Full project description ESR 13

ESR 13: Unravelling the role of B-cells in ANCA-associated vasculitis – POSITION FILLED

PhD research

Hosts:

Prof Dr Geert D’Haens

Gastroenterologist| Professor

Dr Joep Grootjans

Fellow Gastroenterology & Hepatology | PhD

Amsterdam University Medical Centers (location AMC)

Meibergdreef 9

105AZ  Amsterdam

The Netherlands

Duration: 48 months

Background

Patients with inflammatory bowel disease (IBD) have chronic intestinal inflammation. IBD patients also have extraintestinal manifestations, and increased risk of developing several types of cancer, amongst others colorectal cancer (CRC). The etiology of such IBD-associated diseases is incompletely understood.

We recently discovered that chronic inflammatory state in the intestine is accompanied by local and systemic anti-inflammatory responses. These responses include increased production of polyreactive immunoglobulin A (IgA). In addition, chronic inflammation is associated with ‘immune exhaustion’. The current project will focus on understanding the role of these local and systemic changes in immune composition in IBD patients in the development of IBD-associated extraintestinal manifestations and CRC.

Approach 

Work package 1: Are systemic anti-inflammatory B cell responses to chronic intestinal inflammation associated with the development of extraintestinal manifestations in IBD? Key objectives:

1) Investigating B cell repertoire in intestinal tissue and intestinal and peripheral lymph nodes. 2) Investigating Ig(-complex) deposition in affected extraintraintestinal sites such as joints of patients with IBD. 3) Investigating the polyreactive nature of intestinal derived IgA in vitro and in vivo in mouse studies

Work package 2: Is there a role for immune exhaustion in the development of IBD associated dysplasia and colorectal cancer? Key objectives:

1. Analyzing human IBD-associated dysplasia and CRC for immune exhaustion profiles using validated multi-color IHC panels. 2. Analyzing the immunological profile in IBD associated dysplastic lesions in a prospective series using mass cytometry (CyTOF) and single cell RNA-Seq. 3. Understanding the role of immunosurveillance in the setting of chronic inflammation-induced cancer and ‘sporadic’ CRC in mouse models (AOM/DSS models and APC^min mouse models).

Our research team

It is our ambition to better understand etiology of auto-immune diseases such as IBD to improve treatment options. Within the AMC there is a close collaboration between the departments of rheumatology, gastroenterology and surgery. In addition, we are embedded in the Amsterdam Infection and Immunity research Institute as well as in the Amsterdam Gastroenterology and Metabolism research institute and Tytgat institute. We have access to high quality core research facilities of the AMC. This provides an excellent multidisciplinary research environment which form a basis for fruitful scientific collaborations between clinicians and basic scientists on our translational research projects. Prof. Geert D’Haens is gastroenterologist and global key opinion leader in inflammatory bowel disease with a strong translational profile. Dr. Joep Grootjans is a fellow in Gastroenterology and Hepatology and Mucosal Immunologist who has a translational research line on immunopathogenesis of IBD and IBD-associated diseases. This project will be performed in close collaboration with ARCAID PI’s Dr. Lisa van Baarsen.