ESR 5: Study the molecular and cellular features of human lymph node T cells during the earliest phases of systemic autoimmunity – POSITION FILLED

PhD research

Host:

Dr Lisa van Baarsen

PI | Associate Professor | PhD

Amsterdam Rheumatology and immunology Center (ARC)

Rheumatology & Clinical Immunology

Experimental Immunology

Location AMC | K0-105 | Meibergdreef 9 1105 AZ Amsterdam

T: +31205668043  |  E: e.g.vanbaarsen@amsterdamumc.nl

http://ams-rc.com/medewerkers/baarsen/

Duration: 48 months

Background

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease with an unknown etiolology. To ultimately cure or prevent this destructive disease it is essential to understand the earliest changes in the immune system. It is now well established that autoantibodies can be present years before the onset of RA. This indicates that changes in the immune system precede the development of RA and detection of these autoantibodies allows us to identify individuals who are at risk of developing RA. Moreover, we can use these individuals characterized by having systemic autoimmunity but no arthritis, as a model to study the earliest phases of autoimmune disease. In general, immune responses are initiated in lymphoid organs where naïve T cells are activated after antigen recognition presented by antigen presenting cells. Upon activation and influenced by cellular interactions and the cytokine milieu, activated T cells will differentiate towards an inflammatory or regulatory phenotype to ensure an adequate immune response. Since the maintenance of peripheral tolerance to self-antigens and the initiation of adaptive immune responses occur in peripheral lymphoid organs, we set-up a research line focused on studying lymph node (LN) biopsies obtained during the preclinical and earliest phases of RA. T cell responses have been well-studied in peripheral blood and synovial tissues of RA patients. However, not much is known about their initial activation, phenotype and function in LNs during the preclinical and earliest phases of RA and other autoimmune diseases. Recently, we discovered that the frequency and functional capacity of different T cell subsets in both peripheral blood and LN tissue are affected already during the RA-risk phase. A striking discovery in RA-risk and RA patients was the reduced cytokine production in LN T cells (but not blood T cells) upon in vitro stimulation (Ramwadhdoebe et al 2016).

Approach 

We hypothesize that already before the development of autoimmune disease, as a result of loss of tolerance and prolonged antigen exposure, T cells become dysfunctional resulting in an exhaustive phenotype. Longitudinal analyses of RA-risk individuals will determine whether skewed T cell differentiation towards a proinflammatory and/or exhausted phenotype with sustained capacity of delivering B-cell help is associated with changes in autoantibody profile, inflammation and/or disease progression. Using state-of-the-art technologies including flow/mass cytometry, single-cell RNA sequencing and cellular metabolism, the PhD student will determine the frequency, phenotype and function of inflammatory, regulatory and exhausted/senescent T cells in LN biopsies obtained from healthy individuals, RA-risk individuals and RA patients. In addition, the PhD student will delineate the mechanism of the reduced cytokine production observed in LN T cells of RA-risk individuals and RA patients and investigate whether this defect can be restored.  

Our research team

It is our ambition to unravel the molecular and biological processes leading to systemic autoimmune diseases by studying unique human lymphoid and synovial tissue biopsies obtained during the pre-clinical and earliest phases of rheumatoid arthritis. These studies will lay the foundation for the development of novel therapies to prevent and treat this chronic disabling immune-mediated autoimmune disease.

Working within the recently established Amsterdam Rheumatology and immunology Center (ARC) and being embedded within the Amsterdam Infection & Immunity Institute (AI&II) gives us the excellent opportunity to work closely together with both rheumatologists as well as immunologists on translational research projects. Collaboration with several rheumatologists within the ARC enables the use of unique biomaterials from patients with different stages and types of autoimmune diseases. For our research program lymph node biopsy procedures are performed in close collaboration with the department of Radiology, while synovial tissue biopsies are routinely collected within our department. Bone marrow biopsy procedure will be performed in collaboration with haematologist Dr. Hazeberg of the Department of Haematology. We have a close collaboration with Prof.dr. Mebius (VUMC) who has a strong track record in lymph node immunobiology using sophisticated in vivo lymph node transplantation models. 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. 

This multidisciplinary research environment empowers state-of-the-art immunological studies during various stages of autoimmunity as well as the translation of our findings into novel therapeutic approaches. The vanBaarsen group currently consists of 5 PhD students (2 at VUMC), 1 postdoc (at VUMC) and 2 research technicians. This project will be performed in close collaboration with ARCAID PI Prof.dr. Niek de Vries.