Journal
JOURNAL OF IMMUNOLOGY
Volume 194, Issue 4, Pages 1748-1754Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1402105
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Funding
- Wellcome Trust [081667, 084323, 088316, 094000, 085251]
- Medical Research Council of the United Kingdom Grant [U. 1175.02.002.00014.01]
- European and Developing Countries Clinical Trials Partnership Grant [IP.07.32080.002]
- European Union [PIRSES-GA2011-295214, FP7-Health-F3-2012-305578]
- MRC [MR/K012118/1] Funding Source: UKRI
- Medical Research Council [MR/K012118/1] Funding Source: researchfish
- The Francis Crick Institute [10219, 10218] Funding Source: researchfish
- Wellcome Trust [104803/Z/14/Z] Funding Source: researchfish
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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-gamma 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 ELISPOTand flow cytometry. There were significantly increased IFN-gamma 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(+) Va24(+)) 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.
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