Researchers at University Medical Center Utrecht have discovered an underappreciated way in which immune cells quickly respond to infections. Using long-read RNA sequencing, they show that a process called ‘alternative RNA splicing’ plays an important role in shaping immune responses. This is the process by which a single gene can produce different versions of RNA, the molecule that carries genetic instructions to make proteins. The findings help improve our understanding of diseases in which the immune system is overactive, such as rheumatoid arthritis and lupus, and may eventually lead to more targeted treatments.
The study, published in Nature Communications, focused on monocytes. These are early responder immune cells that quickly react when the body is invaded by bacteria or other pathogens. When monocytes detect bacterial signals, such as cell wall components, they must rapidly adjust to fight the infection. Earlier research mainly looked at which genes become more or less active during this response. This new study went a step further by looking at the different RNA versions (called isoforms) that each gene can produce.
Using a new and advanced technique called long-read RNA sequencing, researchers at the Center for Translational Immunology (University Medical Center Utrecht, the Netherlands) created a detailed map of full-length RNA molecules in human monocytes, both before and after activation. They identified more than 24,000 different RNA variants, including thousands that had never been seen before. This shows that immune cells are much more complex at the RNA level than previously thought.
From left to right: PI Jorg van Loosdregt, first author Alejandra Bodelón and co-PI Bas Vastert
A key discovery of the study was that immune activation does not just switch genes on or off. Instead, it also determines which RNA versions are produced. When monocytes become active, they tend to produce longer and more complete RNA molecules that are better suited to making proteins. These RNA forms are more stable and more efficiently translated into proteins. The researchers also confirmed that these changes have real effects: by studying protein production in the cells, they showed that the RNA changes lead to an increased production of immune defense proteins. Researcher Jorg van Loosdregt explains: “These findings mean that RNA splicing directly improves the ability of immune cells to fight infections.”
These findings are also relevant for autoimmune diseases like rheumatoid arthritis and lupus, where the immune system mistakenly attacks the body. Previous studies have shown that genetic differences affecting RNA splicing are linked to these diseases. This new research adds an important insight: it is not only which genes are active that matters, but also which RNA versions are produced and how efficiently they are turned into proteins.
This work highlights the importance of studying gene activity at a more detailed level than is usually done. Traditional methods may miss important changes that only become visible when full-length RNA molecules are studied. New long-read sequencing techniques could therefore significantly improve research into immune diseases. Pediatric rheumatologist Bas Vastert adds: “These insights may also lead to new treatments. If harmful immune responses are driven by specific RNA splicing patterns, it may become possible to target these processes directly. New therapies, such as antisense oligonucleotides or drugs that influence splicing, could help to target the immune system more precisely and a better treatment of immune-mediated diseases.”
Bodelón A, van Haaren MJH, Sobrevals Acaraz P, Sijbers LJPM, Scholman RC, Picavet LW, de Ligt A, van Ginneken D, Erkens RGA, Vos HR, Calis JJA, Vastert SJ, van Loosdregt J. Native long-read RNA sequencing of human monocytes reveals activation-induced alternative splicing toward functional isoforms. Nature Communications 2026, in press.
