TY - JOUR
T1 - Neutrophil activation and enhanced release of granule products in HIV-TB immune reconstitution inflammatory syndrome
AU - Nakiwala, Justine K.
AU - Walker, Naomi F.
AU - Diedrich, Collin R.
AU - Worodria, William
AU - Meintjes, Graeme
AU - Wilkinson, Robert J.
AU - Mayanja-Kizza, Harriet
AU - Colebunders, Robert
AU - Kestens, Luc
AU - Wilkinson, Katalin A.
AU - Lowe, David M.
N1 - NPP; CDOI
PY - 2018
Y1 - 2018
N2 - Background: 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.Setting: Two observational, prospective cohort studies in HIV/TB coinfected patients starting antiretroviral therapy (ART), 1 to analyze gene expression and subsequently 1 to explore neutrophil biology.Methods: nCounter gene expression analysis was performed in patients with TB-IRIS (n = 17) versus antiretroviral-treated HIV/TB coinfected controls without IRIS (n = 17) in Kampala, Uganda. Flow cytometry was performed in patients with TB-IRIS (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 (HNPs). Plasma neutrophil elastase and HNP1-3 were quantified using enzyme-linked immunosorbent assay. Lymph node immunohistochemistry was performed on 3 further patients with TB-IRIS.Results: 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) 2 weeks after ART initiation in Ugandan patients with TB-IRIS versus controls, implicating neutrophil recruitment. Patients with IRIS in both cohorts demonstrated increases in blood neutrophil count, plasma HNP and elastase concentrations from ART initiation to week 2. CD62L (L-selectin) expression on neutrophils increased over 4 weeks in South African controls whereas patients with IRIS demonstrated the opposite. Intense staining for the neutrophil marker CD15 and IL-10 was seen in necrotic areas of the lymph nodes of the patients with TB-IRIS.Conclusions: Neutrophils in TB-IRIS are activated, recruited to sites of disease, and release granule contents, contributing to pathology.
AB - Background: 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.Setting: Two observational, prospective cohort studies in HIV/TB coinfected patients starting antiretroviral therapy (ART), 1 to analyze gene expression and subsequently 1 to explore neutrophil biology.Methods: nCounter gene expression analysis was performed in patients with TB-IRIS (n = 17) versus antiretroviral-treated HIV/TB coinfected controls without IRIS (n = 17) in Kampala, Uganda. Flow cytometry was performed in patients with TB-IRIS (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 (HNPs). Plasma neutrophil elastase and HNP1-3 were quantified using enzyme-linked immunosorbent assay. Lymph node immunohistochemistry was performed on 3 further patients with TB-IRIS.Results: 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) 2 weeks after ART initiation in Ugandan patients with TB-IRIS versus controls, implicating neutrophil recruitment. Patients with IRIS in both cohorts demonstrated increases in blood neutrophil count, plasma HNP and elastase concentrations from ART initiation to week 2. CD62L (L-selectin) expression on neutrophils increased over 4 weeks in South African controls whereas patients with IRIS demonstrated the opposite. Intense staining for the neutrophil marker CD15 and IL-10 was seen in necrotic areas of the lymph nodes of the patients with TB-IRIS.Conclusions: Neutrophils in TB-IRIS are activated, recruited to sites of disease, and release granule contents, contributing to pathology.
KW - tuberculosis
KW - HIV-1
KW - neutrophils
KW - immune reconstitution inflammatory syndrome
KW - IRIS
KW - PULMONARY TUBERCULOSIS
KW - ANTIRETROVIRAL THERAPY
KW - INFECTED ADULTS
KW - COINFECTION
KW - BIOMARKERS
KW - RECEPTOR
KW - SYSTEM
KW - DEATH
KW - CELLS
KW - AXIS
M3 - A1: Web of Science-article
SN - 1525-4135
VL - 77
SP - 221
EP - 229
JO - Journal of Acquired Immune Deficiency Syndromes
JF - Journal of Acquired Immune Deficiency Syndromes
IS - 2
ER -