AUTHOR=Arulraj Theinmozhi , Binder Sebastian C. , Meyer-Hermann Michael TITLE=Investigating the Mechanism of Germinal Center Shutdown JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.922318 DOI=10.3389/fimmu.2022.922318 ISSN=1664-3224 ABSTRACT=

Germinal centers (GCs) are transient structures where affinity maturation of B cells gives rise to high affinity plasma and memory cells. The mechanism of GC shutdown is unclear, despite being an important phenomenon maintaining immune homeostasis. In this study, we used a mathematical model to identify mechanisms that can independently promote contraction of GCs leading to shutdown. We show that GC shutdown can be promoted by antigen consumption by B cells, antigen masking by soluble antibodies, alterations in follicular dendritic cell (FDC) network area, modulation of immune complex cycling rate constants, alterations in T follicular helper signaling, increased terminal differentiation and reduced B cell division capacity. Proposed mechanisms promoted GC contraction by ultimately decreasing the number of B cell divisions and recycling cells. Based on the in-silico predictions, we suggest a combination of experiments that can be potentially employed by future studies to unravel the mechanistic basis of GC shutdown such as measurements of the density of pMHC presentation of B cells, FDC network size per B cell, fraction of cells expressing differentiation markers. We also show that the identified mechanisms differentially affect the efficiency of GC reaction estimated based on the quantity and quality of resulting antibodies.