Researchers find possible cause of self-destructive attacks on the immune system in autoimmune diseases

Autoimmune diseases, in which the body’s immune system attacks healthy tissue, can be life threatening and affect all organs. A research team from the Technical University of Munich (TUM) has now found a possible cause for these self-destructive attacks of the immune system: an overactive RANK protein on the surface of B cells. The research opens the door to new therapeutic possibilities.

The immune system can be a mixed blessing: it is generally very effective in protecting the human body against bacteria, viruses and yeast infections and even cancer. But these defense cells can also turn against the body’s own tissues and trigger autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, a disease involving chronic dermatitis and inflammation of the joints. nervous system and internal organs or even become cancer cells themselves. and develop into leukemia or lymphoma. But what causes these destructive attacks of the immune system?

“The issue has not yet been definitively resolved,” says Professor Juergen Ruland, director of the TUM Institute of Clinical Chemistry and Pathobiochemistry. “B cells, a subgroup of white blood cells produced in the bone marrow, play a central role in regulating immune responses. During a normal immune response, activated B cells produce antibodies that attack foreign substances “Defective activation can lead to the formation of antibodies which attack the body itself, triggering an autoimmune disease. B cell activity is controlled by a variety of signals, some of which are still unknown,” Ruland observes. The immunologist and doctor is also the winner of the Leibniz Prize of the German Research Foundation (DFG) 2021, the most important German research prize.

Ruland and his team succeeded in identifying a decisive signal that influences the activity of B cells: “The objective of our research was to characterize the possible pathological roles of a protein located on the surface of B cells. This receptor, the NF -κB activating receptor, or RANK, shows increased activity in patients with systemic lupus erythematosus and some B-cell lymphomas. We wanted to know whether overactive RANK receptors actually trigger these diseases. “

Chronic signals lead to chronic disease

RANK receptors work like switches in the cell: they generate a signal in the cell when activated by signal molecules. Such a signal molecule is called RANKL, for Receptor Activator of NF-βB Ligand.

Working in the lab to determine the effects of overactive RANK receptors, the team compared healthy mice and genetically engineered animals with altered RANK receptors. After just a few weeks, a large part of the mice with genetically modified receptors contracted systemic lupus erythematosus, while the animals in the control group remained healthy, proving that this autoimmune disease can be triggered by faulty regulation of blood cells. RANK signals.

And that was not all: after about a year, the transgenic mice that survived systemic lupus erythematosus contracted chronic lymphatic leukemia, or CLL. “This result surprised us, because it shows that the activated RANK proteins are also responsible for the degeneration of B cells into cancer of the nodes of the lymphatic system”, says Maike Buchner, LLC specialist and young scientist at the Institute of Clinical . Chemistry and pathobiochemistry at the university hospital TUM Klinikum rechts der Isar.

Interrupt the self-destruct cycle

These new findings will help treat autoimmune diseases and lymphatic leukemia in the future: Therapeutic antibodies that block the interaction of RANK receptors and RANKL ligands were originally developed and used to treat osteoporosis: here, l The goal is to counter the deterioration of bone tissue, which is also triggered by overactive RANK receptors. Scientists have used these blocking antibodies to successfully treat mice with chronic lymphatic leukemia. “Future clinical studies will need to determine whether this therapy is also suitable for humans,” says Ruland.