Abstract
TB-IRIS is an abnormal inflammatory response in a subset of HIV-TB co-infected patients shortly after initiation of anti-retroviral therapy (ART). Therapy in these patients could have greatly improved the life expectancy as ART reconstitutes the function and number of CD4+ T cells and many patients see improvement in symptoms but paradoxically up to 54% of co-infected patients develop TB-IRIS. Different studies have indicated that both innate and adaptive immunity are involved in the pathology of IRIS but the role of macrophages in abnormal activation of CD4+ T cells is poorly understood. Since macrophages are one of the major antigen-presenting cells and are infected by M.tb at a high frequency, they are very much likely to be involved in the development of TB-IRIS. In this study, we have developed a mouse model of experimental IRIS, in which M.tb-infected T-cell knockout mice undergo a fatal inflammatory disease after CD4+ T cell reconstitution. Lung macrophages and blood monocytes from M.tb-infected TCRβ−/− mice showed upregulated expression of cell surface activation markers and also showed higher mRNA expression of inflammation-associated chemokines and matrix metalloproteases responsible for tissue damage. Furthermore, cytokine and TLR signaling feedback mechanism to control excessive inflammation was also found to be dysregulated in these macrophages under lymphopenic conditions. Previous studies have shown that hyperactive CD4+ T cells are responsible for disease induction and our study shows that somehow macrophages are in a higher activated state when infected with M.tb in an immune-deficient condition, which results in excessive activation of the adoptively transferred CD4+ T cells. Understanding of the mechanisms underlying the pathophysiology of TB-IRIS would facilitate identification of prospective biomarkers for disease development in HIV-TB co-infected patients before starting antiretroviral therapy.
Highlights
HIV-M.tb co-infection has been the most challenging concern in the efforts to scale up antiretroviral therapy (ART) because a subset of patients develop a condition called TB-IRIS, which arises as M.tb-specific CD4+ T cells re-emerge after anti-retroviral therapy (ART) initiation [1]
This drop in core and surface body temperature could be because of heightened inflammation as part of the body’s natural defense [17]. These results suggest that adoptive transfer of M.tb primed CD4+ T cells into M.tbinfected mice lacking T cells is sufficient to drive TB-IRIS, resulting in rapid wasting, excessive inflammation, and death
M.tb infection resulted in increased expression of Tumor necrosis factor receptor-associated factor 6 (TRAF6) in TCRb−/− as well as in wild-type mice but transfer of CD4+ T cells further significantly increased the mRNA expression of TRAF6 in TCRb−/− mice while no change was found in wild-type mice. These findings provide evidence that in the absence of T cells, there is inadequate control of inflammatory activation of macrophages due to dysregulated feedback mechanisms; after interaction with reconstituted CD4+ T cells, this leads to the cytokine storm orchestrated by hyperactivated macrophages with higher secretion of Matrix metalloproteinases (MMPs) and chemokines resulting in tissue damage and disease pathology
Summary
HIV-M.tb co-infection has been the most challenging concern in the efforts to scale up antiretroviral therapy (ART) because a subset of patients develop a condition called TB-IRIS, which arises as M.tb-specific CD4+ T cells re-emerge after ART initiation [1]. There are two forms of TB-IRIS, “paradoxical” and “unmasking”; in paradoxical TB-IRIS, before ART initiation, HIV patients have confirmed diagnosis of TB with a positive response to anti-mycobacterial therapy. M.tb survive inside the macrophages in maturation-arrested phagosomes followed by recruitment of M.tb-specific T lymphocytes and other immune cells, which result in granuloma formation [10, 11]. A couple of studies have suggested that dysregulated macrophage function in the CD4+ T lymphocyte-deficient hosts could be responsible for the development of TB-IRIS in patients [14, 15, 16]. Notwithstanding these research studies, mostly done with peripheral blood compartment of humans, the underlying mechanisms mediating TB-IRIS remain to be fully elucidated
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