A research team has identified important cells linked to severe kidney damage in lupus, potentially paving the way for future antibody treatments.
A team from Berlin has discovered key regulators linked to significant kidney damage in lupus patients, a chronic autoimmune disease that affects around five million people globally, predominantly young women. A specific type of immune cell known as innate lymphoid cells (ILCs) plays a crucial role in initiating a series of reactions that lead to harmful kidney inflammation, referred to as lupus nephritis.
The findings, published in Nature, challenge the longstanding belief that autoantibodies—proteins created by immune cells that mistakenly attack the body’s own tissues—are the main cause of lupus nephritis.
“While autoantibodies contribute to tissue damage, they are not the sole cause. Our research shows that ILCs significantly enhance the damage to organs,” explains Dr. Masatoshi Kanda, a senior author of the study who previously worked at the Max Delbrück Center and is currently at the Department of Rheumatology and Clinical Immunology, Sapporo Medical University in Japan.
Lupus, or systemic lupus erythematosus, is commonly diagnosed in individuals between 15 and 45 years old. Its symptoms can vary widely from mild to severe. However, the underlying factors contributing to kidney damage in certain patients—some even requiring dialysis—remained unclear.
“The role of ILCs in lupus or lupus nephritis was previously unknown,” states Professor Antigoni Triantafyllopoulou, a senior author at the German Rheumatology Research Center (DRFZ). “We’ve now mapped the majority of the pathways controlled by ILCs by examining the entire kidney at a single-cell level.”
Unique immune cells
ILCs are a small but distinct group of immune cells that, unlike most immune cells that move throughout the body, reside permanently in specific tissues or organs.
“These cells are present in tissues from the embryonic stage and remain there, making them fundamentally different from other immune cells,” remarks Professor Andreas Diefenbach, a senior author and director at the Institute of Microbiology, Infectious Diseases and Immunology at Charité – Universitätsmedizin Berlin.
Diefenbach’s lab was instrumental in the identification of ILCs in the mid-2000s, focusing predominantly on their role in the gut. For this study, Triantafyllopoulou and Kanda collaborated with his team and Dr. Mir-Farzin Mashreghi at the DRFZ to investigate the presence and role of ILCs in the kidneys concerning lupus nephritis.
The entire single-cell landscape
To explore this issue further, the team utilized single-cell RNA sequencing to identify active genes in individual cells, aiding in the understanding of each cell’s role and function.
Kanda, while studying bioinformatics in Professor Norbert Hübner’s lab at the Max Delbrück Center, developed a specific protocol for performing single-cell RNA sequencing on mouse and human kidneys. “Masatoshi’s method effectively preserved various kidney cell types, enabling us to gain a comprehensive view of how lupus impacts the kidneys,” explains Triantafyllopoulou. The team conducted sequencing on nearly 100,000 individual kidney and immune cells of diverse types.
The crucial receptor
Through murine experiments, the researchers discovered that a subgroup of ILCs equipped with a receptor named NKp46 must be present and activated for lupus nephritis to occur. When NKp46 is activated, this ILC subgroup increases the production of GM-CSF, a protein that promotes the proliferation of macrophages, large immune cells that engulf dying cells and pathogens. In the kidneys, the influx of macrophages leads to significant tissue damage and the formation of scar tissue, known as fibrosis.
“These ILCs act as amplifiers in this process,” Diefenbach remarks. “Although they are few in number, they significantly enhance the entire mechanism.”
When the team inhibited NKp46 with antibodies or genetically eliminated the receptor, they observed minimal tissue damage in the kidneys. Similar protective effects were seen when GM-CSF was blocked.
“Importantly, the levels of autoantibodies did not change when NKp46 was inhibited, yet kidney tissue damage was reduced, indicating that autoantibodies are not the direct cause of kidney inflammation,” Triantafyllopoulou clarifies.
Furthermore, the team compared their results with sequencing data from kidney tissues obtained from lupus patients, confirming the presence of ILCs. However, more research is needed to develop ways to target ILCs in human kidneys effectively. Nevertheless, the insights from these detailed investigations suggest promising new antibody therapies for patients suffering from severe lupus, with the goal of preventing the necessity for dialysis.
