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Cytotoxic mediators in paradoxical HIV-tuberculosis immune reconstitution inflammatory syndrome

Wilkinson, Katalin A., Walker, Naomi F., Meintjes, Graeme, Deffur, Armin, Nicol, Mark P., Skolimowska, Keira H., Matthews, Kerryn, Tadokera, Rebecca ORCID: https://orcid.org/0000-0001-5195-2376, Seldon, Ronnett, Maartens, Gary, Rangaka, Molebogeng X., Besra, Gurdyal S. and Wilkinson, Robert J. (2015) Cytotoxic mediators in paradoxical HIV-tuberculosis immune reconstitution inflammatory syndrome. Journal of immunology (Baltimore, Md. : 1950), 194 (4). pp. 1748-1754.

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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.

Item Type: Article
Status: Published
DOI: https://doi.org/10.4049/jimmunol.1402105
School/Department: School of Science, Technology and Health
URI: https://ray.yorksj.ac.uk/id/eprint/9376

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