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
