Mycobacterial Antigen Driven Activation of CD14++CD16− Monocytes Is a Predictor of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

Abstract

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an aberrant inflammatory response occurring in a subset of TB-HIV co-infected patients initiating anti-retroviral therapy (ART). Here, we examined monocyte activation by prospectively quantitating pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients from a South Indian cohort at baseline and following ART initiation at the time of IRIS, or at equivalent time points in non-IRIS controls. Pro-inflammatory biomarkers of innate and myeloid cell activation were increased in plasma of IRIS patients pre-ART and at the time of IRIS; this association was confirmed in a second cohort in South Africa. Increased expression of these markers correlated with elevated antigen load as measured by higher sputum culture grade and shorter duration of anti-TB therapy. Phenotypic analysis revealed the frequency of CD14++CD16− monocytes was an independent predictor of TB-IRIS, and was closely associated with plasma levels of CRP, TNF, IL-6 and tissue factor during IRIS. In addition, production of inflammatory cytokines by monocytes was higher in IRIS patients compared to controls pre-ART. These data point to a major role of mycobacterial antigen load and myeloid cell hyperactivation in the pathogenesis of TB-IRIS, and implicate monocytes and monocyte-derived cytokines as potential targets for TB-IRIS prevention or treatment.

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].…”

“…Furthermore, innate immune responses involving rapid increases in proinflammatory cytokines such as interleukin 6 (IL-6) on ART have also been relatively consistently implicated in the pathogenesis of TB-IRIS [11,20].…”

Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

“…Prior studies have shown that the development of TB-IRIS is independently associated with expansion of CD14 ++ CD16 2 monocytes (22), which prompted us to investigate whether monocyte activation in TB-IRIS is associated with markers of inflammasome ++ monocyte subsets and compared data across the three clinical groups. We found that all these activation markers were increased to a variable degree in all three monocyte subpopulations across the three groups of patients, with CD64 expression showing consistent elevation in all three monocyte subsets.…”

Early initiation of antiretroviral treatment: Challenges in the Middle East and North Africa

“…The reason why IRIS affects certain patients is not thoroughly understood, but may be linked to monocytederived responses [44] . Our expanding knowledge about human leukocyte antigens associations observed among non-seroconverting partners of HIV patients should uncover a role for genetic factors in the future [45] .…”