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A team of scientists has created a genetic map of all possible receptors the human immune system might generate—also known as the immunome.

The project involved a mind-boggling data set.

“If we were on a treasure hunt, where the cure to many illnesses is the buried treasure, then we’ve just drawn the first map of Treasure Island.”

The possible variation of immune receptors far exceeds the number of genes in our genome, at roughly 10 million times more than the number of stars in the Milky Way galaxy, notes Adam Buntzman, a research assistant professor and immunologist at the University of Arizona.

That’s also about 100-fold the number of ants on Earth.

Buntzman calculates that using traditional computational methods to generate the complete map would take roughly 106 years.

“Waiting that long is clearly impractical,” he says, “but this is where CyVerse comes in.”

Terabytes of data

CyVerse is a project, funded by the National Science Foundation, that provides computational infrastructure for big-data problems in the life sciences.

Buntzman began working with CyVerse collaborator Ali Akoglu of the University of Arizona College of Engineering to develop computational tools to map the immunome using high-performance computing, or HPC, techniques.

The team developed a program to run the analysis in under 17 days on a computer chip housed inside a simple laptop.

“My role was to restructure the algorithm to accelerate the results,” Akoglu says. “This was the first study to generate and process terabytes of data exhaustively, going through all possible combinations of sequences, and in a relatively short amount of time. And CyVerse was the catalyzer that brought us together.”

Buntzman and colleagues have developed a software tool capable of comprehensively mapping the adaptive immune system without limitation, and a computer program that is a community-accessible utility to database these complex immunome datasets, as described at the 2016 conference of the American Association of Immunologists and in an upcoming publication to be released in the journal BMC Bioinformatics.

In addition, Buntzman’s group has developed another computer program to run a novel algorithm called iWAS, or immunome-Wide Association Study, that can mine the immunome for patterns of immune receptors responsible for protecting us from specific diseases or causing autoimmune disorders.

“If we were on a treasure hunt, where the cure to many illnesses is the buried treasure, then we’ve just drawn the first map of Treasure Island,” says Buntzman.

‘Dizzying array of variation’

The adaptive immune system is perhaps the most mysterious—and certainly one of the most vital—systems of the human body, protecting us from everything from common cold germs to serious infections. Cells within the human adaptive immune system produce antibodies and T-cell receptors that identify and remove harmful foreign substances from the body.

Unfortunately, the immune system can become a powerful enemy when it misidentifies a part of the body as pathogenic, leading to autoimmune diseases, or when it overreacts to foreign materials such as pollen, resulting in allergies such as asthma.

The immune system is considered to be “adaptive” because it can respond to our unique environments. Once it has overcome a particular pathogen, the immune system will “remember” and quickly destroy that pathogen if it ever enters our bodies again, thus giving us immunity.

Adaptive immune systems also vary from one person to the next, providing immunity depending upon what microbes an individual has been exposed to throughout their lifetime.

“Humans have about 25,000 genes in our genome, but there are millions of harmful microbes, which begs the question: How does such a small number of genes code for all of the immune receptors needed to recognize the enormous array of microbes that can hurt us?” Buntzman says.

It turns out that immune receptor genes do not code for immune receptors; rather, broken gene fragments combine in novel ways to produce new code.

Every time a new antibody or T-cell receptor is created, the adaptive immune system “shuffles the deck” of gene fragments, blending together the broken pieces through a process called VDJ recombination.

“These gene fragments are then modified by enzymes, creating a dizzying array of variation,” Buntzman explains.

Understanding the role of individual immune receptors could pave the way to developing advanced therapies, potentially revolutionizing the field of adaptive immunity.

“This work will aid in the study of cancer, autoimmunity, transplantation, and vaccination, and assist in developing new precision medical diagnostics and patient-centered immunotherapies, as well as identify biomarkers for inflammatory diseases,” says Yves Lussier, associate vice president for University of Arizona Health Sciences.

Source: University of Arizona