Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps.

Nishant Dwivedi, Jagriti Upadhyay, Indira Neeli, Salar Khan, Debendra Pattanaik, Linda Myers, Kyriakos A. Kirou, Bernhard Hellmich, Bryan Knuckley, Paul R. Thompson, Mary K. Crow, Ted R. Mikuls, Elena Csernok, Marko Radic

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Abstract

To test the hypothesis that autoantigen modifications by peptidylarginine deiminase type 4 (PAD-4) increase immunoreactivity. We assembled sera from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Felty's syndrome (FS), and antineutrophil cytoplasmic antibody-associated vasculitides (AAVs), as well as sera from control subjects without autoimmune diseases. The sera were tested for binding to activated neutrophils, deiminated histones, and neutrophil extracellular chromatin traps (NETs). IgG binding to lipopolysaccharide-activated neutrophils was assessed with confocal microscopy, and binding to in vitro-deiminated histones was measured using enzyme-linked immunosorbent assay (ELISA) and Western blotting. In addition, we quantitated histone deimination in freshly isolated neutrophils from the blood of patients and control subjects. Increased IgG reactivity with activated neutrophils, particularly binding to NETs, was paralleled by preferential binding to deiminated histones over nondeiminated histones by ELISA in a majority of sera from FS patients but only in a minority of sera from SLE and RA patients. Immunoblotting revealed autoantibody preference for deiminated histones H3, H4, and H2A in most FS patients and in a subset of SLE and RA patients. In patients with AAVs, serum IgG preferentially bound nondeiminated histones over deiminated histones. Increased levels of deiminated histones were detected in neutrophils from RA patients. Circulating autoantibodies in FS are preferentially directed against PAD-4-deiminated histones and bind to activated neutrophils and NETs. Thus, increased reactivity with modified autoantigens in FS implies a direct contribution of neutrophil activation and the production of NET-associated nuclear autoantigens in the initiation or progression of FS.

Original languageEnglish (US)
Pages (from-to)982-992
Number of pages11
JournalArthritis and Rheumatism
Volume64
Issue number4
DOIs
StatePublished - Jan 1 2012

Fingerprint

Felty Syndrome
Autoantibodies
Histones
Chromatin
Neutrophils
Rheumatoid Arthritis
Autoantigens
Serum
Systemic Lupus Erythematosus
Immunoglobulin G
Vasculitis
Extracellular Traps
Enzyme-Linked Immunosorbent Assay
Antineutrophil Cytoplasmic Antibodies
Neutrophil Activation
Immunoblotting
Confocal Microscopy
Autoimmune Diseases
Lipopolysaccharides

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

Cite this

Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps. / Dwivedi, Nishant; Upadhyay, Jagriti; Neeli, Indira; Khan, Salar; Pattanaik, Debendra; Myers, Linda; Kirou, Kyriakos A.; Hellmich, Bernhard; Knuckley, Bryan; Thompson, Paul R.; Crow, Mary K.; Mikuls, Ted R.; Csernok, Elena; Radic, Marko.

In: Arthritis and Rheumatism, Vol. 64, No. 4, 01.01.2012, p. 982-992.

Research output: Contribution to journalArticle

Dwivedi, N, Upadhyay, J, Neeli, I, Khan, S, Pattanaik, D, Myers, L, Kirou, KA, Hellmich, B, Knuckley, B, Thompson, PR, Crow, MK, Mikuls, TR, Csernok, E & Radic, M 2012, 'Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps.', Arthritis and Rheumatism, vol. 64, no. 4, pp. 982-992. https://doi.org/10.1002/art.33432
Dwivedi, Nishant ; Upadhyay, Jagriti ; Neeli, Indira ; Khan, Salar ; Pattanaik, Debendra ; Myers, Linda ; Kirou, Kyriakos A. ; Hellmich, Bernhard ; Knuckley, Bryan ; Thompson, Paul R. ; Crow, Mary K. ; Mikuls, Ted R. ; Csernok, Elena ; Radic, Marko. / Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps. In: Arthritis and Rheumatism. 2012 ; Vol. 64, No. 4. pp. 982-992.
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AU - Khan, Salar

AU - Pattanaik, Debendra

AU - Myers, Linda

AU - Kirou, Kyriakos A.

AU - Hellmich, Bernhard

AU - Knuckley, Bryan

AU - Thompson, Paul R.

AU - Crow, Mary K.

AU - Mikuls, Ted R.

AU - Csernok, Elena

AU - Radic, Marko

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