The Genetic Key to Cytokine Storms, ARDS & Respiratory Infections (IL6)
Interleukin-6 (IL-6) is an inflammatory cytokine that helps protect against disease, but too much can lead to dangerous cytokine storms. What is its role in coronavirus infection?
What is Interleukin-6?
Interleukin-6 (IL-6) is a cytokine that has either pro-inflammatory or anti-inflammatory properties, depending on the circumstances and the tissue that secretes it. It has complicated mechanisms of effect and interacts with many other cytokines and inflammatory signals.
IL-6 is typically increased when the body is diseased or stressed. Conditions associated with increased IL-6 include obesity, chronic stress, too little sleep, overeating sugar, smoking, excess alcohol, and overly strenuous exercise.
What is ARDS?
ARDS is a progressive, life-threatening condition that may develop from severe cases of respiratory diseases such as pneumonia. During ARDS, the lungs no longer work properly because they get filled with fluid leaking from the blood vessels. This leads to laboured breathing, insufficient oxygen supply, and eventually organ failure. People with ARDS often need to go on a ventilator, and over 40% of them end up dying.
ARDS has a number of potential causes, and high IL-6 can often predict the development of ARDS. In COVID-19 and other severe respiratory infections, ARDS has a close relationship with another complication called a cytokine storm.
What are Cytokine Storms?
A cytokine storm is a dangerous inflammatory state that results when the immune system overreacts to an infection. During a cytokine storm, inflammatory signals go haywire, and the immune system does more damage than the infection itself. Cytokine storms feature massive increases in many inflammatory signals, including IL-6.
Hyper-reactions may be involved in severe cases of COVID-19.
IL-6 in the Cytokine Storm
IL-6 plays a protective role in the immune system’s response to viruses. It is directly antiviral in a laboratory setting, and some amount of IL-6 is required for a healthy immune response to viral infection. However, too much IL-6 can be very dangerous. There may even be a direct correlation between how high IL-6 spikes and how serious certain viral infections become. Some researchers have even suggested that IL-6 could be a reliable marker to identify severe infections and predict cytokine storms in COVID-19 patients.
Variants Associated with Cytokine Storms
Generally speaking, high IL-6 tends to predict cytokine storms and ARDS. IL6 genetic variants that increase cytokine expression could therefore be a problem.
Many IL6 variants have been found to modify IL-6 expression. At rs1800795, for example, the more common ‘G’ allele is linked to increased IL-6, while the less common ‘C’ allele appears to decrease IL-6.
But, don’t worry if your results show a lot of high IL-6 alleles. In most cases, the high-expression genotypes are actually more common than the low-expression ones. Because of this, it’s better to think of low-expression alleles as being potentially protective against cytokine storms and ARDS!
Initial Infection vs. Disease Severity
It’s important to remember that IL-6 isn’t entirely bad; some amount of IL-6 is required for a healthy and appropriate immune response to a threat.
On the other hand, elevated IL-6 has been predictive of severe pneumonia, hospitalisation, and mortality in COVID-19 patients.
It is possible that high IL-6 could be protective against initial infection, but predispose an already infected patient to severe disease. But generally, IL-6 should be lower, but balanced: ready to respond to infection, but not so high as to potentially trigger dangerous cytokine storms.
High IL-6 is associated with severe pneumonia and poor prognosis in COVID-19 patients.
Different Expression in Different Organ Tissues
Another layer in this complex story of IL6 is that different cell types and tissues have different levels of IL6 expression, and the effect of a SNP in one tissue may not be the same in a different tissue. We don’t actually know how different SNPs will interact in these different tissues, either. It is therefore extremely difficult, if not impossible, to say what the effect of any single genetic variant will be on overall IL6 levels.
For example, while the ‘G’ allele at rs1800796 has been associated with higher IL-6 expression in many studies, one found that white blood cells with the ‘C’ allele expressed higher IL-6 in the presence of viruses.
Different tissues express IL6 in different amounts and may respond to genetic variants in different ways. This makes it difficult to predict what effect any SNP will have.