12 July 2018 from 14:30 to 15:30

PhD Defence: Delineating the deranged immune system in systemic lupus erythematosus and antiphospholipid syndrome

Systemic lupus erythematosus (SLE) is a chronic relapsing autoimmune disease that predominantly affects women of child-bearing age. In SLE, immune complexes are deposited into tissues, including skin, joint and kidneys, leading to tissue inflammation. The pathogenesis of SLE is complex and includes derailments of both the innate and adaptive immune system. Antiphospholipid antibodies (aPL) are strongly associated with thrombotic events and pregnancy morbidity among patients with SLE. Approximately 20% of SLE patients have antiphospholipid syndrome (APS), defined as the persistent presence of aPL in patients who experienced at least one thrombotic or obstetric complication. APS also affects patients without an underlying disease and is then termed primary APS (PAPS).

In this thesis we investigated the role of the immune system in patients with APS as compared with patients with SLE. Key immunological abnormalities characteristic of SLE including the interferon (IFN) signature, release of neutrophil extracellular traps (NETs) and increased levels of B-cell activating factor (BAFF) were studied in patients with PAPS. We found that the IFN signature is present in 50% of PAPS patients as compared with 75% of SLE patients. In patients with APS, the IFN signature is associated with increases in cardiovascular disease associated non-classical monocyte subsets. Furthermore we identified that the IFN status of SLE and APS patients can be easily assessed by measuring galectin-9 levels in peripheral blood. Increases in NETs, low-density granulocytes (LDGs) and BAFF were found both in SLE and APS.

In addition, mechanisms underlying increased activity of both plasmacytoid and myeloid dendritic cells (pDCs and mDCs) were studied in patients with SLE, SLE+APS and PAPS by means of RNA sequencing and microRNA profiling followed by subsequent in vitro studies. pDCs showed an overall reduced expression of microRNAs both in SLE and APS which was a result of the in vivo activation of pDCs by stimulation of Toll-like receptor 7. RNA sequencing identified a self-perpetuating role for type I IFN signalling in the activation of both pDCs and mDCs, both in SLE and APS.

Such shared immunological perturbations among autoimmune diseases may relate to treatment responses of drugs targeting specific pathways. Hopefully, studying autoimmune diseases based on a molecular taxonomy, rather than classification criteria, improves treatment outcomes in patients with autoimmune diseases

Start date and time
12 July 2018 14:30
End date and time
12 July 2018 15:30
PhD candidate
Luuk van den Hoogen
Dissertation
Delineating the deranged immune system in systemic lupus erythematosus and antiphospholipid syndrome
PhD supervisor(s)
prof.dr. T R D J Radstake
Co-supervisor(s)
dr. J A G van Roondr. R D E Fritsch-Stork
Entrance fee
Free