One letter difference in the DNA can generate an immune response

Non-coding RNA drives inflammatory process regulated by interleukin

A difference in the DNA can predict the BCG vaccines which can provide good protection against tuberculosis disease. The impact of a single-letter variation on the immune system’s activation and deactivation has been clarified by researchers at Radboudumc. The finding, reported in Nature Genetics, offers novel avenues for (re)guiding the immune system and offers more understanding of interleukin-driven inflammatory reactions.

Individuals may respond to the same infection or immunization in completely diverse ways. For example, one individual becomes ill from an invading microbe, whereas another does not. Furthermore, certain vaccinations affect some individuals far better than others. The primary cause of these individual variations is found in our genome, which is our genetic makeup. Everybody has a different genome. This variety plays a major role in determining our responses to vaccines and infections.

Vaccine against tuberculosis

We now understand that this so-called “junk DNA,” also known as the non-coding genome, is, in fact, extremely significant. Although that 98% may not produce proteins, it can aid in their shaping, coordinating their synthesis, and other functions. To achieve this, the genome creates fragments of RNA. Such a non-coding RNA fragment tampers with several bodily functions, including the likelihood that a disease may cause you to become ill or not, if a vaccination will adequately protect you.

Consider the BCG vaccination, which offers protection against tuberculosis (TB). By inducing (epigenetic) alterations in bone marrow-derived stem cells that make blood, the vaccination seems to protect against illnesses other than tuberculosis.

Different DNA letter, different immune response

These stem cells, among other things, give rise to the white blood cells that are vital to the immune system. Nevertheless, not everyone responds to the BCG vaccination identically. It turns out that the genetic material behind this differential is driven by a single-letter difference. A single-nucleotide polymorphism, or SNP for short, is a “one letter difference” that is pronounced as “snip.” Immunization is very effective in individuals whose genome contains the letter G, which stands for guanine. The vaccination has just a modest effect on those who have an A (for adenine).

How can one letter difference have such an impact on the functioning of a person’s immune system?

We know that a BCG vaccine activates interleukin-1β. This triggers an inflammatory process through which the immune system builds up protection against tuberculosis and other pathogens. But why does it work really well in people with a G-SNP and is it less efficient in those with an A-SNP? What exactly happens there in that molecular incubator, why do those G and A cause such a big difference in the way our immune system functions?

Ezio Fok

Director of the inflammatory process

The SNP was found to be a component of a long non-coding RNA (lncRNA) segment that the researchers named AMANZI. The central player in the inflammatory process, interleukin-1β (IL-1β), appears to be AMANZI. AMANZI stimulates IL-37 and starts the anti-inflammatory response that controls IL-1β activity after the BCG vaccination is given. In order to develop trained immunity and a long-term memory of vaccination this regulation of IL-1β must take place. In 2013, RUMC professor Mihai Netea made the initial observation that vaccinations such as BCG are protective because of trained immunity.

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But it’s less effective in people with an A-SNP. In them [A-SNP], AMANZI stably maintains the IL-37 ‘brake’. As a result, neither the immune responses to the vaccine and the pathogen proceed properly because IL-1β is dampened. So people with the G-SNP build up a functional defense, where in people with the A-SNP this is not the case. To check, we removed the A-SNP AMANZI variant in white blood cells. As a result we saw pro-inflammatory protection building up again, showing the effect of the one-letter difference in AMANZI once again.

Musa Mhlanga


Turning genes on and off is one way that AMANZI influences the field of epigenetics study. The researchers describe in-depth how long lengths of noncoding RNA (lncRNA) carry out this in the journal Nature Genetics. They also demonstrate how minute changes in a single letter may have a significant impact on such an epigenetic process. They contend that this holds true for many other lncRNAs in addition to AMANZI. These differences may have a neutral effect or may have a favourable or detrimental impact on immune system functions.

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Several lncRNAs play a role in this process, and single-letter differences – SNP’s in other words – may also enhance or attenuate 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 in order to find out their clinical usability. Importantly, nine out of ten SNPs are in noncoding regions of the genome.

Musa Mhlanga

Details of the research

Nature Genetics: A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation – Ezio T. Fok, Simone J. C. F. M. Moorlag, Yutaka Negishi, Laszlo A. Groh, Jéssica Cristina dos Santos, Cathrin Gräwe, Valerie Villacorta Monge, Daphne D. D. Craenmehr, Mellanie van Roosmalen, David Pablo da Cunha Jolvino, Letícia Busato Migliorini, Ary Serpa Neto, Patricia Severino, Michiel Vermeulen, Leo A. B. Joosten, Mihai G. Netea, Stephanie Fanucchi & Musa M. Mhlanga.

Source: Radboud University Medical Centre News items

Journal Reference: Fok, E. T., Moorlag, S. J., Negishi, Y., Groh, L. A., Dos Santos, J. C., Gräwe, C., Monge, V. V., Craenmehr, D. D., Van Roosmalen, M., Pablo, D., Migliorini, L. B., Neto, A. S., Severino, P., Vermeulen, M., Joosten, L. A., Netea, M. G., Fanucchi, S., & Mhlanga, M. M. (2023). A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation. Nature Genetics, 1-15.

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