小鼠脑脊髓炎：针对组蛋白 H2A、H1、H2B、H3 和 H4 及髓鞘碱性蛋白的 IgG 对 H2A 组蛋白的酶切交联位点特异性水解。

EAE of Mice: Enzymatic Cross Site-Specific Hydrolysis of H2A Histone by IgGs against H2A, H1, H2B, H3, and H4 Histones and Myelin Basic Protein.

机构信息

Institute of Chemical Biology and Fundamental Medicine of the Siberian Division of Russian Academy of Sciences, Novosibirsk 630090, Russia.

G. B. Elyakov Pacific Institute of Bioorganic Chemistry, Far East Division, Russian Academy of Sciences, Vladivostok 690022, Russia.

出版信息

Int J Mol Sci. 2023 May 12;24(10):8636. doi: 10.3390/ijms24108636.

DOI:10.3390/ijms24108636

PMID:37239982

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10218518/

Abstract

Histones play vital roles in chromatin function and gene transcription; however, they are very harmful in the intercellular space because they stimulate systemic inflammatory and toxic responses. Myelin basic protein (MBP) is the major protein of the axon myelin-proteolipid sheath. Antibodies-abzymes with various catalytic activities are specific features of some autoimmune diseases. IgGs against individual histones (H2A, H1, H2B, H3, and H4) and MBP were isolated from the blood of experimental-autoimmune-encephalomyelitis-prone C57BL/6 mice by several affinity chromatographies. These Abs-abzymes corresponded to various stages of EAE development: spontaneous EAE, MOG, and DNA-histones accelerated the onset, acute, and remission stages. IgGs-abzymes against MBP and five individual histones showed unusual polyreactivity in the complex formation and enzymatic cross-reactivity in the specific hydrolysis of the H2A histone. All the IgGs of 3-month-old mice (zero time) against MBP and individual histones demonstrated from 4 to 35 different H2A hydrolysis sites. The spontaneous development of EAE over 60 days led to a significant change in the type and number of H2A histone hydrolysis sites by IgGs against five histones and MBP. Mice treatment with MOG and the DNA-histone complex changed the type and number of H2A hydrolysis sites compared to zero time. The minimum number (4) of different H2A hydrolysis sites was found for IgGs against H2A (zero time), while the maximum (35) for anti-H2B IgGs (60 days after mice treatment with DNA-histone complex). Overall, it was first demonstrated that at different stages of EAE evolution, IgGs-abzymes against individual histones and MBP could significantly differ in the number and type of specific sites of H2A hydrolysis. The possible reasons for the catalytic cross-reactivity and great differences in the number and type of histone H2A cleavage sites were analyzed.

摘要

组蛋白在染色质功能和基因转录中起着至关重要的作用；然而，它们在细胞间空间中非常有害，因为它们会刺激全身炎症和毒性反应。髓鞘碱性蛋白 (MBP) 是轴突髓鞘脂蛋白鞘的主要蛋白。具有各种催化活性的抗体-酶是一些自身免疫性疾病的特征。通过几种亲和层析，从实验性自身免疫性脑脊髓炎易感 C57BL/6 小鼠的血液中分离出针对个别组蛋白（H2A、H1、H2B、H3 和 H4）和 MBP 的 IgG 抗体-abzymes。这些 Abs-abzymes 对应于 EAE 发展的各个阶段：自发 EAE、MOG 和 DNA-组蛋白加速了发病、急性和缓解阶段。针对 MBP 和五种个别组蛋白的 IgG-abzymes 在复合物形成中表现出异常的多反应性，在 H2A 组蛋白的特异性水解中表现出酶交叉反应性。所有 3 个月大（零时间）的小鼠 IgG 针对 MBP 和个别组蛋白的 IgG 从 4 到 35 个不同的 H2A 水解位点。自发的 EAE 发展超过 60 天，导致针对五种组蛋白和 MBP 的 IgG 对 H2A 组蛋白水解位点的类型和数量发生显著变化。与零时间相比，用 MOG 和 DNA-组蛋白复合物处理小鼠会改变 H2A 水解位点的类型和数量。针对 H2A（零时间）的 IgG 发现了不同 H2A 水解位点的最小数量（4），而针对 H2B 的 IgG 则发现了最大数量（35）（用 DNA-组蛋白复合物处理小鼠 60 天后）。总的来说，这是首次证明，在 EAE 演变的不同阶段，针对个别组蛋白和 MBP 的 IgG-abzymes 在 H2A 水解的特定位点的数量和类型上可能存在显著差异。分析了催化交叉反应性和组蛋白 H2A 裂解位点数量和类型存在巨大差异的可能原因。