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Re-establishing immunological self-tolerance in autoimmune disease

An Erratum to this article was published on 05 April 2012

This article has been updated

Recent progress has revealed the molecular basis of how self-reactive T cells are normally generated in the immune system and differentiate into autoimmune effector T cells and how they are controlled by central and peripheral mechanisms of self-tolerance. There is also evidence that target tissues and cells in autoimmune disease have different sensitivities to immune mediators. Here we describe how these basic findings can be clinically translated to re-establish self-tolerance in individuals with autoimmune disease.

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Figure 1: Potential points for therapeutic intervention in the development and progression of autoimmune disease.

Change history

  • 05 April 2012

     In the version of this article initially published, the affiliation of one author (R.M.R.) was incorrectly listed. The correct affiliation is Lerner Research Institute and Mellen Center for Multiple Sclerosis Treatment and Research (Neurological Institute). The error has been corrected in the HTML and PDF versions of the article.

References

  1. 1

    Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V.K. Annu. Rev. Immunol. 27, 485–517 (2009).

    CAS  Article  Google Scholar 

  2. 2

    Sakaguchi, S. Nat. Immunol. 6, 345–352 (2005).

    CAS  Article  Google Scholar 

  3. 3

    Mathis, D. & Benoist, C. Annu. Rev. Immunol. 27, 287–312 (2009).

    CAS  Article  Google Scholar 

  4. 4

    The Wellcome Trust Case Control Consortium. Nature 447, 661–678 (2007).

  5. 5

    Bottini, N., Vang, T., Cucca, F. & Mustelin, T. Semin. Immunol. 18, 207–213 (2006).

    CAS  Article  Google Scholar 

  6. 6

    von Boehmer, H. et al. Immunol. Rev. 191, 62–78 (2003).

    CAS  Article  Google Scholar 

  7. 7

    Mueller, D.L. Nat. Immunol. 11, 21–27 (2010).

    CAS  Article  Google Scholar 

  8. 8

    Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. J. Immunol. 155, 1151–1164 (1995).

    CAS  Google Scholar 

  9. 9

    Danke, N.A., Koelle, D.M., Yee, C., Beheray, S. & Kwok, W.W. J. Immunol. 172, 5967–5972 (2004).

    CAS  Article  Google Scholar 

  10. 10

    Danke, N.A., Yang, J., Greenbaum, C. & Kwok, W.W. J. Autoimmun. 25, 303–311 (2005).

    CAS  Article  Google Scholar 

  11. 11

    Wing, K. & Sakaguchi, S. Nat. Immunol. 11, 7–13 (2010).

    CAS  Article  Google Scholar 

  12. 12

    Fife, B.T. & Bluestone, J.A. Immunol. Rev. 224, 166–182 (2008).

    CAS  Article  Google Scholar 

  13. 13

    Starr, T.K., Jameson, S.C. & Hogquist, K.A. Annu. Rev. Immunol. 21, 139–176 (2003).

    CAS  Article  Google Scholar 

  14. 14

    Werlen, G., Hausmann, B., Naeher, D. & Palmer, E. Science 299, 1859–1863 (2003).

    CAS  Article  Google Scholar 

  15. 15

    Kyewski, B. & Klein, L. Annu. Rev. Immunol. 24, 571–606 (2006).

    CAS  Article  Google Scholar 

  16. 16

    Herman, A., Kappler, J.W., Marrack, P. & Pullen, A.M. Annu. Rev. Immunol. 9, 745–772 (1991).

    CAS  Article  Google Scholar 

  17. 17

    Jordan, M.S. et al. Nat. Immunol. 2, 301–306 (2001).

    CAS  Article  Google Scholar 

  18. 18

    Liston, A. & Rudensky, A.Y. Curr. Opin. Immunol. 19, 176–185 (2007).

    CAS  Article  Google Scholar 

  19. 19

    Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Cell 133, 775–787 (2008).

    CAS  Article  Google Scholar 

  20. 20

    Kekäläinen, E. et al. J. Immunol. 178, 1208–1215 (2007).

    Article  Google Scholar 

  21. 21

    Laakso, S.M. et al. J. Autoimmun. 35, 351–357 (2010).

    CAS  Article  Google Scholar 

  22. 22

    Anderson, M.S. et al. Immunity 23, 227–239 (2005).

    CAS  Article  Google Scholar 

  23. 23

    Liston, A., Lesage, S., Wilson, J., Peltonen, L. & Goodnow, C.C. Nat. Immunol. 4, 350–354 (2003).

    CAS  Article  Google Scholar 

  24. 24

    Daniel, C., Weigmann, B., Bronson, R. & von Boehmer, H. J. Exp. Med. 208, 1501–1510 (2011).

    CAS  Article  Google Scholar 

  25. 25

    Tanaka, S. et al. J. Immunol. 185, 2295–2305 (2010).

    CAS  Article  Google Scholar 

  26. 26

    Powrie, F., Leach, M.W., Mauze, S., Caddle, L.B. & Coffman, R.L. Int. Immunol. 5, 1461–1471 (1993).

    CAS  Article  Google Scholar 

  27. 27

    Takahashi, T. et al. Int. Immunol. 10, 1969–1980 (1998).

    CAS  Article  Google Scholar 

  28. 28

    Thornton, A.M. & Shevach, E.M. J. Exp. Med. 188, 287–296 (1998).

    CAS  Article  Google Scholar 

  29. 29

    Vignali, D.A., Collison, L.W. & Workman, C.J. Nat. Rev. Immunol. 8, 523–532 (2008).

    CAS  Article  Google Scholar 

  30. 30

    Shevach, E.M. Immunity 30, 636–645 (2009).

    CAS  Article  Google Scholar 

  31. 31

    Yamaguchi, T., Wing, J.B. & Sakaguchi, S. Semin. Immunol. 23, 424–430 (2011).

    CAS  Article  Google Scholar 

  32. 32

    Wing, K. et al. Science 322, 271–275 (2008).

    CAS  Article  Google Scholar 

  33. 33

    Wing, K., Yamaguchi, T. & Sakaguchi, S. Trends Immunol. 32, 428–433 (2011).

    CAS  Article  Google Scholar 

  34. 34

    Uhlig, H.H. et al. J. Immunol. 177, 5852–5860 (2006).

    CAS  Article  Google Scholar 

  35. 35

    Asseman, C., Mauze, S., Leach, M.W., Coffman, R.L. & Powrie, F. J. Exp. Med. 190, 995–1004 (1999).

    CAS  Article  Google Scholar 

  36. 36

    Strober, W., Fuss, I.J. & Blumberg, R.S. Annu. Rev. Immunol. 20, 495–549 (2002).

    CAS  Article  Google Scholar 

  37. 37

    Suri-Payer, E. & Cantor, H. J. Autoimmun. 16, 115–123 (2001).

    CAS  Article  Google Scholar 

  38. 38

    Barnes, M.J. & Powrie, F. Immunity 31, 401–411 (2009).

    CAS  Article  Google Scholar 

  39. 39

    Glocker, E.O. et al. N. Engl. J. Med. 361, 2033–2045 (2009).

    CAS  Article  Google Scholar 

  40. 40

    Koch, M.A. et al. Nat. Immunol. 10, 595–602 (2009).

    CAS  Article  Google Scholar 

  41. 41

    Zheng, Y. et al. Nature 458, 351–356 (2009).

    CAS  Article  Google Scholar 

  42. 42

    Chaudhry, A. et al. Science 326, 986–991 (2009).

    CAS  Article  Google Scholar 

  43. 43

    Campbell, D.J. & Koch, M.A. Nat. Rev. Immunol. 11, 119–130 (2011).

    CAS  Article  Google Scholar 

  44. 44

    Tang, Q. & Bluestone, J.A. Immunol. Rev. 212, 217–237 (2006).

    CAS  Article  Google Scholar 

  45. 45

    Sakaguchi, S., Miyara, M., Costantino, C.M. & Hafler, D.A. Nat. Rev. Immunol. 10, 490–500 (2010).

    CAS  Article  Google Scholar 

  46. 46

    Grazia Roncarolo, M. et al. Immunol. Rev. 212, 28–50 (2006).

    Article  Google Scholar 

  47. 47

    Collison, L.W. et al. Nat. Immunol. 11, 1093–1101 (2010).

    CAS  Article  Google Scholar 

  48. 48

    Zheng, S.G., Gray, J.D., Ohtsuka, K., Yamagiwa, S. & Horwitz, D.A. J. Immunol. 169, 4183–4189 (2002).

    CAS  Article  Google Scholar 

  49. 49

    Chen, W. et al. J. Exp. Med. 198, 1875–1886 (2003).

    CAS  Article  Google Scholar 

  50. 50

    Laurence, A. et al. Immunity 26, 371–381 (2007).

    CAS  Article  Google Scholar 

  51. 51

    Hall, J.A., Grainger, J.R., Spencer, S.P. & Belkaid, Y. Immunity 35, 13–22 (2011).

    CAS  Article  Google Scholar 

  52. 52

    Huehn, J., Polansky, J.K. & Hamann, A. Nat. Rev. Immunol. 9, 83–89 (2009).

    CAS  Article  Google Scholar 

  53. 53

    Duarte, J.H., Zelenay, S., Bergman, M.L., Martins, A.C. & Demengeot, J. Eur. J. Immunol. 39, 948–955 (2009).

    CAS  Article  Google Scholar 

  54. 54

    Komatsu, N. et al. Proc. Natl. Acad. Sci. USA 106, 1903–1908 (2009).

    CAS  Article  Google Scholar 

  55. 55

    Zhou, X. et al. Nat. Immunol. 10, 1000–1007 (2009).

    CAS  Article  Google Scholar 

  56. 56

    Tsuji, M. et al. Science 323, 1488–1492 (2009).

    CAS  Article  Google Scholar 

  57. 57

    Rubtsov, Y.P. et al. Science 329, 1667–1671 (2010).

    CAS  Article  Google Scholar 

  58. 58

    Tran, D.Q., Ramsey, H. & Shevach, E.M. Blood 110, 2983–2990 (2007).

    CAS  Article  Google Scholar 

  59. 59

    Baecher-Allan, C., Brown, J.A., Freeman, G.J. & Hafler, D.A. J. Immunol. 167, 1245–1253 (2001).

    CAS  Article  Google Scholar 

  60. 60

    Yagi, H. et al. Int. Immunol. 16, 1643–1656 (2004).

    CAS  Article  Google Scholar 

  61. 61

    Miyara, M. et al. Immunity 30, 899–911 (2009).

    CAS  Article  Google Scholar 

  62. 62

    Ahern, P.P. et al. Immunity 33, 279–288 (2010).

    CAS  Article  Google Scholar 

  63. 63

    Hirota, K. et al. J. Exp. Med. 204, 41–47 (2007).

    CAS  Article  Google Scholar 

  64. 64

    Chen, Y. et al. Immunity 34, 409–421 (2011).

    CAS  Article  Google Scholar 

  65. 65

    Anderson, C.F., Oukka, M., Kuchroo, V.J. & Sacks, D. J. Exp. Med. 204, 285–297 (2007).

    CAS  Article  Google Scholar 

  66. 66

    Jankovic, D. et al. J. Exp. Med. 204, 273–283 (2007).

    CAS  Article  Google Scholar 

  67. 67

    Pot, C., Apetoh, L., Awasthi, A. & Kuchroo, V.K. Semin. Immunol. 23, 438–445 (2011).

    CAS  Article  Google Scholar 

  68. 68

    Nadkarni, S., Mauri, C. & Ehrenstein, M.R. J. Exp. Med. 204, 33–39 (2007).

    CAS  Article  Google Scholar 

  69. 69

    Sakaguchi, S. & Sakaguchi, N. Curr. Opin. Immunol. 17, 589–594 (2005).

    CAS  Article  Google Scholar 

  70. 70

    Keffer, J. et al. EMBO J. 10, 4025–4031 (1991).

    CAS  Article  Google Scholar 

  71. 71

    Cua, D.J. & Tato, C.M. Nat. Rev. Immunol. 10, 479–489 (2010).

    CAS  Article  Google Scholar 

  72. 72

    Buonocore, S. et al. Nature 464, 1371–1375 (2010).

    CAS  Article  Google Scholar 

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Correspondence to Shimon Sakaguchi.

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Sakaguchi, S., Powrie, F. & Ransohoff, R. Re-establishing immunological self-tolerance in autoimmune disease. Nat Med 18, 54–58 (2012). https://doi.org/10.1038/nm.2622

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