Loss of function of XBP1 splicing activity of IRE1a favors B cell tolerance breakdown

Tolerance breakdown leads to the development of autoimmune diseases in an increasing manner. B cells strongly contribute to the pathogenesis of these diseases, notably via the production of autoantibodies leading to cell depletion, receptor modulation and organ damages. However, the molecular mechanisms of B cell tolerance breakdown are badly known. Autoimmune diseases are frequently aggregated in families in two or more generations. The study of these familial forms could therefore help to better describe common biological mechanisms leading to B cell tolerance breakdown. By Whole-Exome Sequencing, we describe here in a multiplex family with several members presenting autoantibody-mediated autoimmunity a new heterozygous mutation (p.R594C) in ERN1 gene, coding for IRE1a. Using human cell lines and a knock-in (KI) transgenic mouse model, we showed that this mutation leads to a profound defect of IRE1a ribonuclease activity on XBP1 splicing. The KI mice developed a broad panel of autoantibodies, however in a subclinical manner. These results suggest that a decrease of XBP1s production could contribute to B cell tolerance breakdown and give new insights into the function of IRE1a which are important to consider for the development or IRE1a targeting strategies. Overall design: We performed CITEseq to asses in an unbiased manner whether the R594C mutation in IRE1 affects the immune cell compartment.