Studies of the role of basophils in aspirin-exacerbated respiratory disease pathogenesis

Whitney W. Stevens; Anna G. Staudacher; Kathryn E. Hulse; Julie A. Poposki; Atsushi Kato; Roderick G. Carter; Lydia A. Suh; James E. Norton; Julia H. Huang; Anju T. Peters; Leslie C. Grammer; David B. Conley; Stephanie Shintani-Smith; Bruce K. Tan; Kevin C. Welch; Robert C. Kern; Robert P. Schleimer

doi:10.1016/j.jaci.2021.02.045

Studies of the role of basophils in aspirin-exacerbated respiratory disease pathogenesis

Whitney W. Stevens^*, Anna G. Staudacher, Kathryn E. Hulse, Julie A. Poposki, Atsushi Kato, Roderick G. Carter, Lydia A. Suh, James E. Norton, Julia H. Huang, Anju T. Peters, Leslie C. Grammer, David B. Conley, Stephanie Shintani-Smith, Bruce K. Tan, Kevin C. Welch, Robert C. Kern, Robert P. Schleimer

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

Background: Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and intolerance to cyclooxygenase-1 enzyme inhibitors. The underlying mechanisms contributing to AERD pathogenesis are not fully understood, but AERD is characterized by an enhanced type 2 inflammatory phenotype. Basophils are potent type 2 effector cells, but their involvement in AERD pathophysiology remains unclear. Objective: We sought to characterize the systemic and local basophil responses in patients with AERD compared with patients with CRSwNP. Methods: Sinonasal tissues including inferior turbinate and/or nasal polyps (NPs) and peripheral blood were collected from controls, patients with AERD, and patients with CRSwNP. Expression of cell surface (CD45, FcεRI, CD203c), activation (CD63), and intracellular (2D7) markers associated with basophils was characterized using flow cytometry. Clinical data including Lund-Mackay scores and pulmonary function were obtained. Results: The mean number of basophils (CD45⁺CD203c⁺FcεRI⁺CD117⁻) detected in AERD NPs (147 ± 28 cells/mg tissue) was significantly elevated compared with that detected in CRSwNP NPs (69 ± 20 cells/mg tissue; P = .01). The number of circulating basophils was significantly elevated in patients with AERD (P = .04). Basophils in NPs had significantly higher CD203c and CD63 mean fluorescence intensity compared with blood in both conditions (P < .01). Basophils from AERD NPs had lower expression of the granule content marker 2D7 compared with those from matched blood (P < .01) or NPs of patients with CRSwNP (P = .06), suggesting ongoing degranulation. Basophil 2D7 mean fluorescence intensity significantly correlated with pulmonary function (r = 0.62; P = .02) and inversely correlated with sinonasal inflammation (r = −0.56; P = .004). Conclusions: Increased basophil numbers and extent of ongoing degranulation in NPs of patients with AERD compared with patients with CRSwNP may contribute to the exaggerated disease pathogenesis and severity unique to AERD.

Original language	English (US)
Pages (from-to)	439-449.e5
Journal	Journal of Allergy and Clinical Immunology
Volume	148
Issue number	2
DOIs	https://doi.org/10.1016/j.jaci.2021.02.045
State	Published - Aug 2021

Funding

This research was supported in part by the National Institutes of Health grants (grant no. KL2 TR001424, K23 AI141694, R01 AI137174, U19 AI106683 , and P01 AI145818 ), by grants from the Parker B. Francis Fellowship Foundation and the American Partnership for Eosinophilic Disorders (APFED)/AAAAI HOPE Pilot Grant Award, and by the Ernest S. Bazley Foundation. Disclosure of potential conflict of interest: W. W. Stevens served on an advisory board for GlaxoSmithKline. A. Kato reports personal fees from Astellas Pharmaceuticals and a gift for his research from Lyra Therapeutics. A. T. Peters reports personal fees from Sanofi Regeneron and personal fees and grants from AstraZeneca and Optinose. L. C. Grammer reports personal fees from Astellas Pharmaceuticals. B. K. Tan reports personal fees from Sanofi Regeneron/Genzyme and OptiNose. R. C. Kern reports personal fees from Genentech, GlaxoSmithKline, Sanofi, Novartis, Lyra Pharmaceutical, and Neurent. R. P. Schleimer reports personal fees from Intersect ENT, Merck, GlaxoSmithKline, Sanofi, AstraZeneca/Medimmune, Genentech, Actobio Therapeutics, Lyra Therapeutics, Astellas Pharma, Inc, and Otsuka, Inc, and also has Siglec-8 and Siglec-8 ligand-related patents licensed to Allakos, Inc. The rest of the authors declare that they have no relevant conflicts of interest. This research was supported in part by the National Institutes of Health grants (grant no. KL2 TR001424, K23 AI141694, R01 AI137174, U19 AI106683, and P01 AI145818), by grants from the Parker B. Francis Fellowship Foundation and the American Partnership for Eosinophilic Disorders (APFED)/AAAAI HOPE Pilot Grant Award, and by the Ernest S. Bazley Foundation. Disclosure of potential conflict of interest: W. W. Stevens served on an advisory board for GlaxoSmithKline. A. Kato reports personal fees from Astellas Pharmaceuticals and a gift for his research from Lyra Therapeutics. A. T. Peters reports personal fees from Sanofi Regeneron and personal fees and grants from AstraZeneca and Optinose. L. C. Grammer reports personal fees from Astellas Pharmaceuticals. B. K. Tan reports personal fees from Sanofi Regeneron/Genzyme and OptiNose. R. C. Kern reports personal fees from Genentech, GlaxoSmithKline, Sanofi, Novartis, Lyra Pharmaceutical, and Neurent. R. P. Schleimer reports personal fees from Intersect ENT, Merck, GlaxoSmithKline, Sanofi, AstraZeneca/Medimmune, Genentech, Actobio Therapeutics, Lyra Therapeutics, Astellas Pharma, Inc, and Otsuka, Inc, and also has Siglec-8 and Siglec-8 ligand-related patents licensed to Allakos, Inc. The rest of the authors declare that they have no relevant conflicts of interest.

Keywords

2D7
AERD
Aspirin-exacerbated respiratory disease
CRSwNP
basophil
chronic sinusitis
nasal polyp

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jaci.2021.02.045

Cite this

Stevens, W. W., Staudacher, A. G., Hulse, K. E., Poposki, J. A., Kato, A., Carter, R. G., Suh, L. A., Norton, J. E., Huang, J. H., Peters, A. T., Grammer, L. C., Conley, D. B., Shintani-Smith, S., Tan, B. K., Welch, K. C., Kern, R. C., & Schleimer, R. P. (2021). Studies of the role of basophils in aspirin-exacerbated respiratory disease pathogenesis. Journal of Allergy and Clinical Immunology, 148(2), 439-449.e5. https://doi.org/10.1016/j.jaci.2021.02.045

@article{042ffc4e67f349c7b90d25596c20bc1b,

title = "Studies of the role of basophils in aspirin-exacerbated respiratory disease pathogenesis",

abstract = "Background: Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and intolerance to cyclooxygenase-1 enzyme inhibitors. The underlying mechanisms contributing to AERD pathogenesis are not fully understood, but AERD is characterized by an enhanced type 2 inflammatory phenotype. Basophils are potent type 2 effector cells, but their involvement in AERD pathophysiology remains unclear. Objective: We sought to characterize the systemic and local basophil responses in patients with AERD compared with patients with CRSwNP. Methods: Sinonasal tissues including inferior turbinate and/or nasal polyps (NPs) and peripheral blood were collected from controls, patients with AERD, and patients with CRSwNP. Expression of cell surface (CD45, FcεRI, CD203c), activation (CD63), and intracellular (2D7) markers associated with basophils was characterized using flow cytometry. Clinical data including Lund-Mackay scores and pulmonary function were obtained. Results: The mean number of basophils (CD45+CD203c+FcεRI+CD117−) detected in AERD NPs (147 ± 28 cells/mg tissue) was significantly elevated compared with that detected in CRSwNP NPs (69 ± 20 cells/mg tissue; P = .01). The number of circulating basophils was significantly elevated in patients with AERD (P = .04). Basophils in NPs had significantly higher CD203c and CD63 mean fluorescence intensity compared with blood in both conditions (P < .01). Basophils from AERD NPs had lower expression of the granule content marker 2D7 compared with those from matched blood (P < .01) or NPs of patients with CRSwNP (P = .06), suggesting ongoing degranulation. Basophil 2D7 mean fluorescence intensity significantly correlated with pulmonary function (r = 0.62; P = .02) and inversely correlated with sinonasal inflammation (r = −0.56; P = .004). Conclusions: Increased basophil numbers and extent of ongoing degranulation in NPs of patients with AERD compared with patients with CRSwNP may contribute to the exaggerated disease pathogenesis and severity unique to AERD.",

keywords = "2D7, AERD, Aspirin-exacerbated respiratory disease, CRSwNP, basophil, chronic sinusitis, nasal polyp",

author = "Stevens, {Whitney W.} and Staudacher, {Anna G.} and Hulse, {Kathryn E.} and Poposki, {Julie A.} and Atsushi Kato and Carter, {Roderick G.} and Suh, {Lydia A.} and Norton, {James E.} and Huang, {Julia H.} and Peters, {Anju T.} and Grammer, {Leslie C.} and Conley, {David B.} and Stephanie Shintani-Smith and Tan, {Bruce K.} and Welch, {Kevin C.} and Kern, {Robert C.} and Schleimer, {Robert P.}",

note = "Publisher Copyright: {\textcopyright} 2021 American Academy of Allergy, Asthma & Immunology",

year = "2021",

month = aug,

doi = "10.1016/j.jaci.2021.02.045",

language = "English (US)",

volume = "148",

pages = "439--449.e5",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "2",

}

Stevens, WW, Staudacher, AG, Hulse, KE, Poposki, JA, Kato, A, Carter, RG, Suh, LA, Norton, JE, Huang, JH, Peters, AT , Grammer, LC , Conley, DB , Shintani-Smith, S , Tan, BK , Welch, KC , Kern, RC & Schleimer, RP 2021, 'Studies of the role of basophils in aspirin-exacerbated respiratory disease pathogenesis', Journal of Allergy and Clinical Immunology, vol. 148, no. 2, pp. 439-449.e5. https://doi.org/10.1016/j.jaci.2021.02.045

TY - JOUR

T1 - Studies of the role of basophils in aspirin-exacerbated respiratory disease pathogenesis

AU - Stevens, Whitney W.

AU - Staudacher, Anna G.

AU - Hulse, Kathryn E.

AU - Poposki, Julie A.

AU - Kato, Atsushi

AU - Carter, Roderick G.

AU - Suh, Lydia A.

AU - Norton, James E.

AU - Huang, Julia H.

AU - Peters, Anju T.

AU - Grammer, Leslie C.

AU - Conley, David B.

AU - Shintani-Smith, Stephanie

AU - Tan, Bruce K.

AU - Welch, Kevin C.

AU - Kern, Robert C.

AU - Schleimer, Robert P.

PY - 2021/8

Y1 - 2021/8

N2 - Background: Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and intolerance to cyclooxygenase-1 enzyme inhibitors. The underlying mechanisms contributing to AERD pathogenesis are not fully understood, but AERD is characterized by an enhanced type 2 inflammatory phenotype. Basophils are potent type 2 effector cells, but their involvement in AERD pathophysiology remains unclear. Objective: We sought to characterize the systemic and local basophil responses in patients with AERD compared with patients with CRSwNP. Methods: Sinonasal tissues including inferior turbinate and/or nasal polyps (NPs) and peripheral blood were collected from controls, patients with AERD, and patients with CRSwNP. Expression of cell surface (CD45, FcεRI, CD203c), activation (CD63), and intracellular (2D7) markers associated with basophils was characterized using flow cytometry. Clinical data including Lund-Mackay scores and pulmonary function were obtained. Results: The mean number of basophils (CD45+CD203c+FcεRI+CD117−) detected in AERD NPs (147 ± 28 cells/mg tissue) was significantly elevated compared with that detected in CRSwNP NPs (69 ± 20 cells/mg tissue; P = .01). The number of circulating basophils was significantly elevated in patients with AERD (P = .04). Basophils in NPs had significantly higher CD203c and CD63 mean fluorescence intensity compared with blood in both conditions (P < .01). Basophils from AERD NPs had lower expression of the granule content marker 2D7 compared with those from matched blood (P < .01) or NPs of patients with CRSwNP (P = .06), suggesting ongoing degranulation. Basophil 2D7 mean fluorescence intensity significantly correlated with pulmonary function (r = 0.62; P = .02) and inversely correlated with sinonasal inflammation (r = −0.56; P = .004). Conclusions: Increased basophil numbers and extent of ongoing degranulation in NPs of patients with AERD compared with patients with CRSwNP may contribute to the exaggerated disease pathogenesis and severity unique to AERD.

AB - Background: Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and intolerance to cyclooxygenase-1 enzyme inhibitors. The underlying mechanisms contributing to AERD pathogenesis are not fully understood, but AERD is characterized by an enhanced type 2 inflammatory phenotype. Basophils are potent type 2 effector cells, but their involvement in AERD pathophysiology remains unclear. Objective: We sought to characterize the systemic and local basophil responses in patients with AERD compared with patients with CRSwNP. Methods: Sinonasal tissues including inferior turbinate and/or nasal polyps (NPs) and peripheral blood were collected from controls, patients with AERD, and patients with CRSwNP. Expression of cell surface (CD45, FcεRI, CD203c), activation (CD63), and intracellular (2D7) markers associated with basophils was characterized using flow cytometry. Clinical data including Lund-Mackay scores and pulmonary function were obtained. Results: The mean number of basophils (CD45+CD203c+FcεRI+CD117−) detected in AERD NPs (147 ± 28 cells/mg tissue) was significantly elevated compared with that detected in CRSwNP NPs (69 ± 20 cells/mg tissue; P = .01). The number of circulating basophils was significantly elevated in patients with AERD (P = .04). Basophils in NPs had significantly higher CD203c and CD63 mean fluorescence intensity compared with blood in both conditions (P < .01). Basophils from AERD NPs had lower expression of the granule content marker 2D7 compared with those from matched blood (P < .01) or NPs of patients with CRSwNP (P = .06), suggesting ongoing degranulation. Basophil 2D7 mean fluorescence intensity significantly correlated with pulmonary function (r = 0.62; P = .02) and inversely correlated with sinonasal inflammation (r = −0.56; P = .004). Conclusions: Increased basophil numbers and extent of ongoing degranulation in NPs of patients with AERD compared with patients with CRSwNP may contribute to the exaggerated disease pathogenesis and severity unique to AERD.

KW - 2D7

KW - AERD

KW - Aspirin-exacerbated respiratory disease

KW - CRSwNP

KW - basophil

KW - chronic sinusitis

KW - nasal polyp

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U2 - 10.1016/j.jaci.2021.02.045

DO - 10.1016/j.jaci.2021.02.045

M3 - Article

C2 - 33819512

AN - SCOPUS:85105300710

SN - 0091-6749

VL - 148

SP - 439-449.e5

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 2

ER -

Studies of the role of basophils in aspirin-exacerbated respiratory disease pathogenesis

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UN SDGs

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