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AIDS:
doi: 10.1097/QAD.0b013e3280b079c8
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Immune reconstitution syndrome in tuberculosis and HIV-co-infected patients: Th1 explosion or cytokine storm?

Ruhwald, Morten; Ravn, Pernille

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Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark.

Received 29 November, 2006

Accepted 12 December, 2006

The article ‘Explosion of tuberculin-specific Th1 responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients’ by Bourgarit and colleagues [1] explores the immunological changes underlying the immune reconstitution syndrome (IRS). The paper is the first to apply a broad proteomic approach, and highlights very important aspects of this complex immunological phenomenon.

The authors analyse the in-vitro production of 25 inflammatory and immunomodulatory cytokines, chemokines and soluble cytokine receptors in supernatants of purified protein derivative-stimulated peripheral blood mononuclear cells from four patients (three undergoing IRS, one not undergoing IRS). The authors classify the immune molecules in the following fashion: T helper cell (Th) type 1-related cytokines/chemokines (IFN-γ, IL-2, IL-12, IFN-γ-inducible protein 10 and monokine induced by IFN-γ); Th2 cytokines (IL-4, IL-5, IL-13 and IL-15); inflammatory cytokines/chemokines (TNF-α, IL-6, IL-1b, IL-10, regulated upon activation: normal T cell expressed/secreted and monocyte chemoattractant protein 1). The markers IL-1 receptor antagonist (IL-1RA), IL-2 receptor, IL-7, IL-8, IL-17, granulocyte macrophage colony-stimulating factor, macrophage inflammatory proteins 1α and 1β are measured, but data are not presented. On the basis of this classification of cytokines, the authors propose ‘that an excessive restoration of purified protein derivative-specific Th1 response with no Th2 balance is responsible for the enlargement of TB granuloma lesions and is associated with an acute release of non-specific pro-inflammatory cytokines and chemokines inducing the systemic inflammatory syndrome’. In the present study, however, IL-10 is classified as a non-specific inflammatory cytokine, and IL-15 as a Th2 cytokine. IL-10 is well established as a classic Th2 and anti-inflammatory cytokine [2]. IL-15 is a pro-inflammatory cytokine sharing many functions with IL-2 [3]. With the correct classification of the presented cytokine measurements, the results are an increase in purified protein derivative-specific Th1 cytokines/chemokines (IFN-γ, IL-2, IL-12, IFN-γ-inducible protein 10 and monokine induced by IFN-γ), in non-specific inflammatory cytokines/chemokines (TNF-α, IL-6, IL-1β, regulated upon activation: normal T cell expressed/secreted and monocyte chemoattractant protein 1), and in the Th2/anti-inflammatory cytokine IL-10, coinciding with the development of IRS symptoms. Therefore, on the basis of the data presented in the article, the IRS seems more likely to be induced by an explosion of Th1, Th2, and non-specific inflammatory mediators simultaneously, i.e. a cytokine storm [4].

Although measured, the authors fail to comment on the production of the two non-specific anti-inflammatory immune effectors IL-1RA and soluble IL-2 receptor. As non-specific anti-inflammatory cytokine and soluble receptor production represent naturally occurring inflammation inhibitors, the study of markers from this class is essential for the understanding of IRS. We have recently found high levels of IL-1RA in 1: 8 diluted plasma of whole blood culture stimulated with the tuberculosis specific antigens ESAT-6, CFP-10 and TB7.7 (unpublished observations). Patients with active tuberculosis produced antigen-specific IL-1RA responses of a median 2282 pg/ml (range 162–4432 pg/ml; Fig. 1), equivalent to 18 256 pg/ml in undiluted sample. Future studies are needed to elucidate the effects of these immune mediators during IRS, and should compare whole blood with peripheral blood mononuclear cell culture and take cytokine kinetics into consideration [5].

Fig. 1
Fig. 1
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On the basis of current knowledge it is tempting to hypothesize that the immunological basis of IRS is a HAART-induced rapid clonal expansion and redistribution of Mycobacterium tuberculosis-specific memory T cells [6], which drives a deregulated immune activation [7] and a cytokine storm [1]. The deregulated immune function could be the consequence of the fact that an HIV-induced loss of thymic-derived cell populations (naive T cells [8] and natural regulatory T cells [9,10]) are restored at much slower kinetics compared with the peripheral memory T-cell population after HAART [6,8]. Tuberculosis-specific regulatory T cells have recently been demonstrated [11], and murine data have shown that regulatory T cells dampen the symptoms of IRS [12]. Therefore, because of a lack of naturally occurring regulatory T cells in the first months of HAART treatment, there is a basis of deregulated memory T-cell expansion leading to a cytokine storm and the development of IRS.

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Acknowledgements

The authors would like to thank Kristian Kofoed, MD, for helpful comments.

Sponsorship: MR is a PhD student holding a Scholarship from Copenhagen University Hospital; PR is supported by the Thorvald Madsen, Custer of International Health.

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References

1. Bourgarit A, Carcelain G, Martinez V, Lascoux C, Delcey V, Gicquel B, et al. Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients. AIDS 2006; 20:F1–F7.

2. Mege JL, Meghari S, Honstettre A, Capo C, Raoult D. The two faces of interleukin 10 in human infectious diseases. Lancet Infect Dis 2006; 6:557–569.

3. Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 2006; 6:595–601.

4. Ferrara JL. Cytokine dysregulation as a mechanism of graft versus host disease. Curr Opin Immunol 1993; 5:794–799.

5. Lagrelius M, Jones P, Franck K, Gaines H. Cytokine detection by multiplex technology useful for assessing antigen specific cytokine profiles and kinetics in whole blood cultured up to seven days. Cytokine 2006; 33:156–165.

6. Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997; 277:112–116.

7. Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005; 5:361–373.

8. Carcelain G, Debre P, Autran B. Reconstitution of CD4+ T lymphocytes in HIV-infected individuals following antiretroviral therapy. Curr Opin Immunol 2001; 13:483–488.

9. Nixon DF, Aandahl EM, Michaelsson J. CD4+CD25+ regulatory T cells in HIV infection. Microbes Infect 2005; 7:1063–1065.

10. Oswald-Richter K, Grill SM, Shariat N, Leelawong M, Sundrud MS, Haas DW, et al. HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells. PLoS Biol 2004; 2:E198.

11. Guyot-Revol V, Innes JA, Hackforth S, Hinks T, Lalvani A. Regulatory T cells are expanded in blood and disease sites in patients with tuberculosis. Am J Respir Crit Care Med 2006; 173:803–810.

12. McKinley L, Logar AJ, McAllister F, Zheng M, Steele C, Kolls JK. Regulatory cells dampen pulmonary inflammation and lung injury in an animal model of Pneumocystis pneumonia. J Immunol 2006; 177:6215–6226.

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