Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cigarette smoke exposure attenuates the induction of antigen-specific IgA in the murine upper respiratory tract

Abstract

The upper respiratory tract is highly exposed to airborne pathogens and serves as an important inductive site for protective antibody responses, including mucosal IgA and systemic IgG. However, it is currently unknown to what extent inhaled environmental toxins, such as a cigarette smoke, affect the ability to induce antibody-mediated immunity at this site. Using a murine model of intranasal lipopolysaccharide and ovalbumin (LPS/OVA) immunization, we show that cigarette smoke exposure compromises the induction of antigen-specific IgA in the upper airways and systemic circulation. Deficits in OVA-IgA were observed in conjunction with a reduced accumulation of OVA-specific IgA antibody-secreting cells (ASCs) in the nasal mucosa, inductive tissues (NALT, cervical lymph nodes, spleen) and the blood. Nasal OVA-IgA from smoke-exposed mice also demonstrated reduced avidity during the acute post-immunization period in association with an enhanced mutational burden in the cognate nasal Igha repertoire. Mechanistically, smoke exposure attenuated the ability of the nasal mucosa to upregulate VCAM-1 and pIgR, suggesting that cigarette smoke may inhibit both nasal ASC homing and IgA transepithelial transport. Overall, these findings demonstrate the immunosuppressive nature of tobacco smoke and illustrate the diversity of mechanisms through which this noxious stimulus can interfere with IgA-mediated immunity in the upper airways.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Cigarette smoke exposure compromises the induction of nasal and systemic IgA responses following intranasal LPS/OVA immunization.
Fig. 2: Cigarette smoke exposure attenuates OVA-specific IgA ASC accumulation in the nasal mucosa after intranasal LPS/OVA immunization.
Fig. 3: Cigarette smoke exposure reduces nasal OVA-IgA avidity during the acute post-immunization period while augmenting mutational load in the cognate nasal Igha repertoire.
Fig. 4: The induction of antigen-specific IgA ASC responses is diminished in the NALT, CLNs and spleen in the context of cigarette smoke exposure.
Fig. 5: Cigarette smoke exposure attenuates the transcriptional upregulation of VCAM-1 in the nasal mucosa following immunization.
Fig. 6: Cigarette smoke exposure attenuates the upregulation of pIgR in the nasal mucosa following immunization.
Fig. 7: Prospective mechanisms of cigarette smoke-mediated IgA inhibition in the upper respiratory tract.

References

  1. 1.

    Renegar, K. B., Small, P. A., Boykins, L. G. & Wright, P. F. Role of IgA versus IgG in the control of influenza viral infection in the murine respiratory tract. J. Immunol. 173, 1978–1986 (2004).

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Gould, V. M. W. et al. Nasal IgA provides protection against human influenza challenge in volunteers with low serum influenza antibody titre. Front. Microbiol. 8, 1–9 (2017).

    Article  Google Scholar 

  3. 3.

    Corthésy, B. Multi-faceted functions of secretory IgA at mucosal surfaces. Front. Immunol. 4, 1–11 (2013).

    Article  CAS  Google Scholar 

  4. 4.

    Okuya, K. et al. A potential role of non-neutralizing IgA antibodies in cross-protective immunity against influenza A viruses of multiple hemagglutinin subtypes. J. Virol. (2020). https://doi.org/10.1128/jvi.00408-20.

  5. 5.

    Stämpfli, M. R. & Anderson, G. P. How cigarette smoke skews immune responses to promote infection, lung disease and cancer. Nat. Rev. Immunol. 9, 377–384 (2009).

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Arcavi, L. & Benowitz, N. L. Cigarette Smoking and Infection. Arch. Intern. Med. 164, 2206–2216 (2004).

    PubMed  Article  Google Scholar 

  7. 7.

    Lawrence, H., Hunter, A., Murray, R., Lim, W. S. & McKeever, T. Cigarette smoking and the occurrence of influenza – Systematic review. J. Infect. 79, 401–406 (2019).

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Rylander, R., Wold, A. & Haglind, P. Nasal antibodies against gram-negative bacteria in cotton-mill workers. Int. Arch. Allergy Appl. Immunol. 69, 330–334 (1982).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Barton, J. R., Riad, M. A., Gaze, M. N., Maran, A. G. D. & Ferguson, A. Mucosal immunodeficiency in smokers, and in patients with epithelial head and neck tumours. Gut 31, 378–382 (1990).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Giuca, M. R., Pasini, M., Tecco, S., Giuca, G. & Marzo, G. Levels of salivary immunoglobulins and periodontal evaluation in smoking patients. BMC Immunol. 15, 1–5 (2014).

    Article  CAS  Google Scholar 

  11. 11.

    Bennet, K. R. & Reade, P. C. Salivary immunoglobulin A levels in normal subjects, tobacco smokers, and patients with minor aphthous ulceration. Oral. Surg., Oral. Med. Oral. Pathol. Oral. Radiol. 53, 461–465 (1982).

    CAS  Article  Google Scholar 

  12. 12.

    Agarwal, A., Rao, S., Sowmya, S., Augustine, D. & Patil, S. Estimation of salivary immunoglobulin A and serum immunoglobulin A in Smokers and Nonsmokers: A Comparative Study. J. Int. Oral. Heal. 8, 1008–1011 (2016).

    Google Scholar 

  13. 13.

    Norhagen Engström, G. & Engström, P. E. Effects of tobacco smoking on salivary immunoglobulin levels in immunodeficiency. Eur. J. Oral. Sci. 106, 986–991 (1998).

    PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Mandel, M. A., Dvorak, K. & Decosse, J. J. Salivary immunoglobulins in patients with oropharyngeal and bronchopulmonary carcinoma. Cancer 31, 1408–1413 (1973).

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Wang, J., Li, Q., Xie, J. & Xu, Y. Cigarette smoke inhibits BAFF expression and mucosal immunoglobulin A responses in the lung during influenza virus infection. Respir. Res. 16, 1–12 (2015).

    Article  CAS  Google Scholar 

  16. 16.

    World Health Organization. WHO Report on the Global Tobacco Epidemic. (2015). www.who.int/tobacco

  17. 17.

    Carter, B. D. et al. Smoking and mortality-beyond established causes. N. Engl. J. Med. 372, 631–640 (2015).

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Kiyono, H. & Fukuyama, S. NALT- versus Peyer’s-Patch-mediated mucosal immunity. Nat. Rev. Immunol. 4, 699–710 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Shimoda, M. et al. Isotype-specific selection of high affinity memory B cells in nasal-associated lymphoid tissue. J. Exp. Med. 194, 1597–1607 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Frank, G. M. et al. A simple flow-cytometric method measuring B cell surface immunoglobulin avidity enables characterization of affinity maturation to influenza a virus. MBio 6, 1–11 (2015).

    Article  CAS  Google Scholar 

  21. 21.

    Turchaninova, M. A. et al. High-quality full-length immunoglobulin profiling with unique molecular barcoding. Nat. Protoc. 11, 1599–1616 (2016).

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Klein, F. et al. Somatic mutations of the immunoglobulin framework are generally required for broad and potent HIV-1 neutralization. Cell 153, 126–138 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Gupta, N. T. et al. Change-O: A toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data. Bioinformatics 31, 3356–3358 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Macpherson, A. J., McCoy, K. D., Johansen, F.-E. & Brandtzaeg, P. The immune geography of IgA induction and function. Mucosal Immunol. 1, 11–22 (2008).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Ambrose, C. S., Wu, X., Jones, T. & Mallory, R. M. The role of nasal IgA in children vaccinated with live attenuated influenza vaccine. Vaccine 30, 6794–6801 (2012).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Terauchi, Y. et al. IgA polymerization contributes to efficient virus neutralization on human upper respiratory mucosa after intranasal inactivated influenza vaccine administration. Hum. Vaccines Immunother. 14, 1351–1361 (2018).

    Article  Google Scholar 

  27. 27.

    Amorij, J. P., Hinrichs, W. L. J., Frijlink, H. W., Wilschut, J. C. & Huckriede, A. Needle-free influenza vaccination. Lancet Infect. Dis. 10, 699–711 (2010).

    PubMed  Article  Google Scholar 

  28. 28.

    Lycke, N. Recent progress in mucosal vaccine development: potential and limitations. Nat. Rev. Immunol. 12, 592–605 (2012).

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Gärdby, E. et al. Strong differential regulation of serum and mucosal IgA responses as revealed in CD28-deficient mice using cholera toxin adjuvant. J. Immunol. 170, 55–63 (2003).

    PubMed  Article  Google Scholar 

  30. 30.

    McDermott, M. R. & Bienenstock, J. Evidence for a common mucosal immunologic system. I. Migration of B immunoblasts into intestinal, respiratory, and genital tissues. J. Immunol. 122, 1892–1898 (1979).

    CAS  PubMed  Google Scholar 

  31. 31.

    Johansson, E. L., Wassén, L., Holmgren, J., Jertborn, M. & Rudin, A. Nasal and vaginal vaccinations have differential effects on antibody responses in vaginal and cervical secretions in humans. Infect. Immun. 69, 7481–7486 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Wern, J. E., Sorensen, M. R., Olsen, A. W., Andersen, P. & Follmann, F. Simultaneous subcutaneous and intranasal administration of a CAF01-adjuvanted Chlamydia vaccine elicits elevated IgA and protective Th1/Th17 responses in the genital tract. Front. Immunol. 8, 1–11 (2017).

    Article  CAS  Google Scholar 

  33. 33.

    Mestecky, J., Raska, M., Novak, J., Alexander, R. C. & Moldoveanu, Z. Antibody-mediated Protection and the Mucosal Immune System of the Genital Tract: Relevance to Vaccine Design. J. Reprod. Immunol. 85, 81–85 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Lee, H. et al. Phenotype and function of nasal dendritic cells. Mucosal Immunol. 8, 1–16 (2015).

    Article  CAS  Google Scholar 

  35. 35.

    Takaki, H. et al. Toll-like receptor 3 in nasal CD103+ dendritic cells is involved in immunoglobulin A production. Mucosal Immunol. 11, 82–96 (2018).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Dullaers, M. et al. A T Cell-Dependent Mechanism for the Induction of Human Mucosal Homing Immunoglobulin A-Secreting Plasmablasts. Immunity 30, 120–129 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Teasdale, J. E. et al. Cigarette smoke extract profoundly suppresses TNFα-mediated proinflammatory gene expression through upregulation of ATF3 in human coronary artery endothelial cells. Sci. Rep. 7, 1–10 (2017).

    CAS  Article  Google Scholar 

  38. 38.

    Zhang, X. et al. Similarities and differences between smoking-related gene expression in nasal and bronchial epithelium. Physiol. Genomics 41, 1–8 (2010).

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Schaberg, T. et al. Expression of adhesion molecules in peripheral pulmonary vessels from smokers and nonsmokers. Lung 174, 71–81 (1996).

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Gohy, S. T. et al. Polymeric immunoglobulin receptor down-regulation in chronic obstructive pulmonary disease: Persistence in the cultured epithelium and role of transforming growth factor-β. Am. J. Respir. Crit. Care Med. 190, 509–521 (2014).

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Polosukhin, V. V. et al. Secretory IgA deficiency in individual small airways is associated with persistent inflammation and remodeling. Am. J. Respir. Crit. Care Med. 195, 1010–1021 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Namujju, P. B. et al. Impact of smoking on the quantity and quality of antibodies induced by human papillomavirus type 16 and 18 AS04-adjuvanted virus-like-particle vaccine - A pilot study. BMC Res. Notes 7, 2–7 (2014).

    Article  CAS  Google Scholar 

  43. 43.

    MacKenzie, J. S., MacKenzie, I. H. & Holt, P. G. The effect of cigarette smoking on susceptibility to epidemic influenza and on serological responses to live attenuated and killed subunit influenza vaccines. J Hyg (Lond). 77, 409–417 (1976).

  44. 44.

    Rebuli, M. E. et al. Electronic-cigarette use alters nasal mucosal immune response to live-attenuated influenza virus: A clinical trial. Am. J. Respir. Cell Mol. Biol. 64, 126–137 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Shen, P. et al. Streptococcus pneumoniae colonization is required to alter the nasal microbiota in cigarette smoke-exposed mice. Infect. Immun. 85, 1–14 (2017).

    Article  Google Scholar 

  46. 46.

    Southam, D. S., Dolovich, M., O’Byrne, P. M. & Inman, M. D. Distribution of intranasal instillations in mice: effects of volume, time, body position, and anesthesia. Am. J. Physiol. - Lung Cell. Mol. Physiol. 282, L833–L839 (2002).

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Keating, R. et al. Broadly Reactive Influenza Antibodies Are Not Limited by Germinal Center Competition with High-Affinity Antibodies Rachael. MBio 11, 1–13 (2020).

    Article  Google Scholar 

  48. 48.

    Tennant, R. K., Holzer, B., Love, J., Tchilian, E. & White, H. N. Higher levels of B-cell mutation in the early germinal centres of an inefficient secondary antibody response to a variant influenza haemagglutinin. Immunology 157, 86–91 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Cui, A. et al. A model of somatic hypermutation targeting in mice based on high-throughput ig sequencing data. J. Immunol. 197, 3566–3574 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Joanna Kasinska and Mark R. McDermott for providing technical support for experiments, as well as Mark Inman, Dawn Bowdish, and Judah Denburg for advice regarding experimental design and analysis.

Funding

Funding for this study was provided by The Lung Health Foundation (previously known as the Ontario Lung Association; M.R.S.), the Canadian Institutes for Health Research (CIHR: M.S.M., M.R.S.: PJT-159792), and the Natural Science and Engineering Research Council of Ontario (NSERC: M.S.M.). M.S.M. was partially supported by a CIHR New Investigator Award.

Author information

Affiliations

Authors

Contributions

J.J.C.M., P.S. and M.R.S. conceived the study. J.J.C.M. and M.R.S. designed the experiments. J.J.C.M., D.T., S.P.C., J.P.M., M.F., P.B., B.L., R.H., and J.F.E.K. conducted experiments. L.P.S. provided technical support for experiments. P.Y.F.Z. conducted bioinformatic analysis of raw sequencing data, and J.J.C.M. performed all other analysis including compilation of sequencing data. J.J.C.M., D.T., S.P.C., M.S.M. and M.R.S. were involved in data interpretation. J.J.C.M. and M.R.S. wrote the manuscript with feedback from all authors. M.S.M. and M.R.S. secured funding for the study.

Corresponding author

Correspondence to Martin R. Stämpfli.

Ethics declarations

Competing interests

M.R.S. reports grants from RespiVert Ltd. part of Janssen Pharmaceuticals and personal fees from AstraZeneca and Boehringer Ingelheim outside the submitted work. As of January 2020, M.R.S. is an employee of C.S.L. Behring A.G. All other authors have no conflicts of interest to declare.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

McGrath, J.J.C., Thayaparan, D., Cass, S.P. et al. Cigarette smoke exposure attenuates the induction of antigen-specific IgA in the murine upper respiratory tract. Mucosal Immunol (2021). https://doi.org/10.1038/s41385-021-00411-9

Download citation

Search

Quick links