Sallan Marta C, Filipsky Filip, Shi Christina H, Pontarini Elena, Terranova-Barberio Manuela, Beattie Gordon, Clear Andrew, Bombardieri Michele, Yip Kevin Y, Calado Dinis Pedro, Cragg Mark S, James Sonya, Carter Mathew, Okosun Jessica, Gribben John G, Klymenko Tanya, Braun Andrejs
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
J Clin Invest. 2025 May 15;135(13). doi: 10.1172/JCI178920. eCollection 2025 Jul 1.
Germinal center (GC) B cells are pivotal in establishing a robust humoral immune response and long-term serological immunity while maintaining antibody self-tolerance. GC B cells rely on autophagy for antigen presentation and homeostatic maintenance. However, these functions, primarily associated with the light zone, cannot explain the spatiotemporal autophagy upregulation in the dark zone of GCs. Here, combining imaging, molecular, and genomic approaches, we defined a functional mechanism controlling chromatin accessibility in GC B cells during their dark zone transition. This mechanism links autophagy and nuclear lamin B1 dynamics with their downstream effects, including somatic hypermutation and antibody affinity maturation. Moreover, the autophagy-lamin B1 axis is highly active in the aberrant ectopic GCs in the salivary glands of Sjögren's disease, defining its role in autoimmunity.
生发中心（GC）B细胞在建立强大的体液免疫反应和长期血清学免疫的同时维持抗体自身耐受性方面起着关键作用。GC B细胞依靠自噬进行抗原呈递和稳态维持。然而，这些主要与亮区相关的功能无法解释GC暗区自噬的时空上调现象。在这里，我们结合成像、分子和基因组方法，定义了一种在GC B细胞暗区转变过程中控制染色质可及性的功能机制。该机制将自噬和核纤层蛋白B1动态变化与其下游效应联系起来，包括体细胞高频突变和抗体亲和力成熟。此外，自噬-核纤层蛋白B1轴在干燥综合征患者唾液腺中异常异位的GC中高度活跃，确定了其在自身免疫中的作用。
