Neutrophil activation and enhanced release of granule products in HIV-TB immune reconstitution inflammatory syndrome.

Nakiwala, JK; Walker, NF; Diedrich, CR; Worodria, W; Meintjes, G; Wilkinson, RJ; Mayanja-Kizza, H; Colebunders, R; Kestens, L; Wilkinson, KA; Lowe, DM; (2017) Neutrophil activation and enhanced release of granule products in HIV-TB immune reconstitution inflammatory syndrome. Journal of acquired immune deficiency syndromes (1999). ISSN 1525-4135 DOI:

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Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) remains incompletely understood. Neutrophils are implicated in tuberculosis pathology but detailed investigations in TB-IRIS are lacking. We sought to further explore the biology of TB-IRIS and in particular the role of neutrophils. Two observational, prospective cohort studies in HIV/TB co-infected patients starting antiretroviral therapy, one to analyze gene expression and subsequently one to explore neutrophil biology. nCounter gene expression analysis was performed in TB-IRIS patients (n=17) versus antiretroviral-treated HIV/TB co-infected controls without IRIS (n=17) in Kampala, Uganda. Flow cytometry was performed in TB-IRIS patients (n=18) and controls (n=11) in Cape Town, South Africa to determine expression of neutrophil surface activation markers, intracellular cytokines and Human Neutrophil Peptides (HNP). Plasma neutrophil Elastase and HNP1-3 were quantified using ELISA. Lymph node immunohistochemistry was performed on three further TB-IRIS cases. There was a significant increase in gene expression of S100A9 (p=0.002), NLRP12 (p=0.018), COX-1 (p=0.025) and IL-10 (p=0.045) two weeks after ART initiation in Ugandan TB-IRIS patients versus controls, implicating neutrophil recruitment. IRIS patients in both cohorts demonstrated increases in blood neutrophil count, plasma HNP and elastase concentrations from ART initiation to week two. CD62L (L-selectin) expression on neutrophils increased over 4 weeks in South African controls while IRIS patients demonstrated the opposite. Intense staining for the neutrophil marker CD15 and IL-10 was seen in necrotic areas of TB-IRIS patients' lymph nodes. Neutrophils in TB-IRIS are activated, recruited to sites of disease and release granule contents, contributing to pathology.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Clinical Research
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PubMed ID: 29135655


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