Muller Sylviane, Radic Marko
Immunopathology and Therapeutic Chemistry/Laboratory of Excellence MEDALIS, CNRS, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA.
Clin Rev Allergy Immunol. 2015 Oct;49(2):232-9. doi: 10.1007/s12016-014-8459-2.
The conversion of an arginine residue in a protein to a citrulline residue, a reaction carried out by enzymes called peptidylarginine deiminases (PADs), is rather subtle. One of the terminal imide groups in arginine is replaced by oxygen in citrulline, thus resulting in the loss of positive charge and the gain of 1 dalton. This post-translational modification by PAD enzymes is conserved in vertebrates and affects specific substrates during development and in various mature cell lineages. Citrullination offers a unique perspective on autoimmunity because PAD activity is stringently regulated, yet autoantibodies to citrullinated proteins predictably arise. Autoantigens recognized by anti-citrullinated protein antibodies (ACPA) include extracellular proteins such as filaggrin, collagen II, fibrinogen, and calreticulin; membrane-associated proteins such as myelin basic protein; cytoplasmic proteins such as vimentin and enolase; and even nuclear proteins such as histones. Some ACPA are remarkably effective as diagnostics in autoimmune disorders, most notably rheumatoid arthritis (RA). Several ACPA can be observed before other clinical RA manifestations are apparent. In patients with RA, ACPA may attain a sensitivity that exceeds 70 % and specificity that approaches 96-98 %. The biological context that may account for the induction of ACPA emerges from studies of the cellular response of the innate immune system to acute or chronic stimuli. In response to infections or inflammation, neutrophil granulocytes activate PAD, citrullinate multiple autoantigens, and expel chromatin from the cell. The externalized chromatin is called a neutrophil extracellular "trap" (NET). Citrullination of core and linker histones occurs prior to the release of chromatin from neutrophils, thus implicating the regulation of citrullinated chromatin release in the development of autoreactivity. The citrullination of extracellular autoantigens likely follows the release of NETs and associated PADs. Autoantibodies to citrullinated histones arise in RA, systemic lupus erythematosus, and Felty's syndrome patients. The citrullination of linker histone H1 may play a key role in NET release because the H1 histone regulates the entry and exit of DNA from the nucleosome. Juxtaposition of citrullinated histones with infectious pathogens and complement and immune complexes may compromise tolerance of nuclear autoantigens and promote autoimmunity.
蛋白质中精氨酸残基向瓜氨酸残基的转化是一个相当微妙的反应，由肽基精氨酸脱亚氨酶（PADs）催化。精氨酸末端的一个亚胺基团被瓜氨酸中的氧取代，导致正电荷丢失，分子量增加1道尔顿。PAD酶介导的这种翻译后修饰在脊椎动物中保守存在，并在发育过程及多种成熟细胞谱系中影响特定底物。瓜氨酸化提供了一个关于自身免疫的独特视角，因为PAD活性受到严格调控，但针对瓜氨酸化蛋白的自身抗体却可预测地出现。抗瓜氨酸化蛋白抗体（ACPA）识别的自身抗原包括细胞外蛋白，如丝聚蛋白、胶原蛋白II、纤维蛋白原和钙网蛋白；膜相关蛋白，如髓鞘碱性蛋白；细胞质蛋白，如波形蛋白和烯醇化酶；甚至核蛋白，如组蛋白。一些ACPA在自身免疫性疾病诊断中非常有效，最显著的是类风湿关节炎（RA）。在其他临床RA表现出现之前就能检测到几种ACPA。在RA患者中，ACPA的敏感性可能超过70%，特异性接近96 - 98%。关于ACPA诱导的生物学背景来自对先天免疫系统对急性或慢性刺激的细胞反应的研究。响应感染或炎症时，中性粒细胞激活PAD，使多种自身抗原瓜氨酸化，并将染色质排出细胞。外化的染色质称为中性粒细胞胞外“陷阱”（NET）。核心组蛋白和连接组蛋白的瓜氨酸化发生在染色质从嗜中性粒细胞释放之前，因此表明瓜氨酸化染色质释放的调控在自身反应性发展中起作用。细胞外自身抗原的瓜氨酸化可能发生在NETs和相关PADs释放之后。针对瓜氨酸化组蛋白的自身抗体出现在RA、系统性红斑狼疮和费尔蒂综合征患者中。连接组蛋白H1的瓜氨酸化可能在NET释放中起关键作用，因为H1组蛋白调节DNA进出核小体。瓜氨酸化组蛋白与传染性病原体、补体和免疫复合物并置可能破坏对核自身抗原的耐受性并促进自身免疫。
