Cytotoxic mediators in paradoxical HIV-tuberculosis immune reconstitution inflammatory syndrome

Katalin A. Wilkinson, Naomi F. Walker, Graeme Meintjes, Armin Deffur, Mark P. Nicol, Keira H. Skolimowska, Kerryn Matthews, Rebecca Tadokera, Ronnett Seldon, Gary Maartens, Molebogeng X. Rangaka, Gurdyal S. Besra, Robert J. Wilkinson

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17 Citations (Scopus)

Abstract

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) frequently complicates combined antiretroviral therapy and antituberculosis therapy in HIV-1-coinfected tuberculosis patients. The immunopathological mechanisms underlying TB-IRIS are incompletely defined, and improved understanding is required to derive new treatments and to reduce associated morbidity and mortality. We performed longitudinal and cross-sectional analyses of human PBMCs from paradoxical TB-IRIS patients and non-IRIS controls (HIV-TB-coinfected patients commencing antiretroviral therapy who did not develop TB-IRIS). Freshly isolated PBMC stimulated with heat-killed Mycobacterium tuberculosis H37Rv (hkH37Rv) were used for IFN-γ ELISPOT and RNA extraction. Stored RNA was used for microarray and RT-PCR, whereas corresponding stored culture supernatants were used for ELISA. Stored PBMC were used for perforin and granzyme B ELISPOT and flow cytometry. There were significantly increased IFN-γ responses to hkH37Rv in TB-IRIS, compared with non-IRIS PBMC (p = 0.035). Microarray analysis of hkH37Rv-stimulated PBMC indicated that perforin 1 was the most significantly upregulated gene, with granzyme B among the top five (log2 fold difference 3.587 and 2.828, respectively), in TB-IRIS. Downstream experiments using RT-PCR, ELISA, and ELISPOT confirmed the increased expression and secretion of perforin and granzyme B. Moreover, granzyme B secretion reduced in PBMC from TB-IRIS patients during corticosteroid treatment. Invariant NKT cell (CD3+Vα24+) proportions were higher in TB-IRIS patients (p = 0.004) and were a source of perforin. Our data implicate the granule exocytosis pathway in TB-IRIS pathophysiology. Further understanding of the immunopathogenesis of this condition will facilitate development of specific diagnostic and improved therapeutic options.

Original languageEnglish
Pages (from-to)1748-1754
Number of pages7
JournalJournal of Immunology
Volume194
Issue number4
DOIs
Publication statusPublished - 15 Feb 2015
Externally publishedYes

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    Wilkinson, K. A., Walker, N. F., Meintjes, G., Deffur, A., Nicol, M. P., Skolimowska, K. H., Matthews, K., Tadokera, R., Seldon, R., Maartens, G., Rangaka, M. X., Besra, G. S., & Wilkinson, R. J. (2015). Cytotoxic mediators in paradoxical HIV-tuberculosis immune reconstitution inflammatory syndrome. Journal of Immunology, 194(4), 1748-1754. https://doi.org/10.4049/jimmunol.1402105