Human isotype‐dependent inhibitory antibody responses against Mycobacterium tuberculosis

Abstract

Accumulating evidence from experimental animal models suggests that antibodies play a protective role against tuberculosis (TB). However, little is known about the antibodies generated upon Mycobacterium tuberculosis (MTB) exposure in humans. Here, we performed a molecular and functional characterization of the human B‐cell response to MTB by generating recombinant monoclonal antibodies from single isolated B cells of untreated adult patients with acute pulmonary TB and from MTB‐exposed healthcare workers. The data suggest that the acute plasmablast response to MTB originates from reactivated memory B cells and indicates a mucosal origin. Through functional analyses, we identified MTB inhibitory antibodies against mycobacterial antigens including virulence factors that play important roles in host cell infection. The inhibitory activity of anti‐MTB antibodies was directly linked to their isotype. Monoclonal as well as purified serum IgA antibodies showed MTB blocking activity independently of Fc alpha receptor expression, whereas IgG antibodies promoted the host cell infection. Together, the data provide molecular insights into the human antibody response to MTB and may thereby facilitate the design of protective vaccination strategies.

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

“…Our study addresses an important point of controversy in the TB field: whether antibodies play a role in immunity against Mtb (20,24), and it also identifies components of this immunity, such as the role for CD4+ T cells. A mechanistic understanding of these issues is critical for the rational as opposed to purely empiric approach for the development of effective preventative and therapeutic TB vaccines.…”

“…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 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.…”

Serologic Responses in Childhood Pulmonary Tuberculosis

“…IgA and IgM responses to a number of M. tuberculosis antigens have been demonstrated in serum from TB patients and individuals with latent M. tuberculosis infection, 8,24,25 and recent findings suggest that different antibody isotypes may differentially affect infection of cells by M. tuberculosis . 26 Further, our experimental methods did not assess antibody glycosylation, the extent of which has been associated with activity in vitro. 27 Finally, we cannot exclude the possibility of classification biases within the consensus case definitions.…”

Modulation of Mycobacterium tuberculosis-specific humoral immune responses is associated with Strongyloides stercoralis co-infection

“…Thus, human studies have demonstrated that antibodies in LTBI are functionally more competent than antibodies in those with active TB [11,12]. Moreover, active TB is characterized by altered levels of the B cell growth factors, BAFF and APRIL [13], that are crucial factors for peripheral B cell survival and antibody production [14].…”