The same pathogen can often elicit very different responses from different people. Scientists sought to understand more about what causes these individual differences. They found that both our genomes and our life experiences can shape a person’s reaction to an infection, and whether certain genes are activated or not. Reporting in Nature Genetics, scientists created a catalog of relevant epigenetic changes, which can affect how genes are expressed without altering the underlying sequences of DNA. This catalog, which is a searchable database, can show why immune responses may vary so much from one person to another.
“Our immune cells carry a molecular record of both our genes and our life experiences, and those two forces shape the immune system in very different ways,” noted senior study author Joseph Ecker, Ph.D., a professor and chair at the Salk Institute, and a Howard Hughes Medical Institute investigator. “This work shows that infections and environmental exposures leave lasting epigenetic fingerprints that influence how immune cells behave. By resolving these effects cell by cell, we can begin to connect genetic and epigenetic risk factors to the specific immune cells where disease actually begins.”
In this study, the researchers focused on a wide range of blood samples collected from patients who had been infected with pathogens like influenza, MRSA, SARS-CoV-2 (the cause of COVID-19); as well as people who had been vaccinated for anthrax; or exposed to organophosphate pesticides.
The scientists looked at epigenetic changes in the form of methylation, in which methyl tags are attached top DNA, in these patients. They focused on the methylation patterns in four important types of immune cells: B and T cells, monocytes, and natural killer cells. B and T cells are familiar with past infections, while monocytes and NK cells react in a rapid, broad way to invaders. This effort revealed all of the areas with altered methylation patterns, or the differentially methylated regions (DMRs), in the various cells.
“We found that disease-associated genetic variants often work by altering DNA methylation in specific immune cell types,” explained co-first study author Wubin Ding, Ph.D., a postdoctoral fellow in the Ecker lab. “By mapping these connections, we can begin to pinpoint which cells and molecular pathways may be affected by disease risk genes, potentially opening new avenues for more targeted therapies.”
The investigators were able to distinguish between epigenetic changes that had been genetically inherited (gDMRs) and those that happened after various life experiences (eDMRs). This showed that there are certain parts of the genome where either gDMRs or eDMRs tend to cluster together. The gDMRs tended to arise in parts of genes that are stable, like genes that are active in T and B cells that last for a long time. But eDMRs were typically located in regulatory regions of the genome that can change more frequently, and tend to activate certain immune responses.
Genetic inheritance seems to affect long-term immune function, and the things we experience in our lives can affect immune responses that are dynamic and depend on context. More research will be needed to confirm these findings, and to fully understand these processes. However, it may eventually help researchers develop treatments that can be tailored based on as person’s immune responses.
“Our human population immune cell atlas will also be an excellent resource for future mechanistic research on both infectious and genetic diseases, including diagnoses and prognosis,” noted co-first study author Manoj Hariharan, Ph.D., a senior staff scientist in the Ecker lab. “Often, when people become sick, we are not immediately sure of the cause or potential severity. The epigenetic signatures we developed offer a road map to classify and assess these situations.”
Sources: Salk Institute, Nature Genetics