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. 1988 May;81(5):1511–1518. doi: 10.1172/JCI113483

Complete protein sequences of the variable regions of the cloned heavy and light chains of a human anti-cytomegalovirus antibody reveal a striking similarity to human monoclonal rheumatoid factors of the Wa idiotypic family.

M M Newkirk 1, H Gram 1, G F Heinrich 1, L Ostberg 1, J D Capra 1, R L Wasserman 1
PMCID: PMC442584  PMID: 2452836

Abstract

The complete amino acid and nucleotide sequences of the variable regions of the heavy and light polypeptide chains of a human neutralizing IgGl anti-cytomegalovirus (CMV) antibody reveal a striking homology to IgM rheumatoid factors (RFs) of the Wa idiotypic family. The anti-CMV antibody and Wa RFs have in common VKIIIb, JKl, and VHIa gene segments but use different DH and JH gene segments. The anti-CMV antibody does not have RF activity and does not express the Wa idiotype. The Wa RFs do not have anti-CMV activity. A subset of Wa RFs, however, and the anti-CMV antibody do share several idiotypes on the VHIa and VKIIIb polypeptides. Since there are major differences in the antigen binding characteristics and some of the other expressed idiotypes, these data suggest that the D and J region amino acids are crucial to such specificities. Although the use of such highly homologous gene segments in different immune responses is well-documented in murine systems, these data represent the first such example in the human.

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Selected References

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  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. Agnello V., Barnes J. L. Human rheumatoid factor crossidiotypes. I. WA and BLA are heat-labile conformational antigens requiring both heavy and light chains. J Exp Med. 1986 Nov 1;164(5):1809–1814. doi: 10.1084/jem.164.5.1809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Agnello V., Goñi F., Barnes J. L., de la Vega M. T., Frangione B. Human rheumatoid factor crossidiotypes. II. Primary structure-dependent crossreactive idiotype, PSL2-CRI, present on Wa monoclonal rheumatoid factors is present on Bla and other IgM kappa monoclonal autoantibodies. J Exp Med. 1987 Jan 1;165(1):263–267. doi: 10.1084/jem.165.1.263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Alspaugh M. A., Jensen F. C., Rabin H., Tan E. M. Lymphocytes transformed by Epstein-Barr virus. Induction of nuclear antigen reactive with antibody in rheumatoid arthritis. J Exp Med. 1978 Apr 1;147(4):1018–1027. doi: 10.1084/jem.147.4.1018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Alspaugh M. A., Rosenstock D., Biundo J. J., Gupta R. C. Correlation of antibody to rheumatoid arthritis associated nuclear antigen and immune complexes to disease activity in patients with rheumatoid arthritis. Clin Exp Immunol. 1983 Feb;51(2):278–284. [PMC free article] [PubMed] [Google Scholar]
  6. Andrews D. W., Capra J. D. Amino acid sequence of the variable regions of heavy chains from two idiotypically cross-reactive human IgM anti-gamma-globulins of the Wa group. Biochemistry. 1981 Sep 29;20(20):5822–5830. doi: 10.1021/bi00523a027. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Billings P. B., Hoch S. O., White P. J., Carson D. A., Vaughan J. H. Antibodies to the Epstein-Barr virus nuclear antigen and to rheumatoid arthritis nuclear antigen identify the same polypeptide. Proc Natl Acad Sci U S A. 1983 Dec;80(23):7104–7108. doi: 10.1073/pnas.80.23.7104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bonagura V. R., Kunkel H. G., Pernis B. Cellular localization of rheumatoid factor idiotypes. J Clin Invest. 1982 Jun;69(6):1356–1365. doi: 10.1172/JCI110575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Brooks P., Readett M., Kirov S. Rheumatoid arthritis and generalized vaccinia. JAMA. 1978 Feb 20;239(8):747–748. [PubMed] [Google Scholar]
  11. Capra J. D., Winchester R. J., Kunkel H. G. Cold-reactive rheumatoid factors in infectious mononucleosis and other diseases. Arthritis Rheum. 1969 Apr;12(2):67–73. doi: 10.1002/art.1780120202. [DOI] [PubMed] [Google Scholar]
  12. Carson D. A., Fong S. A common idiotope on human rheumatoid factors identified by a hybridoma antibody. Mol Immunol. 1983 Oct;20(10):1081–1087. doi: 10.1016/0161-5890(83)90116-5. [DOI] [PubMed] [Google Scholar]
  13. Chen P. P., Albrandt K., Orida N. K., Radoux V., Chen E. Y., Schrantz R., Liu F. T., Carson D. A. Genetic basis for the cross-reactive idiotypes on the light chains of human IgM anti-IgG autoantibodies. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8318–8322. doi: 10.1073/pnas.83.21.8318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Chen P. P., Fong S., Normansell D., Houghten R. A., Karras J. G., Vaughan J. H., Carson D. A. Delineation of a cross-reactive idiotype on human autoantibodies with antibody against a synthetic peptide. J Exp Med. 1984 May 1;159(5):1502–1511. doi: 10.1084/jem.159.5.1502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Chen P. P., Houghten R. A., Fong S., Rhodes G. H., Gilbertson T. A., Vaughan J. H., Lerner R. A., Carson D. A. Anti-hypervariable region antibody induced by a defined peptide: an approach for studying the structural correlates of idiotypes. Proc Natl Acad Sci U S A. 1984 Mar;81(6):1784–1788. doi: 10.1073/pnas.81.6.1784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Diamond B., Scharff M. D. Somatic mutation of the T15 heavy chain gives rise to an antibody with autoantibody specificity. Proc Natl Acad Sci U S A. 1984 Sep;81(18):5841–5844. doi: 10.1073/pnas.81.18.5841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ehrlich P. H., Harfeldt K. E., Justice J. C., Moustafa Z. A., Ostberg L. Rhesus monkey responses to multiple injections of human monoclonal antibodies. Hybridoma. 1987 Apr;6(2):151–160. doi: 10.1089/hyb.1987.6.151. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Geltner D., Franklin E. C., Frangione B. Antiidiotypic activity in the IgM fractions of mixed cryoglobulins. J Immunol. 1980 Oct;125(4):1530–1535. [PubMed] [Google Scholar]
  20. Goldfien R. D., Chen P. P., Fong S., Carson D. A. Synthetic peptides corresponding to third hypervariable region of human monoclonal IgM rheumatoid factor heavy chains define an immunodominant idiotype. J Exp Med. 1985 Aug 1;162(2):756–761. doi: 10.1084/jem.162.2.756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Goñi F., Chen P. P., Pons-Estel B., Carson D. A., Frangione B. Sequence similarities and cross-idiotypic specificity of L chains among human monoclonal IgM kappa with anti-gamma-globulin activity. J Immunol. 1985 Dec;135(6):4073–4079. [PubMed] [Google Scholar]
  22. Hamerman D., Gresser I., Smith C. Isolation of cytomegalovirus from synovial cells of a patient with rheumatoid arthritis. J Rheumatol. 1982 Sep-Oct;9(5):658–664. [PubMed] [Google Scholar]
  23. Heinrich G., Traunecker A., Tonegawa S. Somatic mutation creates diversity in the major group of mouse immunoglobulin kappa light chains. J Exp Med. 1984 Feb 1;159(2):417–435. doi: 10.1084/jem.159.2.417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hieter P. A., Maizel J. V., Jr, Leder P. Evolution of human immunoglobulin kappa J region genes. J Biol Chem. 1982 Feb 10;257(3):1516–1522. [PubMed] [Google Scholar]
  25. Hieter P. A., Max E. E., Seidman J. G., Maizel J. V., Jr, Leder P. Cloned human and mouse kappa immunoglobulin constant and J region genes conserve homology in functional segments. Cell. 1980 Nov;22(1 Pt 1):197–207. doi: 10.1016/0092-8674(80)90168-3. [DOI] [PubMed] [Google Scholar]
  26. Jeske D. J., Jarvis J., Milstein C., Capra J. D. Junctional diversity is essential to antibody activity. J Immunol. 1984 Sep;133(3):1090–1092. [PubMed] [Google Scholar]
  27. Kacaki J. N., Balduzzi P. C., Vaughan J. H. A study of rubella haemagglutination inhibition antibodies in rheumatoid arthritis. Clin Exp Immunol. 1970 Jun;6(6):885–889. [PMC free article] [PubMed] [Google Scholar]
  28. Kudo A., Ishihara T., Nishimura Y., Watanabe T. A cloned human immunoglobulin heavy chain gene with a novel direct-repeat sequence in 5' flanking region. Gene. 1985;33(2):181–189. doi: 10.1016/0378-1119(85)90092-7. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Kunkel H. G., Mannik M., Williams R. C. Individual Antigenic Specificity of Isolated Antibodies. Science. 1963 Jun 14;140(3572):1218–1219. doi: 10.1126/science.140.3572.1218. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Ledford D. K., Goñi F., Pizzolato M., Franklin E. C., Solomon A., Frangione B. Preferential association of kappa IIIb light chains with monoclonal human IgM kappa autoantibodies. J Immunol. 1983 Sep;131(3):1322–1325. [PubMed] [Google Scholar]
  33. 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]
  34. Mageed R. A., Walker M. R., Jefferis R. Restricted light chain subgroup expression on human rheumatoid factor paraproteins determined by monoclonal antibodies. Immunology. 1986 Nov;59(3):473–478. [PMC free article] [PubMed] [Google Scholar]
  35. Moynihan J. A., Looney R. J., Abraham G. N. The VKIIIb light chain sub-subgroup: restricted association with mu heavy chain in normal human serum. Immunology. 1985 Feb;54(2):207–213. [PMC free article] [PubMed] [Google Scholar]
  36. Naparstek Y., Duggan D., Schattner A., Madaio M. P., Goni F., Frangione B., Stollar B. D., Kabat E. A., Schwartz R. S. Immunochemical similarities between monoclonal antibacterial Waldenstrom's macroglobulins and monoclonal anti-DNA lupus autoantibodies. J Exp Med. 1985 Jun 1;161(6):1525–1538. doi: 10.1084/jem.161.6.1525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Nepom G. T., Hansen J. A., Nepom B. S. The molecular basis for HLA class II associations with rheumatoid arthritis. J Clin Immunol. 1987 Jan;7(1):1–7. doi: 10.1007/BF00915418. [DOI] [PubMed] [Google Scholar]
  38. Newkirk M. M., Edmundson A., Wistar R., Jr, Klapper D. G., Capra J. D. A new protocol to digest human IgM with papain that results in homogeneous Fab preparations that can be routinely crystallized. Hybridoma. 1987 Oct;6(5):453–460. doi: 10.1089/hyb.1987.6.453. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. Newkirk M., Chen P. P., Carson D., Posnett D., Capra J. D. Amino acid sequence of a light chain variable region of a human rheumatoid factor of the Wa idiotypic group, in part predicted by its reactivity with antipeptide antibodies. Mol Immunol. 1986 Mar;23(3):239–244. doi: 10.1016/0161-5890(86)90049-0. [DOI] [PubMed] [Google Scholar]
  41. Norden C. W., Kuller L. H. Identifying infectious etiologies of chronic disease. Rev Infect Dis. 1984 Mar-Apr;6(2):200–213. doi: 10.1093/clinids/6.2.200. [DOI] [PubMed] [Google Scholar]
  42. Ogra P. L., Chiba Y., Ogra S. S., Dzierba J. L., Herd J. K. Rubella-virus infection in juvenile rheumatoid arthritis. Lancet. 1975 May 24;1(7917):1157–1161. doi: 10.1016/s0140-6736(75)93136-0. [DOI] [PubMed] [Google Scholar]
  43. 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]
  44. Pasquali J. L., Fong S., Tsoukas C., Vaughan J. H., Carson D. A. Inheritance of immunoglobulin M rheumatoid-factor idiotypes. J Clin Invest. 1980 Oct;66(4):863–866. doi: 10.1172/JCI109927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Pasquali J. L., Urlacher A., Storck D. A highly conserved determinant on human rheumatoid factor idiotypes defined by a mouse monoclonal antibody. Eur J Immunol. 1983 Mar;13(3):197–201. doi: 10.1002/eji.1830130304. [DOI] [PubMed] [Google Scholar]
  46. Persselin J. E., Louie J. S., Stevens R. H. Clonally restricted anti-IgG antibodies in rheumatoid arthritis. Arthritis Rheum. 1984 Dec;27(12):1378–1386. doi: 10.1002/art.1780271208. [DOI] [PubMed] [Google Scholar]
  47. Phillips P. E., Waxman J., Hirshaut Y., Kaplan M. H. Virus antibody levels and delayed hypersensitivity in rheumatoid arthritis. Ann Rheum Dis. 1976 Apr;35(2):152–154. doi: 10.1136/ard.35.2.152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Podell D. N., Abraham G. N. A technique for the removal of pyroglutamic acid from the amino terminus of proteins using calf liver pyroglutamate amino peptidase. Biochem Biophys Res Commun. 1978 Mar 15;81(1):176–185. doi: 10.1016/0006-291x(78)91646-7. [DOI] [PubMed] [Google Scholar]
  49. Poljak R. J. Crystallization of immunoglobulins and their fragments for X-ray diffraction studies. Methods Enzymol. 1985;116:190–200. doi: 10.1016/s0076-6879(85)16013-1. [DOI] [PubMed] [Google Scholar]
  50. Posnett D. N., Wisniewolski R., Pernis B., Kunkel H. G. Dissection of the human antigammaglobulin idiotype system with monoclonal antibodies. Scand J Immunol. 1986 Feb;23(2):169–181. doi: 10.1111/j.1365-3083.1986.tb01955.x. [DOI] [PubMed] [Google Scholar]
  51. Procaccia S., Lazzarin A., Colucci A., Gasparini A., Forcellini P., Lanzanova D., Foppa C. U., Novati R., Zanussi C. IgM, IgG and IgA rheumatoid factors and circulating immune complexes in patients with AIDS and AIDS-related complex with serological abnormalities. Clin Exp Immunol. 1987 Feb;67(2):236–244. [PMC free article] [PubMed] [Google Scholar]
  52. Ravetch J. V., Siebenlist U., Korsmeyer S., Waldmann T., Leder P. Structure of the human immunoglobulin mu locus: characterization of embryonic and rearranged J and D genes. Cell. 1981 Dec;27(3 Pt 2):583–591. doi: 10.1016/0092-8674(81)90400-1. [DOI] [PubMed] [Google Scholar]
  53. Rechavi G., Ram D., Glazer L., Zakut R., Givol D. Evolutionary aspects of immunoglobulin heavy chain variable region (VH) gene subgroups. Proc Natl Acad Sci U S A. 1983 Feb;80(3):855–859. doi: 10.1073/pnas.80.3.855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Sela O., el-Roeiy A., Isenberg D. A., Kennedy R. C., Colaco C. B., Pinkhas J., Shoenfeld Y. A common anti-DNA idiotype in sera of patients with active pulmonary tuberculosis. Arthritis Rheum. 1987 Jan;30(1):50–56. doi: 10.1002/art.1780300107. [DOI] [PubMed] [Google Scholar]
  55. 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]
  56. Solomon A., McLaughlin C. L. Bence Jones proteins and light chains of immunoglobulins. II. Immunochemical differentiation and classification of kappa-chains. J Exp Med. 1969 Dec 1;130(6):1295–1311. doi: 10.1084/jem.130.6.1295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med. 1978 Apr 20;298(16):869–871. doi: 10.1056/NEJM197804202981602. [DOI] [PubMed] [Google Scholar]
  58. Takahashi N., Ueda S., Obata M., Nikaido T., Nakai S., Honjo T. Structure of human immunoglobulin gamma genes: implications for evolution of a gene family. Cell. 1982 Jun;29(2):671–679. doi: 10.1016/0092-8674(82)90183-0. [DOI] [PubMed] [Google Scholar]
  59. Venables P. J., Ross M. G., Charles P. J., Melsom R. D., Griffiths P. D., Maini R. N. A seroepidemiological study of cytomegalovirus and Epstein-Barr virus in rheumatoid arthritis and sicca syndrome. Ann Rheum Dis. 1985 Nov;44(11):742–746. doi: 10.1136/ard.44.11.742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Wilkes R. M., Simsarian J. P., Hopps H. E., Roth H., Decker J. L., Aptekar R. G., Meyer H. M., Jr Virologic studies on rheumatoid arthritis. Arthritis Rheum. 1973 Jul-Aug;16(4):446–454. doi: 10.1002/art.1780160403. [DOI] [PubMed] [Google Scholar]
  61. 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]
  62. el-Roiey A., Gross W. L., Luedemann J., Isenberg D. A., Shoenfeld Y. Preferential secretion of a common anti-DNA idiotype (16/6 Id) and anti-polynucleotide antibodies by normal mononuclear cells following stimulation with Klebsiella pneumoniae. Immunol Lett. 1986 Jun;12(5-6):313–319. doi: 10.1016/0165-2478(86)90036-2. [DOI] [PubMed] [Google Scholar]

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