The complete nucleotide sequences of the heavy chain variable regions of six monospecific rheumatoid factors derived from Epstein-Barr virus-transformed B cells isolated from the synovial tissue of patients with rheumatoid arthritis. Further evidence that some autoantibodies are unmutated copies of germ line genes (original) (raw)

Abstract

Structural studies of human monoclonal rheumatoid factors (RF) derived from patients with monoclonal gammapathies have revealed a restriction in the usage of heavy and light chain variable regions. These studies have suggested that germline genes with little if any somatic mutation can generate RF specificity. However, there is no information presently available regarding the primary structure and genetic origin of RF in rheumatoid arthritis. In this study, we have isolated and sequenced the VH regions of six monoclonal RF derived from the synovial membranes of two patients with rheumatoid arthritis and one with the juvenile polyarticular form of the disease. We found the same VH families as previously reported among monoclonal paraproteins with RF activity. However, our sample was diverse regarding the VH, DH, and JH gene segments used. Among VHI RF there was conservation in the length of CDRIII as well as restriction in the amino acid generated at the V-D junction, as opposed to VHIII RF and non-RF VHI molecules that are highly heterogeneous in these two aspects. We also found that different JH gene segments may contribute to RF specificity. The VH, DH, and JH elements of one RF in our study all had clearly identifiable germline counterparts. This RF displays a nearly germline configuration throughout its entire heavy chain and represents another example of an autoantibody encoded by one of the VH gene segments from the preimmune fetal repertoire.

1320

Selected References

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

  1. Agnello V., Arbetter A., Ibanez de Kasep G., Powell R., Tan E. M., Joslin F. Evidence for a subset of rheumatoid factors that cross-react with DNA-histone and have a distinct cross-idiotype. J Exp Med. 1980 Jun 1;151(6):1514–1527. doi: 10.1084/jem.151.6.1514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Andrews D. W., Capra J. D. Complete amino acid sequence of variable domains from two monoclonal human anti-gamma globulins of the Wa cross-idiotypic group: suggestion that the J segments are involved in the structural correlate of the idiotype. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3799–3803. doi: 10.1073/pnas.78.6.3799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berman J. E., Mellis S. J., Pollock R., Smith C. L., Suh H., Heinke B., Kowal C., Surti U., Chess L., Cantor C. R. Content and organization of the human Ig VH locus: definition of three new VH families and linkage to the Ig CH locus. EMBO J. 1988 Mar;7(3):727–738. doi: 10.1002/j.1460-2075.1988.tb02869.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Burastero S. E., Casali P., Wilder R. L., Notkins A. L. Monoreactive high affinity and polyreactive low affinity rheumatoid factors are produced by CD5+ B cells from patients with rheumatoid arthritis. J Exp Med. 1988 Dec 1;168(6):1979–1992. doi: 10.1084/jem.168.6.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cairns E., Kwong P. C., Misener V., Ip P., Bell D. A., Siminovitch K. A. Analysis of variable region genes encoding a human anti-DNA antibody of normal origin. Implications for the molecular basis of human autoimmune responses. J Immunol. 1989 Jul 15;143(2):685–691. [PubMed] [Google Scholar]
  6. Capra J. D., Kehoe J. M. Structure of antibodies with shared idiotypy: the complete sequence of the heavy chain variable regions of two immunoglobulin M anti-gamma globulins. Proc Natl Acad Sci U S A. 1974 Oct;71(10):4032–4036. doi: 10.1073/pnas.71.10.4032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Casali P., Burastero S. E., Nakamura M., Inghirami G., Notkins A. L. Human lymphocytes making rheumatoid factor and antibody to ssDNA belong to Leu-1+ B-cell subset. Science. 1987 Apr 3;236(4797):77–81. doi: 10.1126/science.3105056. [DOI] [PubMed] [Google Scholar]
  8. Chen P. P., Albrandt K., Kipps T. J., Radoux V., Liu F. T., Carson D. A. Isolation and characterization of human VkIII germ-line genes. Implications for the molecular basis of human VkIII light chain diversity. J Immunol. 1987 Sep 1;139(5):1727–1733. [PubMed] [Google Scholar]
  9. Chen P. P., Liu M. F., Glass C. A., Sinha S., Kipps T. J., Carson D. A. Characterization of two immunoglobulin VH genes that are homologous to human rheumatoid factors. Arthritis Rheum. 1989 Jan;32(1):72–76. doi: 10.1002/anr.1780320112. [DOI] [PubMed] [Google Scholar]
  10. Chen P. P., Robbins D. L., Jirik F. R., Kipps T. J., Carson D. A. Isolation and characterization of a light chain variable region gene for human rheumatoid factors. J Exp Med. 1987 Dec 1;166(6):1900–1905. doi: 10.1084/jem.166.6.1900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chen P. P., Siminovitch K. A., Olsen N. J., Erger R. A., Carson D. A. A highly informative probe for two polymorphic Vh gene regions that contain one or more autoantibody-associated Vh genes. J Clin Invest. 1989 Aug;84(2):706–710. doi: 10.1172/JCI114218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chen P. P., Soto-Gil R. W., Carson D. A. The early expression of some human autoantibody-associated heavy chain variable region genes is controlled by specific regulatory elements. Scand J Immunol. 1990 Jun;31(6):673–678. doi: 10.1111/j.1365-3083.1990.tb02818.x. [DOI] [PubMed] [Google Scholar]
  13. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  14. Crowley J. J., Goldfien R. D., Schrohenloher R. E., Spiegelberg H. L., Silverman G. J., Mageed R. A., Jefferis R., Koopman W. J., Carson D. A., Fong S. Incidence of three cross-reactive idiotypes on human rheumatoid factor paraproteins. J Immunol. 1988 May 15;140(10):3411–3418. [PubMed] [Google Scholar]
  15. Dersimonian H., McAdam K. P., Mackworth-Young C., Stollar B. D. The recurrent expression of variable region segments in human IgM anti-DNA autoantibodies. J Immunol. 1989 Jun 1;142(11):4027–4033. [PubMed] [Google Scholar]
  16. Dersimonian H., Schwartz R. S., Barrett K. J., Stollar B. D. Relationship of human variable region heavy chain germ-line genes to genes encoding anti-DNA autoantibodies. J Immunol. 1987 Oct 1;139(7):2496–2501. [PubMed] [Google Scholar]
  17. Førre O., Dobloug J. H., Michaelsen T. E., Natvig J. B. Evidence of similar idiotypic determinants on different rheumatoid factor populations. Scand J Immunol. 1979 Mar;9(3):281–289. doi: 10.1111/j.1365-3083.1979.tb02732.x. [DOI] [PubMed] [Google Scholar]
  18. Gubler U., Hoffman B. J. A simple and very efficient method for generating cDNA libraries. Gene. 1983 Nov;25(2-3):263–269. doi: 10.1016/0378-1119(83)90230-5. [DOI] [PubMed] [Google Scholar]
  19. Gyllensten U. B., Erlich H. A. Generation of single-stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7652–7656. doi: 10.1073/pnas.85.20.7652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hardy R. R., Hayakawa K., Shimizu M., Yamasaki K., Kishimoto T. Rheumatoid factor secretion from human Leu-1+ B cells. Science. 1987 Apr 3;236(4797):81–83. doi: 10.1126/science.3105057. [DOI] [PubMed] [Google Scholar]
  21. Kipps T. J., Tomhave E., Pratt L. F., Duffy S., Chen P. P., Carson D. A. Developmentally restricted immunoglobulin heavy chain variable region gene expressed at high frequency in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5913–5917. doi: 10.1073/pnas.86.15.5913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Koopman W. J., Schrohenloher R. E. In vitro synthesis of IgM rheumatoid factor by lymphocytes from healthy adults. J Immunol. 1980 Aug;125(2):934–939. [PubMed] [Google Scholar]
  23. Kunkel H. G., Agnello V., Joslin F. G., Winchester R. J., Capra J. D. Cross-idiotypic specificity among monoclonal IgM proteins with anti- -globulin activity. J Exp Med. 1973 Feb 1;137(2):331–342. doi: 10.1084/jem.137.2.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kunkel H. G., Winchester R. J., Joslin F. G., Capra J. D. Similarities in the light chains of anti-gamma-globulins showing cross-idiotypic specificities. J Exp Med. 1974 Jan 1;139(1):128–136. doi: 10.1084/jem.139.1.128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mageed R. A., Carson D. a., Jefferis R. Analysis of rheumatoid factor autoantibodies in patients with essential mixed cryoglobulinaemia and rheumatoid arthritis. Scand J Rheumatol Suppl. 1988;75:172–178. doi: 10.3109/03009748809096759. [DOI] [PubMed] [Google Scholar]
  26. Mageed R. A., Dearlove M., Goodall D. M., Jefferis R. Immunogenic and antigenic epitopes of immunoglobulins. XVII--Monoclonal antibodies reactive with common and restricted idiotopes to the heavy chain of human rheumatoid factors. Rheumatol Int. 1986;6(4):179–183. doi: 10.1007/BF00541285. [DOI] [PubMed] [Google Scholar]
  27. Matthyssens G., Rabbitts T. H. Structure and multiplicity of genes for the human immunoglobulin heavy chain variable region. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6561–6565. doi: 10.1073/pnas.77.11.6561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Meek K. D., Hasemann C. A., Capra J. D. Novel rearrangements at the immunoglobulin D locus. Inversions and fusions add to IgH somatic diversity. J Exp Med. 1989 Jul 1;170(1):39–57. doi: 10.1084/jem.170.1.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Munthe E., Natvig J. B. Complement-fixing intracellular complexes of IgG rheumatoid factor in rheumatoid plasma cells. Scand J Immunol. 1972;1(3):217–229. doi: 10.1111/j.1365-3083.1972.tb01813.x. [DOI] [PubMed] [Google Scholar]
  30. Nakamura M., Burastero S. E., Notkins A. L., Casal P. Human monoclonal rheumatoid factor-like antibodies from CD5 (Leu-1)+ B cells are polyreactive. J Immunol. 1988 Jun 15;140(12):4180–4186. [PubMed] [Google Scholar]
  31. Natvig J. B., Gaarder P. I., Turner M. W. IgG antigens of the C gamma 2 and C gamma 3 homology regions interacting with rheumatoid factors. Clin Exp Immunol. 1972 Oct;12(2):177–184. [PMC free article] [PubMed] [Google Scholar]
  32. Natvig J. B., Munthe E. Self-associating IgG rheumatoid factor represents a major response of plasma cells in rheumatoid inflammatory tissue. Ann N Y Acad Sci. 1975 Jun 13;256:88–95. doi: 10.1111/j.1749-6632.1975.tb36038.x. [DOI] [PubMed] [Google Scholar]
  33. Natvig J. B., Randen I., Thompson K., Førre O., Munthe E. The B cell system in the rheumatoid inflammation. New insights into the pathogenesis of rheumatoid arthritis using synovial B cell hybridoma clones. Springer Semin Immunopathol. 1989;11(3):301–313. [PubMed] [Google Scholar]
  34. Natvig J. B., Thompson K., Randen I., Steinitz M., Taussig M., Beale D., Barker P., Sletten K., Waalen K., Førre O. Partial amino acid sequence analysis and variable subgroup determination (VH and VL) of a monoclonal rheumatoid factor derived from a rheumatoid arthritis patient. Scand J Rheumatol Suppl. 1988;75:127–132. doi: 10.3109/03009748809096753. [DOI] [PubMed] [Google Scholar]
  35. Nelson J. L., Nardella F. A., Oppliger I. R., Mannik M. Rheumatoid factors from patients with rheumatoid arthritis possess private repertoires of idiotypes. J Immunol. 1987 Mar 1;138(5):1391–1396. [PubMed] [Google Scholar]
  36. Newkirk M. M., Mageed R. A., Jefferis R., Chen P. P., Capra J. D. Complete amino acid sequences of variable regions of two human IgM rheumatoid factors, BOR and KAS of the Wa idiotypic family, reveal restricted use of heavy and light chain variable and joining region gene segments. J Exp Med. 1987 Aug 1;166(2):550–564. doi: 10.1084/jem.166.2.550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Nickerson K. G., Berman J., Glickman E., Chess L., Alt F. W. Early human IgH gene assembly in Epstein-Barr virus-transformed fetal B cell lines. Preferential utilization of the most JH-proximal D segment (DQ52) and two unusual VH-related rearrangements. J Exp Med. 1989 Apr 1;169(4):1391–1403. doi: 10.1084/jem.169.4.1391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Panush R. S., Bianco N. E., Schur P. H. Serum and synovial fluid IgG, IgA and IgM antigammaglobulins in rheumatoid arthritis. Arthritis Rheum. 1971 Nov-Dec;14(6):737–747. doi: 10.1002/art.1780140609. [DOI] [PubMed] [Google Scholar]
  39. Panush R. S., Bittner A. K., Sullivan M., Katz P., Longley S. IgM rheumatoid factor elaboration by blood, bone marrow, and synovial mononuclear cells in patients with rheumatoid arthritis. Clin Immunol Immunopathol. 1985 Mar;34(3):387–391. doi: 10.1016/0090-1229(85)90187-4. [DOI] [PubMed] [Google Scholar]
  40. Radoux V., Chen P. P., Sorge J. A., Carson D. A. A conserved human germline V kappa gene directly encodes rheumatoid factor light chains. J Exp Med. 1986 Dec 1;164(6):2119–2124. doi: 10.1084/jem.164.6.2119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Randen I., Thompson K. M., Natvig J. B., Førre O., Waalen K. Human monoclonal rheumatoid factors derived from the polyclonal repertoire of rheumatoid synovial tissue: production and characterization. Clin Exp Immunol. 1989 Oct;78(1):13–18. [PMC free article] [PubMed] [Google Scholar]
  42. Ruiz-Arguelles A., Presno-Bernal M. Demonstration of a cross-reactive idiotype (IdRQ) in rheumatoid factors from patients with rheumatoid arthritis but not in rheumatoid factors from healthy, aged subjects. Arthritis Rheum. 1989 Feb;32(2):134–138. doi: 10.1002/anr.1780320204. [DOI] [PubMed] [Google Scholar]
  43. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  44. Sanger F., Coulson A. R., Barrell B. G., Smith A. J., Roe B. A. Cloning in single-stranded bacteriophage as an aid to rapid DNA sequencing. J Mol Biol. 1980 Oct 25;143(2):161–178. doi: 10.1016/0022-2836(80)90196-5. [DOI] [PubMed] [Google Scholar]
  45. Sanz I., Capra J. D. V kappa and J kappa gene segments of A/J Ars-A antibodies: somatic recombination generates the essential arginine at the junction of the variable and joining regions. Proc Natl Acad Sci U S A. 1987 Feb;84(4):1085–1089. doi: 10.1073/pnas.84.4.1085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Sanz I., Casali P., Thomas J. W., Notkins A. L., Capra J. D. Nucleotide sequences of eight human natural autoantibody VH regions reveals apparent restricted use of VH families. J Immunol. 1989 Jun 1;142(11):4054–4061. [PubMed] [Google Scholar]
  47. Sanz I., Dang H., Takei M., Talal N., Capra J. D. VH sequence of a human anti-Sm autoantibody. Evidence that autoantibodies can be unmutated copies of germline genes. J Immunol. 1989 Feb 1;142(3):883–887. [PubMed] [Google Scholar]
  48. Schroeder H. W., Jr, Hillson J. L., Perlmutter R. M. Early restriction of the human antibody repertoire. Science. 1987 Nov 6;238(4828):791–793. doi: 10.1126/science.3118465. [DOI] [PubMed] [Google Scholar]
  49. Schroeder H. W., Jr, Hillson J. L., Perlmutter R. M. Structure and evolution of mammalian VH families. Int Immunol. 1990;2(1):41–50. doi: 10.1093/intimm/2.1.41. [DOI] [PubMed] [Google Scholar]
  50. Shen A., Humphries C., Tucker P., Blattner F. Human heavy-chain variable region gene family nonrandomly rearranged in familial chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8563–8567. doi: 10.1073/pnas.84.23.8563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Shlomchik M. J., Marshak-Rothstein A., Wolfowicz C. B., Rothstein T. L., Weigert M. G. The role of clonal selection and somatic mutation in autoimmunity. 1987 Aug 27-Sep 2Nature. 328(6133):805–811. doi: 10.1038/328805a0. [DOI] [PubMed] [Google Scholar]
  52. Siebenlist U., Ravetch J. V., Korsmeyer S., Waldmann T., Leder P. Human immunoglobulin D segments encoded in tandem multigenic families. Nature. 1981 Dec 17;294(5842):631–635. doi: 10.1038/294631a0. [DOI] [PubMed] [Google Scholar]
  53. Silverman G. J., Carson D. A. Structural characterization of human monoclonal cold agglutinins: evidence for a distinct primary sequence-defined VH4 idiotype. Eur J Immunol. 1990 Feb;20(2):351–356. doi: 10.1002/eji.1830200218. [DOI] [PubMed] [Google Scholar]
  54. Silverman G. J., Goñi F., Fernandez J., Chen P. P., Frangione B., Carson D. A. Distinct patterns of heavy chain variable region subgroup use by human monoclonal autoantibodies of different specificity. J Exp Med. 1988 Dec 1;168(6):2361–2366. doi: 10.1084/jem.168.6.2361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Slaughter L., Carson D. A., Jensen F. C., Holbrook T. L., Vaughan J. H. In vitro effects of Epstein-Barr virus on peripheral blood mononuclear cells from patients with rheumatoid arthritis and normal subjects. J Exp Med. 1978 Nov 1;148(5):1429–1434. doi: 10.1084/jem.148.5.1429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Sonntag D., Weingärtner B., Grützmann R. A member of a novel human DH gene family: DHFL16. Nucleic Acids Res. 1989 Feb 11;17(3):1267–1267. doi: 10.1093/nar/17.3.1267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Steinitz M., Izak G., Cohen S., Ehrenfeld M., Flechner I. Continuous production of monoclonal rheumatoid factor by EBV-transformed lymphocytes. Nature. 1980 Oct 2;287(5781):443–445. doi: 10.1038/287443a0. [DOI] [PubMed] [Google Scholar]
  58. Tabor S., Richardson C. C. DNA sequence analysis with a modified bacteriophage T7 DNA polymerase. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4767–4771. doi: 10.1073/pnas.84.14.4767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Thompson K. M., Randen I., Natvig J. B., Mageed R. A., Jefferis R., Carson D. A., Tighe H., Forre O. Human monoclonal rheumatoid factors derived from the polyclonal repertoire of rheumatoid synovial tissue: incidence of cross-reactive idiotopes and expression of VH and V kappa subgroups. Eur J Immunol. 1990 Apr;20(4):863–868. doi: 10.1002/eji.1830200422. [DOI] [PubMed] [Google Scholar]
  60. WILLIAMS R. C., Jr, KUNKEL H. G. Rheumatoid factor, complement, and conglutinin aberrations in patients with subacute bacterial endocarditis. J Clin Invest. 1962 Mar;41:666–675. doi: 10.1172/JCI104523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Welch M. J., Fong S., Vaughan J., Carson D. Increased frequency of rheumatoid factor precursor B lymphocytes after immunization of normal adults with tetanus toxoid. Clin Exp Immunol. 1983 Feb;51(2):299–304. [PMC free article] [PubMed] [Google Scholar]
  62. Withrington R. H., Teitsson I., Valdimarsson H., Seifert M. H. Prospective study of early rheumatoid arthritis. II. Association of rheumatoid factor isotypes with fluctuations in disease activity. Ann Rheum Dis. 1984 Oct;43(5):679–685. doi: 10.1136/ard.43.5.679. [DOI] [PMC free article] [PubMed] [Google Scholar]