Fc\u03b3RIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human

Marion Espéli,Nagham Alouche,John M Sowerby,Alice E Denton,Rachael Bashford-Rogers,Kenneth G C Smith,Limy Wong,Michelle A Linterman

doi:10.1038/s41467-019-09434-0

Abstract

Several tolerance checkpoints exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies. FcγRIIb is an Fc receptor that inhibits B cell activation and, if defective, is associated with autoimmune disease, yet its impact on specific B cell tolerance checkpoints is unknown. Here we show that reduced expression of FcγRIIb enhances the deletion and anergy of autoreactive immature B cells, but in contrast promotes autoreactive B cell expansion in the germinal center and serum autoantibody production, even in response to exogenous, non-self antigens. Our data thus show that FcγRIIb has opposing effects on pre-immune and post-immune tolerance checkpoints, and suggest that B cell tolerance requires the control of bystander germinal center B cells with low or no affinity for the immunizing antigen.

Highlights

Several tolerance checkpoints exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies
Our results suggest a novel mechanism of Germinal center (GC) tolerance, in which FcγRIIb prevents the emergence of bystander autoreactive B cells
In SWHEL mice, a transgene encoding an Ig heavy chain specific for the protein Hen Egg Lysozyme (HEL) has been knocked-in to the endogenous heavy chain locus, allowing class-switching and somatic hypermutation. These features, together with the fact that SWHEL mice can generate a polyclonal immune response against other antigens as only 10–30% of their B cells are specific for HEL, enables the physiological tracking of a GC B-cell response following immunisation[45]

Summary

Introduction

Several tolerance checkpoints exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies. We show that reduced expression of FcγRIIb enhances the deletion and anergy of autoreactive immature B cells, but in contrast promotes autoreactive B cell expansion in the germinal center and serum autoantibody production, even in response to exogenous, non-self antigens. Our data show that FcγRIIb has opposing effects on pre-immune and post-immune tolerance checkpoints, and suggest that B cell tolerance requires the control of bystander germinal center B cells with low or no affinity for the immunizing antigen. Three major tolerance checkpoints during B-cell development control the generation of autoreactive B-cell clones. Following B-cell activation, autoreactive B cells may be eliminated from the germinal center or corrected by somatic hypermutation, further reducing the chance of generating potentially harmful autoreactive memory B cells and autoantibody-producing plasma cells. The last two checkpoints, taking place outside the BM, contribute to peripheral tolerance[1,6,7]

Methods

Results

Conclusion