P08 (2026 - 2030) Deciphering underlying mechanisms of the dysregulated B-cell function in the pathogenesis of Crohn’s disease (CD)

Stefanie Derer-Petersen (UzL), Larissa Nogueira de Almeida (UzL)

Project Summary 

Crohn's disease (CD) is an inflammatory bowel disease (IBD) whose cause remains unknown. For several decades, there has been growing evidence that a hyperactive B-cell compartment may be involved in the disturbed mucosal immune response in Crohn’s disease (CD) patients. Functional studies utilizing peripheral blood B cells isolated from CD patients revealed higher antibody secretion under basal conditions but decreased antibody titers after stimulation with the pokeweed mitogen compared to control individuals. In addition to less well-differentiated short-lived plasma cells, the human intestine also harbors fully mature long-lived plasma cells that persist for up to several decades and provide efficient and long-lasting intestinal adaptive immunity. There is increasing evidence that cellular metabolism and mitochondria function play a crucial role for B cell activation and differentiation into short-lived or long-lived plasma cells and CD patients have been shown to have multiple metabolic abnormalities, including mitochondrial dysfunction. Our recent studies indicate that the pathogenesis of CD involves a disturbed cellular metabolism which does not affect normal B cell activation and plasmablast differentiation but prevents normal terminal plasma cells maturation and generation of long-lived IgA plasma cells in the intestine. Preliminary data suggest that dysregulation of the crosstalk between p32 & caspase-1 underline the altered metabolism and function of plasma cells in CD. This project will characterize the metabolic dysregulation of the colonic B-cell/plasma cell compartment in CD patients further, and investigate the role of caspase-1 mediated p32 cleavage in colonic B cell/plasma cell subsets and its impact on the intestinal barrier function in depths. The results are expected to identify the cause of the selective IgA deficiency and B cell disfunction in CD and its role for the intestinal barrier function and the pathogenesis.