Abstract
Inflammatory Bowel Disease (IBD) and Ankylosing Spondylitis (AS) have epidemiological, symptomatic and genetic overlap. Many people with IBD develop AS and vice versa, and both groups of patients exhibit pathological inflammation. This suggests a role for the immune system in linking the diseases. The aim of this study was to investigate the balance of macrophage and T cell subsets in the intestinal mucosa of people with IBD, AS, and healthy people. This was to improve our understanding of how innate and adaptive immune responses contribute to pathogenesis of inflammatory gut disorders. I hypothesised that genetic defects of the innate immune system, in people with IBD and AS, cause a shift in the proportion of macrophage subsets. Further, this would lead to chronic intestinal inflammation, characterised by IL-17 and IFNγ producing T cells.
Methods were developed to identify complex T cell and macrophage subsets within human intestinal tissue. Multi-parametric flow cytometry was used to establish these methods, which were subsequently extended. For T cells, additional cytokines with relevance to IBD and AS were incorporated. This allowed detection of an increased frequency of T cells in the terminal ileum compared to the colon. For macrophages, additional phenotypic markers were incorporated to identify gut-specific macrophage subsets.
Intestinal T cell profiles of people with CD, and AS were compared to those of healthy people. This revealed that people with inactive CD, and AS had an intermediate T cell phenotype between actively inflamed tissue and healthy tissue. This profile was characterised by differences in frequencies of IL-2 producing T cells and regulatory T cells. IL-17 producing T cells and regulatory T cells were increased in inflamed tissue compared to healthy, while IFNγ producing T cells were not.
These immunological data, in combination with genetic studies, further elucidate how the immune system may be altered by genetic polymorphisms that lead to the development and maintenance of inflammatory diseases, such as IBD and AS. Based on the data presented here, I hypothesise that combinations of multiple genetic polymorphisms lower the threshold for development of intestinal inflammation, which leads to initiation of inflammatory diseases, including IBD and AS.