Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Aug 1992; 90(2): 326–333.
PMCID: PMC443106

Restricted heterogeneity of T cell receptor transcripts in rheumatoid synovium.


RA is characterized by massive proliferation of synovial tissue, accompanying infiltration of the tissue with CD4+ T lymphocytes, and a genetic linkage to the MHC antigen HLA-DR4. Since T cells are restricted by class II MHC molecules such as DR4, this suggests a direct role for these CD4+ cells in pathogenesis. To investigate T cell receptor (TCR) usage in RA, we used oligonucleotide primers specific for each of the major alpha and beta TCR subfamilies to amplify cDNA derived from whole synovium or synovial tissue T cell lines in a family-specific manner. Detection of amplified DNA was facilitated by utilizing oligonucleotide probes derived from the constant regions of the TCRs. The TCR repertoire present in the synovial T cell lines was quite heterogeneous, with an average of 15 alpha chains and 15.8 beta chains detected. When synovial tissue was analyzed, the predominant TCR subfamilies detected tended to be more restricted, with an average of 4.6 alpha chains and 8.6 beta chains detected. This compared with an average of six alpha chains and 12 beta chains in nonrheumatoid synovial samples. The average percentage of synovia positive per TCR beta family was significantly lower for RA versus non-RA specimens (46.1 vs 65.6%, P = 0.034). These findings indicate that while a polyclonal population of T cells is present in RA synovium, the predominant patterns of TCR transcript expression may be somewhat more restricted, suggesting that TCR-based therapy of RA is possible.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.8M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Duke O, Panayi GS, Janossy G, Poulter LW. An immunohistological analysis of lymphocyte subpopulations and their microenvironment in the synovial membranes of patients with rheumatoid arthritis using monoclonal antibodies. Clin Exp Immunol. 1982 Jul;49(1):22–30. [PMC free article] [PubMed]
  • Gao XJ, Ball EJ, Dombrausky L, Olsen NJ, Pincus T, Khan MA, Wolfe F, Stastny P. Class II human leukocyte antigen genes and T cell receptor polymorphisms in patients with rheumatoid arthritis. Am J Med. 1988 Dec 23;85(6A):14–16. [PubMed]
  • Goronzy J, Weyand CM, Fathman CG. Shared T cell recognition sites on human histocompatibility leukocyte antigen class II molecules of patients with seropositive rheumatoid arthritis. J Clin Invest. 1986 Mar;77(3):1042–1049. [PMC free article] [PubMed]
  • Gregersen PK, Silver J, Winchester RJ. Genetic susceptibility to rheumatoid arthritis and human leukocyte antigen class II polymorphism. The role of shared conformational determinants. Am J Med. 1988 Dec 23;85(6A):17–19. [PubMed]
  • Merryman PF, Crapper RM, Lee S, Gregersen PK, Winchester RJ. Class II major histocompatibility complex gene sequences in rheumatoid arthritis. The third diversity regions of both DR beta 1 genes in two DR1, DRw10-positive individuals specify the same inferred amino acid sequence as the DR beta 1 and DR beta 2 genes of a DR4 (Dw14) haplotype. Arthritis Rheum. 1989 Mar;32(3):251–258. [PubMed]
  • Nepom GT, Hansen JA, Nepom BS. The molecular basis for HLA class II associations with rheumatoid arthritis. J Clin Immunol. 1987 Jan;7(1):1–7. [PubMed]
  • Roudier J, Petersen J, Rhodes GH, Luka J, Carson DA. Susceptibility to rheumatoid arthritis maps to a T-cell epitope shared by the HLA-Dw4 DR beta-1 chain and the Epstein-Barr virus glycoprotein gp110. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5104–5108. [PMC free article] [PubMed]
  • Sakai K, Sinha AA, Mitchell DJ, Zamvil SS, Rothbard JB, McDevitt HO, Steinman L. Involvement of distinct murine T-cell receptors in the autoimmune encephalitogenic response to nested epitopes of myelin basic protein. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8608–8612. [PMC free article] [PubMed]
  • Hashim GA, Vandenbark AA, Galang AB, Diamanduros T, Carvalho E, Srinivasan J, Jones R, Vainiene M, Morrison WJ, Offner H. Antibodies specific for VB8 receptor peptide suppress experimental autoimmune encephalomyelitis. J Immunol. 1990 Jun 15;144(12):4621–4627. [PubMed]
  • Vandenbark AA, Hashim G, Offner H. Immunization with a synthetic T-cell receptor V-region peptide protects against experimental autoimmune encephalomyelitis. Nature. 1989 Oct 12;341(6242):541–544. [PubMed]
  • Beraud E, Reshef T, Vandenbark AA, Offner H, Friz R, Chou CH, Bernard D, Cohen IR. Experimental autoimmune encephalomyelitis mediated by T lymphocyte lines: genotype of antigen-presenting cells influences immunodominant epitope of basic protein. J Immunol. 1986 Jan;136(2):511–515. [PubMed]
  • Oksenberg JR, Stuart S, Begovich AB, Bell RB, Erlich HA, Steinman L, Bernard CC. Limited heterogeneity of rearranged T-cell receptor V alpha transcripts in brains of multiple sclerosis patients. Nature. 1990 May 24;345(6273):344–346. [PubMed]
  • Wucherpfennig KW, Ota K, Endo N, Seidman JG, Rosenzweig A, Weiner HL, Hafler DA. Shared human T cell receptor V beta usage to immunodominant regions of myelin basic protein. Science. 1990 May 25;248(4958):1016–1019. [PubMed]
  • Choi YW, Kotzin B, Herron L, Callahan J, Marrack P, Kappler J. Interaction of Staphylococcus aureus toxin "superantigens" with human T cells. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8941–8945. [PMC free article] [PubMed]
  • Santoli D, Phillips PD, Colt TL, Zurier RB. Suppression of interleukin 2-dependent human T cell growth in vitro by prostaglandin E (PGE) and their precursor fatty acids. Evidence for a PGE-independent mechanism of inhibition by the fatty acids. J Clin Invest. 1990 Feb;85(2):424–432. [PMC free article] [PubMed]
  • Nakao H, Eguchi K, Kawakami A, Migita K, Otsubo T, Ueki Y, Shimomura C, Tezuka H, Matsunaga M, Maeda K, et al. Phenotypic characterization of lymphocytes infiltrating synovial tissue from patients with rheumatoid arthritis: analysis of lymphocytes isolated from minced synovial tissue by dual immunofluorescent staining. J Rheumatol. 1990 Feb;17(2):142–148. [PubMed]
  • Ranki A, Paavonen T, Tolvanen E, Kankaanpä U, Häyry P. T lymphocyte subclasses in rheumatoid synovia as analysed with monoclonal antibodies and functional in vitro tests. Scand J Rheumatol. 1984;13(1):67–76. [PubMed]
  • Lapadula G, Covelli M, Numo R, Tricarico G, Amendoni G, Berlingerio C. Monoclonal antibody investigation in rheumatoid arthritis: presence of a T cell subpopulation bearing a double marker. Clin Rheumatol. 1984 Jun;3(2):137–144. [PubMed]
  • Holmdahl R, Klareskog L, Rubin K, Larsson E, Wigzell H. T lymphocytes in collagen II-induced arthritis in mice. Characterization of arthritogenic collagen II-specific T-cell lines and clones. Scand J Immunol. 1985 Sep;22(3):295–306. [PubMed]
  • Holoshitz J, Naparstek Y, Ben-Nun A, Cohen IR. Lines of T lymphocytes induce or vaccinate against autoimmune arthritis. Science. 1983 Jan 7;219(4580):56–58. [PubMed]
  • Holoshitz J, Matitiau A, Cohen IR. Arthritis induced in rats by cloned T lymphocytes responsive to mycobacteria but not to collagen type II. J Clin Invest. 1984 Jan;73(1):211–215. [PMC free article] [PubMed]
  • van Eden W, Holoshitz J, Nevo Z, Frenkel A, Klajman A, Cohen IR. Arthritis induced by a T-lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans. Proc Natl Acad Sci U S A. 1985 Aug;82(15):5117–5120. [PMC free article] [PubMed]
  • Yoshino S, Schlipköter E, Kinne R, Hünig T, Emmrich F. Suppression and prevention of adjuvant arthritis in rats by a monoclonal antibody to the alpha/beta T cell receptor. Eur J Immunol. 1990 Dec;20(12):2805–2808. [PubMed]
  • Clayton JP, Gammon GM, Ando DG, Kono DH, Hood L, Sercarz EE. Peptide-specific prevention of experimental allergic encephalomyelitis. Neonatal tolerance induced to the dominant T cell determinant of myelin basic protein. J Exp Med. 1989 May 1;169(5):1681–1691. [PMC free article] [PubMed]
  • Donoso LA, Merryman CF, Shinohara T, Dietzschold B, Wistow G, Craft C, Morley W, Henry RT. S-antigen: identification of the MAbA9-C6 monoclonal antibody binding site and the uveitopathogenic sites. Curr Eye Res. 1986 Dec;5(12):995–1004. [PubMed]
  • Donoso LA, Merryman CF, Shinohara T, Sery TW, Smith A. S-antigen. Experimental autoimmune uveitis following immunization with a small synthetic peptide. Arch Ophthalmol. 1987 Jun;105(6):838–840. [PubMed]
  • Lennon VA, McCormick DJ, Lambert EH, Griesmann GE, Atassi MZ. Region of peptide 125-147 of acetylcholine receptor alpha subunit is exposed at neuromuscular junction and induces experimental autoimmune myasthenia gravis, T-cell immunity, and modulating autoantibodies. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8805–8809. [PMC free article] [PubMed]
  • Williams WV, Kyriakos M, Sharp GC, Braley-Mullen H. The cellular basis for the Ia restriction in murine experimental autoimmune thyroiditis. Cell Immunol. 1987 Nov;110(1):35–45. [PubMed]
  • Walker C, Herzog C, Rieber P, Riethmüller G, Müller W, Pichler WJ. Anti-CD4 antibody treatment of patients with rheumatoid arthritis: II. Effect of in vivo treatment on in vitro proliferative response of CD4 cells. J Autoimmun. 1989 Oct;2(5):643–649. [PubMed]
  • Herzog C, Walker C, Müller W, Rieber P, Reiter C, Riethmüller G, Wassmer P, Stockinger H, Madic O, Pichler WJ. Anti-CD4 antibody treatment of patients with rheumatoid arthritis: I. Effect on clinical course and circulating T cells. J Autoimmun. 1989 Oct;2(5):627–642. [PubMed]
  • Brahn E, Trentham DE. Effect of antithymocyte serum on collagen arthritis in rats: evidence that T cells are involved in its pathogenesis. Cell Immunol. 1984 Jul;86(2):421–428. [PubMed]
  • Schluesener H, Brunner C, Vass K, Lassmann H. Therapy of rat autoimmune disease by a monoclonal antibody specific for T lymphoblasts. J Immunol. 1986 Dec 15;137(12):3814–3820. [PubMed]
  • Goldschmidt TJ, Jansson L, Holmdahl R. In vivo elimination of T cells expressing specific T-cell receptor V beta chains in mice susceptible to collagen-induced arthritis. Immunology. 1990 Apr;69(4):508–514. [PMC free article] [PubMed]
  • Kingsley G. Monoclonal antibody treatment of rheumatoid arthritis. Br J Rheumatol. 1991;30 (Suppl 2):33–35. [PubMed]
  • Reiter C, Kakavand B, Rieber EP, Schattenkirchner M, Riethmüller G, Krüger K. Treatment of rheumatoid arthritis with monoclonal CD4 antibody M-T151. Clinical results and immunopharmacologic effects in an open study, including repeated administration. Arthritis Rheum. 1991 May;34(5):525–536. [PubMed]
  • Van Laar JM, Miltenburg AM, Verdonk MJ, Daha MR, De Vries RR, Van den Elsen PJ, Breedveld FC. Lack of T cell oligoclonality in enzyme-digested synovial tissue and in synovial fluid in most patients with rheumatoid arthritis. Clin Exp Immunol. 1991 Mar;83(3):352–358. [PMC free article] [PubMed]
  • Miltenburg AM, van Laar JM, Daha MR, de Vries RR, van den Elsen PJ, Breedveld FC. Dominant T-cell receptor beta-chain gene rearrangements indicate clonal expansion in the rheumatoid joint. Scand J Immunol. 1990 Jan;31(1):121–126. [PubMed]
  • Duby AD, Sinclair AK, Osborne-Lawrence SL, Zeldes W, Kan L, Fox DA. Clonal heterogeneity of synovial fluid T lymphocytes from patients with rheumatoid arthritis. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6206–6210. [PMC free article] [PubMed]
  • Stamenkovic I, Stegagno M, Wright KA, Krane SM, Amento EP, Colvin RB, Duquesnoy RJ, Kurnick JT. Clonal dominance among T-lymphocyte infiltrates in arthritis. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1179–1183. [PMC free article] [PubMed]
  • Sottini A, Imberti L, Gorla R, Cattaneo R, Primi D. Restricted expression of T cell receptor V beta but not V alpha genes in rheumatoid arthritis. Eur J Immunol. 1991 Feb;21(2):461–466. [PubMed]
  • Savill CM, Delves PJ, Kioussis D, Walker P, Lydyard PM, Colaco B, Shipley M, Roitt IM. A minority of patients with rheumatoid arthritis show a dominant rearrangement of T-cell receptor beta chain genes in synovial lymphocytes. Scand J Immunol. 1987 Jun;25(6):629–635. [PubMed]
  • Stamenkovic I, Stegagno M, Wright KA, Krane SM, Amento EP, Colvin RB, Duquesnoy RJ, Kurnick JT. T lymphocyte infiltrates in inflammatory synovia are oligoclonal. Transplant Proc. 1988 Apr;20(2):315–319. [PubMed]
  • Paliard X, West SG, Lafferty JA, Clements JR, Kappler JW, Marrack P, Kotzin BL. Evidence for the effects of a superantigen in rheumatoid arthritis. Science. 1991 Jul 19;253(5017):325–329. [PubMed]
  • Raulet DH. The structure, function, and molecular genetics of the gamma/delta T cell receptor. Annu Rev Immunol. 1989;7:175–207. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...