Promotie: Repurposing established drugs for new indications: leflunomide and hydroxychloroquine combination therapy for Sjögren’

Samenvatting

Systemic sclerosis (SSc) is an autoimmune disease in which the production of autoantibodies and vascular damage precede the development of fibrosis in the skin and internal organs such as the lungs. It is unknown what underlies the development of SSc, but the over-activation of the immune system is seen as an important factor. In addition to the production of autoantibodies, the infiltration of immune cells into the affected organs is an important indication of the role of the immune system in this disease. Many monocytes and cells derived from the monocyte are detected in the affected tissues of SSc patients. This thesis describes the results of our research on the role of monocytes in the pathogenesis of SSc. We describe the intrinsic differences in gene expression and its regulation in monocytes from SSc patients compared to cells of healthy people. We have discovered that changes in gene expression levels are present at an early stage of the disease and that the altered activation of enzymes that regulate the accessibility of the DNA may explain some of these changes. In addition, we have seen that the number of monocytes in the circulation of SSc patients is related to the severity of the disease. Finally, we describe how monocytes are activated by proteins that are elevated in the blood and tissue of SSc patients and we have analyzed how this activation can contribute to the development of fibrosis. Future research should determine whether the prevention of monocyte infiltration and their subsequent activation ameliorates this disease.