Researchers at Michigan Medicine have uncovered the molecular mechanism that drives the disease-causing effects of the most common genetic risk factor for lupus, a study suggests.

Systemic lupus erythematosus is a common, incurable autoimmune disease that affects millions of individuals worldwide, with a particularly high prevalence among women. A genetic variant, called HLA-DRB1*03:01, is the greatest risk factor for the condition, which involves inflammation in many vital organs, and can lead to severe disability and death.

In a study recently published in Communications biology (a Nature Portfolio journal), investigators found that a protein coded by that HLA variant triggers a cascade of molecular and cellular effects that can cause the inflammatory symptoms seen in lupus patients.

“For the first time, we have found the enigmatic mechanism that genetically predisposes people to the worst effects of the most typical form of lupus,” said Joseph Holoshitz, M.D., senior author of the paper and professor of internal medicine and rheumatology at University of Michigan Medical School. “The findings could potentially facilitate the discovery of safe, simple and effective treatments for SLE by targeting this new pathway.”

The results support a novel theory how genetic variants of the kind of HLA-DRB1*03:01 can lead to autoimmune diseases independent of antigen presentation, the traditionally studied mechanism, which has been long proposed but, so far, not directly proven.

“We have identified a chain of events in cell culture, as well as a mouse model of the disease, that demonstrate how the abnormalities that can cause lupus develop from the first effect of the risk gene, to signaling, all the way to immune abnormalities and clinical manifestations of lupus,” said Bruna Miglioranza Scavuzzi, Ph.D., first author of the paper and a postdoctoral research fellow in the Division of Rheumatology at the University of Michigan Medical School.

The findings of this study are reminiscent of previous findings in rheumatoid arthritis, another HLA-associated disease, that have paved the way for the development of small molecules to effectively treat arthritis in mice, Holoshitz says.

“Human trials in RA with those compounds are being carried out, and I hope that our novel findings will lead to similar efforts to ease the burden of millions of lupus patients as well.” he said.

A team of researchers at the University of Houston is reporting the success of their new method for the early diagnosis and monitoring of lupus nephritis – at home. If you’ve taken an at-home COVID-19 or pregnancy test, then you’ve taken what is scientifically called a lateral flow assay (LFA) test, a diagnostic tool widely used because of its rapid results, low cost and ease of operation. The team applied that same technology to assessing lupus nephritis, or inflammation of the kidneys, one of the most severe complications for patients with systemic lupus erythematosus (SLE, or lupus). 

The home test – with results read on a smartphone – is meant to eventually replace the gold standard for diagnosis of active lupus nephritis, an invasive kidney biopsy, with its attendant morbidity which cannot be serially repeated. The test assesses the levels of a protein-coding gene known as ALCAM.  

“Urinary ALCAM (uALCAM) has shown high diagnostic accuracy for renal pathology activity in active lupus nephritis,” reports Chandra Mohan, Hugh Roy and Lillie Cranz Cullen Endowed Professor of biomedical engineering, and one of the nation’s leading lupus researchers, in Frontiers in Immunology. “The LFA tests for both non-normalized and normalized uALCAM exhibited excellent accuracies in distinguishing active lupus nephritis from healthy controls.” 

This test had 86% accuracy in distinguishing active lupus nephritis from all other lupus patients.

Utilizing the ALCAM biomarkers discovered by Mohan, Richard Willson, Huffington-Woestemeyer Professor of chemical and biomolecular engineering and professor of biochemical and biophysical sciences, created the smartphone-based app and test kit based on the technology underlying home pregnancy tests. 

“Periodic monitoring of uALCAM using this easy-to-use LFA test by the patient at home could potentially accelerate early detection of renal involvement or disease flares in lupus patients, reducing morbidity and mortality,” said Willson.

According to the Centers for Disease Control and Prevention, about 204,295 Americans have systemic lupus erythematosus, an autoimmune disease leading to chronic inflammation in multiple organs, including the kidneys. Nephritis flares are hard to recognize because their symptoms often masquerade as something else. A sufferer might think they have a cold or the flu or are tired.

“A point-of-care testing platform’s importance rests on its potential to empower patients to monitor their health status conveniently, thus allowing for early diagnosis and monitoring of disease progression. The LFA represents the most widely used rapid diagnostic POC testing platform,” said Mohan.

“This may allow the proactive institution of therapeutics and even preventive strategies in LN, while minimizing treatment-related side effects,” said Mohan. 

Jeffrey Rathmell, PhD, (left), and Kelsey Voss, PhD, led a multidisciplinary team that identified iron metabolism in T cells as a potential target for treating lupus. CREDIT Vanderbilt University Medical Center

Targeting iron metabolism in immune system cells may offer a new approach for treating systemic lupus erythematosus (SLE) — the most common form of the chronic autoimmune lupus.

A multidisciplinary team of investigators at Vanderbilt University Medical Center has discovered that blocking an iron uptake receptor reduces disease pathology and promotes the activity of anti-inflammatory regulatory T cells in a mouse model of SLE. The findings were published Jan. 13 in the journal Science Immunology. 

Lupus, including SLE, occurs when the immune system attacks a person’s own healthy tissues, causing pain, inflammation and tissue damage. Lupus most commonly affects skin, joints, brain, lungs, kidneys and blood vessels. About 1.5 million Americans and 5 million people worldwide have a form of lupus, according to the Lupus Foundation of America. 

Treatments for lupus aim to control symptoms, reduce immune system attack of tissues, and protect organs from damage. Only one targeted biologic agent has been approved for treating SLE, belimumab in 2011. 

“It has been a real challenge to come up with new therapies for lupus,” said Jeffrey Rathmell, PhD, professor of Pathology, Microbiology and Immunology and Cornelius Vanderbilt Chair in Immunobiology. “The patient population and the disease are heterogeneous, which makes it difficult to design and conduct clinical trials.” 

Rathmell’s group has had a long-standing interest in lupus as part of a broader effort to understand mechanisms of autoimmunity. 

When postdoctoral fellow Kelsey Voss, PhD, began studying T cell metabolism in lupus, she noticed that iron appeared to be a “common denominator in many of the problems in T cells,” she said. She was also intrigued by the finding that T cells from patients with lupus have high iron levels, even though patients are often anemic. 

“It was not clear why the T cells were high in iron, or what that meant,” said Voss, first author of the Science Immunology paper. 

To explore T cell iron metabolism in lupus, Voss and Rathmell drew on the expertise of other investigators at VUMC: 

• Eric Skaar, PhD, and his team are experienced in the study of iron and other metals; 
• Amy Major, PhD, and her group provided a mouse model of SLE; and 
• Michelle Ormseth, MD, MSCI, and her team recruited patients with SLE to provide blood samples. 

First, Voss used a CRISPR genome editing screen to evaluate iron-handling genes in T cells. She identified the transferrin receptor, which imports iron into cells, as critical for inflammatory T cells and inhibitory for anti-inflammatory regulatory T cells. 

The researchers found that the transferrin receptor was more highly expressed on T cells from SLE-prone mice and T cells from patients with SLE, which caused the cells to accumulate too much iron. 

“We see a lot of complications coming from that — the mitochondria don’t function properly, and other signaling pathways are altered,” Voss said. 

An antibody that blocks the transferrin receptor reduced intracellular iron levels, inhibited inflammatory T cell activity, and enhanced regulatory T cell activity. Treatment of SLE-prone mice with the antibody reduced kidney and liver pathology and increased production of the anti-inflammatory factor, IL-10. 

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

In T cells from patients with lupus, expression of the transferrin receptor correlated with disease severity, and blocking the receptor in vitro enhanced production of IL-10. 

The researchers are interested in developing transferrin receptor antibodies that bind specifically to T cells, to avoid any potential off-target effects (the transferrin receptor mediates iron uptake in many cell types). They are also interested in studying the details of their unexpected discovery that blocking the transferrin receptor enhances regulatory T cell activity. 

Skaar is the Ernest W. Goodpasture Professor of Pathology and director of the Vanderbilt Institute for Infection, Immunology, and Inflammation. Major, associate professor of Medicine, and Ormseth, assistant professor of Medicine, are faculty members in the Division of Rheumatology and Immunology. Rathmell is the director of the Vanderbilt Center for Immunobiology. 

A new study has shown that restoring the balance of a protein in the blood may be a promising treatment option for systemic lupus erythematosus, or lupus, an incurable autoimmune disease.

The protein, CXCL5, helps to regulate the immune system through neutrophils, a type of white blood cell. In patients with lupus, the immune system that normally protects them against infections paradoxically attacks their healthy tissues and organs, inflaming them.

Researchers from the Singapore General Hospital (SGH) discovered that CXCL5 levels in the blood of patients with lupus were significantly lower than in healthy individuals, suggesting that the protein may be a reason for lupus activity. Similar results were found in mice models of lupus.

Additionally, the team found that weekly injections of CXCL5 to mice with severe lupus restored CXCL5 balance and improved survival from 25 per cent to over 70 per cent at 10 weeks. There was improved kidney function and reduced lupus activity compared to saline-treated mice. When CXCL5 was given together with cyclophosphamide (a conventional potent immunosuppressive treatment for lupus), CXCL5 seemed to prevent the toxic side effects of cyclophosphamide, enabling the mice to survive up to two years.

The study findings were published last month in one of the top peer-reviewed Rheumatology journals, Arthritis & Rheumatology, and highlighted as an important study in Nature Reviews Rheumatology in November 2022. A patent covering these results was filed by SingHealth, a public healthcare cluster of which SGH is a part of, and has now been granted in the USA and Singapore. 

“We are excited about the possibility of a new treatment option for lupus as 30 to 60 per cent of patients do not respond to conventional medications despite aggressive regimens. In the past 65 years, only three drugs for lupus have been approved by the United States Food and Drug Administration, but these drugs have modest efficacy. There is, therefore, a real and urgent need for better therapies, particularly for the more severe spectrum of lupus that we see in Asia,” said senior author Associate Professor Andrea Low, Head and Senior Consultant, Department of Rheumatology & Immunology, SGH.

“Our study has shown CXCL5 to be safe. There was no liver or kidney toxicity or cancer-inducing effects. Major components of the immune system were also not compromised. We hope to take our findings further to improve the care of patients with lupus,” said principal investigator Dr Fan Xiubo, Senior Research Fellow, Department of Clinical Translational Research, SGH.

Lupus can potentially be life-threatening as it affects major organs such as the kidneys, heart, lungs and brain. The prevalence of lupus is reported to be about 100 per 100,000 people worldwide. The condition is more severe in Asians, affecting more women than men, commonly between the ages of 15 and 45.

“It is gratifying to see that this research started over 8 years ago, has led to a discovery that has the potential to offer patients with lupus new treatment options in future,” said Professor William Hwang, Senior Consultant, Department of Haematology, SGH, who co-led the early phases of the study. Prof Hwang is also CEO of the National Cancer Centre Singapore.

“To be in the forefront of medicine means we have to constantly further our understanding of diseases and offer patients better treatment options through rigorous scientific research. I’m heartened that the team has shed new light on lupus and the possibility of a more efficacious therapy for patients some years down the road,” said Professor Fong Kok Yong, Deputy Group CEO (Medical and Clinical Services), SingHealth, and Senior Consultant, Department Rheumatology & Immunology, SGH

After sun exposure, people with systemic lupus erythematosus (SLE) frequently develop skin rashes, which often are accompanied by a flare of their overall disease. This connection between ultraviolet (UV) light and disease flares in lupus is well known, but the way in which UV exposure actually triggers the disease has been poorly understood.

In a new study being presented at ACR Convergence 2022, the annual meeting of the American College of Rheumatology, researchers from Hospital for Special Surgery (HSS) report that they have found an underlying mechanism that explains this association: decreased lymphatic drainage, which contributes to both photosensitivity and an immune response in the lymph nodes. The research also suggests that boosting lymphatic drainage may be an effective treatment for lupus photosensitivity and autoimmunity.

“When people with lupus have a systemic flare of their disease, it can affect any organ that is part of their disease,” says senior author Theresa T. Lu, MD, PhD, who holds the St. Giles Chair for Research in the HSS Research Institute, is a faculty member in Pediatric Rheumatology and in Rheumatology at HSS and is a professor of microbiology and immunology and of pediatrics at Weill Cornell Medicine. “We wanted to look at why sun exposure at the level of the skin affects internal organs like the kidneys, heart and lungs.”

“This study sheds some light on how sun exposure and UV light cause people with lupus to have more autoantibodies in their blood,” adds first author William Ambler, MD, a former fellow at HSS in Dr. Lu’s lab who is now Metzger Scholar in Translational Medicine at the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health.

The skin communicates with the immune system by sending cells and molecular signals via the lymphatic vessels to the lymph nodes, where immune responses begin. The signals that the skin sends to the lymph nodes control the type of immune responses that occur. Lymphatic vessels also serve the function of removing fluid and cells from the skin. If lymphatic vessels do not work properly to bring signals from skin to lymph nodes, there can be delayed resolution of skin inflammation, leading to faulty signals being sent to the lymph nodes.

Research in the Lu lab suggests that lymphatic flow from the skin to the draining lymph nodes is reduced in people with lupus. The investigators hypothesize that this decreased flow alters lymph node immune responses, making them more pathogenic. They decided to look more closely at this communication and how it impacts immune function. The current research employed both patient samples and mouse models of SLE.

The investigators studied skin biopsies from lupus patients as well as from healthy volunteers who served as controls. When they looked at the samples from the lupus patients, they found these more dilated lymphatic vessels compared with the healthy controls. This provided evidence that people with lupus have poor lymphatic flow.

They then studied mouse models of SLE, using a dye injected into the skin to visualize the flow of lymphatic fluid. They found that when lupus mice were exposed to UV radiation, more dye remained in the skin. This provided evidence that the lymphatics were not clearing the fluid as well as they should.

Importantly, the researchers then looked to see if they could improve certain hallmarks of disease in the mice by using manual lymphatic drainage techniques to manipulate the flow of lymph fluid. This type of therapy is used in people with certain types of cancer, especially breast cancer, to prevent lymphedema (fluid accumulation and swelling) after the surgical removal of lymph nodes. They found that performing lymphatic drainage in the mice reduced the numbers of plasmablasts and germinal center B cells, types of cells that are known to be important players in lupus.

Drs. Ambler and Lu are optimistic that manual lymphatic drainage may benefit lupus patients but emphasize that clinical trials in patients are needed to confirm it would be safe and effective.

The investigators note that this research is also important because it advances the broader field of understanding how skin and organs communicate through the lymph nodes and the immune system.