Role of IL-6 in Mycobacterium avium–Associated Immune Reconstitution Inflammatory Syndrome

Abstract

Immune Reconstitution Inflammatory Syndrome (IRIS) is a major adverse event of antiretroviral therapy (ART) in HIV infection, and paradoxically occurs as HIV viremia is suppressed and CD4 T cell numbers recover. IRIS reflects pathogenic immune responses against opportunistic infections acquired during the period of immunodeficiency, but little is understood about the mechanisms of inflammatory pathology. Here we show that IL-6 and CRP levels transiently rise at the time of the IRIS event in HIV-infected patients umasking Mycobacterium avium complex (MAC) infection after starting ART. To directly test the role of IL-6 in IRIS pathology, we employed a model of experimentally inducible IRIS in which M. avium infected T cell deficient mice undergo a fatal inflammatory disease after reconstitution with CD4 T cells. We find that IL-6 neutralization reduces CRP levels, alleviates wasting disease and extends host survival during experimental IRIS. Moreover, we show that combined blockade of IL-6 and IFNγ further reduces IRIS pathology, even after the onset of wasting disease. The combination of these clinical and experimental-model data show that the IL-6 pathway is not only a biomarker of mycobacterial IRIS but also a major mediator of pathology distinct from IFNγ, and may be a useful target for therapeutic intervention.

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

“…Previous studies noted that many patients without TB-IRIS have similarly rapid increases in pathogen-specific immune responses on ART, questioning the role of these cells in development of the syndrome [16,17]. Our exploratory analysis of changes in IL-6 levels, which is consistently implicated in IRIS immunopathology [11,20], in non-IRIS controls who also had rapid cellular immune recovery needs confirmation, but preliminarily suggests that development of TB-IRIS may be dependent on the coordinated recovery of both adaptive and innate immune function. We have previously documented that granulocyte colony-stimulating factor and TNF-α increase on ART in TB-IRIS patients in this cohort, whereas these biomarker levels (and granulocyte macrophage colony-stimulating factor) decrease in non-IRIS controls [15].…”

“…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].…”

Paradoxical reactions and immune reconstitution inflammatory syndrome in tuberculosis

“…69 Immunotherapy for PR/IRIS has also been explored in the mouse MAC-IRIS model, in which the blockade of interleukin 6 (IL-6) signalling with neutralizing antibodies extended survival and alleviated pathology. 70 However, as both PR and IRIS are self-limiting in many cases, the specific utility of corticosteroids and other immune-modulating treatments should be considered in the context of the impact of inflammation in specific clinical scenarios.…”

Correlation of Interleukin-6 levels and lectins during Schistosoma haematobium infection

“…Similar observations of interaction of IL-6 and the C-reactive protein (CRP) were made in HIV patients with the immune reconstitution inflammatory syndrome (IRIS), where IL-6 and CRP levels were positively correlated [23]. It is clear that MBL and other functional analogues may be modulated by IL-6 stimuli.…”