Autoimmune diseases affect around 10 % of the world population, and are characterized by a complex etiology, combining genetic and environmental factors, leading to a loss of tolerance against autoantigens, and inflammation associated with organ pathology [1,2]. B cells strongly contribute to the pathogenesis of several autoimmune diseases, as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren syndrome (SS), limited cutaneous systemic sclerosis (LCSS), Hashimoto thyroiditis (HT), idiopathic thrombocytopenic purpuras (ITP), by the production of autoantibodies and of inflammatory cytokines, and also by the capacity to present autoantigen to T cells. The important role of B cells is supported by the results of B cell depleting therapies with monoclonal antibodies for some of these diseases [3]. However, the molecular mechanisms leading to B cell tolerance breakdown and to the production of autoantibodies in these diseases are not well understood [2].

Genetic contribution in autoimmune diseases is important, with a concordance rate ranging from 12 to 67 % [4,5]. As an example, the genetic component of SLE is important, taking into account familial aggregation in some cases, and higher concordance rates between monozygotic twins (20–40 %) relative to dizygotic twins and other full siblings (2–5%). SLE is considered to be polygenic in a majority of patients. More than hundred susceptibility loci have been described for SLE. Most of them have been described by GWAS (genome-wide association studies), however in these cases the biological impact of the described variants is frequently not understood. In addition, familial and monogenic forms of SLE or SLE-like disease occur, both syndromic due to complement deficiencies, ACP5 (acid phosphatase 5) mutations or STING (stimulator of interferon genes) gain of function mutations causing SAVI (STING-associated vasculopathy with onset in infancy), and non-syndromic forms, with mutations in DNASE1L3 (deoxyribonuclease-1 like 3), TREX1 (three prime repair exonuclease 1) or PRKCD (protein kinase C delta), for example [6,7].

Globally speaking, many genetic variants and polymorphisms have been described in autoimmune patients, and familial aggregation of different autoimmune diseases is frequently described [8]. In addition, sharing of genetic variants in autoimmune diseases has been described [9,10]. By directly implicating biological pathways, these familial forms of the disease have the potential to inform our understanding of common pathogenic mechanisms leading notably to B cell tolerance breakdown and autoimmune symptoms.

Recently, the role of the unfolded protein response (UPR) emerged as a novel pathway in inflammatory disease and autoimmunity [[11], [12], [13], [14]]. The UPR is typically associated with secretory cells experiencing a high protein folding load in the endoplasmic reticulum (ER), but other cell lineages such as immune cells also show the same abnormality. Three sensors mediate activation of the UPR in response to ER stress: IRE1α, PERK (protein kinase R (PKR)-like ER kinase) and ATF6 (activating transcription factor 6) [13,15,16]. Together, they initiate a transcriptional program to adapt the cell to manage ER stress, and temporarily halt protein import in the ER. IRE1α is the most conserved member of the UPR. It is an endonuclease that becomes activated in response to accumulation of unfolded proteins in the ER through dissociation of the chaperone Bip [17]. This causes IRE1α dimerization/oligomerization promoting its trans-autophosphorylation needed for activation of its kinase and endoribonuclease activity (the latter leading to unconventional splicing of XBP1 mRNA, and to Regulated IRE1-Dependent Decay (RIDD)) [13,15,16]. As noted, UPR and IRE1α dysfunctions have been observed in various disease conditions such as inflammatory and autoimmune diseases [[18], [19], [20]]. As an example, an abnormal UPR profile due to IRE1α-XBP1 and PERK-CHOP (C/EBP homologous protein) activity was observed in a cohort of patients with SLE, which may lead to T and B lymphocytes hyperactivation and increased antibody production [21]. In addition, in SS patients, attenuation of IRE1α/XBP1 pathway has been described in epithelial cells of the salivary glands [22].

Here, we describe by Whole-Exome Sequencing (WES) a heterozygous mutation in ERN1 gene (p.R594C), a novel mutation in IRE1α kinase domain, in a multiplex family with several members presenting autoimmune symptoms and a diagnosis of SLE in the proband. By generating a B-EBV (Epstein-Barr virus) cell line from the proband and the development of a new KI transgenic murine model carrying the IRE1α R594C mutation, we showed that this mutation leads to a profound defect in IRE1α XBP1 splicing activity. We were able to detect the presence of autoantibodies targeting several autoantigens in the transgenic mouse model, with some deposits of immunoglobulins within renal tissues. Therefore, loss of function of IRE1α endonuclease activity on XBP1 splicing could contribute to B cell tolerance breakdown.