NEW YORK (GenomeWeb News) – A pair of studies published online today in Science is providing a look at the genetic variants influencing the innate immune system's response to bacterial or viral pathogens.
For the first of the studies, researchers from the University of Oxford Wellcome Trust Centre for Human Genetics and the University of Cambridge's Wellcome Trust Sanger Institute did array-based genotyping and gene expression profiling on primary monocyte innate immune cells from more than 400 healthy Europeans.
Their results revealed variability in the identity of expression quantitative trait loci — genetic variants influencing gene expression — in cells that had or had not been exposed to factors that stimulated an immune response. They also saw differences related to the time after this exposure and the type of stimuli involved.
"It shows an exquisite context specificity," the study's corresponding author Julian Knight, with the Wellcome Trust Centre for Human Genetics, told GenomeWeb Daily News.
He and his colleagues used Illumina arrays to profile gene expression in monocyte cells before and after exposure to bacterial lipopolysaccharides or with a cytokine called interferon-beta that stimulates a viral and mycobacterial response pathway.
The team's comparison of expression patterns in the cells prior to immune activation, after interferon-beta exposure, two-hours after LPS treatment, and/or 24 hours after LPS treatment made it possible to track down thousands of apparent eQTLs in resting or activated cells.
Along with variants influencing the expression of neighboring genes, the study helped define sets of more distant variants that orchestrate the broader immune response. In monocytes stimulated with the bacterial LPS, for example, the team saw an early immune response involving an eQTL near the IFNB1 gene. The same variant had more distant, trans-effects on gene expression after 24 hours of infection.
Meanwhile, a subset of the eQTLs appeared specific to the stimulated or resting monocyte cells. The complete eQTL collection also included eQTLs active in response to some immune challenges and not others.
In addition, the researchers saw clues that at least some eQTLs mediating immune response early on during a bacterial infection are distinct from those at play later in the infectious process, Knight noted, which may include variants influencing infection severity.
"There may be a signature that you can find in individuals who are more predisposed to having an over-reactive or an under-reactive immune system," he said.
Consequently, such studies are expected to boost researchers' understanding of immune system biology. But they could also have more immediate applications in interpreting existing genome-wide association data, according to Knight and his co-authors.
"The identification of functional regulatory variants and associated modulated genes is key to interpreting GWAS findings and establishing how genes are associated with disease," they wrote.
For example, they found that 467 of the monocyte sites coincided with variants detected through past genome-wide association studies, according to the team's search of a GWAS variant catalog.
That overlap was somewhat enriched for variants associated with immunity, inflammation, autoimmune, and gastroenterological diseases, Knight noted, whereas variants found through GWAS of cancer, reproductive conditions, or cardiovascular disease were under-represented.
In addition to future experiments aimed at understanding the biological mechanisms behind the eQTL-associated genes detected in the current study, that team anticipates doing similar studies in other types of immune cells exposed to various stimuli, including cells from patient samples.
For another study appearing in the same issue of Science, researchers focused on a different type of innate immune cell in their effort to find eQTLs involved in responding to LPS, interferon-beta, or influenza virus.
"We asked the question of how [bacterial sensing and viral sensing by the innate immune system] differs quantitatively between people and whether we could explain that quantitative variation using genetics," co-senior author Nir Hacohen, a researcher affiliated with the Broad Institute, Harvard Medical School, and Massachusetts General Hospital, told GWDN.
For instance, their analysis uncovered inter-individual differences in variants within interferon pathway gene promoter elements influencing individuals' immune responses — a finding that the team verified through targeted mutational experiments focused on one of the variable promoter alleles detected.
Members of that team started by assessing expression profiles in resting or stimulated monocyte-derived dendritic cells isolated from the blood of 30 healthy individuals.
After using computational methods to help narrow in on 415 immune response genes the researchers took those forward for Nanostring-based transcriptional profiling in dendritic cells from 534 healthy individuals. That group included 295 Caucasian, 122 African-American, and 117 East-Asian individuals.
From transcriptional patterns present in the subjects' isolated dendritic cells prior to and proceeding treatment with influenza, LPS, or interferon-beta, the investigators narrowed in on the local and distant eQTLs at work in resting immune cells. They also defined similar sets of eQTLs employed during immune activation, which they dubbed response QTLs, or reQTLs.
Again, the team saw some QTLs that preferentially showed an effect in the presence of specific immune stimuli. In particular, the study highlighted variants that impact both the expression of a gene called IRF7 as well as the targets of the transcription factor it encodes, which is known to mediate response to viral infection.
"If you have a different IRF7 promoter allele, you have a different response to the virus," Hacohen said. "And that, in turn, leads to a different global anti-viral response. So it may explain a lot of the differences between people."
As in the accompanying study, the researchers saw some overlap between variants influencing innate immune response and those implicated in past disease studies, particularly variants contributing to immune-related conditions such as Crohn's disease, type 1 diabetes, and lupus.
"This begins to essentially map those disease [variants] in specific cell types when very specific pathways are being activated," Hacohen said.
To fully explore such interactions, authors of that study are keen to get a look at a range of immune cells in which various immune pathways have been activated. They are already doing similar analyses of T-cells, for example, and anticipate additional studies on still other cell types.