[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Molecular identification of a danger signal that alerts the immune system to dying cells

Nature volume 425, pages 516–521 (2003)Cite this article

Abstract

In infections, microbial components provide signals that alert the immune system to danger and promote the generation of immunity1,2. In the absence of such signals, there is often no immune response or tolerance may develop. This has led to the concept that the immune system responds only to antigens perceived to be associated with a dangerous situation such as infection3,4. Danger signals are thought to act by stimulating dendritic cells to mature so that they can present foreign antigens and stimulate T lymphocytes2,5,6,7. Dying mammalian cells have also been found to release danger signals of unknown identity8,9,10,11. Here we show that uric acid is a principal endogenous danger signal released from injured cells. Uric acid stimulates dendritic cell maturation and, when co-injected with antigen in vivo, significantly enhances the generation of responses from CD8+ T cells. Eliminating uric acid in vivo inhibits the immune response to antigens associated with injured cells, but not to antigens presented by activated dendritic cells. Our findings provide a molecular link between cell injury and immunity and have important implications for vaccines, autoimmunity and inflammation.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Purification of the LMW endogenous adjuvant from cytosol.
Figure 2: Molecular identification of the LMW endogenous adjuvant.
Figure 3: Uric acid has adjuvant activity in vivo and its concentrations increase in injured cells.
Figure 4: Eliminating uric acid in vivo inhibits adjuvant activity from injured cells.
Figure 5: MSU crystals rapidly activate dendritic cells.
Figure 6: Specificity of dendritic cell activation by MSU crystals.

Similar content being viewed by others

References

  1. Hunter, R. L. Overview of vaccine adjuvants: present and future. Vaccine 20 (suppl. 3), S7–S12 (2002)

    Article  CAS  Google Scholar 

  2. Janeway, C. A. Jr Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989)

    Article  CAS  Google Scholar 

  3. Janeway, C. A. Jr The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol. Today 13, 11–16 (1992)

    Article  CAS  Google Scholar 

  4. Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994)

    Article  CAS  Google Scholar 

  5. Cox, J. C. & Coulter, A. R. Adjuvants—a classification and review of their modes of action. Vaccine 15, 248–256 (1997)

    Article  CAS  Google Scholar 

  6. Schijns, V. E. Immunological concepts of vaccine adjuvant activity. Curr. Opin. Immunol. 12, 456–463 (2000)

    Article  CAS  Google Scholar 

  7. Medzhitov, R. & Janeway, C. Jr Innate immune recognition: mechanisms and pathways. Immunol. Rev. 173, 89–97 (2000)

    Article  CAS  Google Scholar 

  8. Albert, M. L., Sauter, B. & Bhardwaj, N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392, 86–89 (1998)

    Article  ADS  CAS  Google Scholar 

  9. Gallucci, S., Lolkema, M. & Matzinger, P. Natural adjuvants: endogenous activators of dendritic cells. Nature Med. 5, 1249–1255 (1999)

    Article  CAS  Google Scholar 

  10. Shi, Y., Zheng, W. & Rock, K. L. Cell injury releases endogenous adjuvants that stimulate cytotoxic T cell responses. Proc. Natl Acad. Sci. USA 97, 14590–14595 (2000)

    Article  ADS  CAS  Google Scholar 

  11. Shi, Y. & Rock, K. L. Cell death releases endogenous adjuvants that selectively enhance immune surveillance of particulate antigens. Eur. J. Immunol. 32, 155–162 (2002)

    Article  CAS  Google Scholar 

  12. Jeha, S. Tumor lysis syndrome. Semin. Hematol. 38, 4–8 (2001)

    Article  CAS  Google Scholar 

  13. Smyth, C. J. & Holers, V. M. Gout, Hyperuricemia, and Other Crystal-Associated Arthropathies (Marcel Dekker, New York, 1998)

    Google Scholar 

  14. Kippen, I., Klinenberg, J. R., Weinberger, A. & Wilcox, W. R. Factors affecting urate solubility in vitro. Ann. Rheum. Dis. 33, 313–317 (1974)

    Article  CAS  Google Scholar 

  15. Iwata, H., Nishio, S., Yokoyama, M., Matsumoto, A. & Takeuchi, M. Solubility of uric acid and supersaturation of monosodium urate: why is uric acid so highly soluble in urine? J. Urol. 142, 1095–1098 (1989)

    Article  CAS  Google Scholar 

  16. Fiddis, R. W., Vlachos, N. & Calvert, P. D. Studies of urate crystallisation in relation to gout. Ann. Rheum. Dis. 42 (suppl. 1), 12–15 (1983)

    Article  CAS  Google Scholar 

  17. Tak, H. K., Cooper, S. M. & Wilcox, W. R. Studies on the nucleation of monosodium urate at 37 °C. Arthritis Rheum. 23, 574–580 (1980)

    Article  CAS  Google Scholar 

  18. Loeb, J. N. The influence of temperature on the solubility of monosodium urate. Arthritis Rheum. 15, 189–192 (1972)

    Article  CAS  Google Scholar 

  19. Talbott, J. H. & Yu, T.-F. Gout and Uric Acid Metabolism (Stratton Intercontinental Medical Book Corp., New York, 1976)

    Google Scholar 

  20. Yagnik, D. R. et al. Noninflammatory phagocytosis of monosodium urate monohydrate crystals by mouse macrophages. Implications for the control of joint inflammation in gout. Arthritis Rheum. 43, 1779–1789 (2000)

    Article  CAS  Google Scholar 

  21. Landis, R. C. et al. Safe disposal of inflammatory monosodium urate monohydrate crystals by differentiated macrophages. Arthritis Rheum. 46, 3026–3033 (2002)

    Article  CAS  Google Scholar 

  22. Koka, R. M., Huang, E. & Lieske, J. C. Adhesion of uric acid crystals to the surface of renal epithelial cells. Am. J. Physiol. Renal Physiol. 278, F989–F998 (2000)

    Article  CAS  Google Scholar 

  23. Majno, G. & Joris, I. Cells, Tissues, and Disease: Principles of General Pathology (Blackwell Science, Cambridge, MA, 1996)

    Google Scholar 

  24. Bosmansky, K. & Trnavsky, K. Serum uric acid levels in disorders of the rheumatic type. Z. Rheumatol. 43, 59–62 (1984)

    CAS  PubMed  Google Scholar 

  25. Vidard, L. et al. Analysis of MHC class II presentation of particulate antigens of B lymphocytes. J. Immunol. 156, 2809–2818 (1996)

    CAS  PubMed  Google Scholar 

  26. Coligan, J. E., Kruisbeek, A. M., Margulies, D. H., Shevach, E. M. & Strober, W. Current Protocols in Immunology (Jon Wiley & Sons, Hoboken, NJ, 1991)

    Google Scholar 

Download references

Acknowledgements

We thank J. Sodrosky, J. Berzofsky, N. Sato, Y. Takeda and T. Vedvick for reagents; B. Zhang, P. Furcinitti and B. Kobertz for advice and technical assistance; and L. Stern and I. York for critically reviewing the manuscript. The work was supported by NIH grants to K.L.R. Y.S. was also supported by a grant from the Pittsfield TB association.

Author information

Authors and Affiliations

  1. Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, 01655, USA

    Yan Shi & Kenneth L. Rock

  2. Proteomics and Mass Spectrometry Facility, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, 01655, USA

    James E. Evans

Authors
  1. Yan Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James E. Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenneth L. Rock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth L. Rock.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shi, Y., Evans, J. & Rock, K. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003). https://doi.org/10.1038/nature01991

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01991

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing