Autoimmunity in the pathogenesis of SSc
SSc is a severe, but heterogeneous autoimmune disease characterized by the presence of SSc-specific anti-nuclear antibodies. Most SSc patients are either anti-topoisomerase 1 antibody (ATA) or anti-centromere antibody (ACA) positive. These autoantibodies are mutually exclusive and associate with distinct clinical complications, e.g. ATA-positive SSc is associated with diffuse skin involvement and interstitial lung disease, whereas ACA-positive disease is associated with limited skin involvement and pulmonary arterial hypertension. Autoantibodies are produced by plasma cells, the antibody producing cells. Although our research has recently shown that higher levels of ATA and ACA and isotype spreading to IgM, an indication of a recently activated plasmablast response, can associate with disease progression, there is a lack of understanding of the exact role of autoreactive B cells and plasmablasts and their produced autoantibodies in the development and progression of SSc. Several projects aim to identify and (functionally) characterize autoreactive B cells and plasma cells, with emphasis on ACA and ATA-specific cells, in order to understand their role in the pathogenesis of SSc.
…SSc is a severe, but heterogeneous autoimmune disease characterized by the presence of SSc-specific anti-nuclear antibodies. Most SSc patients are either anti-topoisomerase 1 antibody (ATA) or anti-centromere antibody (ACA) positive. These autoantibodies are mutually exclusive and associate with distinct clinical complications, e.g. ATA-positive SSc is associated with diffuse skin involvement and interstitial lung disease, whereas ACA-positive disease is associated with limited skin involvement and pulmonary arterial hypertension. Autoantibodies are produced by plasma cells, the antibody producing cells. Although our research has recently shown that higher levels of ATA and ACA and isotype spreading to IgM, an indication of a recently activated plasmablast response, can associate with disease progression, there is a lack of understanding of the exact role of autoreactive B cells and plasmablasts and their produced autoantibodies in the development and progression of SSc. Several projects aim to identify and (functionally) characterize autoreactive B cells and plasma cells, with emphasis on ACA and ATA-specific cells, in order to understand their role in the pathogenesis of SSc.
We use (spectral) flow cytometry, single cell sequencing and serological studies to characterize ATA- and ACA-specific B cell responses.
Autoantibodies and vasculopathy can be detected before clinical symptoms of fibrosis appears. Besides anti-nuclear antibodies, another class of autoantibodies can be detected in SSc. These autoantibodies are less disease-specific, but bind to G-protein coupled receptors (GPCRs) expressed on cells lining the vasculature, endothelial cells. As vasculopathy is one of the earliest signs of SSc, this research project aims to link vasculopathy to autoimmunity by obtaining an in-depth understanding of the molecular and cellular effects of autoantibody binding to these receptors expressed by endothelial cells. In addition, we aim to identify druggable targets to dampen or halt the progression of SSc or the development of specific disease-manifestations.
We use GPCR technology in collaboration with Prof. dr. Laura Heitman (Leiden Academic Centre of Drug Research, Leiden University) and 2D and 3D endothelial cell bioassays in collaboration with Prof. dr. Anton Jan Zonneveld (Einthoven Laboratory for Vascular and Regenerative Medicine, LUMC), next to a broad technological toolbox to study autoantibody-mediated vasculopathy in SSc.
Themes for innovation / Societal Outreach
Key Publications
Our team members
Coordinating scientists:
- Dr Cynthia Fehres
- Dr Hans Ulrich Scherer, MD
Scientific Staff
- Dr Jeska de Vries-Bouwstra, MD
- Prof. Dr Tom W. J. Huizinga, MD
- Prof. Dr Rene E. M. Toes
PhD students
- Saad Ahmed, MD, MSc
- Abdulellah Alzahrani, MSc
- Sophie Liem, MD, MSc
- Sam Neppelenbroek, MSc
- Wieke van Oostveen, Msc
Coordinating scientists:
- Dr Cynthia Fehres
- Dr Hans Ulrich Scherer, MD
Scientific Staff
- Dr Jeska de Vries-Bouwstra, MD
- Prof. Dr Tom W. J. Huizinga, MD
- Prof. Dr Rene E. M. Toes
PhD students
- Saad Ahmed, MD, MSc
- Abdulellah Alzahrani, MSc
- Sophie Liem, MD, MSc
- Sam Neppelenbroek, MSc
- Wieke van Oostveen, Msc
Technical staff:
- Nivine Levarth