Autophagy is an upstream mediator of chromatin dynamics in normal and autoimmune germinal center B cells
Marta C. Sallan, … , Tanya Klymenko, Andrejs Braun
Marta C. Sallan, … , Tanya Klymenko, Andrejs Braun
Published May 21, 2025
Citation Information: J Clin Invest. 2025;135(13):e178920. https://doi.org/10.1172/JCI178920.
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Research Article Autoimmunity Cell biology Immunology

Autophagy is an upstream mediator of chromatin dynamics in normal and autoimmune germinal center B cells

Abstract

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.

Authors

Marta C. Sallan, Filip Filipsky, Christina H. Shi, Elena Pontarini, Manuela Terranova-Barberio, Gordon Beattie, Andrew Clear, Michele Bombardieri, Kevin Y. Yip, Dinis Pedro Calado, Mark S. Cragg, Sonya James, Mathew Carter, Jessica Okosun, John G. Gribben, Tanya Klymenko, Andrejs Braun

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Figure 1

GC B cells upregulate autophagy in the DZ area.

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GC B cells upregulate autophagy in the DZ area. (A) Representative immun...
(A) Representative immunohistochemistry images on sequential slides of human GC from a reactive tonsil. Tonsils were stained with anti-IgD, anti-CD35, anti-Ki67, anti-LC3B, and anti-Atg7 antibodies, and nuclei were counterstained with hematoxylin (blue). Three to 6 GCs per tonsil were analyzed from 3 patients. Scale bars: 200 μm. (B) LC3B intensity was compared in MZ (IgD+CD35–Ki67–) and GC (IgD–CD35+Ki67+). Statistics were obtained using paired 2-tailed Student’s t test. (C) LC3B intensity was compared in DZ (IgD–Ki67+CD35–) and LZ (IgD–Ki67–CD35+) areas. Statistics were obtained using paired 2-tailed Student’s t test. (D) Atg7 intensity was compared in MZ (IgD+CD35–Ki67–) and GC (IgD–CD35+Ki67+). Statistics were obtained using paired 2-tailed Student’s t test. (E) Atg7 intensity was compared in DZ (IgD–Ki67+CD35–) and LZ (IgD–Ki67–CD35+) areas. Statistics were obtained using paired 2-tailed Student’s t test. (F) CB (VD–B220+CD38–CD95+CXCR4+CD86–) and CC (VD–B220+CD38–CD95+CXCR4–CD86+) gated populations followed by LC3B-overlaid dot plots in control mice (WT Atg7 Cγ1Cre+/–) and autophagy-impaired mice (Cγ1Cre+/– Atg7fl/fl). (G) Plots showing LC3B median fluorescence intensity (MFI) at 7 dpi in 2 independent experiments. Statistical analysis was performed using paired 2-tailed Student’s t test. Statistical significance: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).