LPS-Binding Protein and IL-6 Mark Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome in HIV Patients

Abstract

BackgroundTuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains a poorly understood complication in HIV-TB co-infected patients initiating antiretroviral therapy (ART). The role of the innate immune system in TB-IRIS is becoming increasingly apparent, however the potential involvement in TB-IRIS of a leaky gut and proteins that interfere with TLR stimulation by binding PAMPs has not been investigated before. Here we aimed to investigate the innate nature of the cytokine response in TB-IRIS and to identify novel potential biomarkers.MethodsFrom a large prospective cohort of HIV-TB co-infected patients receiving TB treatment, we compared 40 patients who developed TB-IRIS during the first month of ART with 40 patients matched for age, sex and baseline CD4 count who did not. We analyzed plasma levels of lipopolysaccharide (LPS)-binding protein (LBP), LPS, sCD14, endotoxin-core antibody, intestinal fatty acid-binding protein (I-FABP) and 18 pro-and anti-inflammatory cytokines before and during ART. ResultsWe observed lower baseline levels of IL-6 (p = 0.041), GCSF (p = 0.036) and LBP (p = 0.016) in TB-IRIS patients. At IRIS event, we detected higher levels of LBP, IL-1RA, IL-4, IL-6, IL-7, IL-8, G-CSF (p ≤ 0.032) and lower I-FABP levels (p = 0.013) compared to HIV-TB co-infected controls. Only IL-6 showed an independent effect in multivariate models containing significant cytokines from pre-ART (p = 0.039) and during TB-IRIS (p = 0.034). ConclusionWe report pre-ART IL-6 and LBP levels as well as IL-6, LBP and I-FABP levels during IRIS-event as potential biomarkers in TB-IRIS. Our results show no evidence of the possible contribution of a leaky gut to TB-IRIS and indicate that IL-6 holds a distinct role in the disturbed innate cytokine profile before and during TB-IRIS. Future clinical studies should investigate the importance and clinical relevance of these markers for the diagnosis and treatment of TB-IRIS.

Antigen-Specific Interferon-Gamma Responses and Innate Cytokine Balance in TB-IRIS

“…It has been suggested that disturbances in the innate immune system [22] or in the interplay between the innate and adaptive immune system [11] could drive TB-IRIS pathogenesis. This is supported by repeated findings of elevated levels of IL-6 and TNFα, among other innate cytokines, during TB-IRIS [14], [16], [23]–[26]. Interestingly, elevated innate cytokine production has also been reported in TB-IRIS patients after toll-like receptor (TLR) 2 stimulation with lipomannan, a TB pathogen-associated molecular pattern (PAMP) [27].…”

Robust Reconstitution of Tuberculosis-Specific Polyfunctional CD4+T-Cell Responses and Rising Systemic Interleukin 6 in Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

“…Additionally, some control patients have rapid recovery of tuberculosisspecific T-cell function similar to TB-IRIS patients, but do not progress to IRIS [15][16][17]. In an exploratory analysis, we tested the hypothesis that increases in IL-6 levels, which have been associated with IRIS [11,13,15,20], would be less in control patients who also had rapid recovery of cellular immune function compared to TB-IRIS patients using previously determined IL-6 concentrations [15] and rank-sum tests. In this analysis, controls were restricted to those described in this study who had increases at week 4 of ART that were greater than the overall group median for IFN-γ + /IL-2 + /TNF-α + CD4 + T-cells, CD4 cell counts, and tuberculosis-specific IFN-γ responses by enzyme-linked immunospot (ELISpot) assay [15].…”

“…Immunologically, higher pre-ART levels of immune activation and rapid increases in tuberculosis-specific interferon gamma (IFN-γ)-producing cells after ART initiation in HIV-infected adults have been associated with development of TB-IRIS [7,[9][10][11][12]. However, in several recent studies, levels of pre-ART immune activation were actually lower in TB-IRIS patients vs controls [13][14][15], and multiple reports have indicated that patients without TB-IRIS may also have robust increases in levels of pathogen-specific immune responses on ART [16,17]. Existing data are therefore inconclusive about whether higher levels of pre-ART immune activation predispose to TB-IRIS and whether tuberculosis-specific T-cells are involved in TB-IRIS pathogenesis.…”

Persistent High Mortality in Advanced HIV/TB Despite Appropriate Antiretroviral and Antitubercular Therapy: an Emerging Challenge

“…Multiple studies have demonstrated rapid increases in pro-inflammatory cytokines in patients developing TB-IRIS, and immune enhancement with interventions other than ART could therefore be detrimental (74–77). On the other hand, it is equally plausible that IL-7 or other cytokine therapy could decrease TB-IRIS risk if this risk is driven primarily by antigen load during ART, as suggested by data linking IRIS risk with a shorter interval between TB treatment and ART initiation (10, 12).…”