Rationale: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) induced by combination antiretroviral therapy (cART) has been attributed to dysregulated expansion of tuberculin PPD-specific IFN-γ-secreting CD4+ T cells. Objectives: To investigate the role of type 1 helper T cell expansions and regulatory T cells in HIV-TB IRIS. Methods: Longitudinal and cross-sectional studies of Mycobacterium tuberculosis-specific IFN-γ enzyme-linked immunospot responses and flow cytometric analysis of blood cells from a total of 129 adults with HIV-1-associated tuberculosis, 98 of whom were prescribed cART. Measurements and Main Results: In cross-sectional analysis the frequency of IFN-γ- secreting T cells recognizing early secretory antigenic target (ESAT)-6, α-crystallins 1 and 2, and PPD of M. tuberculosis was higher in patients with TB-IRIS than in similar patients treated for both HIV-1 and tuberculosis who did not develop IRIS (non-IRIS; P ≤ 0.03). The biggest difference was in the recognition of α-crystallin molecules: peptide mapping indicated a polyclonal response. Flow cytometric analysis indicated equal proportions of CD4+ and CD8+ cells positive for activation markers HLA-DR and CD71 in both patients with TB-IRIS and non-IRIS patients. The percentage of CD4+ cells positive for FoxP3 (Forkhead box P3) was low in both groups (TB-IRIS, 5.3 ± 4.5; non-IRIS, 2.46 ± 2.46; P = 0.13). Eight weeks of longitudinal analysis of patients with tuberculosis who were starting cART showed dynamic changes in antigen-specific IFN-γ-secreting T cells in both the TB-IRIS and non-IRIS groups: the only significant trend was an increased response to PPD in the TB-IRIS group (P = 0.041). Conclusions: There is an association between helper T-cell type 1 expansions and TB-IRIS, but the occurrence of similar expansions in non-IRIS brings into question whether these are causal. The defect in immune regulation responsible for TB-IRIS remains to be fully elucidated.
|Number of pages||7|
|Journal||American Journal of Respiratory and Critical Care Medicine|
|Publication status||Published - 15 Nov 2008|