The results of this systematic review show that the presence of TB-IRIS was concomitant with the restoration of the Mtb-specific immune response. In the majority of the evaluated studies (11/15), a higher number of Mtb specific-IFN-γ producing cells [18
] and of specific multifunctional T-lymphocytes (IFN-γ and TNF-producing) [22
] as well as higher production of Th1 cytokines [18,23,35,36] were found in TB-IRIS patients compared to non-IRIS individuals. However, the peak in the number of antigen-specific IFN-γ-producing cells did not always coincide with the onset of IRIS, occasionally occurring after IRIS resolution [22
]. In only four out of 15 studies, three using IGRA and one using ELISPOT, differences in IFN-γ production in response to Mtb antigens were not reported between groups [29
]. Interestingly, the aforementioned study using ELISPOT also found a low production of IFN-γ in response to cytomegalovirus and influenza antigens in TB-IRIS patients, suggesting that those patients were immunosuppressed [29
]. None of studies using IGRA found any difference in the production of IFN-g between TB-IRIS and non-IRIS groups. This could indicate that ELISPOT sensitivity to Mtb antigens may be higher than IGRA in patients with advanced HIV infection [38
The low IGRA sensitivity observed could also be explained by the antigenic components of this test, ESAT-6, CFP-10 and TB 7.7, which are derived from region of difference 1 (RD1) in the Mtb genome. In fact, two studies that evaluated ESAT-6 response in patients with paradoxal TB-IRIS using ELISPOT detected low number of spot forming cells (SFC), whereas the number of SFC in response to protein purified derivate to Mtb (PPD) was high [18
]. Conversely, higher IFN-γ-production in response to both PPD and RD1 antigens, including ESAT-6, was observed in patients with unmasking TB-IRIS compared to non-IRIS individuals [31
]. As RD1 antigens are solely derived from Mtb, as opposed to PPD, it has been proposed that the inflammatory
response in unmasking TB-IRIS would be triggered by antigens from live bacteria, while in paradoxal TB-IRIS that response is mainly triggered by antigens from dead bacteria [30
]. Thus, IGRA could be useful distinguishing unmasking and paradoxal TB-IRIS.
This systemic review also found a low frequency of polyfunctional (IFN-g+
T-lymphocytes in response to PPD in TB-IRIS patients. The majority of patients had a specific multifunctional T-lymphocytes secreting IFN-γ and TNF, but not IL-2 in response to Mtb antigens stimulation [22,28]. These findings suggest that the quality of the specific immune response to Mtb antigens recovery is limited [28
]. Mono-functional T-lymphocytes (CD4+
) response is mainly found during persistent infection with high antigen load, as occurs during an infection associated with IRIS. Maintaining a high level of antigens impairs the establishment of a polyfunctional response capable of sustaining its own expansion and effector activity [40
In addition to a high secretion of Th1 cytokines (IFN-γ, IL-2, IL-12) in response to Mtb antigens, several studies found higher production of cytokines and chemokinesreleased from innate immune cells (TNF, IL-6, IL-1β, IL-10, IL-18, CCL-5, CCL-2, CXCL10) [18
] in patients with TB-IRIS compared to non-IRIS individuals. Non-specific release of proinflammatory cytokines and chemokines may induce the systemic inflammatory reaction present in IRIS. It has been proposed that once HAART controls the viral load and promotes the reconstitution of T-lymphocyte repertoires, specific lymphocytes could produce cytokines that stimulate macrophages which were previously infected by intracellular pathogens during the period of immunosuppression (AIDS). In turn, these macrophages and other cells of the innate immune system would secrete high levels of proinflammatory cytokines and chemokines, which would result in the inflammatory manifestations of IRIS [41
Moreover, inflammatory response during TB-IRIS could also be caused by a dysfunction of regulatory T-lymphocytes. Two studies found similar frequencies of Foxp3+
T-cells in patients with TB-IRIS and non-IRIS individuals [20
]. Tan et al studying three patients with TB-IRIS, observed an increase in the proportion of T-cells with regulatory profile (CD4+
) in comparison to healthy controls, but these findings have not been compared to patients who did not develop IRIS [30
]. This review was unable to find studies evaluating the regulatory T-cell function in TB-IRIS patients. This review has some limitation we did not assess the evidence strength of results presented in the articles included and also the risk of bias in these articles.
In conclusion, the findings presented in this review suggest that during TB-IRIS an increase in the specific response to Mtb antigens occurs, as evidenced by a higher number of IFN-γ producing cells and by higher levels of cytokines. The potential role of innate immune
response, with increased production of proinflammatory cytokines and chemokines, as well as activated NK cells and macrophages was also observed during TB-IRIS. Taken together, these data suggest that expansion of Mtb specific cells may not be the determining factor for the occurrence of IRIS. Further studies are needed to better evaluate the dynamic of restoration of Mtb-specific memory cells and to clarify the role of innate immune responses in immunopathogenesis of TB-IRIS. Modulating the proinflammatory cytokine storm observed during IRIS may be beneficial to patients by decreasing morbidity and mortality of TB-IRIS patients.