Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, People's Republic of China.
PLoS One. 2013 Jul 16;8(7):e68520. doi: 10.1371/journal.pone.0068520. Print 2013.
Post-translational modifications on proteins are important in biological processes but may create neo-epitopes that induce autoimmune responses. In this study, we measured the serum IgG and IgM response to a set of non-modified or acetyl- and methyl-modified peptides corresponding to residues 1-19 of the histone 3 N-terminal tail in systemic lupus erythematosus (SLE) patients and healthy subjects. Our results indicated that the SLE patients and healthy subjects produced antibodies (Abs) to the peptides, but the two groups had different Ab isotype and epitope preferences. Abs to the non-modified form, H31-19, were of the IgG isotype and produced by SLE patients. They could not recognize the scrambled H31-19, which contained the same amino acid composition but a different sequence as H31-19. In comparison, healthy subjects in general did not produce IgG against H31-19. However, about 70% of the healthy subjects produced IgM Abs against mono-methylated K9 of H31-19 (H31-19K9me). Our further studies revealed that ε-amine mono-methylated lysine could completely inhibit the IgM binding to H31-19K9me, but lysine had no inhibitory effect. In addition, the IgM Abs could bind peptides containing a mono-methylated lysine residue but with totally different sequences. Thus, mono-methylated lysine was the sole epitope for the IgM. Interestingly, SLE patients had much lower levels of this type of IgM. There was no obvious correlation between the IgM levels and disease activity and the decreased IgM was unlikely caused by medical treatments.We also found that the IgM Abs were not polyreactive to dsDNA, ssDNA, lipopolysaccharide (LPS) or insulin and they did not exist in umbilical cord serum, implying that they were not natural Abs. The IgM Abs against mono-methylated lysine are present in healthy subjects but are significantly lower in SLE patients, suggesting a distinct origin of production and special physiological functions.
蛋白质的翻译后修饰在生物过程中很重要，但可能会产生新的表位，诱导自身免疫反应。在这项研究中，我们测量了系统性红斑狼疮（SLE）患者和健康受试者对一组非修饰或乙酰化和甲基化修饰的组蛋白 3 N 端尾部残基 1-19 对应的肽的血清 IgG 和 IgM 反应。我们的结果表明，SLE 患者和健康受试者均产生针对这些肽的抗体（Abs），但两组的同种型和表位偏好不同。针对非修饰形式 H31-19 的 Abs 为 IgG 同种型，由 SLE 患者产生。它们不能识别 H31-19 的乱序形式，后者包含相同的氨基酸组成，但序列与 H31-19 不同。相比之下，健康受试者通常不产生针对 H31-19 的 IgG。然而，约 70%的健康受试者产生针对 H31-19 单甲基化 K9 的 IgM Abs（H31-19K9me）。我们的进一步研究表明，ε-氨基单甲基化赖氨酸可以完全抑制 IgM 与 H31-19K9me 的结合，但赖氨酸没有抑制作用。此外，IgM Abs 可以结合含有单甲基化赖氨酸残基但具有完全不同序列的肽。因此，单甲基化赖氨酸是 IgM 的唯一表位。有趣的是，SLE 患者这种 IgM 的水平低得多。IgM 水平与疾病活动度之间没有明显相关性，而且降低的 IgM 不太可能是由医疗治疗引起的。我们还发现，IgM Abs 对 dsDNA、ssDNA、脂多糖（LPS）或胰岛素没有多反应性，并且它们不存在于脐带血清中，这意味着它们不是天然的 Abs。针对单甲基化赖氨酸的 IgM Abs 存在于健康受试者中，但在 SLE 患者中明显较低，这表明它们的产生具有明显的起源和特殊的生理功能。
