Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes (original) (raw)

Nature Medicine volume 17, pages 195–199 (2011)Cite this article

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Abstract

Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood1,2,3,4,5,6,7,8,9,10. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex–mediated disease after infection. We detected high titers of serum antibody of low avidity for H1-2009 antigen, and low-avidity pulmonary immune complexes against the same protein, in severely ill individuals. Moreover, C4d deposition—a marker of complement activation mediated by immune complexes—was present in lung sections of fatal cases. Archived lung sections from middle-aged adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a previously unknown biological mechanism for the unusual age distribution of severe cases during influenza pandemics.

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Acknowledgements

Funded by the Fundacion INFANT 2008 Fundraising Campaign and AI-054952 (F.P.P.), the Thrasher Research Fund Early Career Award and Fogarty International Center International Clinical Research Fellows Program at Vanderbilt (R24 TW007988) (G.A.M. and J.P.B.), US Department of Defense grant HDTRA1-08-10-BRCWMD-BAA and US National Institutes of Health grant P01 AI058113 (J.E.C. Jr.). Doctoral awards from the Consejo Nacional de Investigaciones Cientıficas y Técnicas, Argentina (A.C.M. and J.P.B.).

Author information

Author notes

  1. Ana Clara Monsalvo, Juan P Batalle and M Florencia Lopez: These authors contributed equally to this work.

Authors and Affiliations

  1. Fundacion INFANT, Buenos Aires, Argentina
    Ana Clara Monsalvo, Juan P Batalle, M Florencia Lopez, Johanna Zea Hernandez, Jimena Bugna, Romina Libster, Guillermina A Melendi & Fernando P Polack
  2. Department of Pediatrics, Vanderbilt University, Nashville, Tennessee, USA
    Jens C Krause, Jennifer Klemenc, Johanna Zea Hernandez, Kevin P Weller, Kathryn M Edwards, James E Crowe Jr, John V Williams, Guillermina A Melendi & Fernando P Polack
  3. Hospital Nacional Profesor Alejandro Posadas, Buenos Aires, Argentina
    Bernardo Maskin, Liliana Aguilar, Graciela Cabral, Julia Font & Liliana Solari
  4. Hospital Dr. Federico Abete, Malvinas Argentinas, Buenos Aires, Argentina
    Carlos Rubinstein & Leandro Aguilar
  5. Hospital Italiano, Buenos Aires, Argentina
    Liliana Dalurzo
  6. Administración Nacional de Laboratorios e Institutos de Salud Dr. Carlos G. Malbran, Buenos Aires, Argentina
    Vilma Savy & Elsa Baumeister
  7. Department of Pathology, Vanderbilt University, Nashville, Tennessee, USA
    Joyce Johnson & James D Chappell
  8. Department of Microbiology, Centro de Educación Médica e Investigaciones Clínicas, Buenos Aires, Argentina
    Marcela Echavarria

Authors

  1. Ana Clara Monsalvo
  2. Juan P Batalle
  3. M Florencia Lopez
  4. Jens C Krause
  5. Jennifer Klemenc
  6. Johanna Zea Hernandez
  7. Bernardo Maskin
  8. Jimena Bugna
  9. Carlos Rubinstein
  10. Leandro Aguilar
  11. Liliana Dalurzo
  12. Romina Libster
  13. Vilma Savy
  14. Elsa Baumeister
  15. Liliana Aguilar
  16. Graciela Cabral
  17. Julia Font
  18. Liliana Solari
  19. Kevin P Weller
  20. Joyce Johnson
  21. Marcela Echavarria
  22. Kathryn M Edwards
  23. James D Chappell
  24. James E Crowe Jr
  25. John V Williams
  26. Guillermina A Melendi
  27. Fernando P Polack

Contributions

F.P.P., G.A.M., K.M.E., J.D.C., J.E.C. Jr., J.V.W., A.C.M., J.P.B. and M.F.L. designed the project. A.C.M., J.P.B., M.F.L., J.Z.H., B.M., L.D., K.P.W., J.V.W., G.A.M. and F.P.P. performed experiments. J.C.K., J.K., J.B., C.R., Le. A., L.D., R.L., V.S., E.B., Li. A., G.C., J.F., L.S., J.J., M.E., J.E.C. Jr. and J.V.W. developed or provided key reagents or contributed samples. F.P.P. supervised the project. A.C.M., J.P.B., M.F.L., K.M.E., J.D.C., G.A.M. and F.P.P. wrote the paper.

Corresponding authors

Correspondence toGuillermina A Melendi or Fernando P Polack.

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The authors declare no competing financial interests.

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Monsalvo, A., Batalle, J., Lopez, M. et al. Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes.Nat Med 17, 195–199 (2011). https://doi.org/10.1038/nm.2262

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