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    Home > Biochemistry News > Biotechnology News > The key to the wrong activation of the immune system

    The key to the wrong activation of the immune system

    • Last Update: 2023-01-06
    • Source: Internet
    • Author: User
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    Figure: Missing and broken telomers illustrate how DNA damage occurs
    in SAMHD1-deficient cells.
    However, this DNA damage does not cause activation of the interferon system, but rather the cell's own RNA is sensed

    The innate immune system fights infectious agents
    Alarm messenger interferon plays a central role
    in this.
    However, if it is produced in the absence of infection, it can cause an autoimmune disease
    Researchers from the University Hospital Bonn (UKB) and the Technical University of Dresden (TU) investigated an underlying mechanism by studying the rare autoimmune disease Aicardi-Goutières syndrome and deciphered the driving force
    behind uncontrolled interferon production.
    The study has been published in the Journal of Experimental Medicine (JEM


    If our innate immune system recognizes viral genetic information through sensors, the alert messenger type I interferon is produced
    It is a very strong activator of immune cells and is therefore essential
    in defending against many pathogens, not just viruses.
    However, if interferon is produced too much, or for too long, an overactivated immune system can attack healthy cells — a collateral damage
    to an actually good immune response.
    In addition, much of the viral genetic information used for the sensors looks like our own DNA and RNA
    To prevent this misidentification of our own genetic material, every cell has safety mechanisms
    If these fail, interferon is produced
    without viral infection causing inflammation.
    This sterile inflammation, driven by uncontrolled innate immune activation, has been identified as one of
    the factors that trigger collagen diseases such as systemic lupus erythematosus (SLE).
    "Diseases like lupus are hard to study because there are so many genes
    However, as a result of the cell's own nucleic acid recognition, the mechanism of interferon production also occurs in rare single-gene autoimmune diseases, in which case it can be precisely specified as a genetic defect," said
    Professor Rayk Behrendt, team leader at the Institute of Clinical Chemistry and Clinical Pharmacology at the Royal College of Physicians.


    The recognition of DNA and RNA in cells is coupled

    The research team from the University of Bonn and the Technical University of Dresden Medical School took advantage of this to take a closer look
    at the Aicardi-Goutières syndrome in mouse models.
    This interferon-driven single-gene autoimmune disease is triggered by the inactivation of a genetic mutation that degrades cellular nucleic acids, preventing overactivation
    of sensors in the innate immune system.
    One of these genes, called SAMHD1, regulates DNA replication and repair
    in the nucleus.
    As a result, it was previously thought that in affected individuals, it was DNA that drove the disease
    "However, we have now found that, contrary to previous expectations, recognition of cellular RNA is the driving force behind uncontrolled interferon production," Professor Behrendt said
    "In this regard, it seems that it is mainly the viral RNA encoded in our genome that plays a role
    These sequences make up about 40%
    of our genetic material.


    Loss of DNA recognition suppresses the cellular immune system

    But how did it come about? For a long time, it was thought that DNA in cells lacking SAMHD1 activated the interferon system
    It has long been known that even healthy cells always produce a little interferon: the so-called "tonic interferon signal"
    This results in many antiviral gene products always present in low concentrations and allows cells to jump-start an immune response
    This includes many nucleic acid sensors, such as those that recognize RNA
    in the cytoplasm.
    The team observed that the tonic interferon is activated by the DNA sensor cGAS, which recognizes the carrier of genetic information in the nucleus of cellular DNA
    If this DNA sensor is turned off, the cell will be blind not only to DNA, but also to cellular or viral RNA
    This is because the lack of complementary interferons reduces the number of RNA sensors, which are part of
    the antiviral immune system.
    "So if you inactivate cGAS, the DNA sensor in cells that lack samhd1, it seems that DNA is causing the disease because the interferon is
    " In fact, the cell simply cannot see the cell's own unnatural RNA," says
    Tina Schumann, a postdoctoral fellow at the Institute of Immunology at the Technical University of Dresden.


    What do endogenous retroviruses do in our cells?

    Professor Behrendt wants to better understand the causes of these aseptic inflammatory diseases in order to create new treatments
    For example, the deletion of SAMHD1 appears to be a
    driver of cancer cell formation.
    Therefore, the researchers from Bonn wanted to clarify why the accumulation of endogenous retroviral RNA occurs in
    samhd1-deficient cells.
    In addition, he wanted to figure out what activates cGAS in healthy cells, causing a basic alarm
    for the immune system that is vital to us.


    Participating Organisations and Funding:

    In addition to the University College UK, the University of Bonn, the University Hospital of Dresden and the Technical University of Dresden, the Medical School of Hannover, the Universities of Erlangen-Nuremberg and Marburg, the Curie Institute in Paris, the Heidelberg University Hospital, the Dresden State Centre for Oncological Diseases, the German Cancer Society in Dresden and the German Cancer Research Center (DKFZ) in Heidelberg were all involved in the study
    This work was funded
    by the University of Bonn's transregional SFB TRR237 "Nucleic Acid Immunisation" project, funded by the German Economic Development Fund.


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