Department of Microbiology, Immunology, and Biochemistry, and.
Immunopathology and Therapeutic Chemistry, Laboratory of Excellence Medalis, Institut de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS), Strasbourg, France;
FASEB J. 2014 Jul;28(7):2840-51. doi: 10.1096/fj.13-247254. Epub 2014 Mar 26.
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.
自身抗体针对核抗原出现在人类自身免疫性疾病中，但一个统一的发病机制仍然难以捉摸。最近我们报道，中性粒细胞暴露于炎症条件下会诱导肽基精氨酸脱亚氨酶 4（PAD4）使核心组蛋白瓜氨酸化，并且自身免疫性疾病患者产生识别这种瓜氨酸化组蛋白的自身抗体。在这里，我们确定组蛋白 H1 是 PAD4 的另一个底物，将 H1 定位在中性粒细胞细胞外陷阱内，并在 6%的系统性红斑狼疮和干燥综合征患者的血清中检测到针对瓜氨酸化 H1 的自身抗体。在健康对照血清和硬皮病或类风湿关节炎患者的血清中没有观察到对脱亚氨基 H1 的偏好。我们对 H1 的翅膀螺旋进行了结合定位，并确定瓜氨酸 53 是自身抗体表位的关键决定因素。此外，我们定量了成熟人中性粒细胞中 H1 组蛋白亚型的 RNA，并通过液相色谱和串联质谱法鉴定瓜氨酸残基。我们的结果表明，连接组蛋白的脱亚氨基化会产生新的自身抗体表位，增强了刺激自身反应性人类 B 细胞的潜力。-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. 连接组蛋白的脱亚氨基化将中性粒细胞细胞外陷阱的释放与系统性自身免疫中的自身抗体联系起来。
