In the mid-60s, British scientist Brian Greenwood came to Ibadan, Nigeria, hoping to gain experience in the infectious environment, which has become a rarity in Europe. Greenwood previously worked in the UK with patients suffering from rheumatoid arthritis — an autoimmune disease that affects the joints. He immediately drew attention to the fact that this disease is almost not found in Nigeria. Greenwood analyzed the data and found that out of 100,000 patients who were examined at a local hospital over the past decade, only 104 had this diagnosis. This number of cases of rheumatoid arthritis was only a sixth of the prevalence of the disease in England and Wales. Trying to rule out the possibility that this apparent discrepancy is due to limited diagnostic capabilities, Greenwood examined about six hundred residents of Nigerian villages and found only two mild cases of autoimmune arthritis.
Greenwood knew that genetics could not explain this discrepancy. Many African-Americans, whose ancestors came from these parts of West Africa, were more likely to suffer from systemic erythematous (red) lupus (another autoimmune disease) than whites in the United States and Africans in Africa. So what was the difference between the environment in West Africa and the environment in North America? The most obvious reason is the relatively high prevalence of parasitic infections, including P. falciparum.
Then Greenwood made an observation that was three decades ahead of Sotgiu’s: Africans with malaria have antibodies that target Plasmodium, and they also have a variety of antibodies called “rheumatoid factor” that target their own body tissues. In the UK, elevated levels of rheumatoid factor have been associated with autoimmune diseases such as rheumatoid arthritis and lupus. However, in Africa, the rheumatoid factor was associated exclusively with malarial infection: it helped protect against this parasite. Greenwood’s discovery was that immune factors that help repel the attack of infectious agents in one context cause autoimmune disease in another. So what about re-introducing the pathogen to prevent autoimmune disease?
Back in the UK, Greenwood tested this idea on rodents. It infected rats predisposed to rheumatoid arthritis with the rodent-adapted parasite Plasmodium berghei. These rats had a much milder form of rheumatoid arthritis. The same thing happened to mice that were raised to spontaneously develop lupus, a devastating systemic disease that targets many organs, from the skin to the lungs and kidneys, when the immune system is out of control. Infection with the P. berghei parasite also protected these mice.
There was only one question: how did it all happen? What mechanisms explain these results? Scientists knew that malaria suppressed the immune system, but these experiments were conducted decades before the genomic era and, consequently, a deeper understanding of immunity. At the time, there was no easy way to explain these results and use them. In this regard, Greenwood took up other projects, becoming an authoritative researcher in the field of malaria research.
However, in the following decades, scientists continued to note the relatively low prevalence of autoimmune diseases on the sub-Saharan African continent, along with the widespread spread of parasitic infections, especially malaria. Eventually, the British researcher Geoff butcher again drew attention to this relationship. He stated that malaria provided the selection of genes that determine the predisposition to lupus in developed countries, and that these genes explain the higher vulnerability of African Americans to this autoimmune disease in the United States [119]. In Africa, on the other hand, the same gene variants helped protect against malaria without causing autoimmune diseases.
At the beginning of the new Millennium, scientists conducted a new series of experiments with animals aimed at testing this relationship. Mice with the Sle3 gene, which is known to increase the likelihood of developing lupus, have indeed demonstrated a remarkable ability to fight experimentally induced pneumonia and resist sepsis [120]. This “autoimmune” gene helped protect against the invasion of microbes.
What about the people? Some “autoimmune” genes are actually present in large numbers in populations that have suffered from malaria in the past. A variant of the gene that causes a predisposition to lupus is relatively common in sub-Saharan Africa and Southeast Asia, i.e. people living in the so-called malaria belt. In East Africans with two copies of this gene, cerebral malaria is twice as rare as in people without these two copies. Meanwhile, in relatively pure Hong Kong, carriers of two copies have a 70% higher risk of developing lupus. How does this gene work? A team of researchers at the University of Cambridge concluded that a variant of the gene that makes certain white blood cells more aggressive (essentially by disabling the “switch”) also increases the ability of mice to eliminate Plasmodium.
The point is this: the evolutionary purpose of the factors that underlie autoimmune diseases is not to cause suffering through an autoimmune response; their purpose is to protect. It is also important that, according to repeated observations of scientists in the case of infectious diseases, which are aimed at fighting these gene variants, autoimmunity appears much less often. This finding helps explain another mystery: why genes that cause predisposition to autoimmune diseases have become more widespread in our recent evolutionary past.