Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
Department of Autoimmunology, Statens Serum Institut, Copenhagen, Denmark.
PLoS One. 2019 Jun 14;14(6):e0217624. doi: 10.1371/journal.pone.0217624. eCollection 2019.
Antibodies are important for immunity and exist in several classes (IgM, IgD, IgA, IgG, IgE). They are composed of symmetric dimeric molecules with two antigen binding regions (Fab) and a constant part (Fc), usually depicted as Y-shaped molecules. Rheumatoid factors found in patients with rheumatoid arthritis are autoantibodies binding to IgG and paradoxically appear to circulate in blood alongside with their antigen (IgG) without reacting with it. Here, it is shown that rheumatoid factors do not react with native IgG in solution, and that their epitopes only become accessible upon certain physico-chemical treatments (e.g. heat treatment at 57 °C), by physical adsorption on a hydrophobic surface or by antigen binding. Moreover, chemical cross-linking in combination with mass spectrometry showed that the native state of IgG is a compact (closed) form and that the Fab parts of IgG shield the Fc region and thereby control access of rheumatoid factors and presumably also some effector functions. It can be inferred that antibody binding to pathogen surfaces induces a conformational change, which exposes the Fc part with its effector sites and rheumatoid factor epitopes. This has strong implications for understanding antibody structure and physiology and necessitates a conceptual reformulation of IgG models.
抗体对于免疫非常重要，存在于几个类别中（IgM、IgD、IgA、IgG、IgE）。它们由对称的二聚体分子组成，具有两个抗原结合区（Fab）和一个恒定部分（Fc），通常被描绘为 Y 形分子。类风湿关节炎患者体内发现的类风湿因子是与 IgG 结合的自身抗体，奇怪的是，它们似乎与抗原（IgG）一起在血液中循环，而不与之反应。在这里，研究表明类风湿因子在溶液中不会与天然 IgG 反应，并且只有在某些物理化学处理（例如在 57°C 下热处理）、物理吸附在疏水面上或抗原结合后，其表位才变得可及。此外，化学交联结合质谱分析表明，IgG 的天然状态是一种紧凑（闭合）的形式，并且 IgG 的 Fab 部分屏蔽了 Fc 区域，从而控制类风湿因子和可能还有一些效应功能的进入。可以推断，抗体与病原体表面的结合诱导构象变化，暴露出具有效应部位和类风湿因子表位的 Fc 部分。这对理解抗体结构和生理学具有重要意义，需要对 IgG 模型进行概念性重新表述。
