The role of TASL in B cells and autoimmune disease

Thesis

Systemic lupus erythematosus (SLE) is a highly sexually dimorphic chronic autoimmune disease, characterised by auto-antibodies to nuclear antigens. Genome wide association studies (GWAS) have revealed an association between SLE and CXORF21, an X-linked gene, which encodes the protein ’TLR-adaptor interacting with SLC15A4 on the lysosome’ (TASL). TASL acts as an innate immune adaptor in the IRF5 pathway, and is required for the phosphorylation of IRF5 and the downstream transcription of interferon-stimulated genes (ISGs) in response to TLR7 or TLR9 stimulation. In this thesis, I investigated the role of TASL in B cells, both in response to immunisation and in the B6.MRL^Lpr murine model of SLE. I found that TASL is not required for the development or homeostasis of B cells, but is essential for the full activation of B cells by endolysosmal TLR signalling, and the subsequent production of cytokines and expression of ISGs. I also found that TASL plays an important role in the extrafollicular response, and in its absence the production of plasmablasts in response to T-dependent and T-independent antigens is dramatically reduced in females. Additionally, I identified that TASL is essential for the development of age-associated B cells (ABCs), a population that is expanded in aged people and autoimmune disease. TASL deletion also prevented the development of autoimmunity in the B6.MRL^Lpr model. Taken together, the results presented here suggest that TASL is important in the extrafollicular response and development of autoimmunity, and may play a role in the sexual dimorphism observed in SLE. This work also supports further investigation of TASL as a therapeutic target for SLE treatment.

Authors: Johnstone, J

• DOI: 10.5287/ora-nzqrxmawj
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English