Researchers have identified a molecular mechanism by which a very small molecule of RNA, produced in the kidneys, triggers a severe autoimmune reaction, leading to a fatal inflammation of this organ.
Kidney PHOTO: Shutterstock
A recent study offers an explanation for how a seemingly minor genetic mutation can transform the immune system from protector to aggressor.
A team from the University Hospital and University of Bonn, in collaboration with Nanyang Technological University in Singapore and the University Hospital in Würzburg, discovered that a mutation in an immune system receptor called RIG-I triggers a severe autoimmune reaction in the kidneys, News writes.
The results were recently published in the journal Science Immunology.
RIG-I is an essential receptor of the innate immune system, responsible for detecting viral RNA and activating antiviral mechanisms. But certain mutations can make the receptor hypersensitive, mistakenly recognizing the body’s own RNA as a virus.
In animal experiments, mice with the RIG-I E373A mutation, previously identified in patients, spontaneously developed a severe form of lupus-like nephritis, characterized by lethal inflammation of the kidneys.
Unlike classical lupus, where inflammation is triggered by the accumulation of immune structures resulting from the interaction of antibodies with antigens, in this case the inflammation was directly caused by the abnormal activation of the mutant receptor in the kidney tissue.
Further analysis showed that a small regulatory but non-protein-coding RNA molecule called Y-RNA (Y-RNA), produced in large amounts in the kidney, binds directly to the mutant RIG-I receptor, aberrantly activating it.
“We found that Y-RNA acts as a false alarm for the mutated RIG-I receptor, especially in kidney cells. This local dysfunction of the immune system triggers severe inflammation, similar to the lupus nephritis seen in humans.” explained professor Hiroki Kato, director of the Institute of Cardiovascular Immunology at Bonn University Hospital, quoted in a press release.
Using advanced molecular and structural analyses, the researchers demonstrated that the E373A mutation causes an unusual interaction between RIG-I and Y-RNA, leading to activation of the receptor even in the absence of viral infection. This abnormal activation stimulates the kidney cells to produce large amounts of interferons and chemokines (signaling proteins), attracting immune cells and causing tissue inflammation.
The team also identified a possible therapeutic target by blocking the CCR2 signaling pathway, involved in the recruitment of monocytes (a type of white blood cell), which significantly reduced renal inflammation in affected mice.
RIG-I gene mutations are known for their role in rare autoimmune diseases, such as Singleton-Merten syndrome and systemic lupus erythematosus.
The new study provides a detailed understanding of how these mutations can selectively affect certain organs, such as the kidney, and opens perspectives for the development of targeted therapies that block abnormal activation of the mutant receptor or its interaction with Y-RNA molecules.
