Human isotype‐dependent inhibitory antibody responses against Mycobacterium tuberculosis. Issue 11 (11th October 2016) - Zimmermann, Natalie
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. Synopsis: Antibodies against Mycobacterium tuberculosis (MTB) may protect from infection and could be of therapeutic use, but this was never determined. This work identifies and characterizes anti‐MTB antibodies from patients. Over 50 human memory and plasmablast antibodies predominantly targeting MTB surface antigens were identified in the peripheral blood of tuberculosis (TB) patients and healthy donors. The development from preexisting memory B cells and mucosal origin was suggested by the dominance of IgA and somatic hypermutation levels. Inhibition of MTB infection of alveolar epithelial cells was observed for IgA antibodies independent of the IgA Fc receptor CD89. IgG antibodies promoted the infection, presumably via the interaction with the neonatal Fc receptor. Isotype‐dependent differences in MTB inhibition were confirmed with serum IgA and IgG preparations. Abstract : Antibodies against Mycobacterium tuberculosis (MTB) may protect from infection and could be of therapeutic use, but this was never determined. This work identifies and characterizes anti‐MTB antibodies from patients.