B cell development, activation, and autoimmunity in mice with altered B cell receptor signalling

Hudson, Ashley Richard (2023). B cell development, activation, and autoimmunity in mice with altered B cell receptor signalling. University of Birmingham. Ph.D.

Preview

Hudson2023PhD.pdf
Text - Accepted Version
Available under License All rights reserved.
Download (32MB) | Preview

Abstract

B cell receptor (BCR) signalling plays an important role at multiple stages of B cell development, differentiation, and activation. Naïve B cells co-express BCRs of IgM and IgD isotype, but when activated, B cells often class-switch to another isotype such as IgG1. IgG1 transduces stronger BCR signalling, thought to be largely due to inherent signalling capabilities in the cytoplasmic tail. To investigate the effect of altered BCR signalling on B cell development, B cell activation and development of autoimmunity, we have used a mouse model where B cells express chimeric BCRs that have the IgM extracellular region and the IgG1 cytoplasmic tail (IgMg1 mouse), as well as a second mouse model where B cells express fully IgG1 BCRs (IgG1M mouse).

In IgMg1 mice, B cells had evidence of increased negative selection during B cell development, reduced BCR expression and a dampened response to BCR stimulation in vitro, supporting the previous observation that B cells in these mice display an anergic phenotype. Gene expression was analysed in IgMg1 B cells and genes that may play a role in regulating B cell anergy were identified. IgMg1 mice were able to make germinal centre (GC) responses following immunisation with T cell-dependent (TD) antigen. However, there was a higher affinity threshold for B cell participation in the GC, and reduced survival and positive selection. The B cells had greater ability to present antigen and activate T follicular helper cells. Aged IgMg1 mice were more prone to developing spontaneous tissue-specific autoantibodies than aged wildtype mice.

In IgG1M mice, IgG1-only expressing B cells also underwent increased negative selection and BCR downregulation. However, unlike the IgMg1 B cells, this did not result in an anergic phenotype; instead, B cells were hyper-responsive to BCR stimulation in vitro. Despite the hyperactive BCR signalling, T cell-independent and TD responses were unexpectedly impaired.

This work provides insight into how stronger BCR signalling can inhibit or increase B cell activation in different contexts. It also establishes how different BCRs can affect interactions with Tfh cells within the GC. Additionally, the importance of the BCR extracellular region relative to the cytoplasmic region for signalling at different stages of development was explored. These mouse models should be useful to further
investigate how regulation of enhanced BCR signalling can prevent inappropriate activation of B cells and the development of autoimmunity.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):