Nevinsky Georgy A, Buneva Valentina N, Dmitrenok Pavel S
Institute of Chemical Biology and Fundamental Medicine of the Siberian Division of Russian Academy of Sciences, Lavrentiev Ave. 8, 630090 Novosibirsk, Russia.
Pacific Institute of Bioorganic Chemistry, Far East Division, Russian Academy of Sciences, 690022 Vladivostok, Russia.
Biomedicines. 2022 Oct 21;10(10):2663. doi: 10.3390/biomedicines10102663.
Histones have a specific key role in the remodeling of chromatin and gene transcription. In the blood, free histones are damage-connected proteins. Myelin basic protein (MBP) is the major component of the myelin-proteolipid sheath of axons. Antibodies possessing enzymatic activities (abzymes, ABZs) are the specific features of several autoimmune pathologies. IgGs against five histones, MBP, and DNA were obtained from the sera of multiple sclerosis (MS) patients using several affinity chromatographies. The sites of H3 histone splitting by Abs against five individual histones, MBP, and DNA were revealed by MALDI mass spectrometry. It was shown that the number of H3 splitting sites by IgGs against five various histones is different (number of sites): H3 (11), H1 (14), H2A (11), H4 (17), MBP (22), and DNA (29). IgGs against five different histones hydrolyze H3 at different sites, and only a few them coincide. The main reason for the enzymatic cross-reactivity of Abs against H3 and four other histones, as well as MBP, might be the high level of these proteins' homology. The effective hydrolysis of the H3 histone at 29 sites with IgGs against DNA can be explained by the formation of chimeric abzymes against hybrid antigenic determinants formed by different histones and MBP at the junction of these protein sequences with DNA. The active centers of such abzymes contain structural elements of canonical DNases and proteases. Since free histones are pernicious proteins, antibodies-ABZs against five histones, MBP, and DNA could have a negative role in the pathogenesis of MS and probably other various autoimmune diseases.
组蛋白在染色质重塑和基因转录中具有特定的关键作用。在血液中，游离组蛋白是与损伤相关的蛋白质。髓鞘碱性蛋白（MBP）是轴突髓鞘 - 蛋白脂蛋白鞘的主要成分。具有酶活性的抗体（抗体酶，ABZ）是几种自身免疫性疾病的特征。使用多种亲和色谱法从多发性硬化症（MS）患者的血清中获得了针对五种组蛋白、MBP和DNA的IgG。通过基质辅助激光解吸电离质谱法揭示了针对五种单个组蛋白、MBP和DNA的抗体对H3组蛋白的切割位点。结果表明，针对五种不同组蛋白的IgG对H3的切割位点数量不同（位点数量）：H3（11个）、H1（14个）、H2A（11个）、H4（17个）、MBP（22个）和DNA（29个）。针对五种不同组蛋白的IgG在不同位点水解H3，只有少数位点重合。针对H3和其他四种组蛋白以及MBP的抗体具有酶交叉反应性的主要原因可能是这些蛋白质的同源性水平较高。针对DNA的IgG在29个位点对H3组蛋白的有效水解可以通过针对由不同组蛋白和MBP在这些蛋白质序列与DNA的交界处形成的杂合抗原决定簇的嵌合抗体酶的形成来解释。此类抗体酶的活性中心包含典型DNase和蛋白酶的结构元件。由于游离组蛋白是有害蛋白质，针对五种组蛋白、MBP和DNA的抗体 - ABZ可能在MS以及可能其他各种自身免疫性疾病的发病机制中起负面作用。
