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

Wiley - Tập 64 Số 4 - Trang 982-992 - 2012
Nishant Dwivedi1, Jagriti Upadhyay2, Indira Neeli2, Salar N. Khan2, Debendra Pattanaik2, Linda K. Myers2, Kyriakos A. Kirou3, Bernhard Hellmich4, Bryan Knuckley5, Paul R. Thompson6, Mary K. Crow3, Ted R. Mikuls7, Elena Csernok8, Marko Radic2
1University of Tennessee Health Science Center, Memphis, TN 38163, USA
2University of Tennessee Health Science Center, Memphis
3#N# §Hospital for Special Surgery, New York, New York
4Clinic Plochingen and University of Tübingen, Plochingen, Germany
5University of South Carolina, Columbia
6Scripps Research Institute Florida, Jupiter
7Omaha VA Medical Center and University of Nebraska Medical Center Omaha
8University of Lübeck, Lübeck, Germany, and Klinikum Bad Bramstedt, Bad Bramstedt, Germany

Tóm tắt

AbstractObjectiveTo test the hypothesis that autoantigen modifications by peptidylarginine deiminase type 4 (PAD‐4) increase immunoreactivity.MethodsWe 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.ResultsIncreased 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.ConclusionCirculating 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.

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Wiley

Tập 64 Số 4

982-992

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