ESR 4: Clonal isotyping of the B cell response in autoimmunity – POSITION FILLED

PhD research

Host:

Prof. dr. N. de Vries (Niek)

 Dept Clinical Immunology & Rheumatology

Amsterdam Rheumatology and immunology Center (ARC)

 Rheumatology & Clinical Immunology & Experimental Immunology

Location AMC | D3-220 | Meibergdreef 9 1105 AZ Amsterdam

T: +31205667765  |  E: n.devries1@amsterdamumc.nl

https://www.amc.nl/web/research-75/person-1/prof.-dr.-n.-de-vries-md-phd.htm

Duration: 48 months

Background

Many HLA class II associated autoimmune diseases are characterized by the presence of disease-specific antibodies, e.g. rheumatoid arthritis and vasculitis.

These antibody responses come in different isotypes and subtypes, each expressed at selected locations in the body, each having different functional characteristics, potentially having different roles in immune memory. For instance, the IgG4 antibodies have low affinity for complement and the Fc receptor, and have been implied in regulation of the humoral immune response in many instances, e.g. in IgG4-related disease. However, in the skin disease pemphigus the antibodies are thought to be pathogenic, but highly responsive to anti-B cell therapy. We published that high IgG4-responses correlate with disease activity in vasculitis, and showed that their presence differentiates active vasculitis from its disease mimics.

Recently it has been reported that clones might follow specific isotype switches during their development. These development paths might help us to identify the tissue origins of a response, functionally characterize ongoing adaptive responses, differentiate subtypes of disease, and predict therapeutic responses, e.g. to B-cell directed therapies. We recently developed novel B-cell repertoire sequencing technologies that can perform highly accurate quantitative assessment of clonal BCR responses based on the incorporation of unique molecular identifiers (UMI) before large scale amplification. Using this technology we aim to unravel the isotype history and characteristics of the autoantibody response in different diseases, and its relevance for response to B-cell directed therapies.

Approach 

The PhD candidate will get acquainted with existing high-throughput sequencing approaches of the B cell and T cell receptor genes and existing data analysis methods to study lymphocyte repertoires. Samples from patients with different autoimmune disease are available in the biobank locally and from collaborating partners. The technologies will be used to analyse the isotype history of disease associated clones in different diseases, and study the effect of therapy, including B-cell directed therapies.

Our research team

Our team aims to better understand the interactions between HLA-presenting APCs, T-cells and B cells that define specificity in, and regulate the disease-associated adaptive immune responses in autoimmune disease. To this end we study unique biobanked and freshly acquired materials from blood, human lymph nodes, bone marrow and synovial tissue obtained during the pre-clinical and earliest phases of autoimmune disease, e.g. in rheumatoid arthritis and vasculitis. The goal is to improve clinical management of these diseases by developing novel biomarkers and identification of new targets for novel therapies. Our team currently consists of 5 PhD students, 1 postdoc and 2 research technicians. For more information see https://www.amc.nl/web/research-75/person-1/prof.-dr.-n.-de-vries-md-phd.htm.

The project is a close collaboration with prof. dr. Antoine van Kampen of the The Bioinformatics Laboratory. The team is embedded within the recently established Amsterdam Rheumatology and immunology Center (ARC) and the Amsterdam Infection & Immunity Institute (AI&II). We are involved in several national and international research projects, allowing excellent possibilities for collaborations with other research groups in academia as well as industry.