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New research to pinpoint the causes of lupus

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The Medical Research Foundation has announced £1 million of new funding for research into lupus, an autoimmune disease that can cause damage to the skin, organs, joints or any other part of the human body.

Lupus is a long-term illness that is difficult to diagnose and treat. It is currently incurable, although the disease can be managed if detected early. This, however, is a challenge as the symptoms of lupus are common to many illnesses.

Four mid-career researchers from the University of Cambridge, Imperial College London and University College London (UCL) will explore the underlying causes of lupus, which are currently poorly understood. The disease, which affects around 15,000 people in England and Wales, has been linked to a range of potential ‘triggers’, including hormonal changes, sunlight, viral infection, childbirth and strong medications. These triggers result in an irregular immune response, where the body’s own immune system attacks its healthy cells, resulting in inflammation. In mild cases this can cause rashes and joint problems, but in more severe cases, this inflammation affects major organs, resulting in kidney failure, heart disease and neurological damage.

Lupus can affect anyone, but it is more common in those who are of African, Caribbean or Asian origin, and women account for 90 per cent of cases.

One of the new research projects, led by Dr Elizabeth Rosser from UCL, will look at differences between young men and women with lupus, specifically in relation to the break-down of cholesterol, and how this affects immune cell function. It is thought that sex hormones such as oestrogen may affect the onset and severity of lupus, and might also explain why women are much more likely to develop the illness.

Dr Rosser’s project will look at the role of cholesterol metabolism, a specific metabolic pathway that is influenced by sex hormones. As well as increasing our understanding of the disease mechanisms underpinning lupus, Dr Rosser’s work hopes to identify potential new treatment options for patients. The ultimate aim is to understand whether drugs used to treat disorders associated with altered cholesterol metabolism can also be used to treat lupus.

A project led by Dr James Thaventhiran from the University of Cambridge is inspired by his work as a clinician treating patients with immunodeficiencies. He noticed that the leading cause of increased referrals to his clinic were patients with treatment-induced immunodeficiency. Specifically, lupus patients undergoing treatment targeting B lymphocytes. B lymphocyte therapy targets all B cells (white blood cells) non-specifically, meaning that both healthy and disease-causing immune cells are wiped out. This leaves patients susceptible to the infections B cells usually protect against.

Dr Thaventhiran will investigate the progression of B lymphocytes from a healthy to a disease-causing state in order to identify what distinguishes these two cell types. Improving understanding of the disease mechanisms underpinning lupus will help to identify new drug targets that specifically target pathogenic B lymphocytes present in lupus patients, whilst leaving healthy B cells unharmed.

Dr James Peters from Imperial College London will investigate the proteins and genes associated with lupus to better understand the mechanisms of the disease and identify the differences between patients with lupus. He will do this by using so-called ‘omic’ technologies, such as machine learning, capable of measuring thousands of different molecules in a single sample. By measuring proteins and gene expression (i.e. which genes are turned on or off) in white blood cells, the researchers will be able to examine how changes in the former are reflected in the latter – and vice versa.

Dr Peters and his team aim to locate novel therapeutic targets, better biomarkers of lupus and subgroups of patients that may respond to targeting of specific treatment pathways.

Dr Thomas McDonnell from UCL will study the structure and role of a protein (β2GPI) that is critical to the development and diagnosis of lupus and antiphospholipid syndrome (APS). APS is an autoimmune disorder that affects approximately 0.3-1 per cent of the population.

APS and other autoimmune disorders are caused when the body uses its systems of defence (i.e. its immunity) to target the body, rather than bacteria or viruses. Often, this reaction results in the production of 'autoantibodies', which are capable of harming the body, and their presence is commonly associated with the symptoms of an autoimmune disorder. This project will increase our understanding of what leads to the generation of APS antibodies, and how those antibodies alter the structure and therefore function of β2GPI. These insights could lead to improvements in how APS is screened, diagnosed and treated.

These new research projects are possible thanks to a donation from the late Marjorie Ellen Pintoff.