Tzioufas_EU_Cardiology_book_temp 23/12/2009 16:35 Page 55
Epitopes of Autoantigens and their Role in Initiation and Propagation of Systemic Autoimmunity
Serine/Threonine Phosphorylation specific autoantigen epitopes. These arrays are able to perform
Phosphorylation is the most common and ubiquitous form of large-scale multiplex characterisations of autoantibody responses
enzyme-mediated PTM. It has been implicated in the recognition of against structurally diverse autoantigens.
44
Chemical modifications
nuclear autoantigens by the immune system in SLE. of epitopes of autoantigens can provide better antigenic substrates
mimicking naturally occurring PTMs. The lesson of citrullinated
Spliceosomal Antigens peptides taught us that recombinant proteins are not always the
Phosphorylated components of U1 snRNP particles are specifically preferred substrate for autoantibody detection and that synthetic
recognised by autoantibodies of SLE patients and CD4
+
T cells from peptides can be successfully used in diagnostic assays if the exact
lupus-prone mice (MRL/lpr mice). Monneaux et al. demonstrated the structure of the autoantibody target is known.
45
Complementary
importance for antigenicity of phosphorylation on a specific serine peptides can efficiently neutralise anti-idiotypic antibodies,
residue of U1-70K in MRL/lpr mice.
39
Previously, these investigators enhancing the interaction of the idiotypic autoantibodies with their
had identified an epitope at residues 131–150 of the U1-70K protein target epitope.
that was recognised by antibodies as well as by CD4
+
T cells in two
strains of lupus mice.
40
They subsequently synthesised two peptides, The analysis of B-cell epitopes of autoantigens provides a better
one with a phosphate group on serine residue 137 and the other understanding of the origin and evolution of autoimmune response.
with a phosphate group on serine residue 140. It was demonstrated In this regard, epitopes from foreign antigens, mimicking
that the peptide with Ser140P but not the peptide with Ser137P was complementary epitopes or post-translationally modified peptides,
recognised by both antibodies and CD4
+
T cells. could be the initiating agents of autoimmune disease. In addition,
the spreading of autoimmune response from the initial epitope to
La Autoantigen others can be utilised for monitoring the evolution of autoimmune
La protein can be phosphorylated at position 366. La phosphorylated disease. Finally, the analysis of B-cell epitopes of autoantigens can
at serine 366 is nucleoplasmic and is associated with nascent RNA provide potential therapeutic regimens, using epitopes with high
polymerase III transcripts, while non-phosphorylated La is specificity as vaccines, as tolerogens or as modifiers of the
cytoplasmic and is associated with a subset of mRNAs that contain autoimmune response via the idiotypic–anti-idiotypic network.
5’-terminal oligopyrimidine (5’TOP).
41
Thus, La exists in distinct states
that differ in subcellular localisation and is associated RNAs, which Conclusion
can be discriminated by serine 366 phosphorylation. This specific Autoantibodies to intracellular autoantigens remain a significant
phosphorylation resides within the major B-cell epitope that was laboratory tool to evaluate patients with rheumatic autoimmune
previously identified in our laboratory to be located in the diseases. The identification of their B-cell epitopes provides new ways
349–368aa region of La/SSB.
42
Our studies indicate that the of understanding pathogenetic aspects in systemic autoimmunity,
antigenicity of the epitope is significantly enhanced upon including epitope spreading, idiotypic-anti-idiotypic antibody
phosphorylation of serine 366.
43
interaction and neoepitope formation due to PTMs of autoantigens.
Finally, some B-cell epitopes appear to be promising diagnostic
Future Directions markers for the evaluation of systemic autoimmune disorders. n
The extensive study of B-cell epitopes of intracellular autoantigens
provides useful insights into the diagnosis, classification and
Athanasios Tzioufas is an Associate Professor of
prognosis of autoimmune diseases. The successful development of
Rheumatology/Immunology in the School of Medicine
diagnostic assays is hindered by a number of factors concerning at the University of Athens. He is a member of the
epitope recognition in autoimmune disorders, such as cross-
Editorial Board of Clinical Rheumatology, Clinical and
Experimental Rheumatology, the European Journal of
reactivity, epitope spreading, epitope masking and epitope
Clinical Investigation, Current Reports in Rheumatology
modification. Issues regarding the simultaneous analysis of a large and Neuroimmunomodulation. Dr Tzioufas has
number of autoantibody specificities in a single test also have to be
authored over 110 peer-reviewed publications and 22
book chapters. He received his MD from the Medical
considered. The analysis of B-cell epitopes of autoantigens provides
School at the University of Ioannina, followed by a PhD
clues to overcome these problems. Autoantibody screening test in autoimmunity.
methodologies can be improved using large-scale arrays with
1. Hochberg MC, Arthritis Rheum, 1997;40(9):1725. 16. Routsias JG, et al., J Autoimmun, 2003;21(1):17–26. 32. Vossenaar ER, et al., Arthritis Rheum, 2003;48(9):2489–2500.
2. Vitali C, et al., Ann Rheum Dis, 2002;61(6):554–8. 17. Stea EA, et al., Arthritis Rheum, 2006;54(7):2228–34. 33. Schellekens GA, et al., J Clin Invest, 1998;101(1):273–81.
3. ter Borg EJ, et al., Arthritis Rheum, 1990;33(5):634–43. 18. Horsfall AC, et al., J Autoimmun, 1991;4(1):165–76. 34. GA H Visser, et al., Arthritis Rheum, 2000;43(1):155–63.
4. E Bonfa, et al., N Engl J Med, 1987;317(5):265–71. 19. Arbuckle MR, et al., N Engl J Med, 2003;349(16):1526–33. 35. Kroot EJ, et al., Arthritis Rheum, 2000;43(8):1831–5.
5. Moutsopoulos NM, et al., Mol Med, 2000;6(3):141–51. 20. McClain MT, et al., Nat Med, 2005;11(1):85–9. 36. Bizzaro N, et al., Clin Chem, 2001;47(6):1089–93.
6. Brahms H, et al., J Biol Chem, 2000; 275(22):17122–9. 21. Routsias JG, et al., Eur J Clin Invest, 1996;26(6):514–21. 37. Meyer O, et al., Ann Rheum Dis, 2003;62(2):120–26.
7. Aris JP, Blobel G, Proc Natl Acad Sci U S A, 1991;88(3): 22. Lehmann PV, et al., Nature, 1992;358(6382):155–7. 38. Vasishta A, Am Clin Lab, 2002;21(7):34–6.
931–5. 23. McClain MT, et al., Scand J Immunol, 2002;56(4):399–407. 39. Monneaux F, et al., Eur J Immunol, 2003;33(2):287–96.
8. Lapeyre B, et al., J Biol Chem, 1986;261(20):9167–73. 24. Monneaux F, Muller S, Scand J Immunol, 2001;54(1–2):45–54. 40. Monneaux F, et al., Eur J Immunol, 2000;30(8):2191–2200.
9. Jerne NK, Ann Immunol, 1974;125C(1–2):373–89. 25. Monneaux F, Muller S, Arthritis Rheum, 2002;46(6):1430–38. 41. Intine RV, et al., Mol Cell, 2003;12(5):1301–7.
10. Jerne NK, et al., Embo J, 1982;1(2):243–7. 26. Monneaux F, et al., Int Immunol, 2001;13(9):1155–63. 42. Tzioufas AG, et al., Clin Exp Immunol, 1997;108(2):191–8.
11. Blalock JE, Trends Biotechnol, 1990;8(6):140–44. 27. Poole BD, et al., Arthritis Rheum, 2009;60(3):848–59. 43. Terzoglou AG, et al., Clin Exp Immunol, 2006;144(3):432–9.
12. NM Weathington, JE Blalock, Expert Rev Vaccines, 28. James JA, Harley JB, Clin Exp Rheumatol, 1995;13(3):299–305. 44. Robinson WH, et al., Nat Med, 2002;8(3):295–301.
2003;2(1):61–73. 29. Brahms H, et al., RNA, 2001;7(11):1531–42. 45. Routsias JG, et al., Clin Chim Acta, 2004;340(1–2):1–25.
13. Pendergraft WF, et al., J Mol Med, 2005; 83(1):12–25. 30. Mahler M, et al., Arthritis Res Ther, 2005;7(1):R19–29.
14. Pendergraft WF, et al., Nat Med, 2004;10(1):72–9. 31. Miranda MB, et al., Biochem Biophys Res Commun,
15. Routsias JG, et al., Mol Med, 2002;8(6):293–305. 2004;323(2):382–7.
EUROPEAN MUSCULOSKELETAL REVIEW 55
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108 |
Page 109 |
Page 110 |
Page 111 |
Page 112 |
Page 113 |
Page 114 |
Page 115 |
Page 116