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2014 ; 28
(7
): 2840-51
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Deimination of linker histones links neutrophil extracellular trap release with
autoantibodies in systemic autoimmunity
#MMPMID24671707
Dwivedi N
; Neeli I
; Schall N
; Wan H
; Desiderio DM
; Csernok E
; Thompson PR
; Dali H
; Briand JP
; Muller S
; Radic M
FASEB J
2014[Jul]; 28
(7
): 2840-51
PMID24671707
show ga
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.-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.