Editorial Medicalfacts / Janine Budding December 13, 2023 – 11:23 PM
Non-coding RNA drives interleukin-regulated inflammatory process
One letter difference in our DNA determines whether the BCG vaccine offers good protection against tuberculosis or not. Researchers from Radboud University Medical Center have clarified how that one letter difference affects the activation and deactivation of the immune system. The discovery, published in Nature Geneticsnot only provides more insight into interleukin-driven inflammatory responses, but also opens up new possibilities for (adjusting) the immune system.
People can react very differently to the same pathogen or vaccination. For example, one person becomes ill from an invading bacteria, but another does not. And some vaccines work much better for some people than for others. The main reason for these individual differences lies in our genetic material, us genome. A genome differs from person to person. It is this diversity that largely determines how we respond to pathogens and vaccinations. Our entire genome consists of more than 3 billion DNA molecules. Our heredity is stored in these biological DNA letters. Only a small portion of these letters, about 2 percent, contain information for the proteins at work in our bodies. These proteins are the workers in our cells; they build us up, fix us, keep us alive. The 2 percent of the genome that codes for proteins becomes the exoom named. It was long thought that the other 98 percent of our DNA was actually unnecessary. It was genetic waste – ‘junk DNA’ without function.
Vaccine against tuberculosis
We now know that this ‘junk DNA’, hereinafter referred to as the non-coding genome, is indeed very important. That 98 percent may not make proteins, but it does help shape those proteins, coordinate their production, and so on. The non-coding genome does this by making pieces of RNA. Such a piece of non-coding RNA interferes with all kinds of processes in the body. Including the chance that you will (not) get sick from a pathogen and whether or not a vaccine protects you well. Let’s take the BCG vaccine, which protects against tuberculosis (TB), as an example. This vaccine appears to protect not only against TB, but against more infections due to (epigenetic) changes that the vaccine induces in blood-forming stem cells in the bone marrow.
Different DNA letter, different immune response
These stem cells produce, among other things, the white blood cells that are important in the immune system. But the BCG vaccine does not work equally well for everyone! It turns out that only one letter difference in the genetic material drives this distinction. Such a ‘one letter difference’ is called a single-nucleotide polymorphism, for short SNP and pronounced ‘snip’. Vaccination works very well in people with the letter G (for guanine) at this location in the genome. The vaccine only works moderately in people with an A (for adenine). So the question is: how can one letter difference have such a major impact on the functioning of someone’s immune system? Musa Mhlanga and Ezio Fok from Radboud university medical center and their colleagues tried to answer this question. Fok: “We know that a BCG vaccine activates interleukin-1β. This initiates an inflammatory process through which the immune system builds up protection against tuberculosis and other pathogens. But why does the vaccine work very well in people with a G-SNP and is it less efficient in people with an A-SNP? What exactly happens there in that molecular incubator, why do G and A cause such a big difference in the way our immune system functions?”
Director of the inflammatory process
The researchers discovered that the SNP is part of a long stretch of non-coding RNA (lncRNA) that they named AMANZI. AMANZI appears to be the orchestrator of interleukin-1β (IL-1β), which is at the heart of the inflammatory process. After the BCG vaccine is administered, AMANZI activates IL-37 and initiates the inflammatory response that regulates the activity of IL-1β. This process of regulation of IL-1β is important for achieving long-term memory of vaccination through a process called trained immunity. Mihai Netea of Radboud university medical center first discovered this in 2013 trained immunity is important for the protective effect of vaccines such as BCG. “This above process occurs in people with the G-SNP,” says Mhlanga, “but it is less effective in people with an A-SNP. With them [A-SNP] AMANZI keeps the IL-37 ‘brake’ stable. As a result, the immune response to the vaccine and the pathogen does not proceed properly because IL-1β is dampened. People with the G-SNP therefore build up a functional defense, while this is not the case with people with the A-SNP. To check this, we removed the A-SNP AMANZI variant in white blood cells. As a result, we saw that pro-inflammatory protection was built up again, once again demonstrating the effect of the one-letter difference in AMANZI.”
Epigenetics
AMANZI exerts its influence by turning genes on and off, the research area of the epigenetics. In Nature Genetics, the researchers show in detail how long stretches of non-coding RNA (lncRNA) carry out this and how small variations of just one letter influence such an epigenetic process, with far-reaching consequences. This applies not only to AMANZI, but undoubtedly to many more lncRNAs, they say. These variations can be neutral, but can also negatively or positively influence processes in the immune system. In this specific case it concerns an interleukin-driven inflammatory process. Mhlanga: “Various lncRNAs play a role in this process, and differences in one letter – SNPs – can also strengthen or weaken the effect of this inflammatory process. Further research is needed to understand the combined effect of multiple polymorphisms on these IL-1β-driven immune responses. Ultimately, we want to map all components of IL-1β signaling and trained immunity to determine their clinical utility. Importantly, nine out of ten SNPs are located in non-coding regions of the genome.”
Publication in Nature Genetics: A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation – Ezio T. Fok, Simone JCFM Moorlag, Yutaka Negishi, Laszlo A. Groh, Jessica Cristina dos Santos, Cathrin Grẽwe, Valerie Villacorta Monge, Daphne DD Craenmehr, Mellanie van Roosmalen, David Pablo da Cunha Jolvino, Leticia Busato Migliorini, Ary Serpa Neto, Patricia Severino, Michael Vermeulen, Leo AB Joosten, Mihai G. Neto, Stephanie Fanucchi & Musa M. Mhlanga.
Source: Radboud university medical center
Editorial Medicalfacts / Janine Budding
I studied physiotherapy and health care business administration. I am also a registered independent client supporter and informal care broker. I have a lot of experience in various positions in healthcare, the social domain and the medical and pharmaceutical industries, nationally and internationally. And I have broad medical knowledge of most specialties in healthcare. And the healthcare laws from which healthcare is regulated and financed. I attend most of the leading medical conferences in Europe and America every year to keep my knowledge up to date and to keep up with the latest developments and innovations. I am currently doing a Masters in applied psychology.
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2023-12-13 22:50:12
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