Sputum antineutrophil cytoplasmic antibodies in serum antineutrophil cytoplasmic antibody–negative eosinophilic granulomatosis with polyangiitis

Manali Mukherjee, Sruthi R. Thomas, Katherine Radford, Anna Dvorkin-Gheva, Svetlana Davydchenko, Melanie Kjarsgaard, Sarah Svenningsen, Sarah Almas, Lindsey C. Felix, Jennifer Stearns, Quan-zhen Li, Nader Khalidi, Paige Lacy, Parameswaran K. Nair

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Rationale: Eosinophilic granulomatosis with polyangiitis (eGPA) is a small-vessel vasculitis where 40% of patients present with serum antineutrophil cytoplasmic antibodies (ANCAs). We examined the presence and clinical relevance of sputum ANCAs in the serum ANCA 2 patients with eGPA. Methods: ANCA was investigated in matched sputum and blood samples collected from 23 patients with eGPA (n = 10, serum ANCA 1 ), 19 patients with eosinophilic asthma (prednisone dependent), and 13 healthy volunteers. IgG reactivity to common target antigens and cytokine profiles in sputum samples were examined. Pathogenicity of detected sputum ANCA was assessed using in vitro degranulation assays. Measurements and Main Results: Most patients with eGPA (17 of 23, 74%) showed significantly increased sputum ANCAs compared with patients with eosinophilic asthma (P = 0.002) and healthy controls (P, 0.0001), irrespective of their serum ANCA status. In addition, 16 of 17 (94%) of sputum ANCA 1 patients had clinical manifestations of severe asthma compared with 3 of 6 (50%) in the sputum ANCA 2 subset (P = 0.04). Microarray analysis of 123 common antigens failed to reveal a specific target for the ANCA IgG. However, immunoprecipitated immunoglobulins from ANCA 1 sputum allowed extensive extracellular trap formations from both neutrophils and eosinophils in vitro, indicating pathogenicity of detected IgG autoantibodies. Cytokine analysis showed lung-localized increases in CXCL8 (neutrophil/eosinophil chemotaxis), CCL24 (eosinophil recruitment), and CXCL12 (lymphocyte recruitment) in the sputa from ANCA 1 patients (P, 0.01). Conclusions: We report a novel finding of ANCA reactivity in the sputa of patients with eGPA in whom disease severity is driven by respiratory complications. Investigating localized autoimmunity may lead to the discovery of novel pathomechanisms, therapeutic targets, and optimal biomarkers for diagnosing and managing eGPA.

Original languageEnglish (US)
Pages (from-to)158-170
Number of pages13
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume199
Issue number2
DOIs
StatePublished - Jan 15 2019

Fingerprint

Antineutrophil Cytoplasmic Antibodies
Granulomatosis with Polyangiitis
Sputum
Serum
Eosinophils
Asthma
Immunoglobulin G
Virulence
Neutrophils
Cytokines
Antigens
Chemotaxis
Microarray Analysis
Vasculitis
Prednisone
Autoimmunity
Autoantibodies

Keywords

  • ANCA
  • EGPA
  • Eosinophil
  • Severe asthma
  • Sputum

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Sputum antineutrophil cytoplasmic antibodies in serum antineutrophil cytoplasmic antibody–negative eosinophilic granulomatosis with polyangiitis. / Mukherjee, Manali; Thomas, Sruthi R.; Radford, Katherine; Dvorkin-Gheva, Anna; Davydchenko, Svetlana; Kjarsgaard, Melanie; Svenningsen, Sarah; Almas, Sarah; Felix, Lindsey C.; Stearns, Jennifer; Li, Quan-zhen; Khalidi, Nader; Lacy, Paige; Nair, Parameswaran K.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 199, No. 2, 15.01.2019, p. 158-170.

Research output: Contribution to journalArticle

Mukherjee, M, Thomas, SR, Radford, K, Dvorkin-Gheva, A, Davydchenko, S, Kjarsgaard, M, Svenningsen, S, Almas, S, Felix, LC, Stearns, J, Li, Q, Khalidi, N, Lacy, P & Nair, PK 2019, 'Sputum antineutrophil cytoplasmic antibodies in serum antineutrophil cytoplasmic antibody–negative eosinophilic granulomatosis with polyangiitis', American Journal of Respiratory and Critical Care Medicine, vol. 199, no. 2, pp. 158-170. https://doi.org/10.1164/rccm.201804-0809OC
Mukherjee, Manali ; Thomas, Sruthi R. ; Radford, Katherine ; Dvorkin-Gheva, Anna ; Davydchenko, Svetlana ; Kjarsgaard, Melanie ; Svenningsen, Sarah ; Almas, Sarah ; Felix, Lindsey C. ; Stearns, Jennifer ; Li, Quan-zhen ; Khalidi, Nader ; Lacy, Paige ; Nair, Parameswaran K. / Sputum antineutrophil cytoplasmic antibodies in serum antineutrophil cytoplasmic antibody–negative eosinophilic granulomatosis with polyangiitis. In: American Journal of Respiratory and Critical Care Medicine. 2019 ; Vol. 199, No. 2. pp. 158-170.
@article{ad45ccb40b8d4cc09155dbf15161d6f9,
title = "Sputum antineutrophil cytoplasmic antibodies in serum antineutrophil cytoplasmic antibody–negative eosinophilic granulomatosis with polyangiitis",
abstract = "Rationale: Eosinophilic granulomatosis with polyangiitis (eGPA) is a small-vessel vasculitis where 40{\%} of patients present with serum antineutrophil cytoplasmic antibodies (ANCAs). We examined the presence and clinical relevance of sputum ANCAs in the serum ANCA 2 patients with eGPA. Methods: ANCA was investigated in matched sputum and blood samples collected from 23 patients with eGPA (n = 10, serum ANCA 1 ), 19 patients with eosinophilic asthma (prednisone dependent), and 13 healthy volunteers. IgG reactivity to common target antigens and cytokine profiles in sputum samples were examined. Pathogenicity of detected sputum ANCA was assessed using in vitro degranulation assays. Measurements and Main Results: Most patients with eGPA (17 of 23, 74{\%}) showed significantly increased sputum ANCAs compared with patients with eosinophilic asthma (P = 0.002) and healthy controls (P, 0.0001), irrespective of their serum ANCA status. In addition, 16 of 17 (94{\%}) of sputum ANCA 1 patients had clinical manifestations of severe asthma compared with 3 of 6 (50{\%}) in the sputum ANCA 2 subset (P = 0.04). Microarray analysis of 123 common antigens failed to reveal a specific target for the ANCA IgG. However, immunoprecipitated immunoglobulins from ANCA 1 sputum allowed extensive extracellular trap formations from both neutrophils and eosinophils in vitro, indicating pathogenicity of detected IgG autoantibodies. Cytokine analysis showed lung-localized increases in CXCL8 (neutrophil/eosinophil chemotaxis), CCL24 (eosinophil recruitment), and CXCL12 (lymphocyte recruitment) in the sputa from ANCA 1 patients (P, 0.01). Conclusions: We report a novel finding of ANCA reactivity in the sputa of patients with eGPA in whom disease severity is driven by respiratory complications. Investigating localized autoimmunity may lead to the discovery of novel pathomechanisms, therapeutic targets, and optimal biomarkers for diagnosing and managing eGPA.",
keywords = "ANCA, EGPA, Eosinophil, Severe asthma, Sputum",
author = "Manali Mukherjee and Thomas, {Sruthi R.} and Katherine Radford and Anna Dvorkin-Gheva and Svetlana Davydchenko and Melanie Kjarsgaard and Sarah Svenningsen and Sarah Almas and Felix, {Lindsey C.} and Jennifer Stearns and Quan-zhen Li and Nader Khalidi and Paige Lacy and Nair, {Parameswaran K.}",
year = "2019",
month = "1",
day = "15",
doi = "10.1164/rccm.201804-0809OC",
language = "English (US)",
volume = "199",
pages = "158--170",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "2",

}

TY - JOUR

T1 - Sputum antineutrophil cytoplasmic antibodies in serum antineutrophil cytoplasmic antibody–negative eosinophilic granulomatosis with polyangiitis

AU - Mukherjee, Manali

AU - Thomas, Sruthi R.

AU - Radford, Katherine

AU - Dvorkin-Gheva, Anna

AU - Davydchenko, Svetlana

AU - Kjarsgaard, Melanie

AU - Svenningsen, Sarah

AU - Almas, Sarah

AU - Felix, Lindsey C.

AU - Stearns, Jennifer

AU - Li, Quan-zhen

AU - Khalidi, Nader

AU - Lacy, Paige

AU - Nair, Parameswaran K.

PY - 2019/1/15

Y1 - 2019/1/15

N2 - Rationale: Eosinophilic granulomatosis with polyangiitis (eGPA) is a small-vessel vasculitis where 40% of patients present with serum antineutrophil cytoplasmic antibodies (ANCAs). We examined the presence and clinical relevance of sputum ANCAs in the serum ANCA 2 patients with eGPA. Methods: ANCA was investigated in matched sputum and blood samples collected from 23 patients with eGPA (n = 10, serum ANCA 1 ), 19 patients with eosinophilic asthma (prednisone dependent), and 13 healthy volunteers. IgG reactivity to common target antigens and cytokine profiles in sputum samples were examined. Pathogenicity of detected sputum ANCA was assessed using in vitro degranulation assays. Measurements and Main Results: Most patients with eGPA (17 of 23, 74%) showed significantly increased sputum ANCAs compared with patients with eosinophilic asthma (P = 0.002) and healthy controls (P, 0.0001), irrespective of their serum ANCA status. In addition, 16 of 17 (94%) of sputum ANCA 1 patients had clinical manifestations of severe asthma compared with 3 of 6 (50%) in the sputum ANCA 2 subset (P = 0.04). Microarray analysis of 123 common antigens failed to reveal a specific target for the ANCA IgG. However, immunoprecipitated immunoglobulins from ANCA 1 sputum allowed extensive extracellular trap formations from both neutrophils and eosinophils in vitro, indicating pathogenicity of detected IgG autoantibodies. Cytokine analysis showed lung-localized increases in CXCL8 (neutrophil/eosinophil chemotaxis), CCL24 (eosinophil recruitment), and CXCL12 (lymphocyte recruitment) in the sputa from ANCA 1 patients (P, 0.01). Conclusions: We report a novel finding of ANCA reactivity in the sputa of patients with eGPA in whom disease severity is driven by respiratory complications. Investigating localized autoimmunity may lead to the discovery of novel pathomechanisms, therapeutic targets, and optimal biomarkers for diagnosing and managing eGPA.

AB - Rationale: Eosinophilic granulomatosis with polyangiitis (eGPA) is a small-vessel vasculitis where 40% of patients present with serum antineutrophil cytoplasmic antibodies (ANCAs). We examined the presence and clinical relevance of sputum ANCAs in the serum ANCA 2 patients with eGPA. Methods: ANCA was investigated in matched sputum and blood samples collected from 23 patients with eGPA (n = 10, serum ANCA 1 ), 19 patients with eosinophilic asthma (prednisone dependent), and 13 healthy volunteers. IgG reactivity to common target antigens and cytokine profiles in sputum samples were examined. Pathogenicity of detected sputum ANCA was assessed using in vitro degranulation assays. Measurements and Main Results: Most patients with eGPA (17 of 23, 74%) showed significantly increased sputum ANCAs compared with patients with eosinophilic asthma (P = 0.002) and healthy controls (P, 0.0001), irrespective of their serum ANCA status. In addition, 16 of 17 (94%) of sputum ANCA 1 patients had clinical manifestations of severe asthma compared with 3 of 6 (50%) in the sputum ANCA 2 subset (P = 0.04). Microarray analysis of 123 common antigens failed to reveal a specific target for the ANCA IgG. However, immunoprecipitated immunoglobulins from ANCA 1 sputum allowed extensive extracellular trap formations from both neutrophils and eosinophils in vitro, indicating pathogenicity of detected IgG autoantibodies. Cytokine analysis showed lung-localized increases in CXCL8 (neutrophil/eosinophil chemotaxis), CCL24 (eosinophil recruitment), and CXCL12 (lymphocyte recruitment) in the sputa from ANCA 1 patients (P, 0.01). Conclusions: We report a novel finding of ANCA reactivity in the sputa of patients with eGPA in whom disease severity is driven by respiratory complications. Investigating localized autoimmunity may lead to the discovery of novel pathomechanisms, therapeutic targets, and optimal biomarkers for diagnosing and managing eGPA.

KW - ANCA

KW - EGPA

KW - Eosinophil

KW - Severe asthma

KW - Sputum

UR - http://www.scopus.com/inward/record.url?scp=85060015415&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060015415&partnerID=8YFLogxK

U2 - 10.1164/rccm.201804-0809OC

DO - 10.1164/rccm.201804-0809OC

M3 - Article

C2 - 30179583

AN - SCOPUS:85060015415

VL - 199

SP - 158

EP - 170

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 2

ER -