Rationale: Cigarette smoking (CS) impairs B cell function and antibody production, increasing infection risk. The impact of e-cigarette use ('vaping') and combined CS and vaping ('dual-use') on B cell activity is unclear. Objective: To examine B cell receptor sequencing (BCR-seq) profiles associated with CS, vaping, dual-use, COPD-related outcomes, and demographic factors. Methods: BCR-seq was performed on blood RNA samples from 234 participants in the COPDGene study. We assessed multivariable associations of B cell function measures (immunoglobulin heavy chain (IGH) subclass expression and usage, class-switching, V-segment usage, and clonal expansion) with CS, vaping, dual-use, COPD severity, age, sex, and race. We adjusted for multiple comparisons using the Benjamini-Hochberg method, identifying significant associations at 5% FDR and suggestive associations at 10% FDR. Results: Among 234 non-Hispanic white (NHW) and African American (AA) participants, CS and dual-use were significantly positively associated with increased secretory IgA production, with dual-use showing the strongest associations. Dual-use was positively associated with class switching and B cell clonal expansion, indicating increased B cell activation, with similar trends in those only smoking or only vaping. We observed significant associations between race and IgG antibody usage. AA participants had higher IgG subclass proportions and lower IgM usage compared to NHW participants. Conclusions: CS and vaping additively enhance B cell activation, most notably in dual-users. Self-reported race was strongly associated with IgG isotype usage. These findings highlight associations between B cell activation and antibody transcription, suggesting potential differences in immune and vaccine responses linked to CS, vaping, and race.

MM received consulting fees from TheaHealth, 2ndMD, TriNetX, Axon Advisors, Sanofi. CPH reports grant support from Boehringer-Ingelheim, Novartis, Bayer and Vertex, outside of this study. PJC has received grant support from Bayer and Sanofi consulting fees from Verona Pharma. EKS has received institutional grant support from Bayer and Northpond Laboratories. MS has received funding/support from AstraZeneca, Regeneron, and Sanofi, and has a financial interest in Crosswalk Health.

MM is supported by K08HL159318. MR was supported by the Canadian Institutes of Health Research (FRN:194027). PJC is supported by NIH R01HL124233, R01HL147326, R01HL166992, and R01171213HL. MS is supported by R01HL155948. LCA is supported by R01HL137052 and R01HL147326. The COPDGene project was supported by NHLBI grants U01 HL089897 and U01 HL089856 and by NIH contract 75N92023D00011. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Mass General Brigham Institutional Review Board (2007P000554).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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All data are publicly available through dbGaP (COPDGene: phs000179.v1.p1).