A Functional Role for Antibodies in Tuberculosis

Abstract

Summary While a third of the world carries the burden of tuberculosis, disease control has been hindered by the lack of tools including a rapid, point-of-care diagnostic and a protective vaccine. In many infectious diseases, antibodies (Abs) are powerful biomarkers and important immune mediators. However, in Mycobacterium tuberculosis (Mtb) infection, a discriminatory or protective role for humoral immunity remains unclear. Using an unbiased antibody profiling approach we show that individuals with latent tuberculosis infection (Ltb) and active tuberculosis disease (Atb) have distinct Mtb-specific humoral responses, such that Ltb infection is associated with unique Ab Fc functional profiles, selective binding to FcγRIII, and distinct Ab glycosylation patterns. Moreover, compared to Abs from Atb, Abs from Ltb drove enhanced phagolysosomal maturation, inflammasome activation, and most importantly, macrophage killing of intracellular Mtb. Combined, these data point to a potential role for Fc-mediated Ab effector functions, tuned via differential glycosylation, in Mtb control.

Latently and uninfected healthcare workers exposed to TB make protective antibodies against Mycobacterium tuberculosis

“…None of five antibodies tested-from three protective and two nonprotective donors-enhanced phagocytosis by THP-1 cells (Fig. S4A), in keeping with other recent findings that opsonophagocytosis is not associated with protection (20). Given that nude mice do not have a simple T-cell immune defect, the WBA also allowed us to determine whether T cells played a role in antibody-mediated protection in vitro.…”

“…A meta-analysis of risk of active TB found a substantially decreased risk in those with prior LTBI (34). Additional recent work also verified that antibodies from LTBI individuals offered superior protection in a macrophage infection model compared with those isolated from active TB patients (20). Therefore, it may be that some individuals exposed to Mtb with evidence of LTBI may be able to mount protective antibody responses to prevent additional active infection.…”

“…However, the murine protection assay is both costly and cumbersome and requires a large amount of antibody. In vitro assays using macrophage-mediated killing might identify some protective antibodies (20,24,27), but given the dependence of T-cell immunity for full protection of the antibodies identified by our studies, they may not identify all donors making protective antibodies. We wanted to determine whether the WBA could be used to identify donors who make antibodies that are also protective in the murine assay.…”

“…Although it was known that both active TB patients and healthy subjects make detectable antibody responses to Mtb (19)(20)(21), it was not known whether any of these antibodies afford direct protection against infection. We decided to test total antibody from our subjects in a mouse protection assay (Fig.…”

“…Although there were significant differences between the four groups, the only obvious difference between the protective and nonprotective (26) antibody groups was the abundance of IgG3 at days 1 and 3. Antibodies have many functions, only one of which is recognition of specific antigens by the variable portion of the molecule (20,(22)(23)(24), and a recent report suggested that protective effects of anti-TB antibodies may depend on IgA (24). We, therefore, tested the relative abundance of Ig subclasses from the HCWs (Fig.…”