What Causes False Alarms in Autoimmune Disease?

The innate immune system fights infectious agents. The alarm messenger interferon plays a central role in this. However, if it is formed uncontrollably without infection, it can lead to an autoimmune disease. Using the example of Aicardi-Goutières syndrome, a rare autoimmune disease, researchers at the University Hospital Bonn ( UKB ) and the Technical University (TU) Dresden have examined the underlying mechanism and decoded the driving force behind the uncontrolled production of interferon. The study has now been published in the journal "Journal of Experimental Medicine (JEM)".

If our innate immune system recognizes viral genetic information using sensors, the alarm messenger type I interferon is formed. It is a very strong activator of immune cells, therefore essential in the defense against many pathogens, not just viruses. However, if interferon is produced too much or for too long, the overactivated immune system attacks healthy cells - collateral damage to the actually good immune response. In addition, the viral genetic information for the sensors looks mostly like our own genetic material DNA and RNA. However, in order to prevent false recognition of one's own genetic material, there are safety mechanisms in every cell. If these fail, interferon production occurs without virus infection. This sterile infection can activate the innate immune system. The consequences are, for example, collagen diseases such as systemic lupus erythematosus (SLE). “Diseases like lupus are difficult to study because many genes are involved. But the mechanism of interferon production as a result of the recognition of the cell's own nucleic acids also occurs in rare monogenetic autoimmune diseases and can be assigned precisely to a genetic defect," says Prof. Dr. Rayk Behrendt, research group leader at the Institute for Clinical Chemistry and Clinical Pharmacology But the mechanism of interferon production as a result of the recognition of the cell's own nucleic acids also occurs in rare monogenetic autoimmune diseases and can be assigned precisely to a genetic defect," says Prof. Dr. Rayk Behrendt, research group leader at the Institute for Clinical Chemistry and Clinical Pharmacology But the mechanism of interferon production as a result of the recognition of the cell's own nucleic acids also occurs in rare monogenetic autoimmune diseases and can be assigned precisely to a genetic defect," says Prof. Dr. Rayk Behrendt, research group leader at the Institute for Clinical Chemistry and Clinical PharmacologyUKB .

Recognition of DNA and RNA in cells is coupled

The research team from the medical faculties of the University of Bonn and the TU Dresden took advantage of this and took a closer look at the Aicardi-Goutières syndrome in the mouse model. This interferon-driven monogenic autoimmune disease is caused by inactivating mutations in genes that degrade the cell's own nucleic acids and thus prevent sensors of the innate immune system from being activated. One of these genes is called SAMHD1, it regulates the replication and repair of DNA in the cell nucleus. As a result, it was previously assumed that the DNA drives the disease in those affected. "But we have now shown that, contrary to previous expectations, the recognition of the cell's own RNA is the driving force behind the uncontrolled production of interferon," says Prof. Behrendt. "Here it looks like as if primarily RNAs from viruses encoded in our genome play a role. These sequences make up about 40 percent of our genome.”

Loss of DNA recognition suppresses the cellular immune system

But how did it come about that it was thought for a long time that DNA in SAMHD1-deficient cells activates the interferon system. It has long been known that healthy cells also always produce a little interferon: so-called "tonic interferon signaling". This means that many gene products that bring about a virus defense are always present in low concentrations and can switch on an immune response. This includes many nucleic acid sensors, such as those that detect RNA in the cytoplasm. The research team observed that tonic interferon is activated via the DNA sensor cGAS, ie via the recognition of the cell's own DNA, the carrier of our genetic information in the cell nucleus. If this DNA sensor is switched off, the cells not only become blind to DNA, but also to the cell's own or viral RNA. Because the lack of tonic interferon also reduces the number of RNA sensors. "So if you inactivate the DNA sensor cGAS in SAMHD1-deficient cells, it looks as if DNA triggers the disease because the interferon is gone. In truth, the cell simply can no longer see the cell's own unnatural RNA," says Dr. Tina Schumann, Post-Doc at the Institute for Immunology at the TU Dresden.

What do endogenous retroviruses do in our cells?

Prof. Behrendt's motivation to better understand the causes of this type of sterile inflammatory disease is to create novel approaches for therapies. A lack of SAMHD1 seems to be one of the drivers for the formation of cancer cells. The Bonn researcher would therefore like to clarify why RNA from endogenous retroviruses accumulates in SAMHD1-deficient cells. He would also like to clarify what activates cGAS in healthy cells and thus causes the basic alarm of the immune system, which is so vital for us.

Reference: Schumann T, Ramon SC, Schubert N, et al. Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner. J Exp Medic. 2022;220(1):e20220829. doi:10.1084/jem.20220829

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