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

PhD research

Host:

Paul Klarenbeek, MD, PhD

Rheumatologist

Department of Rheumatology & Clinical Immunology

Laboratory for Experimental Immunology

Amsterdam UMC, location AMC

Meibergdreef 9,

1105 AZ, Amsterdam

The Netherlands

Duration: 48 months

Background

Vasculitis is a heterogeneous group of inflammatory diseases that primarily affects blood vessels. The pathogenesis of these diseases is largely unknown; however, vascular inflammation leads to hypoxia leading to organ failure with devastating consequences. The fluctuating course of primary vasculitides together with difficulties in reliable assessment of disease activity on the individual patient level leads to periods of over- and undertreatment with associated side-effects, morbidity and mortality. Clinical scores assume that a physician is certain that symptoms are attributable to vasculitis which is often not the case. Notably, the differentiation of active vasculitis and infection may be difficult. As a result, patients regularly need to undergo intensive additional investigations. Specific and sensitive biomarkers are lacking in vasculitis: the ones that serve as diagnostic biomarkers (e.g. ANCA) do not serve very well as disease activity markers. Thus, from the current clinical perspective, there is a pressing need for specific biomarkers that sensitively reflect disease activity. In addition, more understanding of the pathogenesis of these diseases is needed to further improve clinical care and treatment regimes.

Approach 

Although the role of autoantibodies (e.g. ANCA) has been studied extensively in vasculitis very little is known on the B-cells that produce these antibodies. We do not know what subsets of B-cells (e.g. memory, plasmablast or plasmacells, IgG4 expressing B-cells) are the key-cells involved in flares or disease. Alternatively, it might be that B-cells are involved in dampening the immune responses (this is a leading hypothesis for IgG4+ B-cells). Therefore, we need to characterize these cells in the context of disease activity and disease remission.

In the vasculitis expertise center we are currently performing a longitudinal study to include patients with ANCA-associated vasculitis. Therefore, we have access to many samples during active disease and during remission. In the project we will use these samples to understand the role of different B-cell subsets. A key technique used will be Next-Generation Sequencing of the B-cell receptor repertoire (this is a key-expertise of Paul Klarenbeek). This allows identification of individual B-cell clones. Using this technology B-cell clones that are implicated in the disease can be tracked over time and place (e.g. in active disease and in remission). The technique can be coupled to other techniques such as FACS sorting and single cell sequencing. This allows determination of the specificity of the clones (are they autoreactive?), phenotypes of B-cells over time and other features.

One of the unique aspects of this project is the close collaboration with the clinicians in the vasculitis expertise center. Findings of this study can quickly be translated to the clinics to see whether they improve our current tests to help steer treatment decisions. 

Expected results:

After the project will expect to better understand the role of B-cell subsets in vasculitis. This will help to improve tests and biomarkers in clinical care for patients with vasculitis, improving outcomes and quality of life.

Our research team

The AMC is a Vasculitis Expert Center, recognized by the Ministry of Health, Welfare and Sport. It hosts a dedicated multidisciplinary vasculitis outpatient clinic, and participates in the national vasculitis network. The center has strong collaborations nationally, e.g. with Free University Amsterdam (VUMC) and Leiden University. International collaborations, e.g. within several consortia (IMI grants ABIRISK, BeTheCure, MODIRA) give access to a wide network of international experts.

The PhD student will be supervised by dr. Paul Klarenbeek (NWO VENI recipient 2016) and will be working closely with researchers/PhD-students from the groups of dr. Sander Tas (rheumatology), dr. Marc Hilhorst (nephrology), prof. Niek the Vries (rheumatology), prof Antoine van Kampen (bioinformatics), prof Alexandre Voskuyl (rheumatology) most of whom are PI’s in the ARCAID project. The PhD student will be assisted by MDs from the vasculitis expertise center for samples. We have strong collaborations with the AMC core sequencing facilities in the AUMC and in Leiden (prof. Frank Baas). 

Your profile

      • We are looking for a researcher with:

        • - A master’s degree in Medical Biology or similar
        • - Demonstrated interest in immunological research
        • - Experience in molecular research (and preferably some expreince in bioinformatics)
        • - An enthusiastic can-do attitude that can function in a team
        • - Good communications skills in English

Our offer

All ARCAID ESRs receive a full employment contract for 4 years, according to the Collective Employment Agreement (CAO) of the Dutch University Medical Centres. The monthly salary based on a 36-hour work starts from €2.422,- with yearly increments to a maximum of € 3.103,-. This 4-year PhD position is funded by the  Marie Skłodowska-Curie actions of the European Union's Horizon 2020 COFUND program under grant agreement No 847551. There is no separate budget available for mobility as it is already included in the ESR salary. ESRs may attend external courses, conferences or workshops. If applicable or required, additional expenses for training and conference participation and the travel to a Partner Organisation will be covered by the project. The ESR salary meets the requirements of the Dutch Immigration Department to allow family members to move to the Netherlands. It is at the convenience of the ESR to decide on this family movement since the Amsterdam UMC will not cover additional expenses regarding mobility of spouse nor for the required accompanying residence permits. In addition to their individual scientific projects, all fellows will have the opportunity to attend international progress meetings, scientific conferences and summer schools. Additionally, they benefit from further continuing education, which includes internships and secondments, a variety of training modules as well as transferable skills courses. See recruitment procedure.

Your application

See recruitment procedure. You can apply using the online application form. For more information about the project you can contact Dr. Paul Klarenbeek (This email address is being protected from spambots. You need JavaScript enabled to view it.).