Researchers Discover Possible Causes of Self-Destructive Immune System Attacks in Autoimmune Diseases

Autoimmune diseases in which the body’s own immune system attacks healthy tissues can be life-threatening and can affect all organs. Researchers at the Technische Universität München (TUM) have discovered a possible cause of these self-destructive immune system attacks: the highly active RANK protein on the surface of B cells. This study opens the door to new therapeutic possibilities.

The immune system can be a mixed blessing: it is usually very effective in protecting the human body from bacteria, viruses, mycoses, and even cancer. However, these defense cells also oppose the body’s own tissues, causing autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, chronic dermatitis and diseases associated with inflammation of the joints, nervous system and internal organs, and to cancer cells. It can even be. It develops into leukemia and lymphoma. But what are the causes of these destructive immune system attacks?

“This problem has not yet been finally resolved,” said Professor Juergen Ruland, director of the TUM Institute for Clinical Chemistry and Pathology Biochemistry. “B cells, a subgroup of white blood cells produced in the bone marrow, play a central role in the regulation of the immune response. During a normal immune response, activated B cells produce antibodies that attack foreign substances. Produces. Defects in activation can lead to the formation of antibodies. Attacks the body itself and causes autoimmune disorders. B cell activity is controlled by various signals, some of which It’s not yet understood, “says Ruland. Immunologists and physicians are also recipients of the most important German Research Award, the 2021 German Research Foundation (DFG) Leibniz Prize.

Ruland and his team have succeeded in identifying one definitive signal that affects B cell activity. “The purpose of our study was to characterize the possible pathological role of proteins on the surface of B cells. This receptor, the NF receptor activator-κB (RANK), is systemic. It shows increased activity in patients with erythema erythema and some B-cell lymphomas. I wanted to find out if the hyperactive RANK receptors actually cause these diseases. “

Chronic signals lead to chronic illness

RANK receptors act like switches in cells. When activated by a signal molecule, it produces a signal inside the cell. One such signaling molecule is called RANKL, a receptor activator of the NF-βB ligand.

The team compared healthy mice and genetically modified animals with the modified RANK receptor to investigate the effects of overactive RANK receptors in the laboratory. Only a few weeks later, the majority of mice with recombinant receptors contracted systemic lupus erythematosus, but animals in the control group remained healthy and this autoimmune disease could be caused by dysregulation of the RANK signal. Proved that there is.

And that wasn’t the only thing. Approximately one year later, transgenic mice that survived systemic lupus erythematosus developed chronic lymphocytic leukemia or CLL. “This result was surprising to us because it shows that the activated RANK protein is also involved in the degeneration of B cells into cancer of the lymphoid lymph nodes,” said a CLL specialist. Maike Buchner, a young scientist who is the junior group leader of the clinical laboratory, said. Chemistry and pathological biochemistry of university hospital TUM Klinikum rechts der Isar.

Break the cycle of self-destruction

These new discoveries will help in the treatment of future autoimmune diseases and lymphocytic leukemia. Therapeutic antibodies that block the interaction of RANK receptors and RANKL ligands were originally developed and used in the treatment of osteoporosis. The purpose here is to combat the deterioration of bone tissue. It is also caused by hyperactive RANK receptors. Scientists have used these blocking antibodies to successfully treat mice suffering from chronic lymphocytic leukemia. “Future clinical studies need to determine if this treatment is also suitable for humans,” Ruland points out.