In order to move, a body needs a strong scaffold. This is not only true on a macroscopic level, where animals rely on skeletons to support their muscles. It is also true on a cellular level: the cytoskeleton composed of actin filaments is crucial for every active movement of a cell. By rearranging these filaments, cells can stretch and wander in every direction, squeeze into the smallest gaps or wrap themselves around an object. Those processes are particularly important for the cells of the immune system, which are the most motile cells of the human body in order to fight against infectious agents. Defects of the cytoskeleton thus can have detrimental effects on the immune response and thereby on the ability of the organism to control infections.
In their most recent study, scientists from the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) and CeMM in cooperation with the University of Toulouse III, and INSERM, found that a rare genetic defect, characterized by a malfunctioning of the immune system, affects the ability of lymphocytes – the most important cells of the adaptive immunity - to rearrange their actin cytoskeleton. The study, published in the Journal of Allergy and Clinical Immunology (DOI: 10.1016/j.jaci.2018.04.023) was conducted in collaboration with clinicians from Izmir and Ankara and specialists of lymphocyte biology from the University of Vienna and the University of Rotterdam.
The gene defect was found in six patients who presented with severe infections of the lung, skin and oral mucosa. Genetic analyses of their genomes revealed mutations in a gene for a protein called WDR1, an important factor for the turn-over of actin filaments and thereby the dynamic remodeling of the cytoskeleton. It was recently shown that the innate arm of the immune system is affected by WDR1 mutations - the impact on cells of the adaptive immunity, however, was hitherto unknown. Through a series of extensive analyses, the researchers found that WDR1 deficiency leads to aberrant T-cell activation and B-cell development.
Laurène Pfajfer*, Nina K. Mair*, Raúl Jiménez-Heredia, Ferah Genel, Nesrin Gulez, Ömür Ardeniz, Birgit Hoeger, Sevgi Köstel Bal, MD, Christoph Madritsch, Artem Kalinichenko, Rico Chandra Ardy, Bengü Gerçeker, Javier Rey-Barroso, Hanna Ijspeert, Stuart G. Tangye, Ingrid Simonitsch-Klupp, Johannes B. Huppa, Mirjam van der Burg, Loïc Dupré*, and Kaan Boztug* (*equal contribution). Mutations affecting the actin regulator WD repeat–containing protein 1 lead to aberrant lymphoid immunity. Journal of Allergy and Clinical Immunology, 2018. DOI: 10.1016/j.jaci.2018.04.023
The study was funded by the Vienna Science and Technology Fund, the Austrian Science Fund, the French National Agency for Research, a ZonMW Vidi grant and grants from the National Health and Medical Research Council of Australia.