Springer Seminars in Immunopathology

, Volume 17, Issue 2–3, pp 203–230

The Epstein-Barr virus in autoimmunity

  • John H. Vaughan


EBV, which is one of the viruses that most of us live with throughout most of our lifetimes, is capable of inducing autoantibodies reactive with a variety of normal tissue proteins. Because of this, the virus remains a constant threat for autoimmunization during our lifetimes, and this threat is in fact realized in several autoimmune diseases. We have described here manifestations suggesting this in RA, SjS, SLE, SSc and MS. In RA, MS, and SSc, autoantibodies cross-reactive with the glycine/alanine repeat of EBNA-1 exist, but these cross-reactions seem to be subtly different among the three. In SSc, cross-reacting autoantibody is expressed as anti-p542, while in RA an anti-60 kDa activity without anti-p542 is generally present. In MS cross-reacting autoantibody to an 80- to 82-kDa doublet is predominant.

In SjS and SLE, the autoimmune manifestations are distinctly different from those of the preceding three diseases. In SLE, cross-reacting autoantibody (anti-Sm) is predominantly based on glycine/arginine sequences in EBNA-1, or on its PPPGRRP sequence. In SjS, productive infection by the virus is a dominant feature of the illness, and the principal autoantibodies, anti-Ro/SS-A and anti-La/SS-B, are not derived by cross-reactivity with EBNA-1 or any other EBV protein. Anti-La/SSB may conceivably be derived either from an abnormal display of the autoantigen on the outer cell membrane, or by binding of the autoantigen by EBV-generated EBER molecules.

We have presented no evidence that these autoimmune manifestations are pathogenetically significant, but we believe that further study may prove some or all to be so. This question can be most effectively explored using recombinant EBNA-1 as antigen in selected mouse strains. Further exploration in man will require cloning and identification of the 80- to 82-kDa and ∼ 60-kDa antigens from human neuroglial or lymphocytic cDNA libraries, to clarify the nature of these molecules and explore the ways in which they may be exposed to the immune system in disease. Completion of the sequencing and identification of p542 is needed for the same reasons. Other EBV antigens can be similarly explored, and we have mentioned studies of this nature that are already under way by others using EBV gp 110.

It is highly likely that all autoimmune diseases are significantly impacted by multiple microbial agents, and that final expression of disease in these syndromes is a resultant of all these impactions together. Nevertheless, the number of agents making significant autoimmune contributions is probably limited, and even the number of inciting molecules from a given agent may be limited, so the process may not be so multidispersed as to make an investigation of this part of the autoimmune disease unmanageable. We can even hope that ultimately this approach will provide a useful road towards prevention or therapy.


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  1. 1.
    Aitcheson CT, Wilson GL, Ferrell PB, Tan EM (1983) Frequency of transforming Epstein-Barr virus in oropharyngeal secretions of rheumatoid arthritis patients. Intervirology 19:135Google Scholar
  2. 2.
    Albani S, La Cava A, Schrauder A, Carson DA (1994) Characterization in enteric bacteria of equivalents of E. coli dnaJ, a protein that shares with several HLA alleles the QKRAA susceptibility sequence to rheumaoid arthritis (RA) (abstract). Arthritis Rheum 37:S169Google Scholar
  3. 3.
    Albani S, Ravelli A, Massa M, De Benedetti F, Andree G, Roudier J, Martini A, Carson DA (1994) Immune response to the Escherichia coli heat shock protein in juvenile rheumatoid arthritis and their correlation with disease activity. J Pediatr 124:561Google Scholar
  4. 4.
    Alspaugh M, Tan E (1975) Antibodies to cellular antigen in Sjøgren's syndrome. J Clin Invest 55:1067Google Scholar
  5. 5.
    Alspaugh MA, Tan EM (1976) Serum antibody in rheumatoid arthritis reactive with a cell-associated antigen. Demonstration by precipitation and immunofluorescence. Arthritis Rheum 19:711Google Scholar
  6. 6.
    Alspaugh MA, Jensen FC, Rabin H, Tan EM (1978) Lymphocytes transformed by Epstein-Barr virus induction of nuclear antigen reactive with antibody in rheumatoid arthritis. J Exp Med 147:1018Google Scholar
  7. 7.
    Alspaugh MA, Henle G, Lennette ET, Henle W (1981) Elevated levels of antibodies to Epstein-Barr virus antigens in sera and synovial fluids of patients with rheumatoid arthritis. J Clin Invest 67:1134Google Scholar
  8. 8.
    Alspaugh MA, Shoji H, Nonoyama M (1983) A search for rheumatoid arthritis-associated nuclear antigen and Epstein-Barr virus-specific antigens or genomes in tissues and cells from patients with rheumatoid arthritis. Arthritis Rheum 26:712Google Scholar
  9. 9.
    Auger I, Salvat S, Roudier J (1994) 70kD heat shock proteins from E. coli and salmonella specifically bind to the third hypervariable region of HLA-DRB1*0401. Arthritis Rheum 37:S373iGoogle Scholar
  10. 10.
    Baboonian C, Halliday D, Venables PJW, Pawlowski T, Millman G, Maini RN (1989) Antibodies in rheumatoid arthritis react specifically with the glycine alanine repeat sequence of Epstein-Barr nuclear antigen-1. Rheumatol Int 9:161Google Scholar
  11. 11.
    Baboonian C, Venables PJ, Booth J, Williams DG, Roffe LM, Maini RN (1989) Virus infection induces redistribution and membrane localization of the nuclear antigen La (SS-B): a possible mechanism for autoimmunity. Clin Exp Immunol 78:454Google Scholar
  12. 12.
    Baboonian C, Venables PJ, Williams DG, Williams RO, Maini RN (1991) Cross reaction of antibodies to a glycine/alanine repeat sequence of Epstein-Barr virus nuclear antigen-1 with collagen, cytokeratin, and actin. Ann Rheum Dis 50:772Google Scholar
  13. 13.
    Bang H, Mollenhauer J, Schulmeister A, Nager C, Van Eden W, Wand-Wurttenberger A, Kaufmann SHE, Brune K (1994) Isolation and characterization of a cartilage-specific membrane antigen (CH65): comparison with cytokeratins and heat-shock proteins. Immunology 81:322Google Scholar
  14. 14.
    Bardwick PA, Bluestein HG, Zvaifler NJ, Depper JM, Seegmiller JE (1980) Altered regulation of Epstein-Barr virus induced lymphoblast proliferation in rheumatoid arthritis lymphoid cells. Arthritis Rheum 23:626Google Scholar
  15. 15.
    Becker HE, Vierbuchen C, Federlin K (1989) Influence of Epstein-Barr virus infection on B lymphocyte responses in patients with rheumatoid arthritis. J Autoimmun 2:825Google Scholar
  16. 16.
    Bell DA, Pinto J (1984) Distribution of activated B lymphocytes in the circulation and synovial fluid in rheumatoid arthritis. Clin Immunol Immunopathol 31:272Google Scholar
  17. 17.
    Ben-Chetrit E, Fox RI, Tan EM (1990) Dissociation of immune responses to the SS-A (Ro) 53-kd and 60-kd polypeptides in systemic lupus erythematosus and Sjøgren's syndrome. Arthritis Rheum 33:349Google Scholar
  18. 18.
    Billings PB, Hoch SO, White PJ, Carson DA, Vaughan JH (1983) Antibodies to the Epstein-Barr virus nuclear antigen and to rheumatoid arthritis nuclear antigen identify the same polypeptide. Proc Natl Acad Sci USA 80:7104Google Scholar
  19. 19.
    Birkenfeld P, Haratz N, Klein G, Sulitzeanu D (1990) Cross-reactivity between the EBNA-1 p107 peptide, collagen, and keratin: implications for the pathogenesis of rheumatoid arthritis. Clin Immunol Immunopathol 54:14Google Scholar
  20. 20.
    Bluestein HG, Hasler F (1984) Epstein-Barr virus and rheumatoid arthritis. Surv Immunol Res 3:70Google Scholar
  21. 21.
    Brousset P, Caulier M, Cantagrel A, Dromer C, Mazieres B, Delsol G (1993) Absence of Epstein-Barr virus carrying cells in synovial membranes and subcutaneous nodules of patients with rheumatoid arthritis. Rev Rhum Ed Fr 52:608Google Scholar
  22. 22.
    Burmester GR, Altstidl U, Kalden JR, Emmrich F (1991) Stimulatory response towards the 65kDa heat shock protein and other mycobacterial antigens in patients with rheumatoid arthritis. J Rheumatol 18:171Google Scholar
  23. 23.
    Catalano MA, Carson DA, Slovin SF, Richman DD, Vaughan JH (1979) Antibodies to Epstein-Barr virus-determined antigens in normal subjects and in patients with seropositive rheumatoid arthritis. Proc Natl Acad Sci USA 76:5825Google Scholar
  24. 24.
    Catalano MA, Carson DA, Niederman JC, Feorino P, Vaughan JH (1980) Antibody to the rheumatoid arthritis nuclear antigen: its relationship to in vivo Epstein-Barr virus infection. J Clin Invest 65:1238Google Scholar
  25. 25.
    Catalano MA, Carson DA, Stastny P, Freer S, Vaughan JH (1980) Correlation between anti-RANA and anti-EBNA titers in normal subjects with and without HLA-DRw4. Arthritis Rheum 23:1049Google Scholar
  26. 26.
    Cheng H-M, Foong Y-T, Sam C-K, Prasad U, Dillner J (1991) Epstein-Barr virus nuclear antigen 1 linear epitopes that are reactive with immunoglobulin A (IgA) or IgG in sera from nasopharyngeal carcinoma patients or from healthy donors. J Clin Microbiol 29:2180Google Scholar
  27. 27.
    Clemens MJ (1994) Functional significance of the Epstein-Barr virus-encoded small RNAs. EBV Rep 1:107Google Scholar
  28. 28.
    Corke CF, Gul V, Stierle HE, Huskisson EC, Holborow EJ (1984) Increased numbers of active B cells in the circulation of patients with rheumatoid arthritis. Rheumatol Int 4:19Google Scholar
  29. 29.
    Deacon EM, Matthews JB, Potts AJ, Hamburger J, Bevan IS, Young LS (1991) Detection of EpsteinBarr virus antigens and DNA in major and minor salivary glands using immunocytochemistry and polymerase chain reaction: possible relationship with Sjøgren's syndrome. J Pathol 163:351Google Scholar
  30. 30.
    De Keyser F, Hoch SO, Takei M, Dang H, De Keyser H, Rokeach LA, Talal N (1992) Cross-reactivity of the B B subunit of the Sm ribonucleoprotein. Clin Immunol Immunopathol 62:285Google Scholar
  31. 31.
    Depper JM, Bluestein HG, Zvaifler NJ (1981) Impaired regulation of Epstein-Barr virus-induced lymphocyte proliferation in rheumatoid arthritis is due to a T cell defect. J Immunol 127:1899Google Scholar
  32. 32.
    Depper JM, Zvaifler NJ, Bluestein HG (1982) Oropharyngeal Epstein-Barr virus excretion in rheumatoid arthritis. Arthritis Rheum 25:427Google Scholar
  33. 33.
    Dobloug JH, Chattopadhyay C, Forre O, Hoyeraal HM, Natvig JB (1981) Con A-induced suppressor cell activity and lymphocyte subpopulations in peripheral blood lymphocytes of patients with rheumatoid arthritis and juvenile rheumatoid arthritis. Scand J Immunol 13:367Google Scholar
  34. 34.
    Epstein MA, Achong BG (1979) The Epstein-Barr virus. Springer-Verlag, New York Berlin HeidelbergGoogle Scholar
  35. 35.
    Fawcett M-C, Walker DJ, Griffiths ID (1988) Demonstration of impaired T cell regulation of Epstein-Barr virus stimulated B lymphocytes in rheumatoid arthritis with HLA identical, disease discordant sibling pairs. Ann Rheum Dis 47:372Google Scholar
  36. 36.
    Ferrell PB, Aitcheson CT, Pearson GR, Tan EM (1981) Seroepidemiological study of relationships between Epstein-Barr virus and rheumatoid arthritis. J Clin Invest 67:681Google Scholar
  37. 37.
    Fox RI, Chilton T, Rhodes G, Vaughan JH (1986) Lack of reactivity of rheumatoid arthritis synovial membrane with cloned Epstein-Barr virus DNA probes. J Immunol 137:498Google Scholar
  38. 38.
    Fox RI, Sportsman R, Rhodes GH, Luka J, Pearson G, Vaughan JH (1986) Rheumatoid arthritis synovial membrane contains a 62 Kd protein that shares an antigenic epitope with the Epstein-Barr virus-encoded EBNA-1 antigen. J Clin Invest 77:1539Google Scholar
  39. 39.
    Fox RI, Pearson G, Vaughan JH (1986) Detection of Epstein-Barr virus associated antigens and DNA in salivary gland biopsies from patients with Sjøgren's syndrome. J Immunol 137:3162Google Scholar
  40. 40.
    Fox RI, Scott S, Houghton R, Whalley A, Geltofsky J, Vaughan JH, Smith R (1987) Synthetic peptide derived from the Epstein-Barr virus encoded early diffuse antigen (EA-D) reactive with human antibodies. J Clin Lab Anal 1:140Google Scholar
  41. 41.
    Fox RI, Luppi M, Kang HI, Pisa P (1991) Reactivation of Epstein-Barr virus in Sjøgren's syndrome. Springer Scmin Immunopathol 13:217Google Scholar
  42. 42.
    Fritzler MJ (1993) Autoantibodies in scleroderma. J Dermatol 20:257Google Scholar
  43. 43.
    Garry RF, Fermin CD, Hart DJ, Alexander SS, Donehower LA, Luo-Zhang H (1990) Detection of a human intracisternal A-type retroviral particle antigenically related to HIV. Science 250:1127Google Scholar
  44. 44.
    Gaston JSH, Rickinson AB, Epstein MA (1982) Epstein-Barr virus-specific cytotoxic T cell responses in rheumatoid arthritis patients. Rheumatol Int 2:155Google Scholar
  45. 45.
    Gaston JSH, Rickinson AB, Yao QY, Epstein MA (1986) The abnormal cytotoxic T cell response to Epstein-Barr virus in rheumatoid arthritis is correlated with disease activity and occurs in other arthropathies. Ann Rheum Dis 45:932Google Scholar
  46. 46.
    Gaston JS, Rowe M, Bacon P (1990) Sjøgren's syndrome after infection by Epstein-Barr virus. J Rheumatol 17:558Google Scholar
  47. 47.
    Girbal E, Sebbag M, Gomes-Daudix V, Simon M, Vincent C, Serre G (1993) Characterisation of the rat oesophagus epithelium antigens defined by the so-called ‘antikeratin antibodies’, specific for rheumatoid arthritis. Ann Rheum Dis 52:749Google Scholar
  48. 48.
    Gorgoulis V, Giatromanolaki A, Iliopoulos A, Kanavaros P, Aninos D, Ioakeimidis D, Kontomerkos T, Karameris A (1993) EGF and EGF-r immunoexpression in Sjøgren's syndrome secondary to rheumatoid arthritis. Correlation with EBV expression? Clin Exp Rheumatol 11:623Google Scholar
  49. 49.
    Gratama JW, Oosterveer MAP, Weimar W, Sintnicolaas K, Sizoo W, Bolhuis RLH, Ernberg I (1993) Multiple lymphocyte-transforming Epstein-Barr viral strains in peripheral blood and oropharynx of healthy and diseased carriers. In: Tursz T, Pagano JS, Ablashi DV, de The G, Lenoir G, Pearson GR (eds) The Epstein-Barr virus and associated diseases. Libbey, London, pp 351–356Google Scholar
  50. 50.
    Harley JB, Scofield RH, Reichlin M (1992) Anti-Ro in Sjögren's syndrome and systemic lupus erythematosus. Rheum Dis Clin North America 18:337Google Scholar
  51. 51.
    Harley JB, Sestak AL, Willis LG, Fu SM, Hansen JA, Reichlin M (1989) A model for disease heterogeneity in systemic lupus erythematosus. Relationships between histocompatibility antigens, autoantibodies, and lymphopenia or renal disease. Arthritis Rheum 32:826Google Scholar
  52. 52.
    Hasler F, Bluestein HG, Zvaifler NJ, Epstein LB (1983) Analysis of the defects responsible for the impaired regulation of Epstein-Barr virus-induced B cell proliferation by rheumatoid arthritis lymphocytes. I. Diminished gamma interferon production in response to autologous stimulation. J Exp Med 157:173Google Scholar
  53. 53.
    Hasler F, Bluestein HG, Zvaifler NJ, Epstein LB (1983) Analysis of the defects responsible for the impaired regulation of EBV-induced B cell proliferation by rheumatoid arthritis lymphocytes. II. Role of monocytes and the increased sensitivity of rheumatoid arthritis lymphocytes to prostaglandin E. J Immunol 131:768Google Scholar
  54. 54.
    Haustein U-F, Pustowoit B, Krusche U, Herrmann K (1993) Antibodies to retrovirus proteins in scleroderma. Acta Derm Venereol (Stockh) 73:116Google Scholar
  55. 55.
    Helland DE, Welles JL, Caputo A, Haseltine WA (1991) Transcellular transactivation by the human immunodeficiency virus type I tat protein. J Virol 65:4547Google Scholar
  56. 56.
    Heller M, Flemington E, Kieff E, Deininger P (1985) Repeat arrays in cellular DNA related to the Epstein-Barr virus IR3 repeat. Mol Cell Biol 5:457Google Scholar
  57. 57.
    Hermann M, Baur A, Nebel-Schickel H, Vornagen R, Jahn G, Krapf FE, Kalden JR (1992) Antibodies against p24 of HIV-1 in patients with systemic lupus erythematosus? Viral Immunol 5:229Google Scholar
  58. 58.
    Horvat RT, Wood C, Josephs SF, Balachandran N (1991) Transactivation of the human immunodeficiency virus promoter by human herpesvirus 6 (HHV-6) strains GS and Z-29 in primary human T lymphocytes and identification of transactivating HHV-6 (GS) gene fragments. J Virol 65:2895Google Scholar
  59. 59.
    Irving WL, Walker PR, Lydyard PM, Roitt IM (1982) Defective rheumatoid lymphocyte function assessed by Epstein-Barr virus infection in vitro. Lancet I:1337Google Scholar
  60. 60.
    James JA, Harley JB (1992) Linear epitope mapping of an Sm B/B′ polypeptide. J Immunol 148:2074Google Scholar
  61. 61.
    James JA, Gross T, Scofield RH, Harley JB (1995) Immunoglobulin epitope spreading autoimmune disease after peptide immunization: Sm B/B′-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity. J Exp Med 181:453Google Scholar
  62. 62.
    Johnson GD, Carvalho EJ, Holborow EJ, Goddard DH, Russell G (1981) Antiperinuclear factor and keratin antibodies in rheumatoid arthritis. Ann Rheum Dis 40:263Google Scholar
  63. 63.
    Kahan A, LeFloch JP, Charreire J (1990) Normal suppressive T cell function of Epstein-Barr virus induced B cell activation in type 1 (insulin dependent) diabetes mellitus. Autoimmunity 5:257Google Scholar
  64. 64.
    Karameris A, Gorgoulis V, Iliopoulos A, Frangia C, Kontomerkos T, Ioakeimidis D, Kalogeropoulos N, Sfikakis P, Kanavaros P (1992) Detection of the Epstein-Barr viral genome by an in situ hybridization method in salivary gland biopsies from patients with secondary Sjøgren's syndrome. Clin Exp Rheumatol 10:327Google Scholar
  65. 65.
    Kieff E, Wang F, Birkenbach M, Cohen J, Samples J, Tomkinson B, Swaminathan S, Longnecker R, Marchini A, Mannick J, Tsang S-F, Sample C, Kurilla M (1991) Molecular biology of lymphocyte transformation by Epstein-Barr virus. In: Brugge J, Curran T, Harlow E, McCormick F (eds) Origins of human cancer: a comprehensive review. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 563–576Google Scholar
  66. 66.
    Kitagawa H, Iho S, Hoshino T (1988) Detection of antibodies to the Epstein-Barr virus nuclear antigens in the sera from patients with systemic lupus erythematosus. Immunol Lett 17:249Google Scholar
  67. 67.
    Klein G (1994) The paradoxical coexistence of EBV and the human species. EBV Rep 1:5Google Scholar
  68. 68.
    Klein G, Svedmyr E, Jondal M, et al (1976) EBV determined nuclear antigen (EBNA)-positive cells in the peripheral blood of infectious mononucleosis patients. Int J Cancer 17:21Google Scholar
  69. 69.
    Kohsaka H, Yamamoto K, Fujii H, Miura H, Miyasaka N, Nishioka K, Miyamoto T (1990) Fine epitope mapping of the human SS-B/La protein. Identification of a distinct autoepitope homologous to a viral Gag polyprotein. J Clin Invest 85:1566Google Scholar
  70. 70.
    Kouri T, Petersen J, Rhodes G, Aho K, Palosuo T, Heliovaara M, Isomaki H, von Essen R, Vaughan JH (1990) Antibodies to synthetic peptides from Epstein-Barr nuclear antigen-1 in sera of patients with early rheumatoid arthritis and in preillness sera. J Rheumatol 17:1442Google Scholar
  71. 71.
    Kurki P, Aho K, Palosuo T, Heliovaara M (1992) Immunopathology of rheumatoid arthritis. Arthritis Rheum 35:914Google Scholar
  72. 72.
    La Cava A, Carson DA, Albani S (1994) The QKRAA susceptibility sequence to RA, as expressed on the EDV protein gp110, is a target of immune responses in patients with RA. Arthritis Rheum 37:5312Google Scholar
  73. 73.
    LeClercq SA, Davis P (1982) Anti-RANA antibody in rheumatoid arthritis, seronegative polyarthritis, and normal controls. Rheumatol Int 1:177Google Scholar
  74. 74.
    Lerner MR, Boyle JA, Hardin JA, Steitz JA (1981) Two novel classes of small ribonucleoproteins detected by antibodies associated with lupus erythematosus. Science 211:400Google Scholar
  75. 75.
    Lotz M, Tsoukas, CD, Fong, S, Dinarello CA, Carson DA, Vaughan JD (1986) Release of lymphokines after infection with Epstein Barr virus in vitro. II. A monocyte-dependent inhibitor of interleukin-1 down-regulates the production of interleukin-2 and interferon-γ in rheumatoid arthritis. J Immunol 136:3643Google Scholar
  76. 76.
    Lotz M, Tsoukas CD, Fong S, Dinarello CA, Carson DA, Vaughan JH (1986) Release of lymphokines after Epstein Barr virus infection in vitro I. Sources of and kinetics of production of interferons and interleukins in normal humans. J Immunol 136:3636Google Scholar
  77. 77.
    Lotz M, Tsoukas CD, Curd JG, Carson DA, Vaughan JH (1987) Effects of recombinant human interferons on rheumatoid arthritis B lymphocytes activated by Epstein-Barr virus. J Rheumatol 14:42Google Scholar
  78. 78.
    Luka J, Kreofsky T, Pearson GR, Hennessy K, Kieff E (1984) Identification and characterization of a cellular protein that cross-reacts with the Epstein-Barr virus nuclear antigen. J Virol 52:833Google Scholar
  79. 79.
    Marchini B, Dolcher MP, Sabbatini A, Klein G, Migliorini P (1994) Immune response to different sequences of the EBNA I molecule in Epstein-Barr virus-related disorders and in autoimmune diseases. J Autoimmun 7:179Google Scholar
  80. 80.
    Mariette X, Gozlan J, Clerc D, Bisson M, Morinet F (1991) Detection of Epstein-Barr virus DNA by in situ hybridization and polymerase chain reaction in salivary gland biopsy specimens from patients with Sjøgren's syndrome. Am J Med 90:286Google Scholar
  81. 81.
    McChesney MB, Bankhurst AD (1986) Cytotoxic mechanisms in vitro against Epstein-Barr virus infected lymphoblastoid cell lines in rheumatoid arthritis. Ann Rheum Dis 45:546Google Scholar
  82. 82.
    McNeilage LJ, Umapathysivam K, Macmillan E, Guidoliin A, Whittingham S, Gordon T (1992) Definition of a discontinuous immunodominant epitope at the NH2 terminus of the La/SS-B ribonucleoprotein autoantigen. J Clin Invest 89:1652Google Scholar
  83. 83.
    Mettal D, Brune K, Mollenhauer J (1992) Cytotoxic effects of rheumatoid arthritis sera on chondrocytes. Biochim Biophys Acta 1138:85Google Scholar
  84. 84.
    Michaud EJ, Bultman SJ, Stubbs LJ, Woychik RP (1993) The embryonic lethality of homozygous lethal yellow mice (Ay/Ay) is associated with the disruption of a novel RNA-binding protein. Genes Dev 7:1203Google Scholar
  85. 85.
    Nakabaysahi K, Saito M, Nagasawa T, Takada M (1985) Antibodies to rheumatoid arthritis nuclear antigen (RANA) in Japanese patients with rheumatoid arthritis. Rheumatol Int 5:61Google Scholar
  86. 86.
    Nepom BS (1993) The role of the major histocompatibility complex in autoimmunity. Clin Immunol Immunopathol 57:550Google Scholar
  87. 87.
    Newkirk MM, Watanabe Duffy KN, Leclerc J, Lambert N, Shiroky JB (1994) Detection of cytomegalovirus, Epstein-Barr virus and herpes virus-6 in patients with rheumatoid arthritis with or without Sjøgren's syndrome. Br J Rheumatol 33:317Google Scholar
  88. 88.
    Ng KC, Perry JD, Brown KA, Holborow EJ (1980) Anti-RANA antibody: a marker for seronegative and seropositive rheumatoid arthritis. Lancet I:447Google Scholar
  89. 89.
    Ngou J, Segondy M, Seigneurin J-M, Graafland H (1990) Antibody responses against polypeptide components of Epstein-Barr virus-induced early diffuse antigen in patients with connective tissue diseases. J Med Virol 32:39Google Scholar
  90. 90.
    Ngou J, Graafland H, Segondy M (1992) Antibodies against polypeptides of purified Epstein-Barr virus in sera from patients with connective tissue diseases. J Autoimmun 5:243Google Scholar
  91. 91.
    Oosterveer MA, Markusse HM, Lennette ET, Zou JZ, Bolhuis RL, Gratama JW (1993) Characterization of Epstein-Barr viral strains in parotid gland saliva and peripheral blood of patients with primary Sjøgren's syndrome and healthy EBV carriers. J Med Virol 41:261Google Scholar
  92. 92.
    Origgi L, Perego R, Hu C, Bertetti E, D'Agostino P, Asero R, Riboldi P (1988) Anti-Epstein-Barr virus antibodies in systemic lupus erythematosus. Boll Ist Sieroter Milan 67:116Google Scholar
  93. 93.
    Paimela L, Gripenberg M, Kurki P, Leirisalo-Repo M (1992) Antikeratin antibodies: diagnostic and prognostic markers for early rheumatoid arthritis. Ann Rheum Dis 51:743Google Scholar
  94. 94.
    Petersen J, Rhodes G, Roudier J, Vaughan JH (1990) Altered immune response to glycine-rich sequences of Epstein-Barr nuclear antigen-I in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum 33:993Google Scholar
  95. 95.
    Pflugfelder SC, Crouse CA, Monroy D, Yen M, Rowe M, Atherton SS (1993) Epstein-Barr virus and the lacrimal gland pathology of Sjøgren's syndrome. Am J Pathol 143:49Google Scholar
  96. 96.
    Phillips PE, Waxman J, Hirshaut Y, Kaplan MH (1976) Virus antibody levels and delayed hypersensitivity in rheumatoid arthritis. Ann Rheum Dis 35:152Google Scholar
  97. 97.
    Ranki A, Kurki P, Riepponen S, Stephansson E (1992) Antibodies to retroviral proteins in autoimmune connective tissue disease. Arthritis Rheum 35:1483Google Scholar
  98. 98.
    Rhodes G, Houghten R, Taulane JP, Carson DA, Vaughan JH (1984) The immune response to EpsteinBarr nuclear antigen: conformational and structural features of antibody to synthetic peptides. Mol Immunol 21:1047Google Scholar
  99. 99.
    Rhodes G, Carson DA, Valbracht J, Houghten R, Vaughan JH (1985) Human immune responses to synthetic peptides from the Epstein-Barr nuclear antigen. J Immunol 134:211Google Scholar
  100. 100.
    Rhodes G, Rumpold H, Kurki P, Patrick KM, Carson DA, Vaughan JH (1987) Autoantibodies in infectious monon-specificity for the glycine-alanine repeating region of the Epstein-Barr virus nuclear antigen. J Exp Med 165:1026Google Scholar
  101. 101.
    Rhodes G, Smith RS, Rubin RE, Vaughan J, Horwitz CA (1990) Identical IgM antibodies recognizing glycine-alanine epitope are induced during acute infection with Epstein-Barr virus and cytomegalovirus. J Clin Lab Anal 4:456Google Scholar
  102. 102.
    Ricchiuti V, Briand JP, Meyer O, Isenberg DA, Pruijn G, Muller S (1994) Epitope mapping with synthetic peptides of 52-kD SSA/Ro protein reveals heterogeneous antibody profiles in human autoimmune sera. Clin Exp Immunol 95:397Google Scholar
  103. 103.
    Rickinson AB, Crawford D, Epstein MA (1977) Inhibition of the in vitro outgrowth of Epstein-Barr virus-transformed lymphocytes by thymus-dependent lymphocytes from infectious mononucleosis patients. Clin Exp Immunol 28:72Google Scholar
  104. 104.
    Rivkin E, Vella MJ, Lahita RG (1994) A heterogeneous immune response to an SmD-like epitope by SLE patients. J Autoimmun 7:119Google Scholar
  105. 105.
    Robinson JE (1982) The biology of circulating B lymphocytes infected with Epstein-Barr virus during infectious mononucleosis. Yale J Biol Med 55:311Google Scholar
  106. 106.
    Rother RP, Thomas PS (1991) La/SSB ribonucleoprotein levels increased in transformed cells. Clin Exp Immunol 83:369Google Scholar
  107. 107.
    Roudier J, Rhodes G, Petersen J, Vaughan JH, Carson DA (1988) The Epstein-Barr virus glycoprotein gp110, a molecular link between HLA DR4, HLA DR1, and rheumatoid arthritis. Scand J Immunol 27:367Google Scholar
  108. 108.
    Roudier J, Petersen J, Rhodes GH, Luka J, Carson DA (1989) Susceptibility to rheumatoid arthritis maps to a T-cell epitope shared by the HLA-Îw4 DR β-1 chain and the Epstein-Barr virus glycoprotein gp110. Proc Natl Acad Sci USA 86:5104Google Scholar
  109. 109.
    Roudier J, Sette A, Lamont A, Albani S, Karras JG, Carson DA (1991) Tolerance to a self peptide from the third hypervariable region of the IEβs chain. Implications for molecular mimicry models of autoimmune disease. Eur J Immunol 21:2063Google Scholar
  110. 110.
    Rowe M, Finke J, Szigeti R, Klein G (1988) Characterization of the serological response in man to the latent membrane protein and the six nuclear antigens encoded by Epstein-Barr virus. J Gen Virol 69:1217Google Scholar
  111. 111.
    Rumpold H, Rhodes GH, Bloch PL, Carson DA, Vaughan JH (1987) The glycine-alanine repeating region is the major epitope of the Epstein-Barr nuclear antigen-1 (EBNA-1). J Immunol 138:593Google Scholar
  112. 112.
    Sabbatini A, Bombardieri S, Migliorini P (1993) Autoantibodies from patients with systemic lupus erythematosus bind a shared sequence of SmD and Epstein-Barr virus-encoded nuclear antigen EBNA I. Eur J Immunol 23:1146Google Scholar
  113. 113.
    Sabbatini A, Dolcher MP, Marchini B, Bombardieri S, Migliorini P (1993) Mapping of epitopes on the SmD molecule: the use of multiple antigen peptides to measure autoantibodies in systemic lupus erythematosus. J Rheumatol 20:1679Google Scholar
  114. 114.
    Saito I, Nishimura S, Kudo I, Fox RI, Moro I (1991) Detection of Epstein-Barr virus and human herpes virus type 6 in saliva from patients with lymphoproliferative diseases by the polymerase chain reaction. Arch Oral Biol 36:779Google Scholar
  115. 115.
    Sakane T, Takada S, Murakawa Y, Kotani H, Honda M, Ueda Y (1982) Analysis of suppressor T cell function in patients with rheumatoid arthritis: defects in production of and responsiveness to concanavalin A-induced suppressor T cells. J Immunol 129:1972Google Scholar
  116. 116.
    Scofield RH, Harley JB (1991) Autoantigenicity of Ro/SSA antigen is related to a nucleocapsid protein of vesicular stomatitis virus. Proc Natl Acad Sci USA 88:3343Google Scholar
  117. 117.
    Sculley TB, Walker PJ, Moss DJ, Pope JH (1984) Identification of multiple Epstein-Barr virus-induced nuclear antigens with sera from patients with rheumatoid arthritis. J Virol 52:88Google Scholar
  118. 118.
    Sculley D, Sculley T, Pope T (1986) Reactions of sera from patients with rheumatoid arthritis, systemic lupus and infectious mononucleosis to EBV-induced polypeptides. J Gen Virol 67:2253Google Scholar
  119. 119.
    Sculley TB, Pope JH, Hazelton RA (1986) Correlation between the presence of antibodies to the Epstein-Barr virus nuclear antigen type 2 and antibodies to the rheumatoid arthritis nuclear antigen in patients with rheumatoid arthritis. Arthritis Rheum 29:964Google Scholar
  120. 120.
    Shore A, Klock R, Lee P, Snow KM, Keystone EC (1989) Impaired late suppression of Epstein-Barr virus (EBV)-induced immunoglobulin synthesis: a common feature of autoimmune disease. J Clin Immunol 9:103Google Scholar
  121. 121.
    Silverman SL, Schumacher HR (1981) Antibodies to Epstein-Barr viral antigens in early rheumatoid arthritis. Arthritis Rheum 24:1465Google Scholar
  122. 122.
    Simon M, Girbal E, Sebbag M, Gomes-Daudrix V, Vincent C, Salama G, Serre G (1993) The cytokeratin filament-aggregating protein filaggrin is the target of the so-called “antikeratin antibodies,” autoantibodies specific for rheumatoid arthritis. J Clin Invest 92:1387Google Scholar
  123. 123.
    Sixbey JW, Vesterinen EH, Nedrud JG, Raab-Traub N, Wallon LA, Pagano JS (1983) Replication of Epstein-Barr virus in human epithelial cells infected in vitro. Nature 306:480Google Scholar
  124. 124.
    Slaughter L, Carson DA, Jensen FC, Holbrook TL, Vaughan JH (1978) In vitro effects of EpsteinBarr virus on peripheral blood mononuclear cells from patients with rheumatoid arthritis and normal subjects. J Exp Med 148:1429Google Scholar
  125. 125.
    Slobbe RL, Pruijn GJM, Damen WGM, van der Kemp JWCM, van Venrooij WJ (1991) Detection and occurrence of the 60- and 52-kD Ro (SS-A) antigens and of autoantibodies against these proteins. Clin Exp Immunol 86:99Google Scholar
  126. 126.
    Slovin SF, Kuberski TT, Carson DA, Catalano MA, Reitz EM, Vaughan JH (1983) Antibodies to Epstein-Barr virus associated antigens in Pima Indians with and without rheumatoid arthritis. Rheumatol Int 3:65Google Scholar
  127. 127.
    St.Clair EW, Buren JA Jr, Ward MM, Keene JD, Pisetsky DS (1990) Temporal correlation of antibody responses to different epitopes of the human La autoantigen. J Clin Invest 85:515Google Scholar
  128. 128.
    Stevens DA, Stevens MB, Newell GR, Levine PH, Waggoner DE (1972) Epstein-Barr virus (Herpes-type virus) antibodies in connective tissue diseases. Arch Intern Med 130:23Google Scholar
  129. 129.
    Stierle HE, Brown KA, Perry JD, Holborow EJ (1981) Abnormal responsiveness of rheumatoid B cells to Epstein-Barr virus infection in vitro. Lancet II:1347Google Scholar
  130. 130.
    Stierle HE, Brown KA, Perry JD, Holborow EJ (1983) Increased responsiveness of rheumatoid B lymphocytes to stimulation by Epstein-Barr virus. Rheumatol Int 3:7Google Scholar
  131. 131.
    Suzuki K, Makino M, Okada Y, Kinoshita J, Yui R, Kanazawa H, Asakura H, Fujiwara M, Mizuochi T, Komuro K (1993) Exocrinopathy resembling Sjøgren's syndrome induced by a murine retrovirus. Lab Invest 69:430Google Scholar
  132. 132.
    Syrjanen S, Karja V, Chang FJ, Johansson B, Syrjanen K (1990) Epstein-Barr virus involvement in salivary gland lesions associated with Sjøgren's syndrome. J Oto-Rhino-laryngol 52:254Google Scholar
  133. 133.
    Takagi T, Jasin HE (1992) Interactions of synovial fluid immunoglobulins with chondrocytes. Arthritis Rheum 35:1502Google Scholar
  134. 134.
    Talal N, Dauphinee MJ, Dang H, Alexander SS, Hart DJ, Garry RF (1990) Detection of serum antibodies to retroviral proteins in patients with primary Sjøgren's syndrome (autoimmune exocrinopathy). Arthritis Rheum 33:774Google Scholar
  135. 135.
    Talal N, Flescher E, Dang H (1992) Are endogenous retroviruses involved in human autoimmune disease? J Autoimmun 5:61Google Scholar
  136. 136.
    Tateishi M, Saito I, Yamamoto K, Miyasaka N (1993) Spontaneous production of Epstein-Barr virus by B lymphoblastoid cell lines obtained from patients with Sjøgren's syndrome. Arthritis Rheum 36:827Google Scholar
  137. 137.
    Tosato G, Steinberg AD, Blaese RM (1981) Defective EBV-specific suppressor T-cell function in rheumatoid arthritis. N Engl J Med 305:1238Google Scholar
  138. 138.
    Tosato G, Steinberg AD, Yarchoan R, Heliman CA, Pike SE, DeSeau V, Blaese RM (1984) Abnormally elevated frequency of Epstein-Barr virus-infected B cells in the blood of patients with rheumatoid arthritis. J Clin Invest 73:1789Google Scholar
  139. 139.
    Tsokos GC, Magrath IT, Balow JE (1983) Epstein-Barr virus induces normal B cell responses but defective suppressor T cell responses in patients with systemic lupus erythematosus. J Immunol 131:1797Google Scholar
  140. 140.
    Tsoukas CD, Carson DA, Fong S, Slovin SF, Fox RI, Vaughan JH (1982) Lysis of autologous EpsteinBarr virus infected B cells by cytotoxic T lymphocytes of rheumatoid arthritis patients. Clin Immunol Immunopathol 24:8Google Scholar
  141. 141.
    Vaughan JH, Nguyen M-D, Valbracht JR, Patrick K, Rhodes GH (1995) Epstein Barr virus-induced autoimmune responses. II. IgG autoantibodies to mimicking and non-mimicking epitopes. Presence in autoimmune disease. J Clin Invest 95:1316Google Scholar
  142. 142.
    Vaughan JH (1985) Epstein Barr virus and rheumatoid arthritis with a new look at RANA. In: Clinical laboratory molecular analyses. Nakamura RM, O'Sullivan MB (eds) Grune and Stratum, pp 17–28Google Scholar
  143. 143.
    Vaughan JH, Valbracht JR, Nguyen M-D, Handley HH, Smith RS, Patrick K, Rhodes GH (1995) Epstein-Barr virus-induced autoimmune responses I. IgM autoantibodies to proteins mimicking and not mimicking ENBA-1. J Clin Invest 95:1306Google Scholar
  144. 144.
    Venables P (1988) Epstein-Barr virus infection and autoimmunity in rheumatoid arthritis. Ann Rheum Dis 47:265Google Scholar
  145. 145.
    Venables PJW, Roffe LM, Erhardt CC, Maini RN, Edwards JMB, Porter AD (1981) Titers of antibodies to RANA in rheumatoid arthritis and normal sera. Relationship to Epstein-Barr virus infection. Arthritis Rheum 24:1459Google Scholar
  146. 146.
    Venables PJW, Ross MGR, Melsom CRD, Griffiths PD, Maini RN (1985) A seroepidemiological study of cytomegalovirus and Epstein-Barr virus in rheumatoid arthritis and sicca syndrome. Ann Rheum Dis 44:742Google Scholar
  147. 147.
    Venables PJW, Pawlowski T, Mumford PA, Brown C, Crawford DH, Maini RN (1988) Reaction of antibodies to rheumatoid arthritis nuclear antigen with a synthetic peptide corresponding to part of Epstein-Barr nuclear antigen 1. Ann Rheum Dis 47:270Google Scholar
  148. 148.
    Vivino FB, Maul GG (1990) Histologic and electron microscopic characterization of the antiperinuclear factor antigen. Arthritis Rheum 33:960Google Scholar
  149. 149.
    Westgeest AAA, van Loon AM, van der Logt JTM, van de Putte LBA, Boerbooms AMT (1989) Antiperinuclear factor, a rheumatoid arthritis specific autoantibody: its relation to Epstein-Barr virus. J Rheumatol 16:626Google Scholar
  150. 150.
    Weyand CM, Goronzy JJ (1994) Functional domains on HLA-DR molecules: implications for the linkage of HLA-DR genes to different autoimmune diseases. Clin Immunol Immunopathol 70:91Google Scholar
  151. 151.
    Whittingham S, McNeilage LJ, MacKay IR (1987) Epstein-Barr virus as an etiological agent in primary Sjøgren's syndrome. Med Hypotheses 22:373Google Scholar
  152. 152.
    Wiersbitzky S, Ratzmann GW, Bruns R, Wiersbitzky H (1993) Reactivation in children of juvenile chronic arthritis and chronic iridocyclitis associated with human herpesvirus-6 infection. Pädiatr Grenzgeb 31:203Google Scholar
  153. 153.
    Winrow VR, Norton J, Holborow EJ, Stierle HE, Young A, Sachs JA (1988) T cell cytotoxicity to Epstein-Barr virus infected B cells: comparison of patients with rheumatoid arthritis and their HLA identical siblings. Ann Rheum Dis 47:280Google Scholar
  154. 154.
    Yamaoka K, Miyasaka N, Yamamoto K (1988) Possible involvement of Epstein-Barr virus in polyclonal B cell activation in Sjøgren's syndrome. Arthritis Rheum 31:1014Google Scholar
  155. 155.
    Yang JL, He ZG, Zhang NZ (1991) Sjøgren's syndrome and the infection of Epstein-Barr virus: a preliminary study. Chung Hua Nei Ko Tsa Chih 30:151Google Scholar
  156. 156.
    Yao QY, Rickinson AB, Epstein MA (1985) A re-examination of the Epstein-Barr virus carrier state in healthy seropositive individuals. Int J Cancer 35:35Google Scholar
  157. 157.
    Yao QY, Rickinson AB, Gaston JSH, Epstein MA (1986) Disturbance of the Epstein-Barr virus-host balance in rheumatoid arthritis patients: a quantitative study. Clin Exp Immunol 64:302Google Scholar
  158. 158.
    Yokochi T, Yanagawa A, Kimura Y, Mizushima Y (1989) High titer antibody to the Epstein-Barr virus membrane antigen in sera from patients with rheumatoid arthritis and systemic lupus erythematosus. J Rheumatol 16:1029Google Scholar
  159. 159.
    Youinou P, Buisson M, Berthelot JM, Jamin C, Le Goff P, Genoulaz O, Lamour A, Lydyard PM, Seigneurin JM (1992) Anti-Epstein-Barr virus-nuclear antigen-1, -2A and -2B antibodies in rheumatoid arthritis patients and their relatives. Autoimmunity 13:225Google Scholar
  160. 160.
    Youinou P, Lamour A, Dueymes M, Le Goff P (1993) Infectious origin of rheumatoid arthritis. Rev Rhum Ed Fr 60:30SGoogle Scholar
  161. 161.
    Young BJJ, Mallya RK, Leslie RDG, Clark CJM, Hamblin TJ (1979) Anti-keratin antibodies in rheumatid arthritis. BMJ 11:97Google Scholar
  162. 162.
    Zhang L, Nikkari S, Skurnik M, Ziegler T, Luukkainen R, Mottonen T, Toivanen P (1993) Detection of herpesviruses by polymerase chain reaction in lymphocytes from patients with rheumatoid arthritis. Arthritis Rheum 36:1080Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • John H. Vaughan
    • 1
  1. 1.Department of MedicineUniversity of California, San DiegoLa JollaUSA

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