For immune cells, the actin cytoskeleton is more than a structural scaffold. Immune cells can migrate to sites of infection or form precise, short-lived contacts with other cells, by constantly reshaping their actin cytoskeleton. Genetic errors in the molecular machinery controlling actin dynamics lead to impaired immunity, and often to autoimmunity and chronic inflammation. Prof. Kaan Boztug, recently appointed Clinical Director of Pediatric Immunology and Rheumatology at the University Hospital Bonn (UKB), has specialized in the characterization of inborn errors in immunity. An overview of the current state of research on immune-related actinopathies, prepared in cooperation with Loïc Dupré of the Toulouse Institute for Infectious and Inflammatory Diseases, Toulouse, and Irinka Castanon, senior researcher in the laboratory of Prof. Boztug, has now been published in Nature Reviews Immunology.
The actin cytoskeleton is composed of filaments that organize locally in higher-order networks, giving eukaryotic cells their shape and ability to move. Actin filaments link to nearly every internal organelle, guiding intracellular transport and helping maintain proper cellular balance. To allow actin networks to extend, retract, or reorganize as the cell responds to its environment, specialized actin-regulatory proteins continually assemble and disassemble these filaments. Defects in individual actin-regulatory proteins result in immune-related actinopathies, a significant cause of inborn errors of immunity (IEIs). By today, mutations in genes encoding for nearly 30 actin-regulatory proteins have been found to be associated to IEI occurrence. “By combining our respective expertise in human genetics and immune cell biology, Kaan Boztug and myself have worked over the past years at elucidating the function of some of these disease-related actin regulators.” says Loïc Dupré, Inserm Reseach Director at the Toulouse Institute for Infectious and Inflammatory Diseases, France. “This has lifted our understanding about how immune cells function.”
Inborn Errors of Immunity
Inborn immune-related actinopathies underline the importance of cytoskeleton dynamics for immune-cell function “Individuals affected show a significantly increased susceptibility to infectious diseases, but also often exhibit a variety of autoimmune and autoinflammatory symptoms“ states Prof. Kaan Boztug, head of the Clinic of Pediatric Immunology and Rheumatology at the UKB and member of ImmunoSensation2. “The underlying cellular malfunctions can be manyfold.”
Actinopathies can disrupt the normal regulation of T- and B-cells, leading to impaired immune tolerance and hence, autoimmune reactions. In myeloid cells, that are part of the innate immune system and serve as a first line of defense against infections, actinopathies can trigger excessive inflammatory responses, leading to chronic inflammation.
Implications of Immune Diversity
Not only the mechanisms underlying immune-related actinopathies are diverse. The resulting symptoms can also vary considerably despite similar actin-related mutations. “Additional genetic and environmental factors may explain why patients with similar actin-related mutations can show very different symptoms.” Prof. Boztug explains.
In future research projects, mouse models may help distinguish defects caused directly by actin mutations from those influenced by other factors. „To fully understand immune dysregulation in these disorders, we need to shift the view from individual cells or genes and adopt a systems-level approach that considers how multiple cell types interact within the immune system.” Prof. Boztug adds. Future studies will need to include larger groups of patients to better understand the mechanisms behind immune dysregulation and to identify biomarkers that can predict who is at risk. At the same time, developing more targeted therapies will be essential to turn the growing cellular and molecular understanding of these disorders into improved clinical care for affected patients.
Contribution
This review emerged in close collaboration of ImmunoSensation2 member Prof. Kaan Boztug at the University Hospital Bonn with the St. Anna Children’s Cancer Research Institute in Vienna, the Medical University of Vienna, the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and the Toulouse Institute for Infectious and Inflammatory Diseases.
Publication
Loïc Dupré, Irinka Castanon and Kaan Boztug, Immune-related actinopathies at the cross-road of immunodeficiency, autoimmunity and autoinflammation, Nature Reviews Immunology, DOI: 10.1038/s41577-025-01214-w
Contact
Clinic for Pediatric Immunology and Rheumatology
Venusberg-Campus 1, 53127 Bonn
