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.
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