Identifying pathogenic mechanisms in SYK gain-of-function inflammatory disease

Thesis

Spleen tyrosine kinase (SYK) is a signalling intermediate that is highly expressed in innate immune cells and B lymphocytes, where it has critical roles downstream of multiple immunoreceptors. Gain-of-function (GOF) variants in SYK cause severe immune dysregulation; leading to monogenic inflammatory bowel disease, multi-system inflammation, and humoral immunodeficiency. Studying monogenic immune disorders provides valuable insights into mechanisms that drive inflammation. These insights can inform precision therapies for affected individuals and enhance understanding of pathways relevant to polygenic diseases. This thesis investigates the pathogenic mechanisms underlying SYK GOF immune dysregulation, primarily using a SYK-S544Y GOF mouse model.

SYK GOF causes a complex B cell immunodeficiency. In the bone marrow, a partial block in pre-B cell development limits transitional B cell output. In the spleen, transitional B cells preferentially differentiate into marginal zone B cells, further reducing the pool of naïve follicular B cells. Those that do develop exhibit increased activation and defective class-switch recombination. These abnormalities are associated with impaired humoral responses to model antigens and defective immunity to intestinal Citrobacter rodentium infection. Single-cell analysis of intestinal B cells from a SYK GOF patient revealed conserved features between the human and murine phenotypes.

In addition to immunodeficiency, SYK GOF mice develop intestinal inflammation following colonisation with Helicobacter hepaticus, a gram-negative pathobiont normally tolerated by the mucosal immune system. The mice also develop a spontaneous peripheral and axial spondyloarthropathy which shares clinical, radiological, and histological features with human axial spondyloarthritis. Despite the pronounced B cell abnormalities, both Helicobacter-induced colitis and spontaneous arthritis developed in Rag-deficient SYK GOF mice, indicating that innate immune cells play a primary role in disease pathogenesis. A shared transcriptional signature was identified in colitis and arthritis, characterised by increased expression of genes associated with chronic inflammatory macrophages, pattern recognition receptor signalling, and pro-inflammatory cytokines. These findings were supported by in vitro studies, in which SYK GOF bone marrow-derived macrophages showed enhanced inflammatory responses to TLR2/6, TLR4, TLR9, and NOD2 ligands.

This thesis identifies aberrant PRR signalling in macrophages as a central pathogenic mechanism in SYK GOF associated inflammatory disease. These findings deepen our understanding of SYK as a key regulator of innate immune responses, suggest broader relevance of SYK signalling pathways in the pathogenesis of IBD and spondyloarthropathy, and support the potential of SYK as a therapeutic target in inflammatory diseases.

Authors: Taylor, H

• DOI: 10.5287/ora-9gb6pmy4b
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Genetic disorders; Immunology; Gastrointestinal system