Crohn’s disease (CD) describes an inflammatory condition characterised by chronic gastrointestinal (GI) inflammation. Currently, >1 in 150 people are estimated to be affected in the UK, with the incidence rising. The pathology of CD is linked to an aberrant immune response against the gut microbiota. CD is a heterogenous disease with different disease phenotypes (stricturing and fistulating disease) and locations; it can affect any part of the GI tract. A range of drugs is approved for CD treatment. However, response rates to these specific therapies are low, and 46% of patients still require bowel resective surgery.

The high rates of surgical interventions and unpredictable disease relapse pose challenges for the clinical management of CD. Little is known about the molecular mechanisms underlying the different treatment responses, and cost-effective and feasible approaches to predict these responses are still a long way off. Disease relapse has been linked with decreased T cell immunoreceptor with Ig and ITIM (TIGIT) on CD38+ CD4+ T cells in the peripheral blood of paediatric patients. Other clinical markers of inflammation have been found to lack specificity in predicting disease progression. Several biomarkers predicting non-response to frontline therapeutics blocking the pro-inflammatory cytokine tumour necrosis factor (TNF) have been proposed, including the levels of luminal membrane-bound TNF and gene expression of the pro-inflammatory cytokines oncostatin-M (OSM) and TNF itself. None of these markers are currently used clinically, and there is still a need for reliable ways to predict disease progression and treatment responses. Based on these findings I hypothesised that distinct immunopathotypes in CD drive distinct disease phenotypes and underlie distinct treatment responses to biologic therapies, such as anti-TNF.

My project aimed to elucidate distinct immunopathotypes in the blood and intestines of CD patients and link them to disease phenotype, state of inflammation and treatment response. Two distinct immunopathotypes were identified. One showed decreased circulating T cells and increased intestinal CD8+ and cytotoxic immune responses. The second immunopathotype was defined by IL-1β-driven inflammation and granuloma formation in the intestines of people and was linked to anti-TNF refractory disease.