The Effect of Rare Immune Disorders on Insights on the Immune System's Handling

The Effect of Rare Immune Disorders on Insights on the Immune System's Handling ...

Researchers at Johns Hopkins Medicine have discovered new techniques to combat disease-causing bacteria, fungi, and viruses, such as SARS-CoV-2.

The findings, according to scientists, show a crucial component in the molecular circuitry inside what are now known as B and T cells, which mobilizes the immune system to fight off foreign invaders. While the researchers studied rare disease mutations, they believe they reveal significant genetic variations among all human populations that may be helpful in explaining the wide variation in individual responses to infections.

Three inherited conditions, which are caused by mutations in the CARD11 gene in B and T immune cells, have been reported in iniScience on February 18, 2017. People with these syndromes are unable to support immune defenses against pathogens, and are subject to life-threatening fungal infections, pneumonia, upper respiratory infections, and food and environmental illnesses.

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

If one or both copies of a gene is mutated, the oligomer forms a normal, defective copy overrides the possibility to protect the oligomer. However, some CARD11 mutations have a serious effect on the oligomer, regardless of whether one or both gene copies are mutated.

Proteins in an oligomer sometimes require every protein subunit in the cluster to be fully functional for it to perform its job, according toJoel Pomerantz, an associate professor of biological chemistry at the Johns Hopkins University School of Medicine. In certain CARD11 cases, one bad copy of the gene may cause a disturbance to the whole cluster.

Pomerantz and Jacquelyn Bedsaul, the study''s first author and a graduate student at Johns Hopkins, focused on determining which step in the signaling cascade requires all of the CARD11 protein subunits in the cluster to be functional.

T cells with both functioning and mutated CARD11 genes were tracked by researchers. They discovered that CARD11 mutations have primarily an effect on how the protein cluster opens itself to bind with other proteins in a series of chain reactions that awaken T cells to foreign pathogens.

The mutated version of CARD11 prevents the protein cluster from opening at any time. If the cluster is closed, the CARD11 cluster cannot signal to other proteins to initiate an immune response.

Researchers used genetically modified T cells that have CARD11 proteins permanently in the open state to discover that even when CARD11 proteins are open, a mutation in CARD11 blocks the signaling pathway.

According to Pomerantz, the mutation appears to also hinder the ability of the protein subunits to interact with other signalizing partners and function normally.

CARD11 mutations in their most severe forms are rare in humans. Pomerantz hopes that scientists may develop gene editing techniques to correct CARD11 mutations in immune cells in these patients.

People with genetic variations that are less severe than those studied for this study, Pomerantz claims the findings provide insight into the wide variation among immune system responses and might someday explain why some individuals are at greater risk of bad outcomes when exposed to disease-causing pathogens.

According to Pomerantz, when we understand the fundamental mechanisms of how our immune cells operate, we gain a better understanding of how genetic variation in immune-related genes in the human population can lead to different immunologic results.

You may also like: