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.

Smoking and e-cigarette use: key variables in testing IgA-oriented intranasal vaccines

“…Variables that can interfere with critical readouts need to be categorically accounted for during clinical testing. In this regard, the studies discussed previously 7 , 9 , 10 provide reasonable evidence that cigarette or e-cigarette use can detrimentally impact IgA-based immunity in the upper airways. At a minimum, their use could introduce variability and skew the interpretation of IgA-related data, and at worst, promote discontinuation of intranasal vaccine candidate trials for which IgA induction is a primary outcome.…”

“…Recently, our research groups 9 , 10 showed that cigarette smoke and e-cigarette exposure can interfere with the induction of antigen-specific IgA immunity in the upper airways. In humans, Rebuli and colleagues 9 showed that the induction of influenza-specific IgA was diminished by about 40% in the nasal lavage fluid of smokers and e-cigarette users at day 8 following live-attenuated influenza virus immunisation relative to never-smokers.…”

“…In humans, Rebuli and colleagues 9 showed that the induction of influenza-specific IgA was diminished by about 40% in the nasal lavage fluid of smokers and e-cigarette users at day 8 following live-attenuated influenza virus immunisation relative to never-smokers. In mice, McGrath and colleagues 10 showed that intranasal immunisation with lipopolysaccharide and ovalbumin during concurrent cigarette smoke exposure resulted in diminished nasal ovalbumin-specific IgA responses for at least 1 month relative to room air-exposed controls. This decreased response was associated with a reduced accumulation of ovalbumin-specific IgA antibody-secreting cells in the nasal mucosa, and reduced induction of these cells in the nasal-associated lymphoid tissue, cervical lymph nodes, and spleen.…”

Secretory Cells Are the Primary Source of pIgR in Small Airways

“…Gohy and colleagues previously noted increased PIGR expression in the large airways of smokers 40 . Conversely, McGrath and colleagues found that cigarette smoke attenuated pIgR protein expression in vivo in response to challenge with ovalbumin and lipopolysaccharide 48 . Similarly, Rostami and colleagues showed cigarette smoke extract treatment in vitro reduced multiple secretory cell defense genes including PIGR 37 .…”

The risk profile of electronic nicotine delivery systems, compared to traditional cigarettes, on oral disease: a review

“…Tobacco affects immune status by decreasing immunoglobulin levels, including those of IgA, IgM, and IgG in serum, and IgA in saliva ( 61 , 62 ). Periodontal parameters such as bleeding on probing, probing depth, and attachment loss are also affected.…”