THE BLACK DEATH AND IMMUNITY GENES: IS THERE A LINK?

A recent study that was published in the scientific journal Nature described how a link has been found between people who survived the black plague and the evolution of certain genes. These particular genetic alleles (forms of a gene) linked to the black death are what we see today in the human population. Alleles are different forms or variants of a gene.  A good example of alleles is eye color. The gene is eye color but alleles are the different colors, so you could have say blue, brown, or green. Each different color is an allele of the gene for eye color.

Some of the gene alleles found in the study on the black death are linked to particular autoimmune conditions.  To understand what the scientists found we need to briefly discuss the black death and what the consequences are for the health of people living now when considering these genes.

What is the black death?

The black death is the name that was given to people who suffered from the bubonic plague. The disease is called black death because the tissues of the afflicted people often turn black as gangrene sets in as the tissue dies. Plague in all forms is not common today, and there are only about 5000 cases worldwide each year.

The cause and symptoms of the black death

The black death (bubonic plague) is caused by a bacterial organism called Yersinia pestis. This bacterium is carried by fleas that feed on rats. On occasion, the fleas bite humans, infecting them with this bacterium.

This disease is not as common today due to measures to control rats around humans and improved sanitation and hygiene measures. However, black death outbreaks do still occur in some areas.

The symptoms of bubonic plague are as follows:

• Chills and a high fever of up to 106^oF (41^oC ) are evident.
• Swollen and painful lymph nodes (these are called buboes) are present.
• The spleen and liver can become affected.
• The bacteria may spread to the lungs and cause the more contagious pneumonic plague.

How the black death is treated and how it can be prevented

People with the plague are treated with antibiotic medications such as ciprofloxacin, doxycycline, or streptomycin. If a person has the pneumonic form of the plague, they will need to be isolated since they are contagious.

Measures to prevent catching the plague involve the following:

• Instituting measures to control rodents.
• Removing trash that attracts rodents.
• Keeping pet animals free of fleas that may have also fed on rodents.

How did the black death act in selection?

The scientists analyzed the genes of the DNA of people who lived many years ago during the time of the black death pandemic. They compared the DNA of those who survived the plague versus those who did not. Certain alleles were noted to be more prevalent in the survivors.

Scientists realized that particular alleles became more frequent because of the plague. The assumption is that immunity genes that confer protection would be found more often in surviving generations while other genes would become less frequent over time as people with those genes died from the plague. We can use the theory of natural selection to explain what happened.

• Natural selection is all about the change in the frequency of alleles.
• As individuals who carry the best genes are more likely to survive an illness and leave offspring, one would expect the genes to continue on in future generations.
• This is indeed how natural selection works and is how, in time, populations evolve.

There can sometimes be a trade-off when it comes to what traits are selected for. While the alleles gave protection from the black death and were, thus, selected, they seem to also have increased the odds of autoimmunity.

What genes were found to be helpful in immunity from the black death?

The genes discussed in the study on the black death and immunity are the ERAP (endoplasmic reticulum aminopeptidase) genes. These genes influence how proteins are modified in the endoplasmic reticulum of the cell.  Below we briefly outline how this system works.

• ERAP genes code for a protein that modifies antigens. Antigens are molecules that trigger an immune response.
• The modified antigens then fit into a molecule of the immune system called the major histocompatibility complex 1 (MHC 1). 
• The MHC 1 then alerts the immune system that there is a foreign entity that needs to be attacked.
• T lymphocytes and other immune system cells like macrophages are then activated and take action to rid the body of the intruder.

Using historical data and DNA, the researchers found that people who had two copies of the gene known as ERAP2 were better at surviving the black death than those people who did not have this gene but rather different forms of ERAP genes.

ERAP genes

 Some further relevant facts about ERAP genes are discussed below:

• ERAP genes, in general, are very polymorphic. In other words, there are many variants that occur in human populations.
• Expression of these genes may also be linked to cancer. Knowing that some forms of ERAP are linked to cancer could lead to potential therapies for treating these ailments.
• Both ERAP1 and ERAP2 modulate the immune system and there is evidence that some forms of these genes are linked to autoimmune problems.

What are the consequences of ERAP genes for autoimmune diseases?

It is not uncommon for autoimmune diseases such as lupus and rheumatoid arthritis to be associated with variants in specific genes. Similarly, scientists looking at the ERAP genes have found some association with specific autoimmune diseases.

The ERAP proteins are involved in the molecular pathway in which antigens are processed as we have already mentioned. There appears to be a link between certain forms of ERAP genes and autoimmunity. Links have been found for the following illnesses:

• Rheumatoid arthritis: This autoimmune disease is associated with having the same ERAP 2 variant found in the study on the black death.
• Lupus: This is also linked to the ERAP 2 variant of the study.
• Spondyloarthritis: The interaction between ERAP genes and human leukocyte antigen class I gene (HLA-B27) increases the odds of a person developing this autoimmune illness.
• Inflammatory bowel diseases (IBDs): ERAP 1 genes interacting with certain human leucocyte genes increases the likelihood of IBDs such as Crohn’s disease and ulcerative colitis. The ERAP 2 variant found in the study is linked to a higher risk of getting Crohn’s disease.
• Type I diabetes: This form of diabetes has long been recognized as an autoimmune condition. Now researchers have discovered an association between type I diabetes and variants of the ERAP gene.

Other factors that increase autoimmunity

Besides genes, there are other factors that increase the risk of autoimmune disease. These are listed below:

• Obesity: Obesity increases the risk of many conditions including autoimmune disease.
• Age: People are more prone to autoimmune disorders as they age, and it is commonly first diagnosed in middle age.
• Biological sex: Females are more likely to develop autoimmune illnesses.
• Smoking: Smokers are at increased risk of autoimmunity.

It is likely a combination of genes and environmental factors that impact your odds of developing an autoimmune disease. It is, thus, essential to have a healthy lifestyle including exercise and a healthy diet to reduce your risk.

Conclusion

The black death acted to select certain forms of the ERAP genes. While this allowed greater survival and decreased mortality from the plague, it appears to have increased autoimmunity in the population. The black death is quite uncommon today but the genes that were selected still remain in the population.

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Sources

• Babaie, F., Hosseinzadeh, R., Ebrazeh, M., Seyfizadeh, N., Aslani, S., Salimi, S., ... & Mohammadi, H. (2020). The roles of ERAP1 and ERAP2 in autoimmunity and cancer immunity: New insights and perspective. Molecular immunology, 121, 7-19. https://www.sciencedirect.com/science/article/abs/pii/S0161589019309010
• Bush, L. M. (2022). Plague and other Yersinia infections (Black death, bubonic plague), Merk Manual. https://www.msdmanuals.com/home/infections/bacterial-infections-gram-negative-bacteria/plague-and-other-yersinia-infections
• Castro-Santos, P., Moro-García, M. A., Marcos-Fernández, R., Alonso-Arias, R., & Díaz-Peña, R. (2017). ERAP1 and HLA-C interaction in inflammatory bowel disease in the Spanish population. Innate immunity, 23(5), 476-481. https://pubmed.ncbi.nlm.nih.gov/28651467/
• Klunk, J., Vilgalys, T. P., Demeure, C. E., Cheng, X., Shiratori, M., Madej, J., ... & Barreiro, L. B. (2022). Evolution of immune genes is associated with the Black Death. Nature, 1-8. https://www.nature.com/articles/s41586-022-05349-x
• Vitulano, C., Tedeschi, V., Paladini, F., Sorrentino, R., & Fiorillo, M. T. (2017). The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis. Clinical & Experimental Immunology, 190(3), 281-290. https://pubmed.ncbi.nlm.nih.gov/28759104/

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