Loss of function of XBP1 splicing activity of IRE1 α favors B cell tolerance breakdown

J Autoimmun. 2023 Dec 9;142:103152. doi: 10.1016/j.jaut.2023.103152. Online ahead of print.ABSTRACTAnti-nuclear antibodies are the hallmark of autoimmune diseases such as systemic lupus erythematosus (SLE) and scleroderma. However, the molecular mechanisms of B cell tolerance breakdown in these pathological contexts are poorly known. The study of rare familial forms of autoimmune diseases could therefore help to better describe common biological mechanisms leading to B cell tolerance breakdown. By Whole-Exome Sequencing, we identified a new heterozygous mutation (p.R594C) in ERN1 gene, encoding IRE1α (Inositol-Requiring Enzyme 1α), in a multiplex family with several members presenting autoantibody-mediated autoimmunity. Using human cell lines and a knock-in (KI) transgenic mouse model, we showed that this mutation led to a profound defect of IRE1α ribonuclease activity on X-Box Binding Protein 1 (XBP1) splicing. The KI mice developed a broad panel of autoantibodies, however in a subclinical manner. These results suggest that a decrease of spliced form of XBP1 (XBP1s) production could contribute to B cell tolerance breakdown and give new insights into the function of IRE1α which are important to consider for the development of IRE1α targeting strategies.PMID:38071801 | DOI:10.1016/j.jaut.2023.103152

Source: Journal of Autoimmunity - December 10, 2023 Category: Allergy & Immunology Authors: Quentin Reuschl é Laurien Van Heddegem Victor Bosteels Matthieu Moncan Sabine Depauw Nad ège Wadier Sandra Mar échal Clint De Nolf Virginia Delgado Yosra Messai Marie-Claude Stolzenberg Aude Mag érus Ang élique Werck J érôme Olagne Quan Li Guillaum Source Type: research