IFN-γ-independent immune markers of Mycobacterium tuberculosis exposure

Abstract

SUMMARY Exposure to Mycobacterium tuberculosis (Mtb) results in heterogeneous clinical outcomes including primary progressive tuberculosis (TB) and latent Mtb infection (LTBI). Mtb infection is identified using the tuberculin skin test (TST) and IFN-γ release assay (IGRA), and a positive result may prompt chemoprophylaxis to prevent progression to TB. Here, we report a cohort of Ugandan household contacts, highly exposed to Mtb yet IGRA and TST negative, “resisting” development of classical LTBI. We show that “resisters” possess IgM, class-switched IgG antibody responses and non IFN-γ T-cell responses to Mtb-specific proteins ESAT6 and CFP10, immunologic evidence of exposure to Mtb. Compared to subjects with classical LTBI, “resisters” display enhanced antibody avidity and distinct Mtb-specific IgG Fc profiles. These data reveal a distinct adaptive immune profile among Mtb exposed subjects, supporting an expanded definition of the host response to Mtb exposure with implications for public health and the design of clinical trials.

PD‐1‐expressing MAIT cells from patients with tuberculosis exhibit elevated production of CXCL13

“…The role of humoral immunity in protection against TB has received attention recently . People who are highly exposed to Mtb but resistant to the disease show IgM and IgG antibody responses and enhanced antibody avidity . Antibody Fc functional profiles are different between individual with latent TB infection and patients with active TB, and antibodies from latent TB infection promote enhanced macrophage killing of intracellular Mtb .…”

“…40,41 People who are highly exposed to Mtb but resistant to the disease show IgM and IgG antibody responses and enhanced antibody avidity. 42 Antibody Fc functional profiles are different between individual with latent TB infection and patients with active TB, and antibodies from latent TB infection promote enhanced macrophage killing of intracellular Mtb. 43 Protective antibodies against Mtb infection are identified from latent and uninfected healthcare workers that show effect in aerosol infected mice model.…”

Analysis of cellular and soluble profiles in QuantiFERON nonconverters, converters, and reverters in the Gambia

“…Importantly, longitudinal studies of these “resisters” confirm a much lower rate of progression to TB disease than those with LTBI . However, there are limitations in our interpretation of these cohorts based solely on IFN‐γ production with a recent paper highlighting potential IFN‐γ‐independent immune markers of Mycobacterium tuberculosis exposure . Thus, an expanded definition of the host response to Mtb exposure is needed …”

“…11 However, there are limitations in our interpretation of these cohorts based solely on IFN-γ production with a recent paper highlighting potential IFN-γ-independent immune markers of Mycobacterium tuberculosis exposure. 12 Thus, an expanded definition of the host response to Mtb exposure is needed. 12 Sterilizing immunity is rarely achieved in animal and human Mtb infections.…”

“…12 Thus, an expanded definition of the host response to Mtb exposure is needed. 12 Sterilizing immunity is rarely achieved in animal and human Mtb infections. However, TST reversion was evident in 22% of guinea pigs exposed for up to 5 months to TB patients and this correlated with clearance of an established infection.…”