In Silico Analysis of the Longevity and Timeline of Individual Germinal Center Reactions in a Primary Immune Response.

Theinmozhi Arulraj,Sebastian C Binder,Michael Meyer-Hermann

doi:10.3390/cells10071736

Theinmozhi Arulraj, Sebastian C Binder + Show 1 more

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https://doi.org/10.3390/cells10071736

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Abstract

Germinal centers (GCs) are transient structures in the secondary lymphoid organs, where B cells undergo affinity maturation to produce high affinity memory and plasma cells. The lifetime of GC responses is a critical factor limiting the extent of affinity maturation and efficiency of antibody responses. While the average lifetime of overall GC reactions in a lymphoid organ is determined experimentally, the lifetime of individual GCs has not been monitored due to technical difficulties in longitudinal analysis. In silico analysis of the contraction phase of GC responses towards primary immunization with sheep red blood cells suggested that if individual GCs had similar lifetimes, the data would be consistent only when new GCs were formed until a very late phase after immunization. Alternatively, there could be a large variation in the lifetime of individual GCs suggesting that both long and short-lived GCs might exist in the same lymphoid organ. Simulations predicted that such differences in the lifetime of GCs could arise due to variations in antigen availability and founder cell composition. These findings identify the potential factors limiting GC lifetime and contribute to an understanding of overall GC responses from the perspective of individual GCs in a primary immune response.

Highlights

We developed an agent-based model of Germinal centers (GCs) reaction able to simulate multiple co-evolving GCs and estimate the lifetime of individual GCs formed upon primary immunization
As GCs form asynchronously after a primary immunization, we considered such asynchronous GCs in the simulations corresponding to data from Rao et al [31]
The increase in the number of GCs was assumed to follow a Hill function and initiation time of simulated GCs were chosen as explained in methods such that the simulation result was consistent with the initial phase of data, during which an increase in number of GCs is observed

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Germinal centers (GCs) are transient anatomic structures in secondary lymphoid organs, responsible for affinity maturation of B cells, following an infection [1]. In the GCs, B cells undergo multiple rounds of mutation and selection resulting in the production of high affinity plasma and memory cells [2]. GCs are seeded by 10–100 B cell clones [3]. Evolution of GC results in the formation of two compartments—a dark zone (DZ). A light zone (LZ) [4,5]. In the DZ, GC B cells undergo proliferation and somatic hypermutation, a process where point mutations are randomly incorporated into the

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