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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.

SUBMITTER: Zimmermann N

PROVIDER: S-EPMC5090662 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Human isotype-dependent inhibitory antibody responses against Mycobacterium tuberculosis.

Zimmermann Natalie N Thormann Verena V Hu Bo B Köhler Anne-Britta AB Imai-Matsushima Aki A Locht Camille C Arnett Eusondia E Schlesinger Larry S LS Zoller Thomas T Schürmann Mariana M Kaufmann Stefan He SH Wardemann Hedda H

EMBO molecular medicine 20161102 11

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 healthca ...[more]

PMID: 27729388

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Project description:BackgroundVaccine-induced human antibodies to surface components of Haemophilus influenzae and Streptococcus pneumonia are correlated with protection. Monoclonal antibodies to surface components of Mycobacterium tuberculosis are also protective in animal models. We have characterized human antibodies that bind to the surface of live M. tuberculosis.MethodsPlasma from humans with latent tuberculosis (TB) infection (n = 23), active TB disease (n = 40), and uninfected controls (n = 9) were assayed by ELISA for reactivity to the live M. tuberculosis surface and to inactivated M. tuberculosis fractions (whole cell lysate, lipoarabinomannan, cell wall, and secreted proteins).ResultsWhen compared to uninfected controls, patients with active TB disease had higher antibody titers to the surface of live M. tuberculosis (? = 0.72 log10), whole cell lysate (? = 0.82 log10), and secreted proteins (? = 0.62 log10), though there was substantial overlap between the two groups. Individuals with active disease had higher relative IgG avidity (? = 1.4 to 2.6) to all inactivated fractions. Surprisingly, the relative IgG avidity to the live M. tuberculosis surface was lower in the active disease group than in uninfected controls (? =? -1.53, p = 0.004). Patients with active disease had higher IgG than IgM titers for all inactivated fractions (ratios, 2.8 to 10.1), but equal IgG and IgM titers to the live M. tuberculosis surface (ratio, 1.1). Higher antibody titers to the M. tuberculosis surface were observed in active disease patients who were BCG-vaccinated (? = 0.55 log10, p = 0.008), foreign-born (? = 0.61 log10, p = 0.004), or HIV-seronegative (? = 0.60 log10, p = 0.04). Higher relative IgG avidity scores to the M. tuberculosis surface were also observed in active disease patients who were BCG-vaccinated (? = 1.12, p < 0.001) and foreign-born (? = 0.87, p = 0.01).Conclusions/significanceHumans with active TB disease produce antibodies to the surface of M. tuberculosis with low avidity and with a low IgG/IgM ratio. Highly-avid IgG antibodies to the M. tuberculosis surface may be an appropriate target for future TB vaccines.

Dataset Information

Human isotype-dependent inhibitory antibody responses against Mycobacterium tuberculosis.

Publications

Human isotype-dependent inhibitory antibody responses against Mycobacterium tuberculosis.

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