UCLA life scientists have identified six “words” that specific immune cells use to call immune defense genes – an important step towards understanding the language the body uses to piece together responses to threats.
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, conducted in mice, is published this week in the peer-reviewed journal Immunity (Cellular press).
“Cells have developed an immune response code or language,” said senior author Alexander Hoffmann, Thomas M. Asher professor of microbiology and director of the Institute for Quantitative and Computational Biosciences at UCLA. “We have identified certain words in this 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 were able to start reading Egyptian hieroglyphics. “
The body’s immune cells constantly assess their environment and coordinate their defense functions by using words – or signal codons, in scientific parlance – to tell the nucleus of the cell which genes to activate in response to invaders such as bacteria. pathogens and viruses. Each signal codon consists of several successive actions of a DNA binding protein which, when combined, cause the appropriate gene activation, in the same way that successive electrical signals through a telephone wire combine to produce the words of a conversation.
The researchers focused on the 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 in healthy mice and identified six specific word codons that correlated with immune threats. They then did the same with macrophages from mice that contained a mutation close to Sjögren’s syndrome in humans to determine whether the disease resulted from the misuse of those words.
“Indeed, we found flaws in the use of two of these words,” Hoffmann said. “It is as if instead of saying, ‘Answer the attacker in the street’, the cells mistakenly say ‘Answer the attacker in the house’.”
The results, say the researchers, suggest that Sjögren’s disease does not result from chronic inflammation, as has long been believed, but from codon word confusion that leads to inappropriate gene activation, causing the body to s ‘attack. The next step will be to find ways to correct the confusing word choices.
Many diseases are linked to poor communication in cells, but this study, scientists say, is the first to recognize that immune cells use language, identify words in that language, and demonstrate what can happen when the word choice goes wrong. Hoffman hopes the team’s discovery will serve as a guide to finding words related to other illnesses.
The immune system at war: words and codes
How are immune cells so effective in mounting a specific and appropriate response to each pathogen? The answer, says Hoffman, lies in “signaling pathways,” the communication channels that connect immune cell receptor molecules – which detect the presence of pathogens – with different types of defense genes. The transcription factor NFβB is one such signaling pathway and is recognized as a central regulator of immune cell responses to pathogenic threats.
“The macrophage is able to respond to different types of pathogens and mount different types of defenses. Defense units – army, navy, air force, special operations – are mediated by groups of genes,” he said. he declares. “For each immune threat, the right groups of genes must be mobilized. This requires precise and reliable communication with these units about the nature of the threat. The NF? B dynamic provides the communication code. We have identified the words in it. code, but we still do not fully understand how each defense unit interprets the various combinations of the code words. “
And of course, calling the wrong unit is not only ineffective, Hoffmann notes, but can cause damage, as vehicles destroy roads, accidents happen and worse, as in the case of Sjögren and, perhaps, other diseases.
Algorithms, Computers and Calculus: Identify the Six Words
For the study, scientists analyzed how more than 12,000 cells communicate in response to 27 immune threat conditions. Based on the possible arrangement of the NF dynamics? B temporal, they generated a list of over 900 potential “words” – analogous to any combination 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 appear when macrophages responded to a stimulus, such as a substance derived from a pathogen. They found that six specific dynamic characteristics, or “words,” were most often correlated with this response.
An analogy would be to listen to someone in a conversation and find that certain three letter words tend to be used, such as “the”, “boy”, “toy” and “get”, but not “biy” or “Bey,” said lead author Adewunmi Adelaja, who received his doctorate. in Hoffmann’s lab and is currently working on his doctorate at UCLA.
The team then used a machine learning algorithm to model the immune response of macrophages. If they taught a computer the six words, they asked, would it be able to recognize the stimulus when the computerized versions of the cells “spoke”? They confirmed that it was possible. As they delved deeper, they explored what would happen if the computer only had five words. They found that the computer made more mistakes in recognizing the stimulus, which led the team to conclude that all six words are necessary for reliable cellular communication.
Scientists also used calculus to study biochemical molecular interactions inside the immune cells that produce the words.
Hoffmann and his colleagues revealed in the journal Science in 2014 how and why the B cells of the immune system only respond to real threats. In a study published in Cell in 2013, his team showed for the first time that it was possible to correct poor cellular communication involving the connection of receptors to genes during inflammation without severe side effects.
Hoffmann’s research is supported by the National Institutes of Health.
The other co-authors of the current research are UCLA MD-Ph.D. student Katherine Sheu, UCLA postdoctoral fellows Yi Liu and Stefanie Luecke, and Brooks Taylor, a former UCLA doctoral student who initiated the research. All of them work or have worked in Hoffmann’s laboratory.