Corporate Banner
Satellite Banner
Scientific Communities
Become a Member | Sign in
Home>News>This Article

Taking Immune Cells for a Test Drive

Published: Monday, March 17, 2014
Last Updated: Monday, March 17, 2014
Bookmark and Share
Combining biological experimentation on human white blood cells with advanced computational methods can help explain the functional impact of human genetic variation on immune disease.

You’re on a crowded subway car and someone nearby sneezes. Influenza viruses shed by your fellow rider are expelled in droplets of saliva that land on you and the person next to you. Two days later, you begin suffering from the classic flu symptoms of fever, aches, and runny nose, while the lucky rider next to you somehow dodges the infectious bullet.

The reason is more than luck. Some combination of genetic and environmental factors, and interactions between the two, determine a person’s susceptibility to infection by a pathogen. The tendency for infection, or developing an autoimmune disease, varies naturally among people. Genetic studies have linked dozens of DNA changes to immune disease, but exactly how those variants exert their effects on immune response has been unclear. A better understanding of this variation would not only yield a fuller picture of immune biology, but could also pave the way for new treatments.

A team of Broad scientists, collaborating with colleagues at Brigham and Women’s Hospital (BWH) and Harvard Medical School (HMS), recently demonstrated how combining sophisticated biological experimentation on human white blood cells with advanced computational methods can help explain the functional impact of human genetic variation on immune disease. In a close collaboration between Broad core faculty member Aviv Regev and Broad senior associate member Nir Hacohen, also a faculty member in the Division of Rheumatology at Massachusetts General Hospital (MGH), the team examined gene expression changes in dendritic cells, the “sentinels” of the immune system that detect and relay information to other immune cells, after stimulating the cells with viral or bacterial components. Using this model system, they uncovered dozens of common genetic variants involved in the interplay between DNA and environmental stimuli in the innate immune response and also explained the mechanism underlying this variation. The new work appears in the March 7 issue of Science.

Over the past decade, researchers have identified dozens of genetic risk factors for immune disease, but have not yet pinpointed the functional effects of those factors on the cell. Scientists can investigate the role of variants by associating them with changes in gene activity, but until now, these experiments have largely been done in resting cells. For dendritic cells, this would be like turning on the engine to test-drive a car, but never putting it into gear.

“For every cell type in the immune system, we know of several receptors and pathways that are critical,” explained Hacohen. “But in none of those cases do we know how the genetics affects these pathways in a systematic way.”

In an effort to unravel the mechanisms of immune disease, the researchers designed experiments to watch dendritic cells doing what they do best: mounting an immune response to a bacteria or virus. “Unless you’re infected, dendritic cells are not doing much to ignite the immune system,” said Hacohen, also an associate professor of medicine at HMS. “The healthy immune response is, by definition, an induced state.”

This study of dendritic cells was conducted as part of the ImmVar project, a collaboration among researchers at the Broad Institute, BWH, MGH, HMS, Stanford University, and the Immunological Genome Project. ImmVar aims to broadly analyze the variation in gene expression in immune cells and their genetic regulatory network, and this paper represents the first fruits of that effort.

In this study, the researchers surveyed cells from more than 500 healthy subjects from the PhenoGenetic Project, a “living biobank” based at BWH designed to provide blood samples from subjects along with genetic information from across the genome. There are currently 1,756 subjects enrolled in this resource, which has provided samples to over 20 different investigators. The PhenoGenetic Project was created and is led by Philip De Jager, a Broad associate member and associate professor of neurology at BWH and co-author on the new study.

“The ImmVar collaboration has been a wonderful example of how a recallable cohort of healthy subjects (from the PhenoGenetic Project) with a rigorous blood sampling strategy can enable systematic interrogation of the functional consequences of human genetic variation,” explained De Jager. “It illustrates the way forward as we seek to understand the role of the increasing number of disease-associated genetic variations.”

To study immune response in such a large number of samples, the team developed high-throughput methods for generating dendritic cells from patient blood cells and exposing those cells to immune-stimulatory agents: an E. coli component called LPS, influenza virus, or interferon-beta, an important immune molecule induced by bacteria and viruses. They then measured gene expression changes in both resting and stimulated dendritic cells from 30 healthy volunteers, and identified a signature of 415 genes that captured the bulk of the relevant variation. The researchers then examined the expression of those signature genes in immune-stimulated cells from participants in the PhenoGenetic Project and incorporated data from the 1,000 Genomes Project to reveal 121 genetic variants linked to the induction of immune gene expression.

“Our computational pipeline aims to find the DNA changes that affect gene regulation by combining the genetic information with a map of the regulatory circuit that acts in immune cells,” said Regev.

To this end, the researchers then integrated data from the ENCODE project to more precisely map the variation, and found that the critical variants were often located in known binding sites for transcription factors, which regulate gene activity. This suggested that the variants likely worked by altering how transcription factors bind DNA at those sites.

To confirm their predictions, the scientists inserted different versions of three genetic variants in cells, observing that the variants do, in fact, alter the activity of genes in immune-stimulated cells. They also went a step further and directly edited single letters in the genome using the CRISPR system in stimulated cells, again observing altered gene expression and supporting their hypothesis that the differential binding of transcription factors underlies the variation.

Because some genetic variants had previously been implicated in studies of immune diseases like Crohn’s disease and type 1 diabetes, the team cross-referenced their variants with hits from these studies. Many genes overlapped, such as NOD2 in leprosy, and in lupus, IRF7, a gene shown in this study to be important for the response of dendritic cells to influenza. The data generated here shed more light on hits from genome-wide association studies (GWAS) and can help relate them to causal variants, but this approach could also reveal more genes missed in GWAS.

“GWAS points you to DNA variants that underlie disease,” said Hacohen. “Our study takes you one step further by showing how these variants affect a specific immune pathway in a well-defined immune cell type.”

This work is the first installment from the ImmVar group, explained Christophe Benoist. This analysis was coordinated with parallel studies within the ImmVar project on regulatory genetics in resting blood cells, and in activated T lymphocytes, such that the innate and adaptive arms of the immune system are represented. “It’s been a fun program for all the collaborators,” said Benoist, Broad associate member, professor at HMS, and leader of the ImmVar consortium. “The team has done a fantastic job in putting together this beautiful paper, but stay tuned for other important stories to come.”

This study represents an innovative way of investigating the mechanisms of disease, and could have utility in cell types and diseases beyond the immune system. Following up on important variants in animal models could reveal which pathways can modulate disease safely, representing potential targets for drug development. But for now, building the map relating genetic variants to immune function in all types of immune cells exposed to various stimuli – and explaining why some people get the flu more often than others – will keep the team busy. “Going from the initial associations to final evidence of function took a lot of work by this team,” said Hacohen. “It’s a very powerful approach to study function, but we have a lot more work to do.”

Other authors of this paper include Mark N. Lee, Chun Ye, Alexandra-Chloé Villani, Towfique Raj, Weibo Li, Thomas M. Eisenhaure, Selina H. Imboywa, Portia I. Chipendo, F. Ann Ran, Kamil Slowikowski, Lucas D. Ward, Khadir Raddassi, Cristin McCabe, Michelle H. Lee, Irene Y. Frohlich, David A. Hafler, Manolis Kellis, Soumya Raychaudhuri, Feng Zhang, and Barbara E. Stranger.

Paper cited: Lee M, et al. Common genetic variants modulate the pathogen-sensing responses in human dendritic cells. Science. March 7, 2014. DOI: 10.1126/science.1246980.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,800+ scientific posters on ePosters
  • More Than 4,000+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Screen of Human Genome Reveals Set of Genes Essential for Cellular Viability
Using two complementary analytical approaches, scientists at Whitehead Institute and Broad Institute of MIT and Harvard have for the first time identified the universe of genes in the human genome essential for the survival and proliferation of human cell lines or cultured human cells.
Monday, October 19, 2015
DARPA Awards $32 Million Contract to MIT, Broad Institute Foundry
A facility at the Broad Institute of MIT and Harvard and MIT that aims to achieve the full potential of engineering biology has received a five-year, $32 million contract from the Defense Advanced Research Projects Agency (DARPA).
Monday, September 28, 2015
Diagnostics Breakthrough Brings Viral Sequencing to Doctors’ Toolkit
New screening tool produces up to 10,000-fold improvement in viral matches compared with traditional high-throughput methods.
Monday, September 28, 2015
Scientists Discover New System For Human Genome Editing
CRISPR-Cpf1 system could disrupt both scientific and commercial landscape.
Monday, September 28, 2015
Researchers Develop a New Means of Killing Harmful Bacteria
Engineered particles are capable of producing toxins that are deadly to targeted bacteria.
Friday, June 26, 2015
Broad Institute & Google Genomics Combine Bioinformatics and Computing Expertise
Both companies explore how to break down major technical barriers that increasingly hinder biomedical research.
Thursday, June 25, 2015
CRISP-Disp Leverages CRISPR-Cas9 to Deliver RNA Structures to Targets in the Genome
A team of researchers from the Broad Institute and the Harvard Stem Cell Institute has developed CRISP-Disp, a method that expands on the CRISPR-Cas9 system, allowing researchers to display multiple, large RNA structures on the Cas9 protein.
Wednesday, June 10, 2015
GTEx: Useful Expression For Cancer Research
GTEx Project has recently published several papers reporting on findings from its two-year pilot phase.
Tuesday, May 26, 2015
Single-cell Analysis Hits its Stride
Advances in technology and computational analysis enable scale and affordability, paving the way for translational studies.
Saturday, May 23, 2015
Highly Efficient New Cas9 for In Vivo Genome Editing
New finding is expected to expand therapeutic and experimental applications of CRISPR.
Tuesday, April 07, 2015
Broad Institute of MIT and Harvard and Bayer Healthcare Expand their Partnership
Collaboration to develop therapies for cardiovascular disease.
Thursday, April 02, 2015
In vivo CRISPR-Cas9 Screen Sheds Light On Cancer Metastasis And Tumor Evolution
Genome-scale study points to drivers of tumor evolution and metastasis, provides roadmap for future in vivo Cas9 screens.
Friday, March 06, 2015
Scientists Map the Human Loop-ome, Revealing a New Form of Genetic Regulation
Researchers describe the results of a five-year effort to map, in unprecedented detail, how the 2-meter long human genome folds inside the nucleus of a cell.
Tuesday, December 23, 2014
Disorder in Gene-Control System is a Defining Characteristic of Cancer, Study Finds
Findings indicate that the disarray in the on-off mechanism is one of the defining characteristics of cancer.
Tuesday, December 23, 2014
Two Studies Identify A Detectable, Pre-Cancerous State In The Blood
Findings pave way for new lines of cancer research focused on detection and prevention.
Thursday, November 27, 2014
Scientific News
High Throughput Mass Spectrometry-Based Screening Assay Trends
Dr John Comley provides an insight into HT MS-based screening with a focus on future user requirements and preferences.
How a Genetic Locus Protects Adult Blood-Forming Stem Cells
Mammalian imprinted Gtl2 protects adult hematopoietic stem cells by restricting metabolic activity in the cells' mitochondria.
Genetic Basis of Fatal Flu Side Effect Discovered
A group of people with fatal H1N1 flu died after their viral infections triggered a deadly hyperinflammatory disorder in susceptible individuals with gene mutations linked to the overactive immune response, according to a recent study.
New Tech Vastly Improves CRISPR/Cas9 Accuracy
A new CRISPR/Cas9 technology developed by scientists at UMass Medical School is precise enough to surgically edit DNA at nearly any genomic location, while avoiding potentially harmful off-target changes typically seen in standard CRISPR gene editing techniques.
The MaxSignal Colistin ELISA Test Kit from Bioo Scientific
Kit can help prevent the antibiotic apocalypse by keeping last resort drugs out of the food supply.
"Good" Mozzie Virus Might Hold Key to Fighting Human Disease
Australian scientists have discovered a new virus carried by one of the country’s most common pest mosquitoes.
Non-Disease Proteins Kill Brain Cells
Scientists at the forefront of cutting-edge research into neurodegenerative diseases such as Alzheimer’s and Parkinson’s have shown that the mere presence of protein aggregates may be as important as their form and identity in inducing cell death in brain tissue.
Closing the Loop on an HIV Escape Mechanism
Research team finds that protein motions regulate virus infectivity.
New Class of RNA Tumor Suppressors Identified
Two short, “housekeeping” RNA molecules block cancer growth by binding to an important cancer-associated protein called KRAS. More than a quarter of all human cancers are missing these RNAs.
Potential Treatment for Life-Threatening Viral Infections Revealed
The findings point to new therapies for Dengue, West Nile and Ebola.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos