Researchers at University Medical Center Utrecht have uncovered a previously underappreciated mechanism that helps immune cells to respond rapidly to infections. Using advanced long-read RNA sequencing, the team shows that alternative RNA splicing, which means how genes are edited into different messenger RNA variants, plays a central role in shaping immune responses. The findings provide new insights into immune-mediated diseases (such as infections, rheumatoid arthritis and lupus) and may open the door to more targeted therapies.
The study, published this week in Nature Communications , focused on monocytes , a type of innate immune cell that acts as a first responder to pathogens. When these cells encounter bacterial components such as cell wall components, they must quickly adapt to mount an effective defense. While earlier research has largely examined changes in overall gene expression, this study zoomed in on RNA isoforms, the different transcript variants that a single gene can produce. Using long-read RNA sequencing, researchers at the Center for Translational Immunology (University Medical Center Utrecht, the Netherlands) generated a comprehensive map of full-length RNA transcripts in human monocytes before and after activation. They identified more than 24,000 isoforms, of which the majority have never been described, revealing a previously hidden layer of molecular complexity.
Immune activation drives functional isoform switching
A key finding of the study is that immune activation triggers widespread ‘isoform switching’. Rather than simply turning genes on or off, monocytes shift toward producing longer, fully functional RNA variants that are more likely to be translated into proteins. These isoforms contain complete coding sequences, fewer non-coding interruptions, and greater structural complexity, all features that are associated with more effective protein production.
“In our study we also confirmed that these RNA changes have real functional consequences. By integrating data on protein synthesis and ribosome activity, we demonstrated that the observed isoform shifts are linked to increased production of immune effector proteins. This shows that alternative splicing directly enhances the cell’s ability to respond to infection or inflammation”, said molecular immunologist Jorg van Loosdregt PhD , principal investigator of the study.
Implications for immune-mediated diseases
These findings have also significant implications for understanding immune-mediated diseases such as rheumatoid arthritis and lupus . Previous studies have linked these conditions to genetic variation affecting RNA splicing. This new study adds a new layer of insight, showing that disease mechanisms may depend not only on which genes are expressed, but also on which isoforms are produced and how efficiently they are translated into proteins.
Toward more precise therapies
Jorg van Loosdregt continues: “Our study underscores the importance of studying gene regulation at the isoform level. Traditional methods may overlook critical changes that only become visible with full-length RNA analysis. The adoption of long-read sequencing technologies could therefore transform research into immune function and disease mechanisms.”
Pediatric rheumatologist Bas Vastert MD PhD (Department of Rheumatology and Immunology, UMC Utrecht) adds: “For patients with an immune-mediated disease, the findings point toward new therapeutic opportunities. If harmful immune responses are driven by specific splicing patterns, these processes could potentially be targeted. Emerging approaches, such as antisense oligonucleotides or drugs that influence splicing factors, may enable more precise modulation of the immune system and the development of targeted treatments for immune-mediated diseases in the future.
Publication
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 .
Nature Communications
Experimental study
Human tissue samples
Native long-read RNA sequencing of human monocytes reveals activation-induced alternative splicing toward functional isoforms
29-May-2026
The authors declare no competing interests.