Cytotoxic Mediators in Paradoxical HIV–Tuberculosis Immune Reconstitution Inflammatory Syndrome
Year: 2015
Type: article
Study design: Observational Study
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.
Source: The Journal of Immunology
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,500
Awards: Quadruple intervention against tuberculosis., G2006052962, The use of modern molecular tools to understand and intervene in the spread of multidrug-resistant tuberculosis in rural South Africa., Clinical proteomic and genomic characterisation of the immune reconstitution inflammatory syndrome in HIV-associated tuberculosis, G3526168739, G3713413865, G374283917, Host directed therapies against tuberculosis., European and South African HIV co-infection research consortium, G5719191341, Host directed therapies against tuberculosis., G5858598186, Defining mechanisms driving immunopathology in Tuberculosis-HIV Co-infection., G6079531540, Pathogen COinfection:
HIV, Tuberculosis, Malaria and Hepatitis C virus, G6346810159, G76681233, Establishment of a Centre for Clinical Infectious Diseases Research at the University of Cape Town (Wellcome-UCT-CCIDR).
OpenAlex ID: W2131876280