Immunological aspects of latent tuberculosis infection during pregnancy

Abstract: Pregnancy-induced immune modulation might lead to reactivation of latent tuberculosis infection (LTBI). This thesis explores aspects of immune-based LTBI diagnostics and how pregnancy affects the immune control of Mycobacterium tuberculosis (Mtb) infection. We studied a prospective cohort of women recruited during pregnancy in Ethiopia. LTBI testing was performed by quantification of interferon-γ (IFN-γ) in Mtb-antigen- stimulated whole blood supernatants using the QuantiFERON-TB Gold Plus (QFT) assay.In paper I, we found that 277/829 (33%) of pregnant women had LTBI using the conventional IFN-γ cut-off level (0.35 IU/ml). However, borderline results (0.20-0.70 IU/ml) were common, especially in HIV-positive women. In paper II, we characterized Mtb-antigen cytokine responses for LTBI classification in women with borderline IFN-γ results. A combination of MCP-2, IP-10 and IL-1ra classified 42% of women with borderline IFN-γ as having high likelihood of LTBI. In paper III, we studied longitudinal patterns of Mtb-triggered IFN-γ secretion during pregnancy and post-partum. We observed that Mtb-stimulated IFN-γ response was elevated during the 3rd trimester compared to early pregnancy and post-partum. In paper IV, we investigated longitudinal kinetics of Mtb-specific and -non-specific cytokine responses in women with LTBI. We found elevated expression of Mtb-specific IL-2 and IP-10, and reduced TGF-β1, secretion at the 3rd trimester. Non-specific levels of IL-2, IP-10 and MCP-2 were elevated post-partum in women with LTBI. In conclusion, these findings suggest that cytokines other than IFN-γ, could be used as biomarkers to assess LTBI status of pregnant women. The dynamic immune responses in women with LTBI indicate increased exposure to Mtb at later stages of pregnancy, which in turn suggests that LTBI is transiently reactivated during pregnancy.