ECCO Fellowship Study Synopsis: Mathieu Uzzan
Mathieu Uzzan, ECCO Fellow 2018
Deciphering the gut-specific B cell response in Inflammatory Bowel Disease (IBD)
© Mathieu Uzzan
Aim of the research
Given that there is a large complement of mucosal B cells that plays a pivotal role in the regulation of the microbiome and in mucosal homeostasis, it is likely that they play an important but yet understudied role in the pathogenesis of IBD. Therefore, we hypothesize that mucosal inflammation as seen in IBD will induce a B cell response with homeostatic and perhaps pathogenic properties.
The objective of our study is to comprehensively characterize the B cell response in patients with IBD. Specifically, we will:
a) Define alterations in the B cell subpopulations in circulation and in the gastrointestinal tract of patients with IBD in comparison with healthy volunteers using multiparameter flow cytometry and state-of-the art mass cytometry (CyTOF);
b) Assess the gut homing potential of B cell subsets during active IBD and determine the impact of therapeutic modalities like Vedolizumab and TNF inhibitors;
c) Characterize the immunoglobulin repertoire, its clonality and the IgH gene usage of relevant B cell subsets at the resolution of a single cell;
d) Assess for antigen reactivity by single cell cloning of B cells of interest and determining their reactivity towards a panel of microbial and self antigens;
e) Study the molecular pathways of B-cell response in patients with IBD by analyzing their transcriptome using single cell RNA sequencing techniques.
Progress to date and remaining tasks
Regarding the objectives a) and b), from over one hundred IBD patients and 30 healthy volunteers, we have found that although overall blood B cell frequency was unchanged in IBD, circulating plasmablasts (defined as CD19int/+CD38highCD27+) were significantly expanded in active IBD patients. Interestingly, the expansion correlated with the systemic inflammation and the disease extension. In addition, these plasmablasts significantly upregulated the gut homing α4β7 integrin and CXCR3 while β1 integrin level of expression was decreased. These findings were validated with an independent cohort of more than 300 patients where mass cytometry was performed. We furthermore noticed that the gut-specific plasmablasts dropped significantly as early as week 2 during vedolizumab therapy. The other objectives are all currently on going and we propose the following timelines for their completion: c) September 2018; d) and e) February 2019.