Compartments and Connections Within the Germinal Center.

Domenick E Kennedy,Marcus R Clark

doi:10.3389/fimmu.2021.659151

Abstract

Protective high affinity antibody responses emerge through an orchestrated developmental process that occurs in germinal centers (GCs). While GCs have been appreciated since 1930, a wealth of recent progress provides new insights into the molecular and cellular dynamics governing humoral immunity. In this review, we highlight advances that demonstrate that fundamental GC B cell function, selection, proliferation and SHM occur within distinct cell states. The resulting new model provides new opportunities to understand the evolution of immunity in infectious, autoimmune and neoplastic diseases.

Highlights

Since the histologic identification in 1930, almost a century of investigation has revealed the central importance of germinal centers (GCs) in humoral immunity [1]
Fundamental to GC function is the orchestration of the molecular programs of immunoglobulin gene somatic hypermutation (SHM), selection for antibody affinity and specificity, and proliferative expansion of selected cells
Within the GC, these processes are coordinated with remarkable rapidity such that a B cell transits through these processes in four to six hours allowing for numerous rounds of selection and immune amplification during the course of a typical acute GC reaction of 14 to 21 days [2, 3]

Summary

INTRODUCTION

Since the histologic identification in 1930, almost a century of investigation has revealed the central importance of germinal centers (GCs) in humoral immunity [1]. The GC B cell molecular program establishes a state that promotes survival in the presence of increased genomic stress [7, 8] This both enables SHM and increases the risk of lymphoma [9, 10]. On day 4, B cells re-enter the B cell follicle and proliferate to form early GCs [18,19,20] Contrary to these distinct cellular events, the molecular regulation underlying the early events after antigen encounter is still being defined. Through a combination of imaging and molecular experiments Roco et al found that CSR occurs in the first few days after activation and prior to GC commitment [31] Evidence for this included the observation of predominantly IgM+ GCs as well as the visualization of CSR prior to mature GC formation. As discussed below, these incompatible processes occur in different cell populations each occupying a unique niche within the GC

A Paradox

A New GC Model

CONCLUSION