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.
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.
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