Investigating the genetics and immunopathogenesis of ankylosing spondylitis

Ankylosing spondylitis is an immune-mediated inflammatory arthritis mainly affecting the spine, although the peripheral joints, skin, intestine, and eyes could also be affected. I investigated the genetic risks and immune dysfunction of AS to achieve a better understanding of the underlying pathogenic mechanisms.
Genetic association studies have made significant progress in AS. I hypothesized that studying the common genetic risks among AS and its associated conditions could help prioritize risk genes as potential drug targets and reveal potential opportunities for drug repurposing. I assessed the genetic risks overlapping between AS and 30 other diseases and identified 9 conditions that are genetically close to AS. Utilizing these shared genetic risks, I found a risk locus at the intron of ZMIZ1 shared by AS and IBD, which regulates the expression of PPIF through an enhancer-enhancer-promoter interaction and transcriptional factors RELB and SP1. PPIF has a higher expression in CD4+ T cells from synovial fluid compared to blood, particularly in the proliferating population. Interestingly, PPIF, as a cyclophilin, can bind to Cyclosporin and the latter has been approved to treat IBD. The genetic risk overlapping suggested the opportunity of repurposing Cyclosporin to treat AS.
Additionally, I found that activated T cells can instruct monocytes from AS blood to produce IL-1β and IL-23 in the absence of pathogen-associated molecular patterns (PAMPs). Monocytes in AS patients are known to be hyper-proinflammatory, the cause of which is not clear. T-cell activated monocytes were heterogeneous but included a subset of “hyperinflammatory monocytes” not induced by LPS activation and enriched for expression of AS risk genes, including ERN1. This subset of monocytes exhibited a gene expression profile highly similar to a major population of CD14+ myeloid cells identified in AS synovial fluid (SF), strongly suggesting that T cell-induced myeloid cell activation occurs in vivo in inflamed joints. In line with this, PD1+IFN-γ+ T-cells were enriched in AS SF compared to blood. T-cell instructed activation of primary patient-derived monocytes in vitro was inhibited by silencing the ERN1 gene or by chemical inhibition of its gene product IRE1α.
Lastly, I identified a CXCR6+ Th17/Tph polyfunctional CD4+ T cell subset with the enriched expression of AS GWAS genes through integrating scRNA-seq profiling of AS synovial fluid T cells and genetics approaches. Trajectory analysis revealed these CXCR6+ Th17 / Tph cells were derived from effector Th17 cells, activated by IL-1 and IL-23, followed by antigen engagement. Through demonstrating Tph cells in breast cancer were generated from Tfh cells, I proposed Tph cells are generally derived from different types of effector helper T cells depending on the environment.
My work integrated genetics and immunology approaches to investigate AS pathology and has provided new insights into potential therapeutic targets with genetic support, as well as novel mechanisms of monocyte dysfunctions.

Keywords: ankylosing spondylitis
Advisor: Chen, L
Bowness, P