Journal of Clinical Immunology

, Volume 26, Issue 5, pp 438–446 | Cite as

Autoantibodies to Mitotic Apparatus: Association with Other Autoantibodies and Their Clinical Significance

  • BRANKA BONACI-NIKOLIC
  • SLADJANA ANDREJEVIC
  • MIRJANA BUKILICA
  • IVANA UROSEVIC
  • MILOS NIKOLIC
Article

The most important mitotic apparatus (MA) antigens are centrosome (CE), nuclear mitotic apparatus (NuMA-1, NuMA-2), midbody, and centromere F (CENP-F). We studied associations of anti-MA antibodies with other autoantibodies and their clinical significance. A total of 6270 patients were studied for the presence of anti-MA antibodies on HEp-2 cells. Sera positive for anti-MA were tested for anti-extractable nuclear antigens (ENA) antibodies. Anti-MA antibodies were detected in 56 (45 females and 11 males) of 6270 sera (0.9%). Of these 56, NuMA-1 was found in 23, NuMA-2 in 7, CE in 20, CENP-F in 5, and CENP-F/centrosome in 1 case. Anti-NuMA-1 were associated with anti-ENA antibodies (p < 0.001). Diagnoses were established in 43/56 patients: 22 connective tissue diseases, 7 infections, 6 autoimmune hepatitis, 3 vasculitis, 3 primary antiphospholipid syndrome, 1 malignancy, and 1 fever of unknown origin. The differential diagnosis of anti-NuMA-1-positive patients must include Sjögren’s syndrome, while patients with anti-CE antibodies must be observed for HCV infection.

KEY WORDS:

Mitotic apparatus NuMA ENA HCV Sjögren’s syndrome 

REFERENCES

  1. 1.
    Fritzler MJ, Rattner JB: Autoantibodies to the mitotic apparatus: Biological breakthroughs, clinical application, etiological complexity. In Autoantigens and Autoantibodies: Diagnostic Tools and Clues to Understanding Autoimmunity, K Conrad, RL Humbel, et al. (eds). Berlin, Pabst Science, 2000, pp 58–86Google Scholar
  2. 2.
    Ou Y, Rattner JB: A subset of centrosomal proteins are arranged in a tubular conformation that is reproduced during centrosome duplication. Cell Motil Cytoskeleton 47:13–24, 2000PubMedCrossRefGoogle Scholar
  3. 3.
    Kisurina-Evgenieva O, Mack G, Du Q, Macara I, Khodjakov A, Compton DA: Multiple mechanisms regulate NuMA dynamics at spindle poles. J Cell Sci 117:6391–6400, 2004PubMedCrossRefGoogle Scholar
  4. 4.
    Bradwell AR, Hughes RG, Harden EL: Atlas of HE-p 2 Patterns. Birmingham, Drapkins, 2003Google Scholar
  5. 5.
    Casiano CA, Martin SJ, Green DR, Tan EM: Selective cleavage of nuclear autoantigens during CD95 (Fas/APO-1)-mediated T cell apoptosis. J Exp Med 184:765–770, 1996PubMedCrossRefGoogle Scholar
  6. 6.
    Ramirez-Sandoval R, Sanchez-Rodriguez SH, Herrera-van Oostdam D, Avalos-Diaz E, Herrera-Esparza R: Antinuclear antibodies recognize cellular autoantigens driven by apoptosis. Joint Bone Spine 70:187–194, 2003PubMedCrossRefGoogle Scholar
  7. 7.
    Casciola-Rosen LA, Anhalt G, Rosen A: Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface blebs on apoptotic keratinocytes. J Exp Med 179:1317–1330, 1994PubMedCrossRefGoogle Scholar
  8. 8.
    Andrade LE, Chan EK, Peebles CL, Tan EM: Two major autoantigen–antibody systems of the mitotic spindle apparatus. Arthritis Rheum 39:1643–1653, 1996PubMedCrossRefGoogle Scholar
  9. 9.
    Huidbuchel E, Blaschek M, Seigneurin JM, Lamour A, Berthelot JM, Youinou P: Anti-organelle and anti-cytoskeletal autoantibodies in the serum of Epstein-Barr virus-infected patients. Ann Med Intern (Paris) 142:343–346, 1991Google Scholar
  10. 10.
    Abu-Shakra M, Buskila D, Ehrenfeld M, Conrad K, Shoenfeld Y: Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies. Ann Rheum Dis 60:433–441, 2001PubMedCrossRefGoogle Scholar
  11. 11.
    Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725, 1997PubMedCrossRefGoogle Scholar
  12. 12.
    Sharp GC: Diagnostic criteria for classification of MCTD. In Mixed Connective Tissue Diseases and Antinuclear Antibodies, R Kasukawa, GC Sharp (eds). Amsterdam, Elsevier, 1987, pp 23–32Google Scholar
  13. 13.
    Anonymous: Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association diagnostic and therapeutic criteria committee. Arthritis Rheum 23:581–590, 1980CrossRefGoogle Scholar
  14. 14.
    Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, Talal N, Weisman MH: European Study Group on Classification Criteria for Sjogren’s Syndrome. Classification criteria for Sjogren’s syndrome: A revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554–558, 2002PubMedCrossRefGoogle Scholar
  15. 15.
    Bohan A, Peter JB: Polymyositis and dermatomyositis. N Engl J Med 292:344–347, 1975PubMedCrossRefGoogle Scholar
  16. 16.
    Mosca M, Neri R, Stringini F, Carmignani A, Totti D, Tavoni A, Bombardieri S: Pregnancy outcome in patients with undifferentiated connective tissue disease: A preliminary study on 25 pregnancies. Lupus 11:304–307, 2002PubMedCrossRefGoogle Scholar
  17. 17.
    Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, Brey R, Derksen R, Harris EN, Hughes GR, Triplett DA, Khamashta MA: International consensus statement on preliminary classification for definite antiphospholipid syndrome. Arthritis Rheum 42:1309–1311, 1999PubMedCrossRefGoogle Scholar
  18. 18.
    Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al.: International autoimmune hepatitis group report: Review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 31:929–938, 1999PubMedCrossRefGoogle Scholar
  19. 19.
    Jennette JC, Falk RJ: Small-vessels vasculitis. N Engl J Med 20:1512–1523, 1997CrossRefGoogle Scholar
  20. 20.
    Radice A, Vecchi M, Bianchi MB, Sinico RA: Contribution of immunoflorescence to the identification and characterization of anti-neutrophil cytoplasmic autoantibodies. The role of different fixatives. Clin Exp Rheum 18:707–1712, 2000Google Scholar
  21. 21.
    Auer-Grumbach P, Achleitner B: Epidemiology and clinical associations of NuMA (Nuclear Mitotic Apparatus Protein) autoantibodies. J Rheumatol 21:1779–1781, 1994PubMedGoogle Scholar
  22. 22.
    Fritzler MJ, Pauls JD, Kinsella TD, Bowen TJ: Antinuclear, anticytoplasmic and anti Sjogren syndrome antigen A (SS-A/Ro) antibodies in female blood donors. Clin Immunol Immunopathol 36:120–128, 1985PubMedCrossRefGoogle Scholar
  23. 23.
    Taimen P, Viljamaa M, Kallajoki M: Preferential expression of NuMA in the nuclei of proliferating cells. Exp Cell Res 256:140–149, 2000PubMedCrossRefGoogle Scholar
  24. 24.
    Kammerer S, Roth RB, Hoyal CR, Reneland R, Marnellos G, Kiechle M, et al.: Association of the NuMA region on chromosome 11q13 with breast cancer susceptibility. Proc Natl Acad Sci USA 102:2004–2009, 2005PubMedCrossRefGoogle Scholar
  25. 25.
    Yang CH, Lambie EJ, Snyder M: NuMA: An unusually long coiled-coil related protein in the mammalian nucleus. J Cell Biol 116:1303–1317, 1992PubMedCrossRefGoogle Scholar
  26. 26.
    Whitehead CM, Winkfein RJ, Fritzler MJ, Rattner JB: The spindle kinesin-like protein HsEg5 is an autoantigen in systemic lupus erythematosus. Arthritis Rheum 39:1635–1642, 1996PubMedCrossRefGoogle Scholar
  27. 27.
    Rattner JB, Martin L, Waisman DM, Johnstone SA, Fritzler MJ: Autoantibodies to the centrosome (centrosome) react with determinants present in the glycolytic enzyme enolase. J Immunol 146:2341–2344, 1991PubMedGoogle Scholar
  28. 28.
    Liao H, Winkfein RJ, Mack G, Rattner JB, Yen TJ: CENP-F is a protein of the nuclear matrix that assembles onto kinetochores at late G2 and is rapidly degraded after mitosis. J Cell Biol 130:507–518, 1995PubMedCrossRefGoogle Scholar
  29. 29.
    Casiano CA, Landberg G, Ochs RL, Tan EM: Autoantibodies to a novel cell cycle-regulated protein that accumulates in the nuclear matrix during S phase and is localized in the kinetochores and spindle midzone during mitosis. J Cell Sci 106:1045–1056, 1993PubMedGoogle Scholar
  30. 30.
    Hansen BU, Eriksson S, Lindgren S: High prevalence of autoimmune liver disease in patients with multiple nuclear dot, anti-centromere, and mitotic spindle antibodies. Scand J Gastroenterol 26:707–713, 1991PubMedCrossRefGoogle Scholar
  31. 31.
    Grypiotis P, Ruffatti A, Tonello M, Winzler C, Radu C, Zampieri S, et al.: Clinical significance of fluoroscopic patterns specific for the mitotic spindle in patients with rheumatic diseases. Reumatismo 54:232–237, 2002PubMedGoogle Scholar
  32. 32.
    McCarty GA, Valencia DW, Fritzler MJ: Antibody to the mitotic spindle apparatus: immunologic characteristics and cytologic studies. J Rheumatol 11:213–218, 1984PubMedGoogle Scholar
  33. 33.
    Hassfeld W, Chan EK, Mathison DA, Portman D, Dreyfuss G, Steiner G, Tan EM: Molecular definition of heterogeneous nuclear ribonucleoprotein R (hnRNP R) using autoimmune antibody: Immunological relationship with hnRNP P. Nucleic Acids Res 26:439–445, 1998PubMedCrossRefGoogle Scholar
  34. 34.
    Zeng C, He D, Berget SM, Brinkley BR: Nuclear-mitotic apparatus protein: A structural protein interface between the mucleoskeleton and RNA splicing. Proc Natl Acad Sci USA 91:1505–1509, 1994PubMedCrossRefGoogle Scholar
  35. 35.
    Hsu HL, Yeh NH: Dynamic changes of NuMA during the cell cycle and possible appearance of a truncated form of NuMA during apoptosis. J Cell Sci 109:277–288, 1996PubMedGoogle Scholar
  36. 36.
    Price CM, McCarty GA, Pettijohn DE: NuMA protein is a human autoantigen. Arthritis Rheum 27:774–779, 1984PubMedCrossRefGoogle Scholar
  37. 37.
    Sato S, Fujimoto M, Ihn H, Takehara K: Antibodies to centromere and centrosome in scleroderma spectrum disorders. Dermatology 89:23–26, 1994CrossRefGoogle Scholar
  38. 38.
    Fritzler MJ, Manns MP: Anti-mitochondrial antibodies. Clin Appl Immunol Rev 3:87–113, 2002CrossRefGoogle Scholar
  39. 39.
    Ramos-Casals M, Jara LJ, Medina F, Rosas J, Calvo-Alen, Mana J, et al.: Systemic autoimmune diseases co-existing with chronic hepatitis C virus infection (the Hispamec Registry): Patterns of clinical and immunological expression in 180 cases. J Intern Med 57:549–557, 2005CrossRefGoogle Scholar
  40. 40.
    Gentric A, Blaschek M, Julien C, Jouquan J, Pennec Y, Berthelot JM, et al.: Nonorgan-specific autoantibodies in individuals infected with type 1 human immunodeficiency virus. Clin Immunol Immunopathol 59:487–494, 1991PubMedCrossRefGoogle Scholar
  41. 41.
    Bencimon C, Salles G, Moreira A, Guyomard S, Coiffier B, Bienvenu J, Fabien N: Prevalence of anticentromere F protein autoantibodies in 347 patients with non-Hodgkin’s lymphoma. Ann NY Acad Sci 1050:319–326, 2005PubMedCrossRefGoogle Scholar
  42. 42.
    Zhang JY, Zhu W, Imai H, Kiyosawa K, Chan EK, Tan EM: De-novo humoral immune responses to cancer-associated autoantigens during transition from chronic liver disease to hepatocellular carcinoma. Clin Exp Immunol 125:3–9, 2001PubMedCrossRefGoogle Scholar
  43. 43.
    Rattner JB, Rees J, Whitehead CM, Casiano CA, Tan EM, Humbel RL, et al.: High frequency of neoplasia in patients with autoantibodies to centromere protein CENP-F. Clin Invest Med 20:308–319, 1997PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • BRANKA BONACI-NIKOLIC
    • 1
  • SLADJANA ANDREJEVIC
    • 1
  • MIRJANA BUKILICA
    • 2
  • IVANA UROSEVIC
    • 3
  • MILOS NIKOLIC
    • 4
  1. 1.Institute of Allergy and Clinical ImmunologyClinical Center of SerbiaBelgradeSerbia
  2. 2.Institute of RheumatologyBelgradeSerbia
  3. 3.Institute of Cardiovascular DiseasesClinical Center of SerbiaBelgradeSerbia
  4. 4.Institute of DermatologyClinical Center of SerbiaBelgradeSerbia

Personalised recommendations