• Study of rare disease reveals insights o

    From ScienceDaily@1:317/3 to All on Tue Mar 8 21:30:38 2022
    Study of rare disease reveals insights on immune system response process


    Date:
    March 8, 2022
    Source:
    Johns Hopkins Medicine
    Summary:
    In laboratory experiments involving a class of mutations in people
    with a rare collection of immune system disorders, researchers
    say they have uncovered new details about how immune system cells
    respond to disease- causing bacteria, fungi and viruses such
    as SARS-CoV-2.



    FULL STORY ==========================================================================
    In laboratory experiments involving a class of mutations in people with
    a rare collection of immune system disorders, Johns Hopkins Medicine researchers say they have uncovered new details about how immune system
    cells respond to disease-causing bacteria, fungi and viruses such as SARS-CoV-2.


    ==========================================================================
    The findings, the scientists report, reveal a critical step in the
    molecular circuitry inside what are known as B and T cells that mobilizes
    the immune system to fight off foreign invaders. Though the researchers
    studied rare disease mutations, they believe the findings point to
    subtle genetic variations among all human populations that may help
    explain the wide variability in individual responses to infections.

    Reporting Feb. 18 in iScience, the researchers focused on the cell
    biology and genetics of three inherited conditions classified as primary immunodeficiency syndromes, which are caused by mutations in the CARD11
    gene in B and T immune cells. People with the syndromes are unable to
    mount immune defenses to pathogens, and are prone to life-threatening
    fungal infections, pneumonia, upper respiratory infections, and food
    and environmental allergies.

    The culprit, an altered version of the CARD11 gene, fails to activate
    a signaling pathway that in turn spurs the immune system to recognize
    pathogens and launch defenses against them. The pathway is the same one activated by most vaccines.

    Normally, the CARD11 gene encodes instructions for a cluster of proteins
    called an oligomer. When one or both copies of a gene is mutated,
    producing an abnormal form of the oligomer, the faulty copy overrides
    the potential to launch protective responses. Unlike some other gene
    mutations, in which one normal, functional copy of a gene can provide
    some protection, some CARD11 mutations severely impact the oligomer
    regardless of whether one or both gene copies are mutated.

    "Proteins in an oligomer sometimes need every protein subunit in the
    cluster to be fully functional for it to do its job," says Joel Pomerantz, Ph.D., associate professor of biological chemistry at the Johns Hopkins University School of Medicine. "In certain CARD11-related syndromes,
    one bad copy of the gene can disrupt the whole cluster." To pinpoint how
    this happens, Pomerantz and Jacquelyn Bedsaul, the study report's first
    author and a graduate student at Johns Hopkins, focused on identifying
    which step in the signaling cascade requires all of the CARD11 protein
    subunits in the cluster to be functional.



    ========================================================================== Using laboratory-grown T cells with both functioning and mutated CARD11
    genes, they tracked protein levels and the cells' ability to become
    activated and signal other immune cells. They learned that CARD11
    mutations primarily affect how the protein cluster opens itself to bind
    with other proteins in a series of chain reactions that awaken T cells
    to foreign pathogens.

    Specifically, they found that the mutated version of CARD11 prevents the protein cluster from opening at all. If it's closed, the CARD11 cluster
    can't signal to other proteins to start an immune response.

    The researchers also conducted experiments to learn if the opening
    phase is the only step affected by the mutated CARD11 gene. To determine
    this, they used genetically engineered T cells that have CARD11 proteins perpetually in the open state. The researchers found that even when CARD11 proteins are open, a mutation in CARD11 blocks the signaling pathway.

    "The mutation also appears to disrupt the ability of the protein subunits
    to interact with other signalizing partners and function normally,"
    says Pomerantz.

    The conditions arising from CARD11 mutations in their most severe forms
    are rare in humans. Pomerantz hopes that, eventually, scientists can
    develop gene editing techniques to correct CARD11 mutations in immune
    cells in these patients.



    ==========================================================================
    For people with genetic variants less severe than those studied for
    this report, Pomerantz says the findings offer insight into the wide
    variation among immune system responses, and could someday explain
    why some people are at higher risk of bad outcomes when exposed to disease-causing pathogens.

    "When we understand the fundamental mechanisms of how our immune cells
    operate, we'll gain a better understanding of how genetic variation
    in immune-related genes in the human population can lead to different immunologic outcomes," says Pomerantz.

    In addition to Pomerantz and Bedsaul, Neha Shah and Shelby Hutcherson
    from Johns Hopkins contributed to the research.

    The study was supported by the National Institutes of Health (RO1AI148143, T32AI007247, T32CA009110 and T32GM007445) and funds from the Johns
    Hopkins University School of Medicine Department of Biological Chemistry.


    ========================================================================== Story Source: Materials provided by Johns_Hopkins_Medicine. Note:
    Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Jacquelyn R. Bedsaul, Neha Shah, Shelby M. Hutcherson, Joel
    L. Pomerantz.

    Mechanistic impact of oligomer poisoning by dominant-negative
    CARD11 variants. iScience, 2022; 25 (2): 103810 DOI:
    10.1016/j.isci.2022.103810 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220308102718.htm

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