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Does IgA play a role in protection against pulmonary tuberculosis?
Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
2005 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

More than a century after the identification of the tubercle bacillus and the first attempts at vaccination, tuberculosis (TB) still remains one of the world’s most serious infectious diseases. TB is typically a disease of the lung, which serves both as port of entry and as the major site of disease manifestation. The currently used vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is administered parentally and induces a systemic immune response. However, it fails to protect against pulmonary TB, thereby raising the question whether vaccination targeting the mucosal immunity in the lungs could be favourable.

The respiratory mucosal surfaces represent the first line of defence against a multitude of pathogens. Secretory IgA (sIgA) in mucosal secretions has an important function by blocking entrance of pathogenic organisms and preventing infections. Yet, another role for IgA in protection against intracellular pathogens has lately been appreciated, when sIgA was demonstrated to neutralize viruses intracellulary. We aimed to investigate the relevance of sIgA in protection against mycobacterial infections using mice deficient for IgA and the polymeric Ig receptor. Mice were immunized intranasally with a mycobacterial antigen which elicited, in wild-type mice, a strong IgA response in mucosal secretions in the respiratory tract. Gene-targeted mice failed to induce the same response and more importantly, were more susceptible to mycobacterial infections in the respiratory tract, as demonstrated by higher bacterial loads in the lungs than wild-type mice. Analysis of immune responses after infection revealed reduced production of proinflammatory, and protective, factors such as IFN-γ and TNF-α in the lungs of deficient mice, which was in concordance with the higher bacterial burden seen in the lungs of these mice. The mechanisms explaining the defective proinflammatory responses in the lungs of deficient mice are not clear but might involve impaired signalling through Fcα receptors, or homologous receptors, which could lead to inadequate activation of pulmonary macrophages. This could subsequently result in suboptimal induction and production of cytokines and chemokines important for attraction and migration of cells to sites of infection in the lungs.

Our results demonstrate a role for IgA in protection against mycobacterial infection in the respiratory tract by blocking the entrance of the mycobacterium into the lungs, and/or by modulating the locally induced proinflammatory immune responses.

Place, publisher, year, edition, pages
Stockholm: Wenner-Grens institut för experimentell biologi , 2005.
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:su:diva-552OAI: oai:DiVA.org:su-552DiVA: diva2:195381
Presentation
2005-06-21, Stockholm, 10:00
Opponent
Supervisors
Available from: 2005-06-23 Created: 2005-06-23Bibliographically approved
List of papers
1. Role of IgA in the defense against respiratory infections: IgA deficient mice exhibited increased susceptibility to intranasal infection with Mycobacterium bovis BCG
Open this publication in new window or tab >>Role of IgA in the defense against respiratory infections: IgA deficient mice exhibited increased susceptibility to intranasal infection with Mycobacterium bovis BCG
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2005 (English)In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 23, no 20, 2565-2572 p.Article in journal (Refereed) Published
Abstract [en]

IgA is the predominant Ig isotype in mucosal tissue and is believed to be involved in defense against viral and bacterial infections at these sites. Here, we examined the role of IgA in the protection against intranasal (i.n.) infection with Mycobacterium bovis Bacillus Calmette-Guérin (BCG). IgA deficient (IgA−/−) mice and wild type non-targeted littermate (IgA+/+) mice were immunized by i.n. route with the mycobacterium surface antigen PstS-1 formulated with cholera toxin (CT). Our data showed that IgA−/− mice were more susceptible to BCG infection compared to IgA+/+ mice, as revealed by the higher bacterial loads in the lungs and bronchoalveolar lavage (BAL). Analysis of the Ig levels and the antibody responses to PstS-1 showed that IgA−/− mice had no detectable IgA either in the saliva or in the BAL. However, these mice displayed higher levels of total and specific IgM than IgA+/+ mice in both mucosal fluids. More importantly, analysis of the cytokine responses revealed a reduction in the IFN-γ and TNF-α production in the lungs of IgA−/− compared to IgA+/+ mice. Altogether, our results suggest that IgA may play a role in protection against mycobacterial infections in the respiratory tract by blocking the pathogen entrance and/or by modulating the pro-inflammatory responses.

Keyword
Mucosal immunity, IgA, BCG
National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-23925 (URN)10.1016/j.vaccine.2004.11.032 (DOI)
Available from: 2005-06-23 Created: 2005-06-23 Last updated: 2017-12-13Bibliographically approved
2. Polymeric Ig receptor knockout mice are more susceptible to mycobacteria infection in the respiratory tract
Open this publication in new window or tab >>Polymeric Ig receptor knockout mice are more susceptible to mycobacteria infection in the respiratory tract
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2006 (English)In: International Immunology, ISSN 0953-8178, E-ISSN 1460-2377, Vol. 18, no 5, 807-816 p.Article in journal (Refereed) Published
Abstract [en]

It is generally accepted that cellular, and not humoral immunity, plays the crucial role in defense against intracellular bacteria. However, accumulating data indicate the importance of humoral immunity for the defense against a number of intracellular bacteria, including mycobacteria. We have investigated the role of secretory IgA, the main isotype found in mucosal tissues, in protection against mycobacterial infection, using polymeric IgR (pIgR)-deficient mice. Characterization of the humoral response induced after intra-nasal immunizations with the mycobacterial antigen PstS-1 revealed a loss of antigen-specific IgA response in saliva from the knockout mice. IgA level in the bronchoalveolar lavage of knockout mice was similar to wild-type level, although the IgA antibodies must have reached the lumen by other means than pIgR-mediated transport. Infection with Mycobacterium bovis bacillus Calmette–Guérin (BCG) demonstrated that the immunized pIgR−/− mice were more susceptible to BCG infection than immunized wild-type mice, based on higher bacterial loads in the lungs. This was accompanied by a reduced production of both IFN-γ and tumor necrosis factor-alpha (TNF-α) in the lungs. Additionally, the pIgR−/− mice displayed reduced natural resistance to mycobacterial infection proved by significantly higher bacterial growth in their lungs compared with wild-type mice after infection with virulent Mycobacterium tuberculosis. The knockout mice appeared to have a delayed mycobacteria-induced immune response with reduced expression of protective mediators, such as IFN-γ, TNF-α, inducible nitric oxide synthase and regulated upon activation normal T cell sequence, during early infection. Collectively, our results show that actively secreted IgA plays a role in protection against mycobacterial infections in the respiratory tract, by blocking entrance of bacilli into the lungs, in addition to modulation of the mycobacteria-induced pro-inflammatory response.

Place, publisher, year, edition, pages
oxford university press, 2006
Keyword
mucosal immunity mycobacteria pIgR secretory IgA
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:su:diva-23926 (URN)10.1093/intimm/dxl017 (DOI)
Note
Part of urn:nbn:se:su:diva-552Available from: 2005-06-23 Created: 2005-06-23 Last updated: 2017-12-13Bibliographically approved

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