Immunofluorescent images of kidney tissue show inflammation in green. The kidney tissue shown on the right was treated with an NKp46 receptor-blocking antibody, resulting in significantly reduced inflammation. Credit Charité

A team led by Charité – Universitätsmedizin Berlin, the German Rheumatology Research Center, and the Max Delbrück Center has identified key cells responsible for severe kidney damage in lupus. The research, which was published in “Nature,” can provide valuable insights for future antibody therapies.

A research team in Berlin has discovered key regulators of severe kidney damage in patients with lupus, an autoimmune disorder that affects an estimated five million people worldwide, most of whom are young women. They found that a small, specialized population of immune cells known as innate lymphoid cells (ILCs) triggers a cascade of effects that lead to harmful kidney inflammation, also known as lupus nephritis.

The research published this week in “Nature” challenges the traditional belief that autoantibodies, which are proteins produced by immune cells and mistakenly attack healthy tissues, are the primary cause of lupus nephritis.

“Autoantibodies alone are not enough to cause tissue damage. Our research shows that ILCs (innate lymphoid cells) play a crucial role in amplifying the damage to organs,” explained Dr. Masatoshi Kanda, a senior author of the study. Dr. Kanda was a Humboldt Fellow at Max Delbrück Center and is currently based at the Department of Rheumatology and Clinical Immunology at Sapporo Medical University in Japan.

Lupus, also known as systemic lupus erythematosus, is typically diagnosed between the ages of 15 and 45. The symptoms can vary in severity from mild to severe. However, the reason behind kidney damage in certain patients, to the extent of needing dialysis, has remained unclear.

“We have now identified most of the circuit controlled by ILCs in lupus nephritis by examining the entire kidney at single-cell resolution,” says Professor Antigoni Triantafyllopoulou of the German Rheumatology Research Center.

Unusual immune cells

ILCs are a small group of immune cells that live in a specific tissue or organ, unlike most other immune cells that circulate throughout the body.  

“They are present in the tissues all the time, starting from the embryonic development stage, which sets them apart from other immune cells,” stated Professor Andreas Diefenbach, a senior author of the paper and the director of the Institute of Microbiology, Infectious Diseases, and Immunology at Charité – Universitätsmedizin Berlin.

Diefenbach’s laboratory was one of the first to discover ILCs in the mid-2000s. Most of his research is focused on ILCs in the gut and their effects on tissue function. In this study, Triantafyllopoulou and Kanda collaborated with Diefenbach’s group and Dr. Mir-Farzin Mashreghi at the DRFZ to investigate the presence of ILCs in the kidney and their potential role in lupus nephritis.

The whole single-cell picture

To unravel this mystery, the team utilized single-cell RNA sequencing, which identifies active genes in individual cells, helping researchers understand the cells’ identity and function.

Kanda, a rheumatologist who was studying bioinformatics in Professor Norbert Hübner’s lab at the Max Delbrück Center at the time, developed a specialized protocol for single-cell RNA sequencing of mouse and human kidneys. “Masatoshi’s protocol was very good at pulling out and preserving multiple types of kidney cells, which gave us a much more complete overview of how lupus affects the whole kidney,” explains Triantafyllopoulou. The team sequenced nearly 100,000 individual kidney and immune cells of various types and functions.

The key receptor

The research team found that a specific group of ILCs, which have a receptor called NKp46, play a key role in causing lupus nephritis in mice. When NKp46 is activated, these cells increase their production of a protein called GM-CSF, which in turn stimulates invading macrophages to multiply. Macrophages are large immune cells that consume dying cells and microbes. In the kidney, the influx of macrophages leads to severe tissue damage and the accumulation of scar tissue, known as fibrosis.

“These ILCs are really amplifiers in this system,” Diefenbach says. “They are small in population, but they seem to fertilize the whole process.”

When the team blocked NKp46 with antibodies or genetically removed the receptor, kidney tissue damage was minimal. They also blocked GM-CSF, which had similar anti-inflammatory effects. 

“Critically, autoantibody levels did not change when NKp46 was inhibited, but kidney tissue damage was reduced, which shows autoantibodies are not directly responsible for kidney inflammation,” Triantafyllopoulou explains.

The research team also compared the results to sequencing data from tissue taken from human patients with lupus. They found that ILCs were present, but they stated that more work is needed to fully understand how to target ILCs in human kidneys. However, the detailed studies provided new insights that suggest potential antibody therapies for patients with severe forms of lupus. The ultimate goal is to prevent the need for kidney dialysis in these patients.

· Lupus, an autoimmune disease, affects over 1.5 million people in the U.S.

“Until now, the causes of this disease have remained unclear.”

· Scientists are working to expand research into novel treatments.

Scientists from Northwestern Medicine and Brigham and Women’s Hospital have identified a molecular defect that triggers the pathologic immune response in systemic lupus erythematosus (lupus) and suggest that correcting this defect may reverse the disease.

Lupus affects more than 1.5 million people in the U.S. Until this new study, the causes of this disease were unclear. Lupus can result in life-threatening damage to multiple organs, including the kidneys, brain and heart. Existing treatments often fail to control the disease, the study authors said, and have unintended side effects of reducing the immune system’s ability to fight infections.

“Up until now, all therapy for lupus has been like using a blunt instrument. It involves broad immunosuppression,” said co-corresponding author Dr. Jaehyuk Choi, who is an associate professor of dermatology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine dermatologist. “By identifying the cause of this disease, we have discovered a potential cure that will not have the side effects of current therapies.”

“We have discovered a fundamental imbalance in the immune responses of lupus patients and have identified specific mediators that can correct this imbalance and reduce the pathological autoimmune response,” said co-corresponding author Dr. Deepak Rao, an assistant professor of medicine at Harvard Medical School, a rheumatologist at Brigham and Women’s Hospital, and co-director of its Center for Cellular Profiling.

In a study set to be published in Nature on July 10, scientists are reporting a new pathway that contributes to disease in lupus. They have found that there are changes in multiple molecules in the blood of lupus patients that are linked to the disease. These changes lead to inadequate activation of a pathway regulated by the aryl hydrocarbon receptor (AHR), which controls how cells respond to environmental pollutants, bacteria, or metabolites. Inadequate activation of AHR leads to an excess of disease-promoting immune cells known as T peripheral helper cells, which in turn promote the production of disease-causing autoantibodies.

The researchers demonstrated that the aryl hydrocarbon receptor-activating molecules could be used in treatments by applying them to blood samples from lupus patients. This appeared to transform the cells responsible for causing lupus into a cell known as a Th22 cell, which may help in healing the damage caused by this autoimmune disease.

“We found that by either activating the AHR pathway with small molecule activators or reducing the pathologically excessive interferon in the blood, we can decrease the number of these disease-causing cells,” said Choi, who is also the Jack W. Graffin Professor at Feinberg. “If these effects are long-lasting, this could potentially lead to a cure.”

cSLE is a rare multisystem disorder with significant associated morbidity, but evidence-based guidelines are sparse, and as such, management is often based on clinical expertise. The EULAR/ACR-2019 criteria have shown sensitivity in cSLE patients, which could allow earlier recognition of patients with single or major organ involvement. However, identifying specific predictors in this vulnerable group is vital for preventing long-lasting damage.

The new work, presented at the 2024 EULAR congress, aimed to determine how clinical, demographic, and treatment variables correlate with damage accrual in cSLE. Maria Hanif and colleagues hoped that stratifying patients according to average disease activity levels over the disease course would help them identify independent predictors of damage—even in children with low disease activity.

To achieve this, data were collected from 430 children participating in the UK JSLE Cohort Study. Analyses were performed across the entire cohort and in two subgroups based on disease activity: low activity and moderate-to-high activity.

Over a median follow-up period of 46 months, 23% of children experienced organ damage. Within the entire cohort, multivariable analyses showed three factors associated with damage accrual: methylprednisolone exposure, time-adjusted mean Physician’s Global Assessment (PGA) score, and Adjusted Mean SLE Disease Activity Index (AMS) score. When looking only at the moderate-to-high disease activity subgroup, 28.1% experienced damage – but the same three factors were identified as predictors. Within the low disease activity subgroup, 20.5% of children accrued new damage, and again methylprednisolone exposure and time-adjusted mean PGA score were associated with damage accrual, but not AMS score.

This study underscores the role of corticosteroid exposure as a significant and potentially modifiable risk factor in cSLE, and suggests there is a need to review paediatric dosage limits – which typically exceed adult recommendations.4 Additionally, a direct link was found between disease activity and damage, with every 1-unit increase in SLE Disease Activity Index (SLEDAI) raising the risk of damage by 13–15% in those with moderate-to-high activity. This was not observed in patients with an AMS of 4 or less, suggesting that low disease activity – maintained via treat-to-target strategies – could substantially reduce damage risk. These findings highlight the need for updated treatment protocols limiting corticosteroid use while effectively managing disease activity.