ESR 14: Activated PI3 kinase delta in systemic lupus erythematosus (SLE) -POSITION FILLED

PhD research

Hosts:

Prof. dr. Sergey Nejentsev

Department of Molecular Cell Biology and Immunology

Amsterdam UMC, location VUMC

O2 Building, Room 11 E 59

1007 MB Amsterdam, Netherlands

Prof. dr. Alexandre Voskuyl

Department of Rheumatology

Amsterdam UMC, location VUMC

Duration: 48 months

Background

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease that affects millions of people worldwide. The aetiology of SLE is complex and includes both genetic and environmental factors. SLE patients are very heterogeneous and have a wide range of clinical manifestations, such as skin rash, arthritis, central nervous system involvement and progressive glomerulonephritis resulting in kidney failure. Disease course and outcomes of SLE are extremely variable, ranging from permanent remission to recurrent exacerbation leading to increased morbidity, reduced quality of life, major organ failure or death. The wide range of disease manifestations and unpredictable disease course make SLE patients difficult to treat and difficult to study in the context of clinical trials. Attempts have been made to subgroup patients with SLE according to risk factors associated with outcome and exacerbation. However, very little is known about biomarkers predicting the disease course and treatment responses. There is an urgent need for identification of new biomarkers associated with clinical outcomes of SLE. The identification of such biomarkers may lead to the design of new personalised therapies for SLE patients.

Phosphoinositide 3-kinases (PI3Ks) are lipid kinases that phosphorylate the 3-hydroxyl position of the inositol ring of phosphatidylinositol substrates within the plasma membrane and intracellular compartments. The phosphorylated products control a wide variety of cellular processes, including activation, migration, proliferation, differentiation and vesicular trafficking. Enhanced PI3K signalling has been implicated in SLE development. Thus, genetically engineered mouse strains with enhanced PI3K signalling have been noted to develop a lymphoproliferative syndrome with autoimmune features resembling SLE. At the same time promising results have been obtained from attempts to inhibit PI3K activity in mouse models of SLE.

Approach 

Previously, the group of Prof Sergey Nejentsev discovered a new disease called the Activated PI3 kinase Delta Syndrome or APDS (Angulo et al, Science, 2013). In APDS patients the disease is caused by rare genetic mutations that result in the increased activity of PI3Kδ, a class I PI3K that phosphorylates phosphatidylinositol (4,5)-bisphosphate to produce phosphatidylinositol (3,4,5)-trisphosphate. APDS patients have immunodeficiency that is often associated with autoimmunity, indicating that chronically activated PI3Kδ may play a role in its pathogenesis. PI3Kδ may be activated not only by rare genetic mutations, but also by common factors (e.g. environmental factors) and, therefore, may contribute to pathogenesis of common autoimmune diseases. Here, we will investigate a hypothesis that chronically activated PI3Kδ contributes to SLE. Initially, we will identify specific biomarkers of chronically activated PI3Kδ. This will be done in APDS patients, who represent a bona fide human model of chronically activated PI3Kδ. Then, we will search for subjects with such biomarkers in a cohort of SLE patients established by Prof Voskuyl. This project will aim to identify a subgroup of SLE patients with chronically activated PI3Kδ. Importantly, our study has a clear therapeutic application, because such SLE patients could be treated with PI3Kδ inhibitors, a new class of drugs that were shown to be effective in APDS and cancer patients. Thus, our project will open ways for a novel therapeutic approach – personalized therapy of SLE patients using PI3Kδ inhibitors.

Our research team

Prof. dr. Sergey Nejentsev has a long-standing interest in immune-mediated disorders, including autoimmunity and immunodeficiency (e.g. Nejentsev S. et al, Nature 2007; Nejentsev S. et al, Science 2009; Angulo I. et al, Science 2013; Cuchet-Lourenco D. et al, Science 2018). His group leverages genetic and molecular biology techniques to dissect mechanisms of these diseases. At present, the group consists of two laboratories led by Prof. Nejentsev, one in Amsterdam UMC and one in the University of Cambridge. The Nejentsev lab at Amsterdam UMC, where the current project will take place, now includes two post-doctoral scientists based at the department of Molecular Cell Biology and Immunology (MCBI) in the O2 building of VU Medical Center. The project will be done in close contact with the Cambridge lab of Prof Nejentsev. The working language in both labs is English.

The group of Prof. dr. Alexandre Voskuyl is based at the Department of Rheumatology at the Amsterdam UMC, location VUmc. It has a special interest in SLE research and works with large cohorts of SLE patients.