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Mucosal immunity in the respiratory tract: The role of IgA in protection against intracellular pathogens
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
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 [en]
mucosal immunity, respiratory tract, IgA, intracellular pathogens
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:su:diva-388ISBN: 91-7155-016-X (print)OAI: oai:DiVA.org:su-388DiVA: diva2:193266
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
List of papers
1. B- and T-cell responses to the mycobacterium surface antigen PstS-1 in the respiratory tract and adjacent tissues: Role of adjuvants and routes of immunization
Open this publication in new window or tab >>B- and T-cell responses to the mycobacterium surface antigen PstS-1 in the respiratory tract and adjacent tissues: Role of adjuvants and routes of immunization
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2003 In: Vaccine, ISSN 0264-410X, Vol. 21, no 5-6, 458-467 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-23599 (URN)
Note
Part of urn:nbn:se:su:diva-388Available from: 2005-02-22 Created: 2005-02-22Bibliographically approved
2. 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
3. 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 Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-23601 (URN)10.1093/intimm/dxl017 (DOI)
Note
Part of urn:nbn:se:su:diva-388Available from: 2005-02-22 Created: 2005-02-22 Last updated: 2017-12-13Bibliographically approved
4. Mucosal immunity in protection against intranasal infection with Chlamydia pneumoniae
Open this publication in new window or tab >>Mucosal immunity in protection against intranasal infection with Chlamydia pneumoniae
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-23602 (URN)
Note
Part of urn:nbn:se:su:diva-388Available from: 2005-02-22 Created: 2005-02-22 Last updated: 2010-01-13Bibliographically approved

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