Deimination of linker histones links neutrophil extracellular trap release with autoantibodies in systemic autoimmunity
Authors
Dwivedi, NishantNeeli, Indira
Schall, Nicolas
Wan, Haibao
Desiderio, Dominic M.
Csernok, Elena
Thompson, Paul R
Dali, Hayet
Briand, Jean-Paul
Muller, Sylviane
Radic, Marko
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2014-07-01Keywords
Amino Acid SequenceAutoantibodies
Autoantigens
Autoimmune Diseases
Autoimmunity
Epitopes
Histones
Humans
Immunoglobulin G
Molecular Sequence Data
Neutrophils
Sequence Alignment
Biochemistry
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Therapeutics
Metadata
Show full item recordAbstract
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 Sjogren'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.-Dwivedi, N., Neeli, I., Schall, N., Wan, H., Desiderio, D. M., Csernok, E., Thompson, P. R., Dali, H., Briand, J.-P., Muller, S., Radic, M. Deimination of linker histones links neutrophil extracellular trap release with autoantibodies in systemic autoimmunity.Source
FASEB J. 2014 Jul;28(7):2840-51. doi: 10.1096/fj.13-247254. Epub 2014 Mar 26. Link to article on publisher's siteDOI
10.1096/fj.13-247254Permanent Link to this Item
http://hdl.handle.net/20.500.14038/50001Notes
At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.
Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1096/fj.13-247254