Department of Rheumatology, Yale University School of Medicine, New Haven, Connecticut 06520-8031, USA.
Autoimmunity. 2013 Feb;46(1):6-13. doi: 10.3109/08916934.2012.710859. Epub 2012 Dec 3.
Histone H2B is a common target of autoantibodies in both spontaneous and drug-induced systemic lupus erythematosus (SLE). Recent studies demonstrate that Asp(25) of histone H2B (H2B) spontaneously converts to an isoaspartic acid (isoAsp) in vivo. Our laboratory has demonstrated that the posttranslational modification of an aspartic acid to an isoaspartic acid within self-peptides renders otherwise ignored peptides immunogenic. Analysis of serum from lupus-prone mice and histone antibody positive SLE patients revealed antibodies specific to the Asp and isoAsp H2B(21-35) peptide, and that the expression of these antibodies is dependent on TLR9. IsoAsp H2B(21-35) is immunogenic in non-autoimmune prone mice and mice lacking the ability to repair isoAsp have significantly reduced levels of antibodies to H2B. Asp H2B(21-35) incubated at physiological temperatures and pH acquires the isoAsp modification, demonstrating that H2B(21-35) is prone to spontaneous isoAsp formation in vivo. Autoimmunity to isoAsp H2B suggests that this form of the autoantigen may be critical in the induction of anti-histone autoantibodies in human SLE and in murine models of disease.
组蛋白 H2B 是自发性和药物诱导的系统性红斑狼疮 (SLE) 中自身抗体的共同靶标。最近的研究表明，组蛋白 H2B（H2B）中的 Asp（25）在体内自发转化为异天冬氨酸（isoAsp）。我们的实验室已经证明，在自身肽内将天冬氨酸的翻译后修饰为异天冬氨酸会使原本被忽略的肽具有免疫原性。对狼疮易感小鼠和组蛋白抗体阳性 SLE 患者的血清分析显示，针对 Asp 和异天冬氨酸 H2B（21-35）肽的特异性抗体，并且这些抗体的表达依赖于 TLR9。异天冬氨酸 H2B（21-35）在非自身免疫倾向的小鼠中具有免疫原性，并且缺乏修复异天冬氨酸能力的小鼠对 H2B 的抗体水平显著降低。在生理温度和 pH 下孵育的 Asp H2B（21-35）获得异天冬氨酸修饰，表明 H2B（21-35）在体内易于自发形成异天冬氨酸。对异天冬氨酸 H2B 的自身免疫表明，这种形式的自身抗原可能在人类 SLE 中和疾病的小鼠模型中诱导抗组蛋白自身抗体中起关键作用。
