr;9(2):239–246. [PubMed] [Google Scholar]
- Alspaugh M. A., Buchanan W. W., Whaley K. Precipitating antibodies to cellular antigens in Sjögren's syndrome, rheumatoid arthritis, and other organ and nonorgan-specific autoimmune diseases. Ann Rheum Dis. 1978 Jun;37(3):244–246. doi: 10.1136/ard.37.3.244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Alspaugh M. A., Tan E. M. Antibodies to cellular antigens in Sjögren's syndrome. J Clin Invest. 1975 May;55(5):1067–1073. doi: 10.1172/JCI108007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Arnett F. C., Goldstein R., Duvic M., Reveille J. D. Major histocompatibility complex genes in systemic lupus erythematosus, Sjögren's syndrome, and polymyositis. Am J Med. 1988 Dec 23;85(6A):38–41. doi: 10.1016/0002-9343(88)90381-6. [DOI] [PubMed] [Google Scholar]
- Arnett F. C., Hamilton R. G., Reveille J. D., Bias W. B., Harley J. B., Reichlin M. Genetic studies of Ro (SS-A) and La (SS-B) autoantibodies in families with systemic lupus erythematosus and primary Sjögren's syndrome. Arthritis Rheum. 1989 Apr;32(4):413–419. doi: 10.1002/anr.1780320410. [DOI] [PubMed] [Google Scholar]
- Arnett F. C., Shulman L. E. Studies in familial systemic lupus erythematosus. Medicine (Baltimore) 1976 Jul;55(4):313–322. doi: 10.1097/00005792-197607000-00003. [DOI] [PubMed] [Google Scholar]
- Banerjee S., Haqqi T. M., Luthra H. S., Stuart J. M., David C. S. Possible role of V beta T cell receptor genes in susceptibility to collagen-induced arthritis in mice. J Exp Med. 1988 Mar 1;167(3):832–839. doi: 10.1084/jem.167.3.832. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bell D. A., Maddison P. J. Serologic subsets in systemic lupus erythematosus: an examination of autoantibodies in relationship to clinical features of disease and HLA antigens. Arthritis Rheum. 1980 Nov;23(11):1268–1273. doi: 10.1002/art.1780231107. [DOI] [PubMed] [Google Scholar]
- Berliner N., Duby A. D., Morton C. C., Leder P., Seidman J. G. Detection of a frequent restriction fragment length polymorphism in the human T cell antigen receptor beta chain locus. A potential diagnostic tool. J Clin Invest. 1985 Sep;76(3):1283–1285. doi: 10.1172/JCI112086. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Block S. R., Lockshin M. D., Winfield J. B., Weksler M. E., Imamura M., Winchester R. J., Mellors R. C., Christian C. L. Immunologic observations on 9 sets of twins either concordant or discordant for SLE. Arthritis Rheum. 1976 May-Jun;19(3):545–554. doi: 10.1002/art.1780190306. [DOI] [PubMed] [Google Scholar]
- Block S. R., Winfield J. B., Lockshin M. D., D'Angelo W. A., Christian C. L. Studies of twins with systemic lupus erythematosus. A review of the literature and presentation of 12 additional sets. Am J Med. 1975 Oct;59(4):533–552. doi: 10.1016/0002-9343(75)90261-2. [DOI] [PubMed] [Google Scholar]
- Clark G., Reichlin M., Tomasi T. B., Jr Characterization of a soluble cytoplasmic antigen reactive with sera from patients with systemic lupus erythmatosus. J Immunol. 1969 Jan;102(1):117–122. [PubMed] [Google Scholar]
- Cohen S. N., Chang A. C., Hsu L. Nonchromosomal antibiotic resistance in bacteria: genetic transformation of Escherichia coli by R-factor DNA. Proc Natl Acad Sci U S A. 1972 Aug;69(8):2110–2114. doi: 10.1073/pnas.69.8.2110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Concannon P., Gatti R. A., Hood L. E. Human T cell receptor V beta gene polymorphism. J Exp Med. 1987 Apr 1;165(4):1130–1140. doi: 10.1084/jem.165.4.1130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dunckley H., Gatenby P. A., Serjeantson S. W. T-cell receptor and HLA class II RFLPs in systemic lupus erythematosus. Immunogenetics. 1988;27(5):393–395. doi: 10.1007/BF00395137. [DOI] [PubMed] [Google Scholar]
- Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
- Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
- Fielder A. H., Walport M. J., Batchelor J. R., Rynes R. I., Black C. M., Dodi I. A., Hughes G. R. Family study of the major histocompatibility complex in patients with systemic lupus erythematosus: importance of null alleles of C4A and C4B in determining disease susceptibility. Br Med J (Clin Res Ed) 1983 Feb 5;286(6363):425–428. doi: 10.1136/bmj.286.6363.425. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fronek Z., Lentz D., Berliner N., Duby A. D., Klein K. A., Seidman J. G., Schur P. H. Systemic lupus erythematosus is not genetically linked to the beta chain of the T cell receptor. Arthritis Rheum. 1986 Aug;29(8):1023–1025. doi: 10.1002/art.1780290812. [DOI] [PubMed] [Google Scholar]
- Ghatak S., Sainis K., Owen F. L., Datta S. K. T-cell-receptor beta- and I-A beta-chain genes of normal SWR mice are linked with the development of lupus nephritis in NZB x SWR crosses. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6850–6853. doi: 10.1073/pnas.84.19.6850. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goldstein R., Arnett F. C., McLean R. H., Bias W. B., Duvic M. Molecular heterogeneity of complement component C4-null and 21-hydroxylase genes in systemic lupus erythematosus. Arthritis Rheum. 1988 Jun;31(6):736–744. doi: 10.1002/art.1780310606. [DOI] [PubMed] [Google Scholar]
- Grumet F. C., Coukell A., Bodmer J. G., Bodmer W. F., McDevitt H. O. Histocompatibility (HL-A) antigens associated with systemic lupus erythematosus. A possible genetic predisposition to disease. N Engl J Med. 1971 Jul 22;285(4):193–196. doi: 10.1056/NEJM197107222850403. [DOI] [PubMed] [Google Scholar]
- Hamilton R. G., Harley J. B., Bias W. B., Roebber M., Reichlin M., Hochberg M. C., Arnett F. C. Two Ro (SS-A) autoantibody responses in systemic lupus erythematosus. Correlation of HLA-DR/DQ specificities with quantitative expression of Ro (SS-A) autoantibody. Arthritis Rheum. 1988 Apr;31(4):496–505. doi: 10.1002/art.1780310406. [DOI] [PubMed] [Google Scholar]
- Harley J. B., Alexander E. L., Bias W. B., Fox O. F., Provost T. T., Reichlin M., Yamagata H., Arnett F. C. Anti-Ro (SS-A) and anti-La (SS-B) in patients with Sjögren's syndrome. Arthritis Rheum. 1986 Feb;29(2):196–206. doi: 10.1002/art.1780290207. [DOI] [PubMed] [Google Scholar]
- Harley J. B., Gaither K. K. Autoantibodies. Rheum Dis Clin North Am. 1988 Apr;14(1):43–56. [PubMed] [Google Scholar]
- Harley J. B., Reichlin M., Arnett F. C., Alexander E. L., Bias W. B., Provost T. T. Gene interaction at HLA-DQ enhances autoantibody production in primary Sjögren's syndrome. Science. 1986 May 30;232(4754):1145–1147. doi: 10.1126/science.3458307. [DOI] [PubMed] [Google Scholar]
- Harley J. B., Sestak A. L., Willis L. G., Fu S. M., Hansen J. A., Reichlin M. A model for disease heterogeneity in systemic lupus erythematosus. Relationships between histocompatibility antigens, autoantibodies, and lymphopenia or renal disease. Arthritis Rheum. 1989 Jul;32(7):826–836. [PubMed] [Google Scholar]
- Hochberg M. C., Boyd R. E., Ahearn J. M., Arnett F. C., Bias W. B., Provost T. T., Stevens M. B. Systemic lupus erythematosus: a review of clinico-laboratory features and immunogenetic markers in 150 patients with emphasis on demographic subsets. Medicine (Baltimore) 1985 Sep;64(5):285–295. [PubMed] [Google Scholar]
- Howard P. F., Hochberg M. C., Bias W. B., Arnett F. C., Jr, McLean R. H. Relationship between C4 null genes, HLA-D region antigens, and genetic susceptibility to systemic lupus erythematosus in Caucasian and black Americans. Am J Med. 1986 Aug;81(2):187–193. doi: 10.1016/0002-9343(86)90250-0. [DOI] [PubMed] [Google Scholar]
- Kassan S. S., Akizuki M., Steinberg A. D., Reddick R. L., Chused T. M. Antibody to a soluble acidic nuclear antigen in Sjögren's syndrome. Am J Med. 1977 Sep;63(3):328–335. doi: 10.1016/0002-9343(77)90269-8. [DOI] [PubMed] [Google Scholar]
- Kemp M. E., Atkinson J. P., Skanes V. M., Levine R. P., Chaplin D. D. Deletion of C4A genes in patients with systemic lupus erythematosus. Arthritis Rheum. 1987 Sep;30(9):1015–1022. doi: 10.1002/art.1780300908. [DOI] [PubMed] [Google Scholar]
- Kotzin B. L., Barr V. L., Palmer E. A large deletion within the T-cell receptor beta-chain gene complex in New Zealand white mice. Science. 1985 Jul 12;229(4709):167–171. doi: 10.1126/science.2990044. [DOI] [PubMed] [Google Scholar]
- Kotzin B. L., Palmer E. The contribution of NZW genes to lupus-like disease in (NZB x NZW)F1 mice. J Exp Med. 1987 May 1;165(5):1237–1251. doi: 10.1084/jem.165.5.1237. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Krimpenfort P., de Jong R., Uematsu Y., Dembic Z., Ryser S., von Boehmer H., Steinmetz M., Berns A. Transcription of T cell receptor beta-chain genes is controlled by a downstream regulatory element. EMBO J. 1988 Mar;7(3):745–750. doi: 10.1002/j.1460-2075.1988.tb02871.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kronenberg M., Siu G., Hood L. E., Shastri N. The molecular genetics of the T-cell antigen receptor and T-cell antigen recognition. Annu Rev Immunol. 1986;4:529–591. doi: 10.1146/annurev.iy.04.040186.002525. [DOI] [PubMed] [Google Scholar]
- LEONHARDT T. FAMILY STUDIES IN SYSTEMIC LUPUS ERYTHEMATOSUS. Acta Med Scand. 1964;176:SUPPL 416–416:1+. [PubMed] [Google Scholar]
- Lee L. A., Gaither K. K., Coulter S. N., Norris D. A., Harley J. B. Pattern of cutaneous immunoglobulin G deposition in subacute cutaneous lupus erythematosus is reproduced by infusing purified anti-Ro (SSA) autoantibodies into human skin-grafted mice. J Clin Invest. 1989 May;83(5):1556–1562. doi: 10.1172/JCI114052. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lehman T. J., Hanson V., Zvaifler N., Sharp G., Alspaugh M. Antibodies to nonhistone nuclear antigens and antilymphocyte antibodies among children and adults with systemic lupus erythematosus and their relatives. J Rheumatol. 1984 Oct;11(5):644–647. [PubMed] [Google Scholar]
- Lerner M. R., Boyle J. A., Hardin J. A., Steitz J. A. Two novel classes of small ribonucleoproteins detected by antibodies associated with lupus erythematosus. Science. 1981 Jan 23;211(4480):400–402. doi: 10.1126/science.6164096. [DOI] [PubMed] [Google Scholar]
- Maddison P. J., Reichlin M. Deposition of antibodies to a soluble cytoplasmic antigen in the kidneys of patients with systemic lupus erythematosus. Arthritis Rheum. 1979 Aug;22(8):858–863. doi: 10.1002/art.1780220808. [DOI] [PubMed] [Google Scholar]
- Maddison P., Mogavero H., Provost T. T., Reichlin M. The clinical significance of autoantibodies to a soluble cytoplasmic antigen in systemic lupus erythematosus and other connective tissue diseases. J Rheumatol. 1979 Mar-Apr;6(2):189–195. [PubMed] [Google Scholar]
- Mond C. B., Peterson M. G., Rothfield N. F. Correlation of anti-Ro antibody with photosensitivity rash in systemic lupus erythematosus patients. Arthritis Rheum. 1989 Feb;32(2):202–204. doi: 10.1002/anr.1780320213. [DOI] [PubMed] [Google Scholar]
- Oksenberg J. R., Gaiser C. N., Cavalli-Sforza L. L., Steinman L. Polymorphic markers of human T-cell receptor alpha and beta genes. Family studies and comparison of frequencies in healthy individuals and patients with multiple sclerosis and myasthenia gravis. Hum Immunol. 1988 Jun;22(2):111–121. doi: 10.1016/0198-8859(88)90041-9. [DOI] [PubMed] [Google Scholar]
- Reichlin M. Significance of the Ro antigen system. J Clin Immunol. 1986 Sep;6(5):339–348. doi: 10.1007/BF00915372. [DOI] [PubMed] [Google Scholar]
- Reveille J. D., Arnett F. C., Wilson R. W., Bias W. B., McLean R. H. Null alleles of the fourth component of complement and HLA haplotypes in familial systemic lupus erythematosus. Immunogenetics. 1985;21(4):299–311. doi: 10.1007/BF00430796. [DOI] [PubMed] [Google Scholar]
- Robinson M. A., Kindt T. J. Molecular genotyping of human T-cell antigen receptor variable gene segments. Immunogenetics. 1986;24(4):259–266. doi: 10.1007/BF00364530. [DOI] [PubMed] [Google Scholar]
- Robinson M. A., Kindt T. J. Segregation of polymorphic T-cell receptor genes in human families. Proc Natl Acad Sci U S A. 1985 Jun;82(11):3804–3808. doi: 10.1073/pnas.82.11.3804. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rupp F., Brecher J., Giedlin M. A., Mosmann T., Zinkernagel R. M., Hengartner H., Joho R. H. T-cell antigen receptors with identical variable regions but different diversity and joining region gene segments have distinct specificities but cross-reactive idiotypes. Proc Natl Acad Sci U S A. 1987 Jan;84(1):219–222. doi: 10.1073/pnas.84.1.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scott J. S., Maddison P. J., Taylor P. V., Esscher E., Scott O., Skinner R. P. Connective-tissue disease, antibodies to ribonucleoprotein, and congenital heart block. N Engl J Med. 1983 Jul 28;309(4):209–212. doi: 10.1056/NEJM198307283090403. [DOI] [PubMed] [Google Scholar]
- Smolen J. S., Morimoto C., Steinberg A. D., Wolf A., Schlossman S. F., Steinberg R. T., Penner E., Reinherz E., Reichlin M., Chused T. M. Systemic lupus erythematosus: delineation of subpopulations by clinical, serologic, and T cell subset analysis. Am J Med Sci. 1985 Apr;289(4):139–147. doi: 10.1097/00000441-198504000-00003. [DOI] [PubMed] [Google Scholar]
- Sontheimer R. D., Maddison P. J., Reichlin M., Jordon R. E., Stastny P., Gilliam J. N. Serologic and HLA associations in subacute cutaneous lupus erythematosus, a clinical subset of lupus erythematosus. Ann Intern Med. 1982 Nov;97(5):664–671. doi: 10.7326/0003-4819-97-5-664. [DOI] [PubMed] [Google Scholar]
- Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
- 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]
- Taylor P. V., Taylor K. F., Norman A., Griffiths S., Scott J. S. Prevalence of maternal Ro (SS-A) and La (SS-B) autoantibodies in relation to congenital heart block. Br J Rheumatol. 1988 Apr;27(2):128–132. doi: 10.1093/rheumatology/27.2.128. [DOI] [PubMed] [Google Scholar]
- Toyonaga B., Yoshikai Y., Vadasz V., Chin B., Mak T. W. Organization and sequences of the diversity, joining, and constant region genes of the human T-cell receptor beta chain. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8624–8628. doi: 10.1073/pnas.82.24.8624. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Urban J. L., Kumar V., Kono D. H., Gomez C., Horvath S. J., Clayton J., Ando D. G., Sercarz E. E., Hood L. Restricted use of T cell receptor V genes in murine autoimmune encephalomyelitis raises possibilities for antibody therapy. Cell. 1988 Aug 12;54(4):577–592. doi: 10.1016/0092-8674(88)90079-7. [DOI] [PubMed] [Google Scholar]
- Wasicek C. A., Reichlin M. Clinical and serological differences between systemic lupus erythematosus patients with antibodies to Ro versus patients with antibodies to Ro and La. J Clin Invest. 1982 Apr;69(4):835–843. doi: 10.1172/JCI110523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Watson R. M., Lane A. T., Barnett N. K., Bias W. B., Arnett F. C., Provost T. T. Neonatal lupus erythematosus. A clinical, serological and immunogenetic study with review of the literature. Medicine (Baltimore) 1984 Nov;63(6):362–378. [PubMed] [Google Scholar]
- Wilson W. A., Scopelitis E., Michalski J. P. Association of HLA-DR7 with both antibody to SSA(Ro) and disease susceptibility in blacks with systemic lupus erythematosus. J Rheumatol. 1984 Oct;11(5):653–657. [PubMed] [Google Scholar]
- Wong D. W., Bentwich Z., Martinez-Tarquino C., Seidman J. G., Duby A. D., Quertermous T., Schur P. H. Nonlinkage of the T cell receptor alpha, beta, and gamma genes to systemic lupus erythematosus in multiplex families. Arthritis Rheum. 1988 Nov;31(11):1371–1376. doi: 10.1002/art.1780311105. [DOI] [PubMed] [Google Scholar]
- Yanagi Y., Hirose S., Nagasawa R., Shirai T., Mak T. W., Tada T. Does the deletion within T cell receptor beta-chain gene of NZW mice contribute to autoimmunity in (NZB X NZW)F1 mice? Eur J Immunol. 1986 Sep;16(9):1179–1182. doi: 10.1002/eji.1830160925. [DOI] [PubMed] [Google Scholar]
- Yanagi Y., Yoshikai Y., Leggett K., Clark S. P., Aleksander I., Mak T. W. A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature. 1984 Mar 8;308(5955):145–149. doi: 10.1038/308145a0. [DOI] [PubMed] [Google Scholar]