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

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: This email address is being protected from spambots. You need JavaScript enabled to view it.

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.

Your profile

We are looking for a highly motivated and enthusiastic researcher with:

  • - A master degree Biomedical Sciences, with affinity for Immunology and translational research;
  • - Experience with cellular responses, molecular biology, and preferably affinity with bioinformatics;
  • - You have a flexible, pro-active team spirit but you can also work independently;
  • - You like to show initiative and you have talent for focus and organization
  • - You have excellent communications skills in English, both written and verbal.

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 Lisa van Baarsen (This email address is being protected from spambots. You need JavaScript enabled to view it.) , telephone: +31205668043.