Autoantibodies and B cells in the pathogenesis of Sjögren's disease

Abstract

Sjögren’s disease (SjD) is a common autoimmune epithelitis that causes significant dryness, fatigue and joint pain. B cell hyper-activity along with autoantibodies are characteristic features of this condition. The reasons for self-reactive B cells in SjD have not been completely elucidated and this thesis will examine the role and pathology for autoantibodies and B cells in this disorder.

A series of studies were undertaken to firstly explore a common autoantibody found in SjD, anti-Ro52/TRIM21. I found that anti-Ro52 can help predict clinical features of patients presenting for autoimmune testing, and can help identify SjD patients with a severer clinical phenotype (Chapters 2 and 3). I then looked at another common autoantibody in SjD, rheumatoid factor (RhF), to track the evolution of this in an SjD patient that developed B cell lymphoma. We show that his RhF evolved over time into a lymphoma clone, but losing self-reactivity, providing unique insight into lymphomagenesis in SjD (Chapter 4).

I then examined the nature and repertoire of B cells in SjD patients in the blood and salivary glands, characterising self-reactive B cells and finding increased self-reactivity in all blood B cell developmental stages compared to healthy donors (Chapter 5). B cells were also more developmentally mature in salivary glands compared to the blood in SjD patients (Chapter 6). Finally, I turned to the process of apoptosis which produce apoptotic bodies and examined how they contribute to self-reactive B cells via age-associated B cells in SjD (Chapter 7).

Overall, this thesis contributes to important basic and clinical science of SjD, focusing on autoantibodies and the B cells. Future mechanistic studies of self-reactive B cells are required, particularly in terms of antigen presentation and their interactions with cognate self-reactive T cells. These studies will inform the development of novel therapeutic strategies in SjD.