Sputum autoantibodies in patients with severe eosinophilic asthma

Manali Mukherjee, David C. Bulir, Katherine Radford, Melanie Kjarsgaard, Chynna Margaret Huang, Elizabeth Jacobsen, Sergei I. Ochkur, Ana Catuneanu, Hanah Lamothe-Kipnes, James Mahony, James J. Lee, Paige Lacy, Parameswaran K. Nair

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: The persistence of eosinophils in sputum despite high doses of corticosteroids indicates disease severity in asthmatic patients. Chronic inflamed airways can lose tolerance over time to immunogenic entities released on frequent eosinophil degranulation, which further contributes to disease severity and necessitates an increase in maintenance corticosteroids. Objectives: We sought to investigate the possibility of a polyclonal autoimmune event in the airways of asthmatic patients and to identify associated clinical and molecular characteristics. Methods: The presence of autoantibodies against eosinophil peroxidase (EPX) and anti-nuclear antibodies was investigated in patients with eosinophilic asthma maintained on high-dose corticosteroids, prednisone, or both. The ability of sputum immunoglobulins to induce eosinophil degranulation in vitro was assessed. In addition, the associated inflammatory microenvironment in patients with detectable autoantibodies was examined. Results: We report a "polyclonal" autoimmune event occurring in the airways of prednisone-dependent asthmatic patients with increased eosinophil activity, recurrent pulmonary infections, or both, as evident by the concomitant presence of sputum anti-EPX and anti-nuclear antibodies of the IgG subtype. Extensive cytokine profiling of sputum revealed a TH2-dominated microenvironment (eotaxin-2, IL-5, IL-18, and IL-13) and increased signalling molecules that support the formation of ectopic lymphoid structures (B-cell activating factor and B cell-attracting chemokine 1). Immunoprecipitated sputum immunoglobulins from patients with increased autoantibody levels triggered eosinophil degranulation in vitro, with release of extensive histone-rich extracellular traps, an event unsuppressed by dexamethasone and possibly contributing to the steroid-unresponsive nature of these eosinophilic patients. Conclusion: This study identifies an autoimmune endotype of severe asthma that can be identified by the presence of sputum autoantibodies against EPX and autologous cellular components.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
DOIs
StateAccepted/In press - Jan 1 2017

Fingerprint

Sputum
Autoantibodies
Asthma
Eosinophils
Eosinophil Peroxidase
Adrenal Cortex Hormones
Prednisone
Immunoglobulins
Anti-Idiotypic Antibodies
Chemokine CCL24
B-Cell Activating Factor
Interleukin-18
Interleukin-13
Interleukin-5
Chemokines
Histones
Dexamethasone
B-Lymphocytes
Immunoglobulin G
Steroids

Keywords

  • Anti-nuclear antibodies
  • Autoantibodies
  • Autoimmunity
  • Eosinophil degranulation
  • Eosinophil peroxidase
  • Eosinophilia
  • Severe asthma
  • Sputum

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Mukherjee, M., Bulir, D. C., Radford, K., Kjarsgaard, M., Huang, C. M., Jacobsen, E., ... Nair, P. K. (Accepted/In press). Sputum autoantibodies in patients with severe eosinophilic asthma. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2017.06.033

Sputum autoantibodies in patients with severe eosinophilic asthma. / Mukherjee, Manali; Bulir, David C.; Radford, Katherine; Kjarsgaard, Melanie; Huang, Chynna Margaret; Jacobsen, Elizabeth; Ochkur, Sergei I.; Catuneanu, Ana; Lamothe-Kipnes, Hanah; Mahony, James; Lee, James J.; Lacy, Paige; Nair, Parameswaran K.

In: Journal of Allergy and Clinical Immunology, 01.01.2017.

Research output: Contribution to journalArticle

Mukherjee, M, Bulir, DC, Radford, K, Kjarsgaard, M, Huang, CM, Jacobsen, E, Ochkur, SI, Catuneanu, A, Lamothe-Kipnes, H, Mahony, J, Lee, JJ, Lacy, P & Nair, PK 2017, 'Sputum autoantibodies in patients with severe eosinophilic asthma', Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2017.06.033
Mukherjee, Manali ; Bulir, David C. ; Radford, Katherine ; Kjarsgaard, Melanie ; Huang, Chynna Margaret ; Jacobsen, Elizabeth ; Ochkur, Sergei I. ; Catuneanu, Ana ; Lamothe-Kipnes, Hanah ; Mahony, James ; Lee, James J. ; Lacy, Paige ; Nair, Parameswaran K. / Sputum autoantibodies in patients with severe eosinophilic asthma. In: Journal of Allergy and Clinical Immunology. 2017.
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AU - Bulir, David C.

AU - Radford, Katherine

AU - Kjarsgaard, Melanie

AU - Huang, Chynna Margaret

AU - Jacobsen, Elizabeth

AU - Ochkur, Sergei I.

AU - Catuneanu, Ana

AU - Lamothe-Kipnes, Hanah

AU - Mahony, James

AU - Lee, James J.

AU - Lacy, Paige

AU - Nair, Parameswaran K.

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N2 - Background: The persistence of eosinophils in sputum despite high doses of corticosteroids indicates disease severity in asthmatic patients. Chronic inflamed airways can lose tolerance over time to immunogenic entities released on frequent eosinophil degranulation, which further contributes to disease severity and necessitates an increase in maintenance corticosteroids. Objectives: We sought to investigate the possibility of a polyclonal autoimmune event in the airways of asthmatic patients and to identify associated clinical and molecular characteristics. Methods: The presence of autoantibodies against eosinophil peroxidase (EPX) and anti-nuclear antibodies was investigated in patients with eosinophilic asthma maintained on high-dose corticosteroids, prednisone, or both. The ability of sputum immunoglobulins to induce eosinophil degranulation in vitro was assessed. In addition, the associated inflammatory microenvironment in patients with detectable autoantibodies was examined. Results: We report a "polyclonal" autoimmune event occurring in the airways of prednisone-dependent asthmatic patients with increased eosinophil activity, recurrent pulmonary infections, or both, as evident by the concomitant presence of sputum anti-EPX and anti-nuclear antibodies of the IgG subtype. Extensive cytokine profiling of sputum revealed a TH2-dominated microenvironment (eotaxin-2, IL-5, IL-18, and IL-13) and increased signalling molecules that support the formation of ectopic lymphoid structures (B-cell activating factor and B cell-attracting chemokine 1). Immunoprecipitated sputum immunoglobulins from patients with increased autoantibody levels triggered eosinophil degranulation in vitro, with release of extensive histone-rich extracellular traps, an event unsuppressed by dexamethasone and possibly contributing to the steroid-unresponsive nature of these eosinophilic patients. Conclusion: This study identifies an autoimmune endotype of severe asthma that can be identified by the presence of sputum autoantibodies against EPX and autologous cellular components.

AB - Background: The persistence of eosinophils in sputum despite high doses of corticosteroids indicates disease severity in asthmatic patients. Chronic inflamed airways can lose tolerance over time to immunogenic entities released on frequent eosinophil degranulation, which further contributes to disease severity and necessitates an increase in maintenance corticosteroids. Objectives: We sought to investigate the possibility of a polyclonal autoimmune event in the airways of asthmatic patients and to identify associated clinical and molecular characteristics. Methods: The presence of autoantibodies against eosinophil peroxidase (EPX) and anti-nuclear antibodies was investigated in patients with eosinophilic asthma maintained on high-dose corticosteroids, prednisone, or both. The ability of sputum immunoglobulins to induce eosinophil degranulation in vitro was assessed. In addition, the associated inflammatory microenvironment in patients with detectable autoantibodies was examined. Results: We report a "polyclonal" autoimmune event occurring in the airways of prednisone-dependent asthmatic patients with increased eosinophil activity, recurrent pulmonary infections, or both, as evident by the concomitant presence of sputum anti-EPX and anti-nuclear antibodies of the IgG subtype. Extensive cytokine profiling of sputum revealed a TH2-dominated microenvironment (eotaxin-2, IL-5, IL-18, and IL-13) and increased signalling molecules that support the formation of ectopic lymphoid structures (B-cell activating factor and B cell-attracting chemokine 1). Immunoprecipitated sputum immunoglobulins from patients with increased autoantibody levels triggered eosinophil degranulation in vitro, with release of extensive histone-rich extracellular traps, an event unsuppressed by dexamethasone and possibly contributing to the steroid-unresponsive nature of these eosinophilic patients. Conclusion: This study identifies an autoimmune endotype of severe asthma that can be identified by the presence of sputum autoantibodies against EPX and autologous cellular components.

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KW - Eosinophil peroxidase

KW - Eosinophilia

KW - Severe asthma

KW - Sputum

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