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.
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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 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.
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.
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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