Surprising trigger for kidney damage in lupus

Berlin, 14 August 2024

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Researchers at Charité – Universitätsmedizin Berlin, the German Rheumatism Research Centre (DRFZ) and the Max Delbrück Center have now discovered which cells are responsible for kidney damage in lupus patients. The study, published in Nature*, could pave the way for future antibody therapies against the autoimmune disease.

Around five million people worldwide, mostly young women, are affected by the autoimmune disease lupus erythematosus (lupus for short), which can lead to severe kidney damage. A Berlin research team has now uncovered the mechanism responsible for the kidney damage: a small, specialised group of immune cells – the so-called innate lymphoid cells (ILC) – triggers an avalanche of effects that lead to kidney inflammation. This is also known as lupus nephritis.

The research findings call into question the conventional view that lupus nephritis is solely due to autoantibodies attacking healthy tissue. ‘Although autoantibodies are a prerequisite for tissue damage, they are not sufficient on their own. Our work shows that ILC are responsible for enhancing organ damage,’ says Dr Masatoshi Kanda, one of the three lead authors of the study. He worked as a Humboldt Fellow at the Max Delbrück Centre and now works in the Department of Rheumatology and Clinical Immunology at Sapporo Medical University in Japan.

Lupus mainly affects women between the ages of 15 and 45. The symptoms vary in severity. What causes only some patients to develop kidney damage – some so severe that they require dialysis – was previously unclear. ‘We have now identified most of the circuits controlled by the ILCs by looking at the entire kidney cell by cell,’ says Prof Antigoni Triantafyllopoulou, head of the study from Charité’s Department of Medicine with a focus on rheumatology and clinical immunology. She also heads a liaison working group at the DRFZ, a Leibniz Institute.

Unusual immune cells

ILCs are a small group of immune cells that live in a specific tissue or organ. ‘They are constantly present in the tissue from embryonic development onwards. This distinguishes them from most other immune cells that circulate throughout the body,’ says Prof Andreas Diefenbach, third leader of the study and Director of the Institute of Microbiology and Infection Immunology at Charité.

His laboratory was one of the discoverers of ILC in the mid-2000s. Most of his research focusses on ILC in the gut and how they alter tissue function there. For the current study, Antigoni Triantafyllopoulou and Masatoshi Kanda have teamed up with his group and Dr Mir-Farzin Mashreghi’s team at the DRFZ to find out whether ILCs are present in the kidney and what role they play in lupus nephritis.

The overall picture of a cell

To unravel this mystery, the team used single-cell RNA sequencing. This provides information about the activity of individual cells by identifying which genes are switched on or off. Not only certain types of immune cells were analysed, but the entire kidney. In total, the team sequenced almost 100,000 individual kidney and immune cells of different types and functions for the project.

When the team blocked the cells with the NKp46 receptor with antibodies or genetically removed the receptor, the damage to the kidney tissue was minimal. A similar anti-inflammatory effect was seen when the GM-CSF proteins were blocked. ‘Crucially, the amount of autoantibodies did not change when NKp46 was deactivated, but the damage to the kidney tissue was still less,’ emphasises Antigoni Triantafyllopoulou. ‘This shows that the autoantibodies alone do not trigger the kidney inflammation.’ As the antibodies used are not yet approved for use in humans, much of the work was carried out on mouse models. The team compared the results with sequencing data from lupus patients and found that ILCs with a similar gene activity pattern are also present there.

Further work is needed to understand how exactly ILC can be therapeutically inhibited in human kidneys. However, the research team is convinced that the knowledge gained will pave the way for the development of new antibody therapies for patients with severe forms of lupus – in the hope that such new treatment options will help to spare them kidney dialysis.

*Biniaris-Georgallis SI, Aschman T, Stergioula K et al. Amplification of autoimmune organ damage by NKp46-activated ILC1. Nature 2024 Aug 13. doi: 10.1038/s41586-024-07907-x

Image: Kidney tissue (lupus mouse model) with signs of incipient fibrosis (green). If the NKp46 receptor of the ILC cells is blocked, the lupus nephritis recedes. Blue: cell nuclei. Charité | Frauke Schreiber