A malaria-infested mosquito comes at night to bite you while you sleep; a contagious virus travels through the air in droplets expelled from the mouth of an infected person who is talking near you, and enters your nose and mouth; a bacterial toxin from spoiled food makes its way from your stomach into your bloodstream …
We live in a world dominated by billions of viruses and bacteria. Our immune defenses are responsible for keeping us alive against its constant attacks. But the very origin of those defenders remains a mystery to immunologists themselves. Its operation is complex and exquisitely sophisticated, based on three lines of defense, according to Alfredo Corell, professor of Immunology at the University of Valladolid.
The first is the skin that covers every millimeter of our body, tears and mucus, which prevent invaders from entering . But if any of these succeed, the second line of defense is activated, natural immunity : a group of cells and molecules with which we are born, which never change throughout our lives, nor can they be trained.
There are cells – macrophages – that devote themselves to swallowing the invaders they encounter whole in their continuous patrolling of the pipes of the human body and its tissues. They are all a kind of cellular gluttons. “They are in many places, in the blood, as monocytes; or in tissues, like macrophages, “adds Corell. “They eat every foreign substance .”
At this second level there are also natural killer cells ( nk lymphocytes , natural killers ), they are specialists in killing viruses; and substances such as interferon, a protein that prevents the microorganisms that have entered from growing. This defensive line is activated locally at the point of infection, where the mosquito bites or the site of the invasion of pathogens (the epithelium of the respiratory tract, if we have breathed them, or the digestive epithelium, if we ingest it).
And the third line of defense is much more sophisticated: specific immunity . Three types of cells are found here: coordinator or helper T lymphocytes, which act “like the conductors of an orchestra and decide what to do”, although they secrete B lymphocytes that produce antibodies or killer T lymphocytes against the invader. The response does not occur at the site of infection, but in the lymph nodes close to the site of the attack, distributed throughout the human body.
The recognition mechanism of this cellular system represents an elite memory whose ability to produce variants leaves in diapers the most powerful artificial intelligence programs that recognize faces in a crowd.
Our immune system is capable of recognizing, at least, a trillion different pathogens, including bacteria, viruses, fungi … and of manufacturing up to a trillion different antibodies, a trillion different lines of killer cells, a trillion kinds of cells. coordinators… The variability is simply astonishing.
Elite immunity is nothing but a prodigious memory. It is normally built a week after infection, but within twenty days it produces memory cells that patrol the body and instantly recognize the invader if it reappears in the future. When did such a sophisticated system emerge? And because?
We have to go back in time, since this defensive memory capacity is only found, within the animal world, in vertebrates. It was such a dramatic event that some immunologists speak of the big bang of immunology . And perhaps it happened some 450 million years ago , when in jawed vertebrates, white blood cells – lymphocytes, in short – acquired that sensational ability to place the invader on a precise and custom-made target under a new and powerful telescopic sight born of biology. It is possible that this event is due to an infection that some marine creature suffered from a virus or a microbe, in those remote times.
To understand this time travel, we must ask ourselves: how is it possible that the human genome, which consists of some 15,000 genes, is capable of recognizing a trillion different things? “I was petrified when I studied it,” confesses our professor. “Before I believed that if I had an infection, my immune system built the specific elements to fight it, but it is not like that.” It is as if one were prepared to face all the infections in the world, even though throughout his life he suffered a tiny part of them.
At the end of the 1970s, research by Susumu Tonegawa, from the Massachusetts Institute of Technology (MIT) – which ultimately earned him the Nobel Prize in Medicine – revealed the existence of two genes, called RAG1 and RAG2, in B lymphocytes. These genes allow them to make this astonishing number of variants. It’s better understood if we go to the National Lottery, suggests Corell. To make a hundred thousand numbers, you have to build a hundred thousand marbles. But the ONCE lottery only needs five drums (for units, tens, hundreds …) and ten balls in each drum. “With fifty balls you already get those 100,000 numbers.”
The incredible versatility of B lymphocytes allows them to carry out all kinds of genetic combinations until they find the one that fits the invader and traps it like a glove. It is determined by the two RAG genes, and it is genetics itself that allows us to track them in remote time. Sharks, which are an extraordinarily ancient group – the first arose 450 million years ago – already have them. RAG genes are present in all jawed vertebrates, also called gnathostomes . They arose in the Silurian period and are part of 99% of vertebrates. In contrast, jawless or agnate fish, such as witchfish and lampreys, and in general all invertebrates lack these RAG genes.
What was its origin? Craig Thompson of the University of Chicago, Illinois, suggested in 1995 that the RAG1 and RAG2 genes were once mobile genetic elements, in short what scientists call transposons: pieces of DNA that are capable of jumping and integrating in different places. along a long DNA sequence as if they were genetic mountebanks. Thomson himself even suggested that these mobile elements were carried by a virus that infected the germ cells of a vertebrate with jaws 450 million years ago, when the two vertebrate branches separated. It is called the hypothesis of the transposon , or, if you will, the invasion of the transposons: an infection by some virus or bacteria forever transformed the immune defenses of vertebrates and has made us what we are today .
An investigation carried out in 2006 revealed that in a species of violet sea urchin – in short, an invertebrate – there are genes that are very similar to RAGs. Although invertebrates do not have immune cell memory, they could have suffered a transposon infection , only that in the end they could not acquire it. Why it was successful in some animals while in others it will not continue to fuel the scientific debate. Some speak of a single big bang, a single event, while others suggest that immunological memories were acquired gradually and independently in various groups of organisms.
The truth is that 90% of animals do not have acquired immunity , but they cope quite well with their innate immunity in a world where viruses and bacteria are always lurking. This immunity is fundamentally based on the existence of cellular receptors that allow the cells that patrol our body to recognize the invader. Up to two hundred types of receptors have been found in sea urchins and sea sponges. And plants also have receptors that look like them. Natural immunity was probably born with the first multicellular animals around 600 million years ago.
Plants, for their part, have a sophisticated immune system. Many species, such as cabbage, mustard, turnip, and broccoli, contain receptors called LORE. These are capable of detecting the fat and sugar molecules present on the walls of the bacteria that attack them. Their immune system manufactures proteins that destroy invaders, reinforce plant cell walls in other areas to prevent them from entering, and even slaughter leaves and entire branches that have already been infected, detaching them to cut the problem apart .
“Plants have highly developed innate immunity,” says Corell. “There are substances called defensins that are natural antibiotics. We have them in tears and mucus, and plants also have them. Antibiotics kill microorganisms directly ”.
If we go even further back in time, we enter the domain of the world exclusively inhabited by microbes . The first signs of life probably appeared about 3.8 billion years ago. Until the appearance of multicellular beings, that leaves us a planet inhabited by bacteria and viruses, staunch enemies of each other, for at least three billion years! To defend themselves against these attacks, they had to develop a kind of molecular defenses. Even viruses that defend themselves from other viruses called virophages, explains José Antonio López Guerrero, professor of Microbiology at the Department of Molecular Biology at the Autonomous University of Madrid. “The largest or giant viruses are called mimiviruses and they have developed a system called CRISPR capable of degrading the genome of these virophagous viruses.” Bacteria have a similar defense mechanism to degrade the DNA of the invaders, and to their arsenal they add a type of restriction enzymes that are like scissors that cut the DNA of the invader, enzymes for which they are protected.
And as for single-cell animals, protozoa, like amoebae, have a “pattern recognition system for possible invaders and a system to engulf it, which would constitute a type of primary immunity that would be the precursor to immunity. natural ”, concludes this virologist. The immune system is the consequence of a living world constantly struggling to get ahead.
