A study published in Nature Genetics earlier this month has detailed, for the first time, the mechanism that allows the immune system to remember prior exposures to, for example, pathogens (micro-organisms causing infection), and then trigger the right response to reinfection.

The study was conducted by scientists from the University of Cape Town’s (UCT’s) Institute for Infectious Disease and Molecular Disease, which is based in the university’s health sciences faculty, and the Council for Scientific and Industrial Research (CSIR).

“The immune system sits at the apex of our protection against all diseases, ranging from infectious diseases to chronic diseases, such as cancer and diabetes,” stated first author and CSIR researcher Dr Stephanie Fanucchi.

The study explained that, within the immune system, two important actors reside – the innate and adaptive immune systems.

The adaptive system is made up of lymphoid cells (T-cells and B-cells) which retain a memory of prior exposures to pathogens, infections and diseases. This memory can be “written” to lymphoid cells by vaccines, for example, resulting in accelerated responses by the immune system to re-exposure to the infection or pathogen or even chronic diseases like cancer.

The innate immune system is made up of myeloid cells (monocytes and macrophages) which, historically, have been thought to possess no such memory of prior exposures to pathogens, infections or disease.

In recent years, a phenomenon termed “trained immunity” has been discovered and described by a laboratory manned by Professor Mihai Netea in the Netherlands, said a CSIR statement.

Netea and others have observed that myeloid cells also retain a memory of prior exposures, though the mechanism was unknown. This memory appeared to be “written” in chemical changes at the level of proteins associated with deoxyribonucleic acid, or DNA, encoding individual genes regulating the immune system in myeloid cells.

In this study, the scientists, with international collaborators from China, Germany, Italy, Singapore and the US, have unraveled and clarified the mechanism.

Using the tools of genomics, bioinformatics, single-molecule imaging and gene editing, the authors demonstrated that another recently discovered group of biological molecules, called long noncoding Ribonucleic acids (lncRNA), regulate the epigenetic acquisition of memory by immune genes that occurs during trained immune responses.

Their study characterises an example of one lncRNA called Umulilo, aptly named after the Zulu word for fire, which regulates how inflammatory genes retain a memory of prior exposures.

These genes regulate inflammatory responses implicated in several major diseases including tuberculosis, chronic obstructive pulmonary disease, ischaemic heart disease, cystic fibrosis and autoimmune disease.

Fanucchi said this groundbreaking discovery of these lncRNAs can now be exploited therapeutically to discretely alter the immune response to treat a plethora of inflammatory-based diseases such as cancer and inflammatory bowel disease.

“Alternatively, this knowledge may be useful to boost the training of the immune system, to enable individuals with weakened immune systems to clear infections."

The study provided the first mechanistic explanation for how trained immunity works and exposes it to highly targeted intervention in immunomodulation, one of the largest therapeutic areas in the pharmaceutical industry.

“Broadly, it contributes to our fundamental understanding of immunology and gene regulation in general by indicating how gene expression can be influenced and maintain a persistent and heritable memory of environmental exposures. This memory can be 'written' and 'erased' continuously through environmental exposures over the lifetime of an individual,” the CSIR states.

Second author and UCT Doctorate student Ezio Fok saw the immediate practical result pertinent to South Africa from the study.

"Recent studies have, for example, implicated trained immunity in the mechanism by which yellow fever vaccine and BCG (a tuberculosis vaccine) work. This indicates that measuring specific lncRNA levels may be a useful biomarker for assessing effective innate immune activation (for example, BCG-induced vaccination).

“This could be of major importance in public health today in assessing vaccine efficacy."