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Immune Macrophages Use Their Own ‘Morse Code’

Posted on by Dr. Francis Collins

Credit: Hoffmann Lab, UCLA

In the language of Morse code, the letter “S” is three short sounds and the letter “O” is three longer sounds. Put them together in the right order and you have a cry for help: S.O.S. Now an NIH-funded team of researchers has cracked a comparable code that specialized immune cells called macrophages use to signal and respond to a threat.

In fact, by “listening in” on thousands of macrophages over time, one by one, the researchers have identified not just a lone distress signal, or “word,” but a vocabulary of six words. Their studies show that macrophages use these six words at different times to launch an appropriate response. What’s more, they have evidence that autoimmune conditions can arise when immune cells misuse certain words in this vocabulary. This bad communication can cause them incorrectly to attack substances produced by the immune system itself as if they were a foreign invaders.

The findings, published recently in the journal Immunity, come from a University of California, Los Angeles (UCLA) team led by Alexander Hoffmann and Adewunmi Adelaja. As an example of this language of immunity, the video above shows in both frames many immune macrophages (blue and red). You may need to watch the video four times to see what’s happening (I did). Each time you run the video, focus on one of the highlighted cells (outlined in white or green), and note how its nuclear signal intensity varies over time. That signal intensity is plotted in the rectangular box at the bottom.

The macrophages come from a mouse engineered in such a way that cells throughout its body light up to reveal the internal dynamics of an important immune signaling protein called nuclear NFκB. With the cells illuminated, the researchers could watch, or “listen in,” on this important immune signal within hundreds of individual macrophages over time to attempt to recognize and begin to interpret potentially meaningful patterns.

On the left side, macrophages are responding to an immune activating molecule called TNF. On the right, they’re responding to a bacterial toxin called LPS. While the researchers could listen to hundreds of cells at once, in the video they’ve randomly selected two cells (outlined in white or green) on each side to focus on in this example.

As shown in the box in the lower portion of each frame, the cells didn’t respond in precisely the same way to the same threat, just like two people might pronounce the same word slightly differently. But their responses nevertheless show distinct and recognizable patterns. Each of those distinct patterns could be decomposed into six code words. Together these six code words serve as a previously unrecognized immune language!

Overall, the researchers analyzed how more than 12,000 macrophage cells communicated in response to 27 different immune threats. Based on the possible arrangement of temporal nuclear NFκB dynamics, they then generated a list of more than 900 pattern features that could be potential “code words.”

Using an algorithm developed decades ago for the telecommunications industry, they then monitored which of the potential words showed up reliably when macrophages responded to a particular threatening stimulus, such as a bacterial or viral toxin. This narrowed their list to six specific features, or “words,” that correlated with a particular response.

To confirm that these pattern features contained meaning, the team turned to machine learning. If they taught a computer just those six words, they asked, could it distinguish the external threats to which the computerized cells were responding? The answer was yes.

But what if the computer had five words available, instead of six? The researchers found that the computer made more mistakes in recognizing the stimulus, leading the team to conclude that all six words are indeed needed for reliable cellular communication.

To begin to explore the implications of their findings for understanding autoimmune diseases, the researchers conducted similar studies in macrophages from a mouse model of Sjögren’s syndrome, a systemic condition in which the immune system often misguidedly attacks cells that produce saliva and tears. When they listened in on these cells, they found that they used two of the six words incorrectly. As a result, they activated the wrong responses, causing the body to mistakenly perceive a serious threat and attack itself.

While previous studies have proposed that immune cells employ a language, this is the first to identify words in that language, and to show what can happen when those words are misused. Now that researchers have a list of words, the next step is to figure out their precise definitions and interpretations [2] and, ultimately, how their misuse may be corrected to treat immunological diseases.


[1] Six distinct NFκB signaling codons convey discrete information to distinguish stimuli and enable appropriate macrophage responses. Adelaja A, Taylor B, Sheu KM, Liu Y, Luecke S, Hoffmann A. Immunity. 2021 May 11;54(5):916-930.e7.

[2] NF-κB dynamics determine the stimulus specificity of epigenomic reprogramming in macrophages. Cheng QJ, Ohta S, Sheu KM, Spreafico R, Adelaja A, Taylor B, Hoffmann A. Science. 2021 Jun 18;372(6548):1349-1353.


Overview of the Immune System (National Institute of Allergy and Infectious Diseases/NIH)

Sjögren’s Syndrome (National Institute of Dental and Craniofacial Research/NIH)

Alexander Hoffmann (UCLA)

NIH Support: National Institute of General Medical Sciences; National Institute of Allergy and Infectious Diseases



    The amazing odyssey of macrophages-mediated immunomodulation in complex endotoxin-mediated inflammatory diseases warrants future public health-oriented dynamic research efforts for deciphering the underlying cellular/molecular/genetic basis of myriad diseases ranging from airway inflammation/asthma., sepsis, carcinomas, neurodegeneration and reproductive disorders/infertility!
    One of my elegantly published reviews focused on Aldose Reductase Inhibitor Fidarestat and endotoxin/LPS-mediated inflammatory diseases in Expert Opinion on Investigational Drugs (2012), and therefore, these innovative data-sets on “macrophages” appear immunotherapeutically attractive for successful design of pharmacological scaffolds and predictive biomarkers in complex human diseases in the current Covid-19 pandemic era.
    Congratulations to my scientist-clinical researcher contemporaries for an excellent snapshot.
    Once again, the NIH USA Director’s critical crisp meaningful insights were enlightening for developing the ever-expanding medical research globally.

  • DIck says:

    Apparently some fungi in North America (Cryptococcus gatti) have evolved to evade macrophages. There is some cosmic justice in the petri dish of planet earth where Homo sapiens are considered debris by other organisms that don’t even have a prefrontal lobe!

    One question to certainly keep in mind is, if cellular processes used by other organisms are targeted to get rid of them and human cells also utilize similar pathways, is that considered acceptable collateral damage?

  • Peter Wolczko says:

    In the last 15 to 20 years, there has been and still is a move to describe somethings that are serious, by another name. But people have been describing them in a more friendly manner. When the COVID-19 started to change it’s design, I use the description as Mutations. The COVID-19 virus is Mutating. This is extremely serious. At no time should we describe anything that is as grave as the Corona virus as just a variant. I willing to say that if you put a 100 people in a room,and ask which they think is more dangerous, a variant or a mutation, I feel most would say mutation is more serious. Please call the design change in the Coronavirus a Mutation. Do not try to sugar coat anything like this.

    • Conrad Miller MD says:

      @Peter Wolczko Let’s define the 3 important words here: mutation: change in genetic code sequence or genome, via amino acid change, deletion, addition. Variant: for a virus, the functional result/altered virus, from the mutation that may or may not become prominent or die away; strain: what we worry most about, a variant that evolves in our nomenclature to “a strain” especially when it is potent like all the Greek monikered strains we are worried about from Alpha to Delta to Kappa. Though the terms variant and strain are being used more interchangeably right now, as what has happened with droplets and drops and droplet nuclei and aerosols. New language. Thanks to COVID-19. And now we have the language of macrophages and its decoding as so well explained by Dr. Collins. Love the SOS analogy. Or did you borrow that from the paper itself, Dr. C?? Have to watch those abbreviations though, without defining what each letter means, for your non-virologist reader. Thank You for this fascinating description! Now I have to go watch that video 4 times (at least).

  • M. Robinson says:

    What are the adverse effects from most importantly young adults’ and children that have a natural immunity or already been infected and now have the natural anti-bodies who are vaccinated with the mRNA. Where are the studies of the effects, and do the children really even need to be vaccinated??? I think there is too much lab-rat experiences being done on humans.

    • Hasnat says:

      If you induce immunity using any form of adjuvant, however you want to define that, the immune reaction is likely to be more robust. Hepatitis vaccinations routinely have titer checks, and yet?

      How covid “buds” from an infected cell is very relevant. Given the history of viruses with known causes of autoimmunity, something to chew on. Auto-immunity effects are not likely seen in 3-6 months or even a year. Perhaps why there is relevance of EUA while clinical trials are ongoing for an additional 3 years. Recall, what landed people in emergency rooms with the original covid strain is opportunistic pneumonia in the lungs. With the delta strain, that seems to have become opportunistic black fungus. We don’t live in a vacuum, the human body is very much a symbiotic relationship with a bunch of different organisms. If you ever got chicken pox, you are cohabitating with the virus. Without overt symptoms, what difference does it make?

      When you got your shot(s), you also got a piece of paper clearly outlining the premise of EUA. This is not lab rat scenario, which is early preclinical, but has graduated to macaques and other primates. Is it any wonder billionaires are jetting off to space this month?

  • Gianni Zuccheri says:

    I thank Dr. Collins for the opportunity of this important topic.
    With the hope that the Covid19 will vanish without having first completed the entire Greek alphabet with its variants, I would like to ask you some reflections after reading this interesting article on macrophages:
    “ ..macrophages.. evidence that autoimmune conditions can arise when immune cells misuse certain words in this vocabulary. This bad communication can cause them incorrectly to attack substances produced by the immune system itself as if they were a foreign invaders..-“
    I therefore link to the proposal for third COVID-19 vaccine booster shot.
    Side effects (with any type of Covid-19 vaccine) are generally reported more frequent and more pronounced after the second dose, both for common ones (e.g. temperature rise, headache, joint pain and persistent asthenia for several days) and for the most severe ones (allergic shock, myocarditis, etc.).
    “..when macrophages responded to a particular threatening stimulus, such as a bacterial or viral toxin. This narrowed their list to six specific features, or “words,” that correlated with a particular response…”
    We also remember the post-vaccination solar photosensitivity reactions (I cite an example, researchers at Massachusetts General Hospital . . . ) In the article , macrophages: “.. result, they activated the wrong responses, causing the body to mistakenly perceive a serious threat and attack itself…”
    How can we think are side effects negligible with the third dose?
    We think of cardiac tissues, subjected to continuous and incessant work, with the risk of inflammation (myocarditis and pericarditis) if the immune cells (macrophages) are deceived by the encoding of false messages.
    Finally, in the case of a third dose that is directed towards the Delta variant, two antibody lines will be present at the same time, with a competitive dynamic between them for the common epitopes of the Spike.
    In addition to the risk of immune complex disease and the various adverse effects, there could be a paradoxical effect with a lower expected result due to the competition between ineffective and valid antibody. Looking for some sort of analogies with diseases already known , I dwell on the Dengue disease and find in the Merck Manual (MSD): “.. a more serious disease can result from the exacerbation of the antibody-dependent infection, in which patients have a non-neutralizing antibody from a previous infection with one dengue serotype and then contract another infection with a different dengue serotype. ”
    Thank you for your attention

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