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Maintaining system homeostasis: the third law of Newtonian immunology

Nature Immunology volume 13, pages 902–906 (2012)Cite this article

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Abstract

Because of the potent effector mechanisms of the immune system, the potential for self-destructive immune responses is especially high and many negative regulatory modalities exist to prevent excessive tissue damage. This Commentary places such regulatory mechanisms in the larger context of system organization on many scales. The sometimes counterintuitive nature of feedback control is discussed and a case is made for greater attention to quantitative spatiotemporal aspects of regulation, rather than limiting the discussion to the qualitative descriptions of pathways that dominate at present.

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Figure 1: The effect of tonic suppression on lymphocyte activation in response to signaling input induced by self ligand.

Debbie Maizels

Figure 2: Lymphocyte activation in tissues.

Debbie Maizels

Figure 3: In many signaling systems, a strong stimulus results in strong and rapid induction of negative feedback pathways that quickly suppress the signaling response.

Debbie Maizels

References

  1. Sissons, J.G. & Oldstone, M.B. J. Infect. Dis. 142, 114–119 (1980).

    CAS  PubMed  Google Scholar 

  2. Harty, J.T., Tvinnereim, A.R. & White, D.W. Annu. Rev. Immunol. 18, 275–308 (2000).

    CAS  PubMed  Google Scholar 

  3. Cullen, S.P. & Martin, S.J. Cell Death Differ. 15, 251–262 (2008).

    CAS  PubMed  Google Scholar 

  4. Bogdan, C., Rollinghoff, M. & Diefenbach, A. Curr. Opin. Immunol. 12, 64–76 (2000).

    CAS  PubMed  Google Scholar 

  5. Kohchi, C., Inagawa, H., Nishizawa, T. & Soma, G. Anticancer Res. 29, 817–821 (2009).

    CAS  PubMed  Google Scholar 

  6. Lambeth, J.D. Nat. Rev. Immunol. 4, 181–189 (2004).

    CAS  PubMed  Google Scholar 

  7. Segel, L.A. & Bar-Or, R.L. J. Immunol. 163, 1342–1349 (1999).

    CAS  PubMed  Google Scholar 

  8. Chatenoud, L. Eur. J. Immunol. 36, 2296–2298 (2006).

    CAS  PubMed  Google Scholar 

  9. Joller, N., Peters, A., Anderson, A.C. & Kuchroo, V.K. Immunol. Rev. 248, 122–139 (2012).

    PubMed  PubMed Central  Google Scholar 

  10. Gallucci, S. & Matzinger, P. Curr. Opin. Immunol. 13, 114–119 (2001).

    CAS  PubMed  Google Scholar 

  11. Matzinger, P. Annu. Rev. Immunol. 12, 991–1045 (1994).

    CAS  PubMed  Google Scholar 

  12. Allam, R. & Anders, H.J. Curr. Opin. Rheumatol. 20, 538–544 (2008).

    CAS  PubMed  Google Scholar 

  13. Lleo, A., Selmi, C., Invernizzi, P., Podda, M. & Gershwin, M.E. J. Autoimmun. 31, 257–262 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kholodenko, B., Yaffe, M.B. & Kolch, W. Sci. Signal. 5, re1 (2012).

    PubMed  Google Scholar 

  15. Cheng, A. & Lu, T.K. Annu. Rev. Biomed. Eng. 14, 155–178 (2012).

    CAS  PubMed  Google Scholar 

  16. Alon, U. Nat. Rev. Genet. 8, 450–461 (2007).

    CAS  PubMed  Google Scholar 

  17. Frankenstein, Z., Alon, U. & Cohen, I.R. Biol. Direct 1, 32 (2006).

    PubMed  PubMed Central  Google Scholar 

  18. Kashtan, N., Itzkovitz, S., Milo, R. & Alon, U. Phys. Rev. E 70, 031909 (2004).

    CAS  Google Scholar 

  19. Shen-Orr, S.S., Milo, R., Mangan, S. & Alon, U. Nat. Genet. 31, 64–68 (2002).

    CAS  PubMed  Google Scholar 

  20. Yeger-Lotem, E. et al. Proc. Natl. Acad. Sci. USA 101, 5934–5939 (2004).

    CAS  PubMed  Google Scholar 

  21. Greene, D. Nat. Immunol. 13, 907–915 (2012).

    Google Scholar 

  22. Fraser, I.D. & Germain, R.N. Nat. Immunol. 10, 327–331 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Murray, P.J. & Smale, S.T. Nat. Immunol. 13, 916–924 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Germain, R.N. Science 293, 240–245 (2001).

    CAS  PubMed  Google Scholar 

  25. Aoki, C.A. et al. Autoimmun. Rev. 4, 450–459 (2005).

    CAS  PubMed  Google Scholar 

  26. Zhu, J., Yamane, H. & Paul, W.E. Annu. Rev. Immunol. 28, 445–489 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wahl, S.M., Swisher, J., McCartney-Francis, N. & Chen, W. J. Leukoc. Biol. 76, 15–24 (2004).

    CAS  PubMed  Google Scholar 

  28. Li, M.O., Wan, Y.Y. & Flavell, R.A. Immunity 26, 579–591 (2007).

    CAS  PubMed  Google Scholar 

  29. Pesu, M. et al. Nature 455, 246–250 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Stefanová, I., Dorfman, J.R. & Germain, R.N. Nature 420, 429–434 (2002).

    PubMed  Google Scholar 

  31. Kastenmuller, W. et al. J. Immunol. 187, 3186–3197 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Mempel, T.R. et al. Immunity 25, 129–141 (2006).

    CAS  PubMed  Google Scholar 

  33. Schildknecht, A. et al. Proc. Natl. Acad. Sci. USA 107, 199–203 (2010).

    CAS  PubMed  Google Scholar 

  34. Wuest, T.Y., Willette-Brown, J., Durum, S.K. & Hurwitz, A.A. J. Leukoc. Biol. 84, 973–980 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Pandiyan, P., Zheng, L., Ishihara, S., Reed, J. & Lenardo, M.J. Nat. Immunol. 8, 1353–1362 (2007).

    CAS  PubMed  Google Scholar 

  36. Feinerman, O. et al. Mol. Syst. Biol. 6, 437 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Chung, Y. et al. Nat. Med. 17, 983–988 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Linterman, M.A. et al. Nat. Med. 17, 975–982 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Ozaki, Y., Sasagawa, S. & Kuroda, S. J. Biochem. 137, 659–663 (2005).

    CAS  PubMed  Google Scholar 

  43. Avraham, R. & Yarden, Y. Nat. Rev. Mol. Cell Biol. 12, 104–117 (2011).

    CAS  PubMed  Google Scholar 

  44. Glauser, D.A. & Schlegel, W. FASEB J. 21, 3240–3249 (2007).

    CAS  PubMed  Google Scholar 

  45. Chalmers, C.J., Gilley, R., March, H.N., Balmanno, K. & Cook, S.J. Cell. Signal. 19, 695–704 (2007).

    CAS  PubMed  Google Scholar 

  46. Paolino, M. & Penninger, J.M. Eur. J. Immunol. 39, 2337–2344 (2009).

    CAS  PubMed  Google Scholar 

  47. Bour-Jordan, H. et al. Immunol. Rev. 241, 180–205 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Egen, J.G. & Allison, J.P. Immunity 16, 23–35 (2002).

    CAS  PubMed  Google Scholar 

  49. Chambers, C.A., Kuhns, M.S., Egen, J.G. & Allison, J.P. Annu. Rev. Immunol. 19, 565–594 (2001).

    CAS  PubMed  Google Scholar 

  50. Barber, D.L. et al. Nature 439, 682–687 (2006).

    CAS  PubMed  Google Scholar 

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Acknowledgements

I thank the colleagues with whom I have discussed, over many years, aspects of the ideas presented in this Commentary, and W. Kastenmuller for reading of this manuscript and suggestions for improvements. Supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health.

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Authors and Affiliations

  1. Ronald N. Germain is in the Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.,

    Ronald N Germain

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Correspondence to Ronald N Germain.

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Germain, R. Maintaining system homeostasis: the third law of Newtonian immunology. Nat Immunol 13, 902–906 (2012). https://doi.org/10.1038/ni.2404

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