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Role of IgA in the defense against respiratory infections: IgA deficient mice exhibited increased susceptibility to intranasal infection with Mycobacterium bovis BCG
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
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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.

Place, publisher, year, edition, pages
2005. Vol. 23, no 20, 2565-2572 p.
Keyword [en]
Mucosal immunity, IgA, BCG
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:su:diva-23925DOI: 10.1016/j.vaccine.2004.11.032OAI: oai:DiVA.org:su-23925DiVA: diva2:195379
Available from: 2005-06-23 Created: 2005-06-23 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Does IgA play a role in protection against pulmonary tuberculosis?
Open this publication in new window or tab >>Does IgA play a role in protection against pulmonary tuberculosis?
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:nbn:se:su:diva-552 (URN)
Presentation
2005-06-21, Stockholm, 10:00
Opponent
Supervisors
Available from: 2005-06-23 Created: 2005-06-23Bibliographically approved
2. Mucosal Immunity in Mycobacterial infections
Open this publication in new window or tab >>Mucosal Immunity in Mycobacterial infections
2007 (English)Doctoral 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, caused by the bacterium Mycobacterium tuberculosis, 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, BCG, is administered parenterally 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, in mucosal secretions has an important function by blocking entrance of pathogenic organisms and preventing infections. Additionally, a role for IgA in modulation of immune responses is currently being revealed. In this work, we investigated the relevance of mucosal IgA in protection against mycobacterial infections using mice deficient for IgA and the polymeric Ig receptor, the receptor responsible for mucosal secretions of IgA. Gene-targeted mice were more susceptible to mycobacterial infections in the respiratory tract and displayed reduced production of proinflammatory, and protective, factors such as IFN-γ and TNF-α in the lungs. The mechanisms explaining the defective proinflammatory responses in the lungs of deficient mice 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 immune cells to the site of infection.

Induction of optimal adaptive immune responses to combat mycobacterial infections requires prompt innate immune activation. Toll-like receptors (TLRs) are vital components of the innate branch of the immune system, ensuring early recognition of invading pathogens. Using TLR-deficient mice we demonstrated an important role for TLR2, and partly TLR4, in protection against mycobacterial infection in the respiratory tract. TLR2-deficient mice failed to induce proper proinflammatory responses at the site of infection, and macrophages derived from the knockout mice displayed impaired anti-mycobacterial activity.

Experimental evidence has concluded that the immune response upon an infection can influence the outcome of succeeding infections with other pathogens. Concurrent infections might additionally interfere with responses to vaccinations and have deleterious effects. We developed an in vitro model to study the effect of a malaria infection on a successive M. tuberculosis infection. Our results demonstrate that a malaria blood-stage infection enhances the innate immune response to a subsequent M. tuberculosis infection with a Th1 prone profile. Reduced infectivity of malaria-exposed dendritic cells implies that a malaria infection could impose relative resistance to ensuing M. tuberculosis infection. However, a prolonged Th1 response may interfere with malaria parasite control.

The outcome of this work emphasizes the importance of generating effective immune responses in the local mucosal environment upon respiratory mycobacterial infections. It furthermore puts new light on the immunological interaction between parasites and mycobacteria, which could have implications for future vaccine research.

Place, publisher, year, edition, pages
Stockholm: Wenner-Grens institut för experimentell biologi, 2007. 80 p.
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-6782 (URN)91-7155-388-6 (ISBN)
Public defence
2007-06-01, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00
Opponent
Supervisors
Available from: 2007-05-11 Created: 2007-05-09 Last updated: 2011-05-30Bibliographically approved
3. Mucosal immunity in the respiratory tract: The role of IgA in protection against intracellular pathogens
Open this publication in new window or tab >>Mucosal immunity in the respiratory tract: The role of IgA in protection against intracellular pathogens
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The lungs and upper airways are mucosal surfaces that are common site for infection with an enormous variety of inhaled pathogens. Therefore, induction of immune responses in the respiratory tract is crucial for protection against respiratory diseases.

One of the pathogens infecting the host via the respiratory tract is Mycobacterium Tuberculosis. The reported efficacy of the currently used Bacillus Calmette-Guérin (BCG) vaccine against tuberculosis is highly variable, ranging from 50% against pulmonary tuberculosis to 80% against disseminated tuberculosis. Recently, the current route of vaccination (intradermal) has been considered as a possible factor influencing the protective capacity of the BCG vaccine. In this regard, intradermal route most likely induces protective systemic responses while it fails to induce optimal responses in the lungs. Therefore, our working hypothesis is that vaccination should be directed towards the respiratory mucosal immunity in order to improve the degree of host protection in the lungs.

In this thesis we studied the effect of the route of immunization as well as of different mucosal adjuvants on the induction of mucosal immune responses against the mycobacterial surface antigen PstS-1. We found that, the intranasal (i.n.) route of immunization was a more favorable route inducing strong local immune responses, than intraperitoneal (i.p.) route. Indeed, i.n. route immunization, unlike the i.p. route, elicited strong IgA responses in the lungs accompanied by a major influx of CD4+ T cells and a significant local production of IFN-gamma.

IgA, being the predominant Ig isotype at mucosal tissues, is considered a major effector molecule involved in defense mechanisms against viral and bacterial pathogens at these sites. Therefore, we investigated the possible role of IgA in the protection of the respiratory mucosa against mycobacterial infections, using mice deficient in IgA and in the polymeric Ig receptor. We show that, deficient mice are more susceptible to mycobacterial infections than wild type mice, thereby demonstrating a role for IgA in protection against mycobacteria. Importantly, our studies revealed a reduced production of protective factors, such as INF-gamma and TNF-alpha in the lungs of deficient mice that was associated with the higher susceptibility seen in these mice compared to wild-type mice. We also conducted challenge experiments against another respiratory pathogen, Chlamydia pneumoniae, using IgA deficient mice. Likewise to mycobacteria, our data support a role for IgA in the protection of the respiratory tract against C. pneumoniae infection.

Finally, we investigated the possible mechanisms explaining the reduced pro-inflammatory responses in IgA deficient mice. Our data indicated that IgA deficient mice present a defective response to stimulation with LPS or 19kDa which appears to be both, essentially due to suboptimal stimulation of macrophages and restricted to the lungs.

Place, publisher, year, edition, pages
Stockholm: Wenner-Grens institut för experimentell biologi, 2005. 80 p.
Keyword
mucosal immunity, respiratory tract, IgA, intracellular pathogens
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:su:diva-388 (URN)91-7155-016-X (ISBN)
Public defence
2005-04-01, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00
Opponent
Supervisors
Available from: 2005-02-22 Created: 2005-02-22 Last updated: 2011-05-30Bibliographically approved

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