Human isotype‐dependent inhibitory antibody responses against Mycobacterium tuberculosis

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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.

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Most cited references 40

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Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells.

Gui-Mei Li, Christopher Chiu, Jens Wrammert … (2012)

We have previously shown that broadly neutralizing antibodies reactive to the conserved stem region of the influenza virus hemagglutinin (HA) were generated in people infected with the 2009 pandemic H1N1 strain. Such antibodies are rarely seen in humans following infection or vaccination with seasonal influenza virus strains. However, the important question remained whether the inactivated 2009 pandemic H1N1 vaccine, like the infection, could also induce these broadly neutralizing antibodies. To address this question, we analyzed B-cell responses in 24 healthy adults immunized with the pandemic vaccine in 2009. In all cases, we found a rapid, predominantly IgG-producing vaccine-specific plasmablast response. Strikingly, the majority (25 of 28) of HA-specific monoclonal antibodies generated from the vaccine-specific plasmablasts neutralized more than one influenza strain and exhibited high levels of somatic hypermutation, suggesting they were derived from recall of B-cell memory. Indeed, memory B cells that recognized the 2009 pandemic H1N1 HA were detectable before vaccination not only in this cohort but also in samples obtained before the emergence of the pandemic strain. Three antibodies demonstrated extremely broad cross-reactivity and were found to bind the HA stem. Furthermore, one stem-reactive antibody recognized not only H1 and H5, but also H3 influenza viruses. This exceptional cross-reactivity indicates that antibodies capable of neutralizing most influenza subtypes might indeed be elicited by vaccination. The challenge now is to improve upon this result and design influenza vaccines that can elicit these broadly cross-reactive antibodies at sufficiently high levels to provide heterosubtypic protection.

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Mouse model recapitulating human Fcγ receptor structural and functional diversity.

Stylianos Bournazos, Patrick Smith, Jeffrey V. Ravetch … (2012)

The in vivo biological activities of IgG antibodies result from their bifunctional nature, in which antigen recognition by the Fab is coupled to the effector and immunomodulatory diversity found in the Fc domain. This diversity, resulting from both amino acid and glycan heterogeneity, is translated into cellular responses through Fcγ receptors (FcγRs), a structurally and functionally diverse family of cell surface receptors found throughout the immune system. Although many of the overall features of this system are maintained throughout mammalian evolution, species diversity has precluded direct analysis of human antibodies in animal species, and, thus, detailed investigations into the unique features of the human IgG antibodies and their FcγRs have been limited. We now report the development of a mouse model in which all murine FcγRs have been deleted and human FcγRs, encoded as transgenes, have been inserted into the mouse genome resulting in recapitulation of the unique profile of human FcγR expression. These human FcγRs are shown to function to mediate the immunomodulatory, inflammatory, and cytotoxic activities of human IgG antibodies and Fc engineered variants and provide a platform for the detailed mechanistic analysis of therapeutic and pathogenic IgG antibodies.

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The heparin-binding haemagglutinin of M. tuberculosis is required for extrapulmonary dissemination.

G Delogu, C. Locht, A. J. Brennan … (2001)

Tuberculosis remains the world's leading cause of death due to a single infectious agent, Mycobacterium tuberculosis, with 3 million deaths and 10 million new cases per year. The infection initiates in the lungs and can then spread rapidly to other tissues. The availability of the entire M. tuberculosis genome sequence and advances in gene disruption technologies have led to the identification of several mycobacterial determinants involved in virulence. However, no virulence factor specifically involved in the extrapulmonary dissemination of M. tuberculosis has been identified to date. Here we show that the disruption of the M. tuberculosis or Mycobacterium bovis Bacille Calmette-Guérin (BCG) hbhA gene encoding the heparin-binding haemagglutinin adhesin (HBHA) markedly affects mycobacterial interactions with epithelial cells, but not with macrophage-like cells. When nasally administered to mice, the mutant strains were severely impaired in spleen colonization, but not in lung colonization. Coating wild-type mycobacteria with anti-HBHA antibodies also impaired dissemination after intranasal infection. These results provide evidence that adhesins such as HBHA are required for extrapulmonary dissemination, and that interactions with non-phagocytic cells have an important role in the pathogenesis of tuberculosis. They also suggest that antibody responses to HBHA may add to immune protection against tuberculosis.

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Author and article information

Contributors

Hedda Wardemann: h.wardemann@dkfz.de

Journal

Journal ID (nlm-ta): EMBO Mol Med

Journal ID (iso-abbrev): EMBO Mol Med

Journal ID (doi): 10.1002/(ISSN)1757-4684

Journal ID (publisher-id): EMMM

Journal ID (hwp): embomm

Title: EMBO Molecular Medicine

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 1757-4676

ISSN (Electronic): 1757-4684

Publication date (Electronic): 11 October 2016

Publication date (Print): November 2016

Volume: 8

Issue: 11 ( doiID: 10.1002/emmm.v8.11 )

Pages: 1325-1339

Affiliations

[ ¹ ] Research Group Molecular ImmunologyMax Planck Institute for Infection Biology BerlinGermany

[ ² ] Department of ImmunologyMax Planck Institute for Infection Biology BerlinGermany

[ ³ ] B Cell ImmunologyGerman Cancer Research Center HeidelbergGermany

[ ⁴ ] Department of Molecular BiologyMax Planck Institute for Infection Biology BerlinGermany

[ ⁵ ] U1019 ‐ UMR 8204 ‐ CIIL ‐ Centre for Infection and Immunity of LilleUniversity of Lille LilleFrance

[ ⁶ ] CNRSUMR 8204 LilleFrance

[ ⁷ ]Inserm, U1019 LilleFrance

[ ⁸ ]CHU Lille LilleFrance

[ ⁹ ]Institut Pasteur de Lille LilleFrance

[ ¹⁰ ] Center for Microbial Interface Biology Department of Microbial Infection and ImmunityThe Ohio State University Columbus OHUSA

[ ¹¹ ] Department of Infectious Diseases and Respiratory MedicineCharité University Medical Center BerlinGermany

Author notes

[*] [* ]Corresponding author. Tel: +49 6221 42 1270; Fax: +49 6221 42 1279; E‐mail: h.wardemann@ 123456dkfz.de

Author information

Stefan HE Kaufmann http://orcid.org/0000-0001-9866-8268

Article

Publisher ID: EMMM201606330

DOI: 10.15252/emmm.201606330

PMC ID: 5090662

PubMed ID: 27729388

SO-VID: c1ae13a6-5a25-4726-9663-160e9360c7fc

License:

This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 23 February 2016

Date revision received : 30 August 2016

Date accepted : 06 September 2016

Page count

Figures: 8, Tables: 0, Pages: 15, Words: 9681

Funding

Funded by: European Union's Seventh Framework Programme

Award ID: HEALTH‐F4‐2011‐280873

Funded by: European Union's Framework Programme for Research and Innovation Horizon 2020

Award ID: 643381

Funded by: Deutsche Forschungsgemeinschaft (DFG)

Award ID: TRR130 P10

Funded by: Max‐Planck‐Gesellschaft

Custom metadata

source-schema-version-number 2.0

component-id emmm201606330

cover-date November 2016

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.6 mode:remove_FC converted:02.11.2016

ScienceOpen disciplines: Molecular medicine

Keywords: antibodies,b cells,infection,isotype,mycobacterium tuberculosis,immunology,microbiology, virology & host pathogen interaction

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ScienceOpen disciplines: Molecular medicine

Keywords: antibodies, b cells, infection, isotype, mycobacterium tuberculosis, immunology, microbiology, virology & host pathogen interaction

Human isotype‐dependent inhibitory antibody responses against Mycobacterium tuberculosis

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Most cited references 40

Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells.

Mouse model recapitulating human Fcγ receptor structural and functional diversity.

The heparin-binding haemagglutinin of M. tuberculosis is required for extrapulmonary dissemination.

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