Scientists have identified “words” that immune cells use to call immune defense genes and have discovered that in an autoimmune disease (such as Sjögren’s syndrome) two of these words are used incorrectly, activating the wrong genes causing the disease. The cells have developed an immune response code or language and some important words have been identified in that language. It is as fascinating as when archaeologists discovered the Rosetta stone and could read Egyptian hieroglyphics.
Immune cells in the body constantly evaluate their environment and coordinate their defense functions using words – or signaling codons – to dictate to the cell nucleus, which genes will be activated against pathogenic bacteria and viruses. Each signal codon, when combined, triggers gene activation, as successive electrical signals via a telephone cable combine to produce the words of a conversation.
The researchers focused on words used by macrophages, and by using advanced microscopy techniques, “listened” to macrophages in healthy mice and identified SIX specific codon words that were associated with immune threats. Then, they did the same with macrophages from mice with a mutation similar to human Sjögren’s syndrome and found defects in two of these words. Macrophages can function as immune guard cells that respond to pathogen invasion and tissue injury by initiating and coordinating both local and immune system-wide immunity. These cells are distributed throughout tissues and detect inflammatory cytokines and pathogen-related molecular patterns (PAMPs) that indicate viral, bacterial, or fungal invasion. The findings suggest that Sjögren is not due to chronic inflammation, but to codon-word confusion that leads to improper gene activation, causing the body to attack itself.
Many diseases are associated with miscommunication of cells, but it is the first time it has been recognized that immune cells use a language to identify words. The effectiveness of immune cells in generating a response, specific and appropriate for each pathogen, lies in the “signaling pathways”, the communication channels that connect immune cell receptor molecules – which sense the presence of pathogens – with different types of defense genes. The NF-κB transcription factor is one of these signaling pathways and is recognized as a central regulator of immune cell responses to pathogen threats and macrophages initiate inflammatory responses through this factor. The NF-κB activity timeline determines which genes are expressed and therefore the type of response that follows. The defense units for each immune threat must mobilize the right gene groups, and this requires accurate and reliable communication with these units about the nature of the threat. NF-κB provides the communication code and calling the wrong unit is not only inefficient but can cause damage, as in Sjogren and other diseases.
For the study, the scientists analyzed how more than 12,000 cells communicate in response to 27 immune threat situations. Based on the possible order of the NF-κB time dynamics, they created a list of more than 900 possible “words” – corresponding to all three-letter word combinations with a vowel for the second letter.
Then, using an algorithm first developed in the 1940s for the telecommunications industry, they tracked which of the possible words seemed to appear when macrophages responded to a stimulus, such as a pathogen-derived substance. They found that SIX specific dynamic characteristics, or “words”, were more often associated with this response. The team then used a machine learning algorithm to model the macrophage immune response. They taught a computer the SIX words and asked if he could recognize the stimulus when the computerized cells were “talking” and he confirmed that he could. Examining further, they explored what would happen if the computer had only five words available instead of EXI, and found that it made many errors in recognizing the stimulus, which means that EXI words are also required for reliable communication.
The scientists also used calculus to study the biochemical molecular interactions within the word-producing immune cells. It was revealed in the journal Science how and why TB cells respond only to real threats, while in another study published in Cell, it was found for the first time that it was possible to correct a cellular misalignment of receptors with genes during inflammation, without serious side effects.
SOURCE: UCLA. Immunity (Cell Press May 2021)