Glycobiology of rheumatic diseases.
Glycobiology of rheumatic diseases.
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DOI：
10.1038/s41584-022-00867-4
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发表时间：
2023-01
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--
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糖基化通过多种机制对蛋白质活性和细胞生物学产生深远的影响，例如蛋白质稳定性、受体相互作用和信号转导。在许多风湿性疾病中，蛋白质糖基化发生变化，并且与炎症过程和疾病进展相关。例如，（自身）抗体上的 Fc-聚糖组成与疾病活动相关，并且某些自身反应性 B 细胞受体的抗原结合域中存在其他聚糖可能会影响 B 细胞激活。此外，滑膜成纤维细胞表面糖基化的变化可以改变滑膜微环境，并与类风湿性关节炎炎症状态和疾病活动的改变相关。我们对血浆蛋白（特别是（自身）抗体）、细胞和组织的糖基化在风湿病理条件下的作用的了解的进展表明，基于糖基化的干预措施可用于治疗这些疾病。糖基化是一种常见的修饰，可以影响蛋白质的稳定性和相互作用。在这篇综述中，作者讨论了糖基化在风湿性疾病中的作用，以及基于糖基化的干预措施的治疗潜力。风湿性疾病患者的自身抗原特异性 IgG 在可结晶片段 (Fc) 结构域中具有独特的 N-糖基化特征，其特征是岩藻糖基化，没有唾液酸化或半乳糖基化。在类风湿性关节炎 (RA) 和抗中性粒细胞胞浆抗体 (ANCA) 相关血管炎中，自身抗原特异性 IgG 以及自身反应性 B 细胞受体在片段抗原结合 (Fab) 结构域中广泛 N-糖基化。特定的 Fc 和 Fab IgG 聚糖特征与 RA 疾病活动性和缓解相关。关于岩藻糖基化、半乳糖基化 IgG Fc 聚糖如何可能在人类中引起促炎表型，尚缺乏机制证据。 RA 与滑膜成纤维细胞表面唾液酸化的减少有关，影响其与半乳糖凝集素 3 的相互作用，并导致细胞因子诱导的向促炎表型的转变。基于聚糖的疗法可以通过改变糖基化或通过特异性靶向和消耗自身反应性 B 细胞和自身抗体来干预炎症过程。
Glycosylation has a profound influence on protein activity and cell biology through a variety of mechanisms, such as protein stability, receptor interactions and signal transduction. In many rheumatic diseases, a shift in protein glycosylation occurs, and is associated with inflammatory processes and disease progression. For example, the Fc-glycan composition on (auto)antibodies is associated with disease activity, and the presence of additional glycans in the antigen-binding domains of some autoreactive B cell receptors can affect B cell activation. In addition, changes in synovial fibroblast cell-surface glycosylation can alter the synovial microenvironment and are associated with an altered inflammatory state and disease activity in rheumatoid arthritis. The development of our understanding of the role of glycosylation of plasma proteins (particularly (auto)antibodies), cells and tissues in rheumatic pathological conditions suggests that glycosylation-based interventions could be used in the treatment of these diseases. Glycosylation is a common modification that can affect protein stability and interactions. In this Review, the authors discuss the role of glycosylation in rheumatic diseases, as well as the therapeutic potential of glycosylation-based interventions. Autoantigen-specific IgG in patients with rheumatic diseases has a distinct N-glycosylation signature in the fragment crystallizable (Fc) domain, characterized by fucosylation without sialylation or galactosylation. In rheumatoid arthritis (RA) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, autoantigen-specific IgG, as well as autoreactive B cell receptors, are extensively N-glycosylated in the fragment antigen-binding (Fab) domain. Specific Fc and Fab IgG glycan signatures are associated with RA disease activity and remission. Mechanistic evidence is lacking on how fucosylated, agalactosylated IgG Fc glycans possibly cause a pro-inflammatory phenotype in humans. RA is associated with reduction of cell-surface sialylation of synovial fibroblasts, affecting their interactions with galectin-3 and resulting in a cytokine-induced switch towards a pro-inflammatory phenotype. Glycan-based therapies could intervene in inflammatory processes by alteration of glycosylation, or by specific targeting and depletion of autoreactive B cells and autoantibodies.
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