One of the joys of having tried to teach Immunology for more than two decades to students of Medicine, Pharmacy and Biotechnology has been to contemplate, albeit from a distance, how this discipline grew, evolved and matured, at the same time that very interesting therapeutic strategies were developed based on in its growing knowledge, among which we can mention the vaccines of ARN and T-tumor immunotherapyCAR o NK-CAR. Without going any further, when I started teaching Immunology, in the last year of the 20th century, not all types of lymphocytes had been discovered yet; certain organelles that are structured during the inflammatory response, such as the inflammasome, had not been discovered either, and innate immunity, which depends on cells such as macrophages and neutrophils, but not lymphocytes, was a defense mechanism without memory capacity . The investigations carried out in recent decades have revealed that this last idea is false, and this issue, the memory capacity of innate immunity cells, is what I want to talk to you about today.
To begin, I would like to try to demystify what is immune memory. When I speak about it to the students for the first time, I see, looking at their astonished faces ¾astonishment that goes through even masks in times of pandemic¾ that they do not understand how a cell can remember anything, if the cells do not have a brain. I explain to them that it is not about spatial or photographic memory, but only about the ability to perform a function again faster and more efficiently than the first time. Cells can easily do this by simply changing the level of function of a few genes, keeping active, or ready to be rapidly activated, the genes needed to perform whatever defensive function. These genes are the ones that produce the proteins, the molecular tools, that make it possible to perform this function, so having them activated or ready means that the cell “remembers” what it did to defend the organism the first time it it had to, when it activated the same genes (or almost).
And why don’t immune cells have their defensive genes ready at all times, some may wonder? Well, because that would cost a lot of energy and, furthermore, it is dangerous to circulate in “easy fight” mode through the body if there is no reason for it. And the reason is to have encountered a specific enemy that has been necessary to eradicate to stay alive. That first hostile encounter indicates that the enemy is prowling the surroundings and it is likely to meet him or his descendants again, so being better prepared than the first time to face him is undoubtedly a “good idea” to survive. to his attack.
trained immunity
Once it is clarified that immune memory is nothing more than a particular type of cell differentiation ¾that is, a process in which cells become different from their ancestors through changes in the functioning of genes¾, it becomes easier to accept that any type of immune cells, not only B or T lymphocytes, as was initially believed, but also cells of innate immunity, such as macrophages, for example, can develop memory. To do this, it would suffice for the level of functioning of their genes, or the ease with which those genes can be activated, to change after a first encounter with an enemy.
Obviously, it is not possible to maintain memory once the cell is dead. The death of many lymphocytes and leukocytes occurs by apoptosis once they have finished with the infection. Cells activated for defense are no longer needed and are kindly invited to get out of the way by committing suicide, which they usually do with admirable obedience and molecular self-sacrifice. For this reason, one of the necessary differences between memory cells and activated cells, the so-called effector cells, is the increased expression of genes that extend their life. These are usually anti-apoptotic genes, reluctant to let cells commit suicide with too much glee. Of course, in addition to these genes, other genes, such as those responsible for the production of cytokines or chemokines, are also modified.
The memory of innate immunity cells has been called trained immunity. Trained immunity was revealed for the first time in 2012, in a research paper that revealed the protective effects of the tuberculosis vaccine against microorganisms other than the mycobacteria that cause it (1). These protective effects were observed in mice lacking T and B lymphocytes, and therefore unable to develop memory of adaptive immunity. However, vaccination with bacillus Calmette-Guerin (BCG), the one used in the tuberculosis vaccine, conferred protection to these immunodeficient mice against infections by the fungus Candida albicans. This superior protection could only be due in this case to a “training” of the innate immunity cells, training that occurs during the fight against the bacillus.
Since that first paper, the accumulated evidence on the new phenomenon of trained immunity has only grown. This evidence also confirms that, in effect, the tuberculosis vaccine administered intramuscularly leads to the generation of trained macrophages that will be located in the pulmonary mucosa (2), where its defensive activity will be more effective. These results carry important implications for the development of new effective vaccines.
epigenetic memories
How do innate immune cells acquire memory? As I have suggested before, memory is just a different state in which cells are able to react more effectively to a stimulus, or in this case even to a class of stimuli. Since the reaction against the stimulus depends on the functioning of the genes, the state of memory depends on the genes responsible for the activation and effector functions being activated more easily in the face of a relevant stimulus. This state of increased ease for activation, in the case of innate immunity memory, is achieved through epigenetic modifications (3).
Epigenetic modifications are actually molecular modifications that alter the chemical properties of the drug molecule. ADN ¾without altering the genetic information it contains¾ or the histones that bind to it and around which the ADN Rolls up and stays organized. These changes modify the ability of the ADN to interact with transcription factors, among other proteins, and facilitates gene transcription. In the case of innate immune memory, it is generally the histones that are chemically modified. Not surprisingly, these chemical modifications occur in the places where genes related to the inflammatory response, among others, are found wrapped in them, for example, those necessary for the production of some cytokines, such as IL-6 and TNF-a.
The epigenetic modification in the histones of the pertinent genes occurs when the cell first acquires a state of activation, by recognizing some molecule of the microorganisms through its molecular pattern recognition receptors (PRRs, for pattern recognition receptors). These molecular patterns are molecules made up of repeating units that are found in microorganisms, but not in our cells. Binding of a receptor on the membrane to one of these patterns produces an intracellular signal that leads to activation of proinflammatory genes, “opens” them, and allows access to enzymes that chemically modify the histones that interact with them. These chemical changes can be long-lasting or, what amounts to the same thing, memory can be very long-lasting, leading to an enhanced state of protection by innate immunity against various threats.
metabolic changes
However, epigenetic modification of pro-inflammatory genes is not all that needs to happen for cells to acquire a memory state and be better equipped against future threats. It is also necessary for the cells to modify their metabolic state so that they are prepared to dedicate the energy and material resources necessary for their defensive function. These changes translate, among other things, into an increase in both glycolysis and oxidative phosphorylation in mitochondria.
The existence of trained innate immunity and its clear protective effects is perhaps part of the explanation for the phenomenon of the higher incidence of infectious respiratory diseases that children, in particular, have been suffering in recent months. The use of masks has undoubtedly reduced exposure to various microorganisms that, even without being particularly dangerous, could be participating in the generation of a well-trained innate immunity.
Thus, just as we must move daily to avoid losing muscle mass, and we must also keep our brain active by avoiding watching too much television and encouraging reading, the immune system needs some daily activity to stay in a trained state and be effective. We still do not know where the optimal balance between hygiene and unsanitary conditions that confers the ideal state of immune protection can be found, but we are beginning to understand why both excessive hygiene and its absence can be detrimental, not only for the development of immune pathologies, such as allergies ¾which are related to excessive hygiene during childhood¾, but also to achieve adequate protection against infections throughout life.
Jorge Laborda (01/15/2023)
References:
Jordi Ochando et al. Trained immunity — basic concepts and contributions to immunopathology. Nature Reviews Nephrology (2022) https://doi.org/10.1038/s41581-022-00633-5.
Kleinnijenhuis, J. et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl Acad. Sci. USA 109, 17537–17542 (2012).
Mangalakumari Jeyanathan et al. Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut–lung axis. Nature Immunology volume 23, pages1687–1702 (2022)
Jorge Laborda is Professor of Biochemistry and Molecular Biology at the Faculty of Pharmacy of the University of Castilla-La Mancha and author of the book We are surrounded. He discovers the extraordinary power of a healthy immune system. (Ed Platform, 2022).
Works by Jorge Laborda.
WE’RE SURROUNDED!
WE’RE SURROUNDED!
Your defenses against coronavirus
Your defenses against coronavirus
Deflamed immunology: An introduction to the immune system and its pathologies
Deflamed immunology: An introduction to the immune system and its pathologies
Deflamed immunology: An introduction to the immune system and its pathologies
Kilo of Science Volume XII eBook
Kilo of Science Volume XII Paper
Kilo of Science Volume I. Jorge Laborda
Kilo of Science Volume II. Jorge Laborda
Kilo of Science Volume III. Jorge Laborda
Kilo of Science Volume IV. Jorge Laborda
Kilo of Science Volume V. Jorge Laborda
Kilo of Science Volume VI. Jorge Laborda
Kilo of Science Volume VII. Jorge Laborda
Kilo of Science Volume VIII. Jorge Laborda
Kilo of Science Volume IX. Jorge Laborda
Kilo of Science Volume X. Jorge Laborda
Kilo of Science Volume XI. Jorge Laborda
Matrix of homeopathy
Chained circumstances. Ed.Lulu
Chained circumstances. Amazon
One moon, one civilization. Why the Moon tells us that we are alone in the Universe
One moon, one civilization. Why the Moon tells us that we are alone in the Universe
One Moon one civilization why the Moon tells us we are alone in the universe
The thousand and one bases of ADN and other science stories
Adenius Fidelius
The intelligence funnel and other essays
The gods have been cloned