Deimination of linker histones links neutrophil extracellular trap release with autoantibodies in systemic autoimmunity

Nishant Dwivedi, Indira Neeli, Nicolas Schall, Haibao Wan, Dominic M. Desiderio, Elena Csernok, Paul R. Thompson, Hayet Dali, Jean Paul Briand, Sylviane Muller, Marko Radic

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Autoantibodies to nuclear antigens arise in human autoimmune diseases, but a unifying pathogenetic mechanism remains elusive. Recently we reported that exposure of neutrophils to inflammatory conditions induces the citrullination of core histones by peptidylarginine deiminase 4 (PAD4) and that patients with autoimmune disorders produce autoantibodies that recognize such citrullinated histones. Here we identify histone H1 as an additional substrate of PAD4, localize H1 within neutrophil extracellular traps, and detect autoantibodies to citrullinated H1 in 6% of sera from patients with systemic lupus erythematosus and Sjögren's syndrome. No preference for deiminated H1 was observed in healthy control sera and sera from patients with scleroderma or rheumatoid arthritis. We map binding to the winged helix of H1 and determine that citrulline 53 represents a key determinant of the autoantibody epitope. In addition, we quantitate RNA for H1 histone subtypes in mature human neutrophils and identify citrulline residues by liquid chromatography and tandem mass spectrometry. Our results indicate that deimination of linker histones generates new autoantibody epitopes with enhanced potential for stimulating autoreactive human B cells.

Original languageEnglish (US)
Pages (from-to)2840-2851
Number of pages12
JournalFASEB Journal
Volume28
Issue number7
DOIs
StatePublished - Jul 1 2014

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Autoimmunity
Autoantibodies
Histones
Citrulline
Epitopes
Neutrophils
Serum
Nuclear Antigens
Liquid chromatography
Tandem Mass Spectrometry
Liquid Chromatography
Systemic Lupus Erythematosus
Autoimmune Diseases
Mass spectrometry
Rheumatoid Arthritis
B-Lymphocytes
Cells
Extracellular Traps
RNA
Substrates

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Deimination of linker histones links neutrophil extracellular trap release with autoantibodies in systemic autoimmunity. / Dwivedi, Nishant; Neeli, Indira; Schall, Nicolas; Wan, Haibao; Desiderio, Dominic M.; Csernok, Elena; Thompson, Paul R.; Dali, Hayet; Briand, Jean Paul; Muller, Sylviane; Radic, Marko.

In: FASEB Journal, Vol. 28, No. 7, 01.07.2014, p. 2840-2851.

Research output: Contribution to journalArticle

Dwivedi, N, Neeli, I, Schall, N, Wan, H, Desiderio, DM, Csernok, E, Thompson, PR, Dali, H, Briand, JP, Muller, S & Radic, M 2014, 'Deimination of linker histones links neutrophil extracellular trap release with autoantibodies in systemic autoimmunity', FASEB Journal, vol. 28, no. 7, pp. 2840-2851. https://doi.org/10.1096/fj.13-247254
Dwivedi, Nishant ; Neeli, Indira ; Schall, Nicolas ; Wan, Haibao ; Desiderio, Dominic M. ; Csernok, Elena ; Thompson, Paul R. ; Dali, Hayet ; Briand, Jean Paul ; Muller, Sylviane ; Radic, Marko. / Deimination of linker histones links neutrophil extracellular trap release with autoantibodies in systemic autoimmunity. In: FASEB Journal. 2014 ; Vol. 28, No. 7. pp. 2840-2851.
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