Five advancements in lupus research over the past year

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Lupus research

A condition that affects around five million people worldwide, lupus has no proven cure. But various treatments for the disease have been around for more than a century, and lupus research has grown over the years.

The first kind of therapy for the autoimmune disease – which occurs due to an overactive immune system that attacks its own tissues – was the antimalarial quinine, introduced in the 1890s. By the twentieth century, the wave of corticosteroid therapy had taken over, and subsequently, it became an approach to relieving pain, swelling and rash-like symptoms of lupus.

Over the years, immunosuppressants became a popular method to treat lupus, where immune responses were suppressed, and inflammation was contained. Soon enough, biological agents – a new class of drugs for autoimmune disorders – widened treatment options. The first-ever biologic, developed in 2006, which targets the B cells, was rituximab. Since then, the drug has also been used to treat lymphomas – cancers that affect the lymphatic system.

The most common type of lupus, systemic lupus erythematosus (SLE) – which causes widespread inflammation and tissue damage – was specifically treated for the first time with the U.S. Food and Drug Administration (FDA)-approved drug Benlysta, in 2011. The mechanism of the drug is to suppress the B lymphocyte stimulator protein (BLyS), as people with SLE tend to have elevated levels of the protein. By inhibiting BLyS, it was observed that patients’ symptoms became more manageable. 

As various treatment measures aim to fight lupus, to commemorate Lupus Awareness Month in May, here are five advancements in lupus research over the past year.

New research finds that enzyme restoration could treat lupus

The expression of various enzymes has been studied in mapping how a disease manifests itself. In a recent study conducted by Trinity College Dublin in Ireland, scientists found that the enzyme fumarate hydratase – which is responsible for generating energy in cells during metabolism – might have links to autoimmune disorders like lupus.

The repression of the enzyme in macrophages – white blood cells that stimulate cells involved in immune function, and are an inflammatory cell type – was found in people with lupus, arthritis, sepsis and COVID-19. 

“We have made an important link between fumarate hydratase and immune proteins called cytokines that mediate inflammatory diseases. We found that when fumarate hydratase is repressed, RNA is released from mitochondria which can bind to key proteins ‘MDA5’ and ‘TLR7’ and trigger the release of cytokines, thereby worsening inflammation. This process could potentially be targeted therapeutically,” said Christian Peace, co-author of the study.

Restoring fumarate hydratase by possibly targeting proteins like MDA5 and TLR7 could be an anti-inflammatory approach to battling lupus and other conditions that affect the immune system.

Lupus research: the age of CAR-T therapy

Chimeric antigen receptor T-cell (CAR-T) therapy has been lauded as a new era in cancer immunotherapy. Now, researchers have found that it could even treat lupus.

The process behind CAR-T therapy begins when T cells from a patient are extracted and modified such that the cells’ receptors attach to the specific antigen – in the case of cancer, tumorous cells – to attack the antigens when infused back into the body. 

A study led by researchers at Friedrich Alexander University Erlangen-Nuremberg in Germany examined five patients who had been unresponsive to immunosuppressive treatment prior to the trial. After enrolling for the CAR-T therapy programme, all five patients were observed to be recovering from lupus and were able to withdraw from medication for around three to 17 months.

The therapy eliminated the B cells that aggravated the condition, and severe symptoms like arthritis, fatigue and lung inflammation were alleviated. Despite the recovery of B cells in four months, the participants of the trial remained disease-free.

Researchers have also noted that since the B cells that induce lupus are fewer in number as compared to other autoimmune diseases, a low dose of CAR-T therapy would result in limited side effects. A consequential side effect to CAR-T treatment is cytokine release syndrome (CRS) where cytokines – cell signaling proteins – are rapidly released by the CAR-T cells, which cause fever, nausea, headaches, rapid heartbeat and low blood pressure and sometimes, can be life-threatening. So a reduced dosage would help manage CRS.

Although a more large-scale study is required to determine how long the effect of CAR-T cell therapy for lupus will last, this is a breakthrough in autoimmune disorder research as it paves the way for possible alternatives to immunosuppressants to treat SLE.

Genetic link to lupus discovered

It has long been understood that lupus is not a hereditary disease. However, recent findings have suggested that genetics could drive the pathogenesis of lupus. 

The study led by The Francis Crick Institute in England unearthed the link between the TLR7 gene and lupus. A mutation on the TLR7 gene – found on the X chromosome – causes the TLR7 protein to promptly bind to guanosine, – a purine nucleoside – making it more active. This leads to healthy tissues being incorrectly recognized as foreign, and attacked, due to the increased sensitivity of immune cells.

“While it may only be a small number of people with lupus who have variants in TLR7 itself, we do know that many patients have signs of overactivity in the TLR7 pathway. By confirming a causal link between the gene mutation and the disease, we can start to search for more effective treatments,” said professor Nan Shen, co-director of China Australia Centre of Personalised Immunology (CACPI). 

As females have a pair of X chromosomes, unlike males who have just the one, the research also points to why females may be about 10 times more prone to lupus than males. 

The research, which was based on DNA sequencing that was carried out on a seven-year-old girl who was diagnosed with severe lupus, was further established when genetically engineered mice were examined. The mice, which were delivered the mutated gene via CRISPR gene editing, showed signs of the disease, proving TLR7’s role in the development of the disease.

The identification of the mutation as the cause of lupus, brings hope for targeted therapies that people with lupus could benefit from, according to Carmen de Lucas Collantes, a co-author of the study.

Link between iron buildup in T cells and lupus found

Despite 50% of people with lupus experiencing anemia, an iron deficiency does not indicate the manifestation of SLE. In fact, a recent study states the contrary.

The research by Vanderbilt University Medical Center in the U.S. uncovered that patients with lupus have higher levels of iron in their T cells. 

To recognize the mechanism behind this spike, a CRISPR genome editing screen was used to monitor the genes responsible for iron regulation in T cells. It was found that the transferrin receptor takes on the role of importing iron into T cells. In T cells from patients with SLE as well as in mice models of SLE, the expression of the transferrin receptor was high, meaning that iron molecules were more likely to get accumulated in the cells.

“It was really surprising and exciting to find different effects of the transferrin receptor in different types of T cells,” said Kelsey Voss, lead researcher of the study.

When mice were treated with an antibody that blocks the receptor, a decline in iron levels was observed in the T cells, following which there was a surge in IL-10 – an anti-inflammatory factor – in cells. Moreover, the effects of lupus in the kidney and liver had diminished.

 “If you’re trying to target an autoimmune disease by affecting T cell function, you want to inhibit inflammatory T cells but not harm regulatory T cells. That’s exactly what targeting the transferrin receptor did,” said Voss. 

With this discovery, new treatment approaches could be examined, especially because there is an unmet need where the patient population is heterogeneous, and the manner in which the disease presents itself varies from person to person.

Gaming could improve cognitive functioning for people with lupus

While symptoms of lupus include muscle and joint aches, kidney problems, rashes, hair loss, extreme fatigue, blood clotting, and so on, sometimes, lupus can also have an effect on cognitive functioning. For instance, around 70% of people with lupus experience what is called ‘lupus fog’ – causing an inability to think clearly and retain information – at some point during their life. To tackle this, a team of researchers at the National Jewish Health in the U.S. believe that playing video games could help.

The study, which was led by Elizabeth Kozora, a research and clinical neuropsychologist at National Jewish Health, segregated individuals into treatment and control groups, after patients had completed a written test to evaluate their psychomotor speed, flexibility and attention span. As part of the randomized trial, patients in the treatment group completed five sessions of a video game intervention, where participants gamed five times a week for four weeks. 

After the time was up, it was distinguished that those in the treatment group had developed visuomotor speed and had an improved attention span, when compared to the control group. Similar studies designed to evaluate hyperactivity disorder and depression, in the past, have had success alike, proving the effectiveness of this trial for lupus.

“We believe that SLE patients would benefit from participation in digital interventions designed to interact with the prefrontal networks of the brain,” said Kozora.

 New technologies related to lupus (powered by IN-PART)

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