PhD defence E. (Erika) Huijser

Dissertation in short:

In most patients with primary Sjögren’s syndrome (pSS), the type I IFN (IFN-I) signaling pathway is continuously activated. The research in this thesis aimed to expand the knowledge of the mechanisms that activate the IFN-I signaling pathway in pSS and the implications thereof. The IFN-I was measured in blood of pSS patients using an ultrasensitive technology (Simoa). These data showed a strong correlation between the IFN-I concentrations in blood and the IFN-I score, a surrogate marker for IFN-I. The highest IFN-I levels were measured in blood of patients with symptoms caused by either autoantibodies or overactivity of immune cells that produce antibodies. Nucleic acid sensors are able to stimulate IFN-I production. This thesis summarizes the evidence from literature for the involvement of RIG-I-like receptors and DNA sensors, two of the nucleic acid sensing pathways, in pSS. In a laboratory experiment, immune cells were stimulated with an activator of DNA sensors. The monocytes and plasmacytoid dendritic cells – two immune cell types – from pSS patients showed higher activity of the DNA-sensing pathway and produced more IFN-I compared with immune cells from healthy donors. These results support a potential involvement of nucleic acid sensing pathways in IFN-I activation in pSS. Finally, this thesis describes the reciprocal interaction between IFN-I, ‘trained immunity’ and cholesterol uptake by immune cells, an interaction that could be relevant in pSS. In summary, this thesis provides insight into the role of nucleic acid sensing pathways, ‘trained immunity’ and cellular metabolism of immune cells in IFN-I activation in pSS.