Investigating The Immunology Of Crohn’s Disease

Abstract

Crohn’s disease is a chronic autoimmune disease characterised by chronic inflammation in the gastrointestinal tract caused by an uncontrolled immune reaction to commensal bacteria. It is steadily increasing in incidence across the globe, especially in young adults. Current treatments act to reduce inflammation but there is no cure. This is because this disease is still poorly understood especially regarding the specific immune cells involved. Defining these cells and their functions could provide critical insights into the causes and progression of this disease and pave the way for therapeutic interventions.

Our group has privileged access to large human intestinal explants from patients undergoing surgery to remove Crohn’s affected tissue. We are also experts in the biology of mononuclear phagocytes, which are key cells in mediating immune tolerance and inflammation and represent an obvious class of cells that may play a role in Crohn’s disease.

Here we have firstly optimised intestinal tissue digestion protocols to extract mononuclear phagocytes (and other immune cells) from fresh human intestinal tissue in a viable and functional state. We then designed and optimised high-parameter flow cytometry panels to comprehensively identify and characterise all known subsets of mononuclear phagocytes as well as innate lymphoid cells, mucosal-associated invariant T cells, natural killer cells and  T cells.

We then accurately defined the mononuclear phagocyte subsets present in tissue affected by Crohn’s Disease compared to uninflamed tissue and inflamed non-Crohn’s tissue. We revealed that langerin+ type-2-conventional dendritic cells (cDC2) were significantly reduced in Crohn’s affected ileum. We went on to show that in healthy tissues these cells drove the induction of CD4+ T helper 2 and T helper 17 cells that highly expressed GATA3, RORt and AHR.

Restoration of langerin+ cDC2 in Crohn’s Disease patients may therefore provide a therapeutic avenue to treat this illness.