Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome-An Extempore Game of Misfiring with Defense Arsenals

Abstract

The lethal combination involving TB and HIV, known as "syndemic" diseases, synergistically act upon one another to magnify the disease burden. Individuals on anti-retroviral therapy (ART) are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). The underlying inflammatory complication includes the rapid restoration of immune responses following ART, eventually leading to exaggerated inflammatory responses to MTB antigens. TB-IRIS continues to be a cause of morbidity and mortality among HIV/TB coinfected patients initiating ART, and although a significant quantum of knowledge has been acquired on the pathogenesis of IRIS, the underlying pathomechanisms and identification of a sensitive and specific diagnostic marker still remain a grey area of investigation. Here, we reviewed the latest research developments into IRIS immunopathogenesis, and outlined the modalities to prevent and manage strategies for better clinical and diagnostic outcomes for IRIS.

Keywords: ART; HIV; IRIS; biomarkers; inflammation; tuberculosis.

Figure 1

Schematic representation of HIV/TB-immune reconstitution inflammatory disease. Following the initiation of anti-retroviral treatment (ART), some individuals with HIV and active TB disease display strong immune activation resulting in new or recurrent TB symptoms referred to as paradoxical TB-IRIS [11,32]. Paradoxical TB-IRIS usually develops during the first four weeks of ART and results in the flaring up of TB symptoms such as a new infiltrate, serous effusions, worsening of existing lesions, and soft tissue abscesses [33]. Unmasking TB-IRIS represents a subcategory of ART-associated TB observed in patients with undiagnosed or subclinical TB before initiation of ART. In unmasking TB-IRIS, a subclinical TB infection remains undiagnosed until ART-induced immune reconstitution elicits an exaggerated presentation of the disease [35,36]. Unmasking TB-IRIS usually occurs within three months of starting ART with high levels of clinical manifestations including lymphadenitis, abscess, and respiratory failure [37].

Figure 2

Proposed model of inflammasome-mediated pathogenesis of TB-IRIS. (1–2) In a microenvironment with low levels of IFN-γ, by interfering with the phagosome-lysosome fusion, MTB can evade the monocyte/macrophage bactericidal effectors [89] thereby continuing intracellular replication [90] leading to mitochondrial stress [91]. (3) Intracellular MTB accumulation and mtDNA result results inNLRP3 and AIM2 inflammasome assembly and activation of casp1. (4–5) In order to become active, the inactive form (pro-IL 18) of the potent pro-inflammatory cytokine IL-18 must first be processed by casp1 (6–9) In addition to processing IL-18, casp1 also promotes pyroptosis, an inflammatory form of programmed cell death. Pyroptosis results in the expulsion of mtDNA into the bloodstream which in turn amplifies inflammatory responses. (10) IFN-γ and NO negatively regulate NLRP3 and AIM2.