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.

  • Opinion
  • Published:

Immune reconstitution inflammatory syndrome: the trouble with immunity when you had none

Nature Reviews Microbiology volume 10, pages 150–156 (2012)Cite this article

Subjects

Abstract

Some individuals who are infected with HIV rapidly deteriorate shortly after starting antiretroviral therapy, despite effective viral suppression. This reaction, referred to as immune reconstitution inflammatory syndrome (IRIS), is characterized by tissue-destructive inflammation and arises as CD4+ T cells re-emerge. It has been proposed that IRIS is caused by a dysregulation of the expanding population of CD4+ T cells specific for a co-infecting opportunistic pathogen. Here, we argue that IRIS instead results from hyper-responsiveness of the innate immune system to T cell help, a mechanism that may be shared by the many manifestations of IRIS that occur following the reversal of other types of immunosuppression in pathogen-infected hosts.

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: Experimental IRIS requires chronic mycobacterial infection of lymphopenic hosts.
Figure 2: Model of IRIS.

Similar content being viewed by others

References

  1. Zolopa, A. et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS ONE 4, e5575 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Abdool Karim, S. S. et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N. Engl. J. Med. 362, 697–706 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Castelnuovo, B. et al. Cause-specific mortality and the contribution of immune reconstitution inflammatory syndrome in the first 3 years after antiretroviral therapy initiation in an urban african cohort. Clin. Infect. Dis. 49, 965–972 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Abdool Karim, S. S. et al. Integration of antiretroviral therapy with tuberculosis treatment. N. Engl. J. Med. 365, 1492–1501 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hoyo-Ulloa, I. et al. Impact of the immune reconstitution inflammatory syndrome (IRIS) on mortality and morbidity in HIV-infected patients in Mexico. Int. J. Infect. Dis. 15, e408–e414 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Blanc, F.-X. et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N. Engl. J. Med. 365, 1471–1481 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Havlir, D. V. et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N. Engl. J. Med. 365, 1482–1491 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. French, M. A. et al. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Med. 1, 107–115 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Ratnam, I., Chiu, C., Kandala, N.-B. & Easterbrook, P. J. Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV type 1-infected cohort. Clin. Infect. Dis. 42, 418–427 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Murdoch, D. M., Venter, W. D. F., Feldman, C. & Van Rie, A. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS 22, 601–610 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Grant, P. M. et al. Risk factor analyses for immune reconstitution inflammatory syndrome in a randomized study of early vs. deferred ART during an opportunistic infection. PLoS ONE 5, e11416 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Breton, G. et al. Immune reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis. AIDS 20, 119–121 (2006).

    Article  PubMed  Google Scholar 

  13. Nolan, R. C., Chidlow, G. & French, M. A. Parvovirus B19 encephalitis presenting as immune restoration disease after highly active antiretroviral therapy for human immunodeficiency virus infection. Clin. Infect. Dis. 36, 1191–1194 (2003).

    Article  PubMed  Google Scholar 

  14. Connick, E., Kane, M. A., White, I. E., Ryder, J. & Campbell, T. B. Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma during potent antiretroviral therapy. Clin. Infect. Dis. 39, 1852–1855 (2004).

    Article  PubMed  Google Scholar 

  15. Mueller, M. et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect. Dis. 10, 251–261 (2010).

    Article  Google Scholar 

  16. Manabe, Y. C., Campbell, J. D., Sydnor, E. & Moore, R. D. Immune reconstitution inflammatory syndrome: risk factors and treatment implications. J. Acquir. Immune Defic. Syndr. 46, 456–462 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Meintjes, G. et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect. Dis. 8, 516–523 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Bourgarit, A. et al. Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients. AIDS 20, F1–F7 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Bourgarit, A. et al. Tuberculosis-associated immune restoration syndrome in HIV-1-infected patients involves tuberculin-specific CD4 Th1 cells and KIR-negative γδ T cells. J. Immunol. 183, 3915–3923 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Meintjes, G. et al. Type 1 helper T cells and FoxP3-positive T cells in HIV-tuberculosis-associated immune reconstitution inflammatory syndrome. Am. J. Respir. Crit. Care Med. 178, 1083–1089 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Roths, J. B., Marshall, J. D., Allen, R. D., Carlson, G. A. & Sidman, C. L. Spontaneous Pneumocystis carinii pneumonia in immunodeficient mutant scid mice. Natural history and pathobiology. Am. J. Pathol. 136, 1173–1186 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Roths, J. B. & Sidman, C. L. Both immunity and hyperresponsiveness to Pneumocystis carinii result from transfer of CD4+ but not CD8+ T cells into severe combined immunodeficiency mice. J. Clin. Invest. 90, 673–678 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Roths, J. B. & Sidman, C. L. Single and combined humoral and cell-mediated immunotherapy of Pneumocystis carinii pneumonia in immunodeficient scid mice. Infect. Immun. 61, 1641–1649 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Gigliotti, F., Xu, H. & Wright, T. Contribution of T cell subsets to the pathophysiology of Pneumocystis-related immunorestitution disease. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L1256–L1266 (2006).

    Article  PubMed  Google Scholar 

  25. Atochina-Vasserman, E. N. et al. Immune reconstitution during pneumocystis lung infection: disruption of surfactant component expression and function by S-nitrosylation. J. Immunol. 182, 2277–2287 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. French, M. A., Mallal, S. A. & Dawkins, R. L. Zidovudine-induced restoration of cell-mediated immunity to mycobacteria in immunodeficient HIV-infected patients. AIDS 6, 1293–1297 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Barber, D. L. et al. Th1-driven immune reconstitution disease in Mycobacterium avium-infected mice. Blood 116, 3485–3493 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Elliott, J. H. et al. Immunopathogenesis and diagnosis of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome during early antiretroviral therapy. J. Infect. Dis. 200, 1736–1745 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Antonelli, L. R. V. et al. Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome. Blood 116, 3818–3827 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tan, D. B. A. et al. TLR2-induced cytokine responses may characterize HIV-infected patients experiencing mycobacterial immune restoration disease. AIDS 25, 1455–1460 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Krupica, T., Fry, T. J. & Mackall, C. L. Autoimmunity during lymphopenia: a two-hit model. Clin. Immunol. 120, 121–128 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Sprent, J. & Surh, C. D. Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nature Immunol. 131, 478–484 (2011).

    Article  Google Scholar 

  33. Brown, I. E., Blank, C., Kline, J., Kacha, A. K. & Gajewski, T. F. Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection. J. Immunol. 177, 4521–4529 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. King, C., Ilic, A., Koelsch, K. & Sarvetnick, N. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 117, 265–277 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Tan, J. T. et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl Acad. Sci. USA 98, 8732–8737 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Schluns, K. S., Kieper, W. C., Jameson, S. C. & Lefrançois, L. Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nature Immunol. 1, 426–432 (2000).

    Article  CAS  Google Scholar 

  37. Kieper, W. C. et al. Recent immune status determines the source of antigens that drive homeostatic T cell expansion. J. Immunol. 174, 3158–3163 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Keane, J. et al. Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent. N. Engl. J. Med. 345, 1098–1104 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Wallis, R. S., van Vuuren, C. & Potgieter, S. Adalimumab treatment of life-threatening tuberculosis. Clin. Infect. Dis. 48, 1429–1432 (2009).

    Article  PubMed  Google Scholar 

  40. Yoon, Y. K. et al. Paradoxical response during antituberculous therapy in a patient discontinuing infliximab: a case report. J. Med. Case Rep. 3, 6673 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Belknap, R., Reves, R. & Burman, W. Immune reconstitution to Mycobacterium tuberculosis after discontinuing infliximab. Int. J. Tuberc. Lung Dis. 9, 1057–1058 (2005).

    PubMed  Google Scholar 

  42. Arend, S. M., Leyten, E. M. S., Franken, W. P. J., Huisman, E. M. & van Dissel, J. T. A patient with de novo tuberculosis during anti-tumor necrosis factor-α therapy illustrating diagnostic pitfalls and paradoxical response to treatment. Clin. Infect. Dis. 45, 1470–1475 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Szerszen, A., Gupta, S., Seminara, D., Jarrett, M. & Goldstein, M. Peritoneal tuberculosis complicated by immune reconstitution inflammatory syndrome in a patient treated with infliximab?: a case for adjuvant immunosuppressive therapy. J. Clin. Rheumatol. 15, 417–418 (2009).

    Article  PubMed  Google Scholar 

  44. Garcia Vidal, C. et al. Paradoxical response to antituberculous therapy in infliximab-treated patients with disseminated tuberculosis. Clin. Infect. Dis. 40, 756–759 (2005).

    Article  PubMed  Google Scholar 

  45. Rivoisy, C., Amrouche, L., Carcelain, G., Sereni, D. & Bourgarit, A. Paradoxical exacerbation of tuberculosis after TNFα antagonist discontinuation: beware of immune reconstitution inflammatory syndrome. Joint Bone Spine 78, 312–315 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Khatri, B. O. et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 72, 402–409 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Clifford, D. B. et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 9, 438–446 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Johnson, T. & Nath, A. Immune reconstitution inflammatory syndrome and the central nervous system. Curr. Opin. Neurol. 24, 284–290 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Van Assche, G. et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N. Engl. J. Med. 353, 362–368 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Lindå, H. et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N. Engl. J. Med. 361, 1081–1087 (2009).

    Article  PubMed  Google Scholar 

  51. Ryschkewitsch, C. F. et al. JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab. Ann. Neurol. 68, 384–391 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Miravalle, A., Jensen, R. & Kinkel, R. P. Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Arch. Neurol. 68, 186–191 (2011).

    Article  PubMed  Google Scholar 

  53. Sun, H. Y. & Singh, N. Opportunistic infection-associated immune reconstitution syndrome in transplant recipients. Clin. Infect. Dis. 53, 168–176 (2011).

    Article  PubMed  Google Scholar 

  54. Legris, T. et al. Immune reconstitution inflammatory syndrome mimicking relapsing cryptococcal meningitis in a renal transplant recipient. Transpl. Infect. Dis. 13, 303–308 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Singh, N. et al. An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients. Clin. Infect. Dis. 40, 1756–1761 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Crespo, G. et al. Immune reconstitution syndrome after voriconazole treatment for cryptococcal meningitis in a liver transplant recipient. Liver Transpl. 14, 1671–1674 (2008).

    Article  PubMed  Google Scholar 

  57. Lanternier, F. et al. Cellulitis revealing a cryptococcosis-related immune reconstitution inflammatory syndrome in a renal allograft recipient. Am. J. Transplant. 7, 2826–2828 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Singh, N. Novel immune regulatory pathways and their role in immune reconstitution syndrome in organ transplant recipients with invasive mycoses. Eur. J. Clin. Microbiol. Infect. Dis. 27, 403–408 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Boulware, D. R. et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med. 7, e1000384 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Boulware, D. R. et al. Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome. J. Infect. Dis. 202, 962–970 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Strutt, T. M. et al. Memory CD4+ T cells induce innate responses independently of pathogen. Nature Med. 16, 558–564 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Barber, D. L., Mayer-Barber, K. D., Feng, C. G., Sharpe, A. H. & Sher, A. CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition. J. Immunol. 186, 1598–1607 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Tadokera, R. et al. Hypercytokinaemia accompanies HIV-tuberculosis immune reconstitution inflammatory syndrome. Eur. Respir. J. 37, 1248–1259 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Boulware, D. R. et al. Higher levels of CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk of AIDS or death. J. Infect. Dis. 203, 1637–1646 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Oliver, B. G. et al. Mediators of innate and adaptive immune responses differentially affect immune restoration disease associated with Mycobacterium tuberculosis in HIV patients beginning antiretroviral therapy. J. Infect. Dis. 202, 1728–1737 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Lawn, S. D., Wainwright, H. & Orrell, C. Fatal unmasking tuberculosis immune reconstitution disease with bronchiolitis obliterans organizing pneumonia: the role of macrophages. AIDS 23, 143–145 (2009).

    Article  PubMed  Google Scholar 

  67. Lawn, S. D., Myer, L., Bekker, L.-G. & Wood, R. Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS 21, 335–341 (2007).

    Article  PubMed  Google Scholar 

  68. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescencents, 10 Jan 2011. AIDSinfo [online] (2011).

  69. Török, M. E. et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)-associated tuberculous meningitis. Clin. Infect. Dis. 52, 1374–1383 (2011).

    Article  PubMed  Google Scholar 

  70. Meintjes, G. et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 24, 2381–2390 (2010).

    CAS  PubMed  Google Scholar 

  71. French, M. A. Immune reconstitution inflammatory syndrome: a reappraisal. Clin. Infect. Dis. 48, 101–107 (2009).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank J. Keane for stimulating discussions during the preparation of this article. Work in the authors' laboratories is supported by the intramural research programme of the US National Institute for Allergy and Infectious Diseases, National Institutes of Health.

Author information

Authors and Affiliations

  1. Daniel L. Barber, Bruno B. Andrade and Alan Sher are at the Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rm 6146, 50 South Drive, Bethesda, Maryland, 20892, USA.,

    Daniel L. Barber, Bruno B. Andrade & Alan Sher

  2. Irini Sereti is at the Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rm 11B07, 10 Center Drive, Bethesda, Maryland 20892, USA.,

    Irini Sereti

Authors
  1. Daniel L. Barber
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Bruno B. Andrade
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Irini Sereti
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Alan Sher
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Daniel L. Barber.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barber, D., Andrade, B., Sereti, I. et al. Immune reconstitution inflammatory syndrome: the trouble with immunity when you had none. Nat Rev Microbiol 10, 150–156 (2012). https://doi.org/10.1038/nrmicro2712

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro2712

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

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