Autoimmune diseases; when the body loses control of dormant viral DNA

A significant portion of human DNA is of viral origin. Under certain conditions, these post-viral genetic elements become overactive, which can lead to autoimmune diseases. This is the conclusion of the latest research by an international team of scientists, including Polish scientist Magdalena Madej.

"This discovery helps us better understand why, in some people, the immune system begins to attack its own body. I hope that in the future, these results may facilitate diagnosis and open the way to research on RNA therapies for autoimmune diseases," Magdalena Madej, a PhD student at Lund University and the first author of the Cell Reports paper, told PAP.

Viruses require host cells to replicate. They must integrate their genes into the DNA of, for example, a bacterium, animal, plant, or fungus. These genes are then replicated by the host's cellular machinery. Sometimes, these foreign DNA fragments become permanently embedded in the genome and passed down from generation to generation.

Today, it is known that over 40% of human DNA consists of so-called mobile genetic elements, including endogenous retroviruses and retrotransposons, many of which are of viral origin. These are remnants of ancient infections from millions of years ago, which have become embedded in our genome and inherited. Some of these genetic elements have been "assimilated" by the body and perform useful functions, others are neutral, and some can be harmful—for example, by damaging active genes or provoking an immune response.

New research from Cell Reports confirms that the body has its own ways of regulating the activation of these viral fragments. If something goes wrong with this mechanism, certain autoimmune diseases can develop.

And so the researchers described the action of the PUS10 enzyme, which acts a bit like a guard that maintains order among genes of viral origin.

- When this enzyme is missing, old post-viral sequences begin to be activated, and the immune system interprets it as an external attack - said the doctoral student.

PUS enzymes, long known, regulate numerous cellular processes, such as protein production and alternative RNA splicing. In the case of PUS10, the subject of the new study, a key regulatory function independent of its enzymatic activity proved to be crucial.

Researchers have shown that abnormal functioning of the PUS10 enzyme is associated with the occurrence of lupus (an autoimmune disease, one of the symptoms of which is a butterfly-shaped rash on the face) and non-specific colitis (e.g. Crohn's disease).

"To better investigate the role of PUS10 in IBD in vivo, we compared the susceptibility to colitis (induced by a certain compound – DSS) in wild-type and PUS10-deficient mice. The results showed that the lack of PUS10 led to increased inflammation, while in wild-type mice such symptoms were minimal," the researcher describes.

As he points out, this indicates that PUS10 plays a significant role in regulating the inflammatory response in the intestine. Chronic inflammation of the colon, such as in inflammatory bowel disease, is a known risk factor for the development of colon cancer, underscoring the importance of understanding the role of PUS10 in controlling inflammatory processes.

Researchers also investigated which genes are dysregulated when PUS10 is not functioning properly in the body. They found that this genetic signature is similar in people with lupus. Therefore, this enzyme may contribute to the development of the disease.

- The role of the PUS10 enzyme that we have described can be compared to that of a guard that protects cells so that viral echoes from the past do not raise unnecessary alarms - describes Dr. Madej.

Although the genetic sequences of viral origin are "ours" because they are encoded in DNA, their uncontrolled activity resembles a viral infection to the body. The immune system, failing to recognize the situation, begins to attack its own cells—leading to autoimmunity. This mechanism is already known from previous scientific publications. Now, research has revealed another molecular mechanism related to the activation of post-viral sequences, and has also shown how this can lead to autoimmunity in the body's cells.

Ludwik Tomal (PAP)

Science in Poland

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