Elinor Riley from the London school of hygiene and tropical medicine is studying the immune response to malaria in sub-Saharan Africa. She found that, as with other chronic parasitic infections, prolonged infection with Plasmodium falciparum causes the development of a strong immune response through regulatory T cells. In areas of Africa where malaria is widespread, the population has more T cells circulating in the peripheral blood. However, in urban centers where malaria is less common, there are fewer such cells.
Scientists are debating whether this is a good thing or a bad thing. Those of them who put forward arguments for, pay attention to the existence of a correlation between the number of regulatory T-lymphocytes and a higher parasitic load. “You give them carte Blanche,” they claim. And evidence suggests that limiting regulatory T cells helps fight malaria. Take the Fulani tribe of Burkina Faso in West Africa as an example. Italian scientists have found that members of this tribe have an unusual resistance to malaria. However, Fulani resistance to malaria is not based on sickle cell genes. Instead, they often have variants of HLA genes that are associated with autoimmune diseases. Their regulatory T cells have a genetic defect, and their suppressor cells are blocked. As a result, members of the Fulani tribe form a very strong inflammatory response, even compared to other ethnic groups living nearby, such as the mossi tribe. The Fulani are very confident in eliminating Plasmodium parasites that invade their bodies. However, the price they pay for blocking their own suppressor cells is a higher vulnerability to autoimmune diseases such as type one diabetes.
The Fulani example highlights both the disadvantages and advantages of regulatory T cells, and also suggests that at least in the environment in which members of a given tribe live, the benefits of blocking the “switch” may outweigh the obvious disadvantages.
However, the Fulani approach to overcoming malaria is only one of many possible approaches. For example, Riley and her colleagues believe that in areas where P. falciparum is widespread, more regulatory T cells (the opposite approach) may increase the likelihood of preventing fatal complications such as cerebral malaria. Unlike the Fulani, the inhabitants of these areas do not destroy the parasites immediately. Instead, they use a strategy that can be called “tolerance of the enemy”: allowing the parasite to survive, allowing it to take away more resources than might be ideally appropriate, but at the same time avoiding the destruction of their own home.
The inhabitants of Sardinia offer other evidence that balanced, rather than rampant, aggression is the key to overcoming malaria. In this case, the evidence is presented in the form of an autoimmune disease that is fortunately absent in Sardinia — ankylosing spondylitis. A specific variant of the human leukocyte antigen (called HLA-B*2705) causes a predisposition to severe inflammatory spine disease, symptoms of which include vertebral fusion and stooping posture. What benefits does this variant of the HLA gene bring? It increases protection against retroviruses such as the hepatitis C virus or HIV. This gene is distributed around the world in a strange way. It is found only in areas relatively free of malaria, particularly at high altitudes above sea level. However, in places like Sardinia, this variant of HLA is almost completely absent.
Alessandro Mathieu and Rosa Sorrentino from the University of Cagliari believe that the presence of this gene variant in malarial regions such as Sardinia is simply too dangerous. Rampant ferocity can be useful in the fight against viruses, but the same frenzy in the fight against P. falciparum can lead to an explosion.
Riley believes that in fact, despite the Fulani case, during the malaria season in rural Africa, the number of regulatory and attacking cells increases simultaneously, not just one or the other. “In my opinion, the balance between the inflammatory and anti — inflammatory immune response plays a crucial role,” says Riley. The eradication of malaria requires subtlety, not brute force. If there are too many regulatory T cells, the parasites will pull all the juice out of you. But if there are too many attacking cells, there is a risk of developing life-threatening malaria.
Why this obsession with suppressor cells? As a rule, people with autoimmune or allergic diseases have a deficit or dysfunction of regulatory T cells [132]. Based on the results of Riley’s work in Africa, it can be concluded that in the old malarial times, the inhabitants of Sardinia, in all likelihood, had more regulatory T-cells that protect not only from P. falciparum, but also from pathogens of other chronic infectious diseases, such as tuberculosis and helminths. (As recently as the 70s, half of the schoolchildren in the capital of Sardinia, Cagliari, had helminths.)
Did the regulatory T cells induced by these parasitic infections counterbalance the Sardinian predisposition to autoimmune diseases? Is it possible that in such circumstances, the ability of Sardinians to cope with Plasmodium infection provides all the advantages without any negative consequences? The data obtained in the countries of Africa South of the Sahara, give an affirmative answer to these questions. On the contrary, the appearance of multiple sclerosis in Sardinia suggests that if the malarial regions in the past are completely rid of the pathogen of this disease, they can expect an unpleasant surprise.
The broader question concerns the evolutionary context. The genes that cause predisposition to autoimmune diseases have evolved in a completely different environment from today’s environment — an environment characterized by a large number of pathogens of chronic infections (such as helminths, malaria, and tuberculosis) and a relative excess of regulatory T cells. If these environmental stimuli are removed, the regulatory aspects that they generated will disappear. However, the distinctive features encoded in our genes remain unchanged. They are written into our genetic code.
Rick Maisels, about whom I will talk a little later, uses the term allelic rheostats to refer to such variants of genes — alleles that make small changes to certain aspects of the immune system, but in the absence of infection can “miss” and cause an autoimmune or allergic disease. These alleles are two-faced: they provide opposite results (enhanced protection or degenerative disease) depending on the broader context. Although the Sardinians, with their unique history of malaria exposure, are an exceptional example, this lesson can be summarized.
Whoever we are, we have evolved with far more parasites and commensals (large and small) than we are dealing with today. The consequence of this and (let’s face it) the reason for hope is that the resumption of contact with some of these organisms can restore the balance of the immune system. For his part, Sotgiu dreams of using the replacement of P. falciparum to help the inhabitants of Sardinia suffering from multiple sclerosis. Ten years ago, neurologist Giovanni Ristori and his colleagues at the Sapienza University in Rome injected twelve patients with multiple sclerosis with the Bacillus Calmette-guérin (BCG), a weakened microbacterium that is used to immunize against tuberculosis. According to the results of magnetic resonance imaging, the development of multiple sclerosis significantly slowed down and remained much less active than before vaccination, even two years later. For reasons that are not entirely clear, the m bacterium bovis, which was part of the tuberculosis vaccine, was able to correct the dysfunction underlying this autoimmune disease and stop its development.
Now scientists around the world are developing this idea, using multicellular parasites (helminths) instead of bacteria to treat autoimmune diseases.Why this obsession with suppressor cells? As a rule, people with autoimmune or allergic diseases have a deficit or dysfunction of regulatory T cells. Based on the results of Riley’s work in Africa, it can be concluded that in the old malarial times, the inhabitants of Sardinia, in all likelihood, had more regulatory T cells that protect not only from P. falciparum, but also from pathogens of other chronic infectious diseases, such as tuberculosis and helminths. (As recently as the 70s, half of the schoolchildren in the capital of Sardinia, Cagliari, had helminths.)
Did the regulatory T cells induced by these parasitic infections counterbalance the Sardinian predisposition to autoimmune diseases? Is it possible that in such circumstances, the ability of Sardinians to cope with Plasmodium infection provides all the advantages without any negative consequences? The data obtained in the countries of Africa South of the Sahara, give an affirmative answer to these questions. On the contrary, the appearance of multiple sclerosis in Sardinia suggests that if the malarial regions in the past are completely rid of the pathogen of this disease, they can expect an unpleasant surprise.
The broader question concerns the evolutionary context. The genes that cause predisposition to autoimmune diseases have evolved in a completely different environment from today’s environment — an environment characterized by a large number of pathogens of chronic infections (such as helminths, malaria, and tuberculosis) and a relative excess of regulatory T cells. If these environmental stimuli are removed, the regulatory aspects that they generated will disappear. However, the distinctive features encoded in our genes remain unchanged. They are written into our genetic code.
Rick Maisels, about whom I will talk a little later, uses the term allelic rheostats to refer to such variants of genes — alleles that make small changes to certain aspects of the immune system, but in the absence of infection can “miss” and cause an autoimmune or allergic disease. These alleles are two-faced: they provide opposite results (enhanced protection or degenerative disease) depending on the broader context. Although the Sardinians, with their unique history of malaria exposure, are an exceptional example, this lesson can be summarized.
Whoever we are, we have evolved with far more parasites and commensals (large and small) than we are dealing with today. The consequence of this and (let’s face it) the reason for hope is that the resumption of contact with some of these organisms can restore the balance of the immune system. For his part, Sotgiu dreams of using the replacement of P. falciparum to help the inhabitants of Sardinia suffering from multiple sclerosis. Ten years ago, neurologist Giovanni Ristori and his colleagues at the Sapienza University in Rome injected twelve patients with multiple sclerosis with the Bacillus Calmette-guérin (BCG), a weakened microbacterium that is used to immunize against tuberculosis. According to the results of magnetic resonance imaging, the development of multiple sclerosis significantly slowed down and remained much less active than before vaccination, even two years later. For reasons that are not entirely clear, the m bacterium bovis, which was part of the tuberculosis vaccine, was able to correct the dysfunction underlying this autoimmune disease and stop its development.
Now scientists around the world are developing this idea, using multicellular parasites (helminths) instead of bacteria to treat autoimmune diseases.