Five advances in lupus research over the past year

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

The first type of therapy for autoimmune disease – which results from an overactive immune system attacking its own tissues – was the antimalarial quinine, which was introduced in the 1890s. In the 20th century, a wave of corticosteroid therapy took over, and later became an approach to relieve pain, swelling, and the rash-like symptoms of lupus.

Over the years, immunosuppressants have been a popular method of treating lupus, in which the immune response is suppressed, and inflammation is managed. Before long, biologic agents – a new class of drugs for autoimmune disorders – expanded treatment options. The first biologic developed in 2006, which targets B cells, is rituximab. Since then, the drug has also been used to treat lymphoma – a cancer that affects 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 US Food and Drug Administration (FDA)-approved drug Benlysta, in 2011. The mechanism of action of the drug is to suppress B lymphocyte stimulatory protein (BLyS), because SLE sufferers tend to have elevated protein levels. By inhibiting BLyS, it was observed that the patient’s symptoms became more manageable.

As various therapeutic measures aim to fight lupus, in honor of Lupus Awareness Month in May, here are five advances in lupus research over the past year.

New research finds that enzyme restoration can 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 – may have a link to autoimmune disorders such as lupus.

Repression of enzymes in macrophages – white blood cells that stimulate cells involved in immune function, and are a type of inflammatory cell – has been found in people with lupus, arthritis, sepsis and COVID-19.

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

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

Lupus research: age of CAR-T therapy

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

The process behind CAR-T therapy begins when T cells from a patient are extracted and modified in such a way that the cell’s receptors attach to specific antigens – in the case of cancer, tumor cells – to attack the antigen when it is reinfused into the body.

A study led by researchers at the Friedrich Alexander University Erlangen-Nuremberg in Germany examined five patients who were unresponsive to immunosuppressive treatment before the trial. After signing up for the CAR-T therapy program, all five patients were observed to recover from lupus and were able to go off treatment for about three to 17 months.

The therapy removes the B cells that aggravate the condition, and severe symptoms such as arthritis, fatigue and pneumonia are reduced. Despite recovery of B cells within four months, trial participants remained disease free.

The researchers also note that because the B cells that induce lupus are less numerous than other autoimmune diseases, low-dose CAR-T therapy will produce limited side effects. A consequential side effect to CAR-T treatment is cytokine release syndrome (CRS) in which cytokines – cell signaling proteins – are released rapidly by CAR-T cells, leading to fever, nausea, headache, fast heart rate and low blood pressure and sometimes -sometimes, can be life threatening. So reducing the dose will help manage CRS.

Although larger-scale studies are needed to determine how long the effects of CAR-T-cell therapy for lupus will last, they represent a breakthrough in autoimmune disorder research because they pave the way for possible immunosuppressant alternatives to treat SLE.

Genetic link with lupus found

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

A study led by The Francis Crick Institute in England found a link between the TLR7 gene and lupus. Mutations in the TLR7 gene – found on the X chromosome – cause the TLR7 protein to bind immediately to guanosine, – a purine nucleoside – making it more active. This causes healthy tissue to be mistaken for foreign, and attacked, due to the increased sensitivity of immune cells.

“While it may be that only a small number of people with lupus have the TLR7 variant itself, we know that many patients have signs of overactivity in the TLR7 pathway. By confirming a causal link between gene mutations and disease, we can start looking for more effective treatments,” said professor Nan Shen, deputy director of the China Australia Center of Personalized Immunology (CACPI).

Because women have one pair of X chromosomes, as opposed to men who only have one, research has also shown why women may be 10 times more susceptible to lupus than men.

The research, which is based on DNA sequencing performed on a seven-year-old girl diagnosed with severe lupus, was further established when genetically engineered mice were examined. Mice that were transmitted the mutated gene through editing the CRISPR gene, showed signs of the disease, proving the role of TLR7 in disease development.

The identification of the mutation as a cause of lupus holds promise for targeted therapies that can be utilized by people with lupus, according to Carmen de Lucas Collantes, a co-author of the study.

A link between iron accumulation in T cells and lupus has been found

Although 50% of people with lupus are anemic, iron deficiency is not a manifestation of SLE. In fact, a recent study states otherwise.

Research by Vanderbilt University Medical Center in the US found that lupus patients had higher levels of iron in their T cells.

To identify the mechanisms behind this spike, the CRISPR genome editing screen was used to monitor genes responsible for iron regulation in T cells. It was found that transferrin receptors play a role in importing iron into T cells in T cells from patients with SLE as well as in models In SLE mice, transferrin receptor expression is high, which means that iron molecules are more likely to accumulate in cells.

“It was surprising and exciting to find different effects of transferrin receptors in different types of T cells,” said Kelsey Voss, principal investigator of the study.

When the mice were treated with a receptor-blocking antibody, a decrease in iron levels was observed in the T cells, after which a spike in IL-10 – an anti-inflammatory factor – occurred in the cells. Moreover, the effect of lupus on the kidneys and liver has been reduced.

“If you are trying to target an autoimmune disease by affecting T cell function, you want to inhibit inflamed T cells but not destroy regulatory T cells. That’s what targeting transferrin receptors does,” says Voss.

With these findings, new treatment approaches can be examined, especially as there are unmet needs where patient populations are heterogeneous, and the mode of presentation of the disease itself varies from person to person.

Playing games can improve cognitive function for people with lupus

While lupus symptoms include muscle and joint pain, kidney problems, rashes, hair loss, extreme tiredness, blood clots, and so on, sometimes lupus can also affect cognitive function. For example, about 70% of people with lupus experience what is called ‘lupus fog’ – causing an inability to think clearly and retain information – at some point in their life. To overcome this, a research team at National Jewish Health in the US believes that playing video games can help.

That Study, led by Elizabeth Kozora, a researcher and clinical neuropsychologist at National Jewish Health, separated individuals into treatment and control groups, after patients completed written tests to evaluate their psychomotor speed, flexibility, and attention span. As part of a randomized trial, patients in the treatment group completed five video game intervention sessions, in which participants played five times a week for four weeks.

After the time was up, it was found that the treatment group had developed visuomotor speed and had a better attention span, when compared to the control group. Similar studies designed to evaluate hyperactivity disorder and depression have, in the past, had similar success, proving the effectiveness of these trials for lupus.

“We believe that SLE patients will benefit from participating in digital interventions designed to interact with the prefrontal brain network,” said Kozora.

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

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