Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps.
Authors
Dwivedi, NishantUpadhyay, 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
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2012-04-01Keywords
AdolescentAdult
Aged
Aged, 80 and over
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Arthritis, Rheumatoid
Autoantibodies
Autoantigens
Felty Syndrome
Female
Histones
Humans
Lupus Erythematosus, Systemic
Male
Middle Aged
Neutrophils
Biochemistry
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Musculoskeletal Diseases
Therapeutics
Metadata
Show full item recordAbstract
OBJECTIVE: To test the hypothesis that autoantigen modifications by peptidylarginine deiminase type 4 (PAD-4) increase immunoreactivity. METHODS: 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. RESULTS: 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. CONCLUSION: 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.Source
Arthritis Rheum. 2012 Apr;64(4):982-92. doi: 10.1002/art.33432. Epub 2011 Oct 27. Link to article on publisher's siteDOI
10.1002/art.33432Permanent Link to this Item
http://hdl.handle.net/20.500.14038/50027Notes
At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.
Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1002/art.33432