Increased autoreactivity and maturity of EBI2+ antibody-secreting cells from nasal polyps

Junqin Bai, Atsushi Kato, Kathryn E. Hulse, Joshua B. Wechsler, Vikram Gujar, Julie A. Poposki, Regan Harmon, Naruhito Iwasaki, Bao Feng Wang, Julia H. Huang, Whitney W. Stevens, David B. Conley, Kevin C. Welch, Robert C. Kern, Anju T. Peters, Stephanie C. Eisenbarth, Robert P Schleimer, Bruce K. Tan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Elevated numbers of antibody-secreting cells (ASCs) and anti–double-stranded DNA (anti-dsDNA) antibodies are found in nasal polyp (NP) tissue. The presence of anti-dsDNA IgG in tissue prospectively predicts recurrent NP but the characteristics of the source ASCs are unknown. Here, we investigated whether NP B cells expressing the extrafollicular marker EBI2 have increased propensity for autoantibody production and evaluated the molecular characteristics of NP ASCs. NPs showed increased frequencies of anti-dsDNA IgG and total IgG ASCs compared with tonsils, with more pronounced differences among EBI2+ cells. In NPs, EBI2+ cells were frequently double negative (IgDCD27) and ASCs. Single-cell RNA-Seq analysis of tonsils and NPs revealed substantial differences in B lineage composition, including differences in percentages of ASCs, germinal centers, proliferative cells, and non-ASCs. NPs exhibited higher expression of specific isotypes (IGHE, IGHA1, IGHA2, and IGHG4) and mature plasma genes, including SDC1 and XBP1, than tonsils. Gene Ontology biological processes indicated upregulated NF-κB and downregulated apoptosis pathways in NP ASCs. Together, these data indicate that NP EBI2+ ASCs secret increased total and anti-dsDNA IgG compared with those from tonsils and had molecular features of mature plasma cell differentiation.

Original languageEnglish (US)
Article numbere177729
JournalJCI Insight
Volume9
Issue number17
DOIs
StatePublished - Sep 10 2024

Funding

consulting fees from Intersect ENT and XORAN. KCW reports consultant fees from Baxter, OptiNose, and Acclarent. ATP reports personal fees from AstraZeneca and GlaxoSmithKline and personal fees and grants from Sanofi Regeneron, Merck, and OptiNose. AK reports a research grant from Regeneron Pharmaceuticals/Sanofi and support for his research from Lyra Therapeutics. JBW reports consultant fees from Regeneron/Sanofi, Allakos, Astrazeneca, Bristol Myers Squibb, and Ellodi; JBW has received research support from Regeneron/Sanofi, Allakos, and InVea Therapeutics. WWS has served on advisory boards for GlaxoSmithKline and Regeneron. RPS reports personal fees from Intersect ENT, Merck, GlaxoSmithKline, Sanofi, AstraZeneca/Medimmune, Genentech, Actobio Therapeutics, Lyra Therapeutics, Astellas Pharma Inc, Allakos, Aqualung, and Otsuka Inc; in addition, RPS receives royalties from Siglec-8\u2013 and Siglec-8 ligand\u2013related patents (US patent No. 9,546,215) licensed by Johns Hopkins University to Allakos Inc. BKT reports personal fees from Sanofi Regeneron/Genzyme and GlaxoSmithKline. We would like to gratefully acknowledge James Norton, Lydia A. Suh, Aditi Agarwal, and Roderick Carter (Northwestern University Feinberg School of Medicine) for their skillful technical assistance. We appreciate Patrick Wilson from the University of Chicago for sharing the 3H9 plasmids used as our positive control for dsDNA-binding ELISpot. This work was supported by NIH grants R01 AI134952 and R01 DC016645, Chronic Rhinosinusitis Integrative Studies Program 2 P01 AI145818, and the American Academy of Allergy, Asthma, & Immunology Interest-Section Fellow-in-Training (FIT) Abstract Award.

ASJC Scopus subject areas

  • General Medicine

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