TY - JOUR
T1 - Pulmonary Eosinophilic Granulomatosis with Polyangiitis Has IgG4 Plasma Cells and Immunoregulatory Features
AU - Dong, Zachary M.
AU - Lin, Edwin
AU - Wechsler, Michael E.
AU - Weller, Peter F.
AU - Klion, Amy D.
AU - Bochner, Bruce S.
AU - Delker, Don A.
AU - Hazel, Mark W.
AU - Fairfax, Keke
AU - Khoury, Paneez
AU - Akuthota, Praveen
AU - Merkel, Peter A.
AU - Dyer, Anne Marie
AU - Langford, Carol
AU - Specks, Ulrich
AU - Gleich, Gerald J.
AU - Chinchilli, Vernon M.
AU - Raby, Benjamin
AU - Yandell, Mark
AU - Clayton, Frederic
N1 - Funding Information:
Supported by NIH grant NIAID-U-01 AI097073 (M.E.W.); the Division of Intramural Research, National Institute of Allergy and Infectious Diseases , NIH; and National Cancer Institute award number P30CA042014 .
Funding Information:
Supported by NIH grant NIAID-U-01 AI097073 (M.E.W.); the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH; and National Cancer Institute award number P30CA042014.Disclosures: P.A.M. consults for AbbVie, AstraZeneca, Biogen, Boeringher-Ingelheim, Bristol-Myers Squibb, Celgene, ChemoCentryx, CSL Behring, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Insmed, Jannsen, Kiniksa, and Sparrow; research support from AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, Celgene, ChemoCentryx, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Kypha, and Terumo BCT; B.S.B. has ongoing scientific advisory board arrangements with Allakos, Inc., and owns stock in Allakos, Inc., is a co-inventor on existing Siglec-8?related patents and thus may be entitled to a share of royalties received by Johns Hopkins University on the potential sales of such products, is also a cofounder of Allakos, Inc., which makes him subject to certain restrictions under university policy (the terms of this arrangement are being managed by John Hopkins University and Northwestern University in accordance with their conflict of interest policies); P.A. has advisory board, consulting, and clinical trial site relationships with GSK and AstraZeneca; U.S. consults for AstraZeneca, ChemoCentryx, and Insmed, and has research support from AstraZeneca, Bristol-Myers Squibb, ChemoCentryx, Genentech/Roche, GlaxoSmithKline, and InflaRx.
Publisher Copyright:
© 2020 American Society for Investigative Pathology
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2020.03.005
DO - 10.1016/j.ajpath.2020.03.005
M3 - Article
C2 - 32251643
AN - SCOPUS:85086646133
SN - 0002-9440
VL - 190
SP - 1438
EP - 1448
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 7
ER -