Understanding how immune defense genes are called to action

May 14, 2021

UCLA life scientists have identified six “words” that specific immune cells use to call up immune defense genes — an important step toward understanding the language the body uses to marshal responses to threats, according to a news release from the university.

In addition, they discovered that the incorrect use of two of these words can activate the wrong genes, resulting in the autoimmune disease known as Sjögren’s syndrome. The research is published this week in the peer-reviewed journal Immunity (Cell Press).

“Cells have evolved an immune response code, or language,” said senior author Alexander Hoffmann, the Thomas M. Asher Professor of Microbiology and Director of the Institute for Quantitative and Computational Biosciences at UCLA. “We have identified some words in that language, and we know these words are important because of what happens when they are misused. Now, we need to understand the meaning of the words, and we are making rapid progress. It’s as exciting as when archaeologists discovered the Rosetta stone and could begin to read Egyptian hieroglyphs.”

TImmune cells in the body constantly assess their environment and coordinate their defense functions by using words — or signaling codons, in scientific parlance — to tell the cell’s nucleus which genes to turn on in response to invaders like pathogenic bacteria and viruses. Each signaling codon consists of several successive actions of a DNA binding protein that, when combined, elicit the proper gene activation, in much the same way that successive electrical signals through a telephone wire combine to produce the words of a conversation.

The researchers focused on words used by macrophages, specialized immune cells that rid the body of potentially harmful particles, bacteria, and dead cells. Using advanced microscopy techniques, they “listened” to macrophages and identified six specific codon–words that correlated to immune threats. They then did the same with macrophages that contained a mutation akin to Sjögren’s syndrome to determine whether this disease results from the defective use of these words.

“Indeed, we found defects in the use of two of these words,” Hoffmann said. “It’s as if instead of saying, ‘Respond to attacker down the street,’ the cells are incorrectly saying, ‘Respond to attacker in the house.’”

The findings, the researchers say, suggest that Sjögren’s doesn’t result from chronic inflammation, as long thought, but from a codon–word confusion that leads to inappropriate gene activation, causing the body to attack itself.

Many diseases are related to miscommunication in cells, but this study, the scientists say, is the first to recognize that immune cells employ a language, to identify words in that language and to demonstrate what can happen when word choice goes awry. Hoffman hopes the team’s discovery will serve as a guide to the discovery of words related to other diseases.

And, of course, calling up the wrong unit is not only ineffective, Hoffmann notes, but may do damage, as in the case of Sjogren’s and, possibly, other diseases.

For the study, the scientists analyzed how more than 12,000 cells communicate in response to 27 immune threat conditions. Based on the possible arrangement of temporal NF?B dynamics, they generated a list of more than 900 potential “words” — analogous to all combinations of three-letter words with a vowel for the second letter.

Then, using an algorithm originally developed in the 1940s for the telecommunications industry, they monitored which of the potential words tended to show up when macrophages responded to a stimulus, such as a pathogen-derived substance. They discovered that six specific dynamical features, or “words,” were most frequently correlated with that response.

The scientists also used calculus to study the biochemical molecular interactions inside the immune cells that produce the words.

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