Pulmonary Eosinophilic Granulomatosis with Polyangiitis Has IgG4 Plasma Cells and Immunoregulatory Features

Zachary M. Dong, Edwin Lin, Michael E. Wechsler, Peter F. Weller, Amy D. Klion, Bruce S. Bochner, Don A. Delker, Mark W. Hazel, Keke Fairfax, Paneez Khoury, Praveen Akuthota, Peter A. Merkel, Anne Marie Dyer, Carol Langford, Ulrich Specks, Gerald J. Gleich, Vernon M. Chinchilli, Benjamin Raby, Mark Yandell, Frederic Clayton*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

The immunologic mechanisms promoting eosinophilic granulomatosis with polyangiitis (EGPA) are unclear. To characterize the mechanisms underlying pulmonary EGPA, we examined and compared EGPA paraffin-embedded lung biopsies with normal lung biopsies, using immunostaining, RNA sequencing, and RT-PCR. The results revealed novel type 2 as well as immuneregulatory features. These features included basophils and increased mast cell contents; increased immunostaining for tumor necrosis factor ligand superfamily member 14; sparse mast cell degranulation; numerous forkhead box protein P3 (FoxP3)+ regulatory T cells and IgG4 plasma cells; and abundant arachidonate 15-lipoxygenase and 25-hydroxyvitamin D-1 α hydroxylase, mitochondrial. Significantly decreased 15-hydroxyprostaglandin dehydrogenase [NAD(+)], which degrades eicosanoids, was observed in EGPA samples. In addition, there was significantly increased mRNA for chemokine (C-C motif) ligands 18 and 13 and major collagen genes, IgG4-rich immune complexes coating alveolar macrophages, and increased immunostaining for phosphorylated mothers against decapentaplegic homolog 2/SMAD2, suggesting transforming growth factor-β activation. These findings suggest a novel self-promoting mechanism of activation of alveolar macrophages by arachidonate 15-lipoxygenase–derived eicosanoids to express chemokines that recruit a combined type 2/immunoregulatory immune response, which produces these eicosanoids. These results suggest that the pulmonary EGPA immune response resembles the immune response to a tissue-invasive parasite infection.

Original languageEnglish (US)
Pages (from-to)1438-1448
Number of pages11
JournalAmerican Journal of Pathology
Volume190
Issue number7
DOIs
StatePublished - Jul 2020

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Fingerprint Dive into the research topics of 'Pulmonary Eosinophilic Granulomatosis with Polyangiitis Has IgG4 Plasma Cells and Immunoregulatory Features'. Together they form a unique fingerprint.

  • Cite this

    Dong, Z. M., Lin, E., Wechsler, M. E., Weller, P. F., Klion, A. D., Bochner, B. S., Delker, D. A., Hazel, M. W., Fairfax, K., Khoury, P., Akuthota, P., Merkel, P. A., Dyer, A. M., Langford, C., Specks, U., Gleich, G. J., Chinchilli, V. M., Raby, B., Yandell, M., & Clayton, F. (2020). Pulmonary Eosinophilic Granulomatosis with Polyangiitis Has IgG4 Plasma Cells and Immunoregulatory Features. American Journal of Pathology, 190(7), 1438-1448. https://doi.org/10.1016/j.ajpath.2020.03.005