Welcome to the twentieth century: Sardinia does the cleaning

Unlike most of Western Europe, where the prevalence of infectious diseases has been gradually decreasing since the nineteenth century, the epidemiological transition of Sardinia has occurred relatively recently, and in a very short period. In the late 1940s, the Rockefeller Foundation, which had initiated a campaign to eliminate hookworms in the United States several decades earlier, sent its employees to the island on bicycles and mules. Armed with tanks of DDT insecticide, they sprayed swamps, ponds, and any other bodies of stagnant water they encountered.

These actions were successful. In 1947, authorities reported 40,000 cases of malaria on an island of about 1.2 million people. Three years later, the number of new cases dropped to zero. For thousands of years, the Plasmodium parasite caused countless cases of malaria, and in just a few years it disappeared. And ten years later, the number of cases of multiple sclerosis began to slowly increase.

In General, there is a trend towards the spread of multiple sclerosis in the world along a North — South gradient, with the prevalence of this disease increasing as it approaches the poles and decreasing as it approaches the equator. In the latitude of Sardinia, this disease is not as widespread as, for example, in Scandinavia or Scotland, two regions with extremely high rates of disease. In this regard, when in the 70s and 80s, Sardinian scientists first recorded an upward trend in the prevalence of multiple sclerosis, noting that Sardinians born in the 60s develop this disease more often than their parents, grandparents, they even had doubts about the truth of this alleged increase. They thought that this trend could be attributed to improved diagnosis or increased survival rates for patients with multiple sclerosis.

However, the results of comparative studies have refuted these doubts. In the province of Ferrara on the Italian mainland, the incidence of multiple sclerosis has remained at the level of two cases per 100,000 inhabitants for a long period of time. In Sardinia, the increase in the prevalence of this disease was accelerated. Between the late ’70s and early’ 90s, the incidence of multiple sclerosis more than doubled, from two to five cases per 100,000 inhabitants per year. And in the late 90s, this indicator increased again to 6.8 cases.

Then a paper published in the mid-90s drew Sotgiu’s attention to the paradoxical effects of malaria on the human genome. The study described there found gene variants in Africans that determined the outcome of malaria infection. One option reduces the risk of cerebral malaria, but increases the risk of anemia. Another option increases the risk of anemia, but reduces the risk of cerebral malaria. How do these genes work? They inhibit or activate the production of an inflammatory signaling molecule known as” tumor necrosis factor alpha”, or TNF-alpha? An excessive amount of TNF-alpha allows you to quickly repel the attack of the parasite, but also increases the risk of complications. On the other hand, a smaller amount of TNF-alpha, which is produced over a longer period (the second option), avoids cerebral malaria, but increases the likelihood of anemia. It is simply impossible to win in this situation.

Sotgiu also knew that high levels of TNF-alpha are a hallmark of autoimmune diseases. In fact, medications that are widely used to treat inflammatory diseases (such as Remicade and Humira) block this signaling molecule. In Sotgiu’s mind, the idea that the constant severe impact of malaria on Sardinia could lead to the selection of those genes that naturally increase the level of TNF-alpha, and therefore increase the risk of autoimmune diseases. Sotgiu started looking for evidence in the Sardinian genome and very soon found it.

White blood cells Express the human leukocyte antigen (HLA) receptor. They use this receptor (which can be thought of as a molecular grappling hook) to show fragments of the pathogen to other immune cells, to tell them that something bad may be happening, and to demonstrate what this alien looks like.

In 2001, geneticists discovered that human leukocyte antigens, known to cause a predisposition to multiple sclerosis, are more common in Sardinia than in any other region of the world. In the context of Sotgiu’s hypothesis, the most important thing was that these variants were found most often in the areas of Sardinia that were most affected by malaria in the past. If malaria had left its mark on the Sardinian genome, this would have been the pattern to expect.

However, Sotgiu did not find a similar distribution of variants of genes that increase TNF-alpha levels in Sardinia. On the contrary, all inhabitants of Sardinia were found to have gene variants that increase TNF-alpha levels, regardless of altitude or the intensity of malaria infection in previous times. All the inhabitants of Sardinia had a lot of these options — ten times more than the inhabitants of neighboring Sicily, for example. It seemed that the Sardinians had an innate predisposition to a relatively strong inflammatory response.

The question now was: did all this inflammatory potential benefit the Sardinians in the fight against a parasite like Plasmodium? Sotgiu tested this idea in the course of the experiment. He mixed P. falciparum with white blood cells taken from Sardinians suffering from multiple sclerosis (that is, patients who had both a human leukocyte antigen that increases the risk of autoimmune diseases and a variant of the genes that increase TNF-alpha levels). Sotgiu’s control group included healthy Sardinians and multiple sclerosis patients from the Italian mainland. All groups demonstrated a similar inflammatory response to bacterial products. (Plasmodia are not bacteria, but protozoa, distant relatives of animals.) However, compared to the two control groups, the white blood cells of multiple sclerosis patients from Sardinia had the ability to destroy this parasite. These cells were about three times more effective in controlling P. falciparum compared to the control groups. “This is an immunological memory embedded at the genetic level,” says Sotgiu.

Other observers have noted that the inhabitants of Sardinia have a natural enhanced immune defense. Their blood circulates almost twice as much of the enzyme chitotriosidase as the Sicilians. An increased content of this protein means a higher protective potential, but it also leads to an increased risk of multiple sclerosis and stroke. The main discovery was that a high content of chitotriosidase does not increase the risk of multiple sclerosis everywhere. Although Sardinians in General produce almost twice as much chitotriosidase as Sicilians, residents of sub-Saharan Africa, where multiple sclerosis is very rare, have 40% more of this protein than Sardinians, and 3.5 times more than Sicilians. What is it?

In Africa, these immune defense tools are mobilized in the event of infection. In Sardinia, they remain active always, as a genetic trace of the forced fight against malaria for thousands of years. In the absence of the need to fight a real threat, this once profitable adaptation has become pernicious.

When this happened, the observation that malaria prevents autoimmune diseases, as well as the logical conclusion from this observation (consisting in the fact that intentional infection can stop the autoimmune disease) there was already a certain history.

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