CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in patients with chronic lymphocytic leukemia (CLL). Important functional properties are associated with CD5 expression in B cells, including signal transducer and activator of transcription 3 activation, IL-10 production and the promotion of B-lymphocyte survival and transformation. However, the pathway(s) by which CD5 influences the biology of B cells and its dependence on B-cell receptor (BCR) co-signaling remain unknown. In this study, we show that CD5 expression activates a number of important signaling pathways, including Erk1/2, leading to IL-10 production through a novel pathway independent of BCR engagement. This pathway is dependent on extracellular calcium (Ca) entry facilitated by upregulation of the transient receptor potential channel 1 (TRPC1) protein. We also show that Erk1/2 activation in a subgroup of CLL patients is associated with TRPC1 overexpression. In this subgroup of CLL patients, small inhibitory RNA (siRNA) for CD5 reduces TRPC1 expression. Furthermore, siRNAs for CD5 or for TRPC1 inhibit IL-10 production. These findings provide new insights into the role of CD5 in B-cell biology in health and disease and could pave the way for new treatment strategies for patients with B-CLL.

Autoantibodies related to APLS (aCL and aβ2GPI) were present in the majority of patients with PBC, reflecting the ability of these antibodies to engage mediators of damage.

Background Dysregulation in calcium (Ca 2+ ) signaling is a hallmark of chronic lymphocytic leukemia (CLL). While the role of the B cell receptor (BCR) Ca 2+ pathway has been associated with disease progression, the importance of the newly described constitutive Ca 2+ entry (CE) pathway is less clear. In addition, we hypothesized that these differences reflect modifications of the CE pathway and Ca 2+ actors such as Orai1, transient receptor potential canonical (TRPC) 1, and stromal interaction molecule 1 (STIM1), the latter being the focus of this study. Methods An extensive analysis of the Ca 2+ entry (CE) pathway in CLL B cells was performed including constitutive Ca 2+ entry, basal Ca 2+ levels, and store operated Ca 2+ entry (SOCE) activated following B cell receptor engagement or using Thapsigargin. The molecular characterization of the calcium channels Orai1 and TRPC1 and to their partner STIM1 was performed by flow cytometry and/or Western blotting. Specific siRNAs for Orai1, TRPC1 and STIM1 plus the Orai1 channel blocker Synta66 were used. CLL B cell viability was tested in the presence of an anti-STIM1 monoclonal antibody (mAb, clone GOK) coupled or not with an anti-CD20 mAb, rituximab. The Cox regression model was used to determine the optimal threshold and to stratify patients. Results Seeking to explore the CE pathway, we found in untreated CLL patients that an abnormal CE pathway was (i) highly associated with the disease outcome; (ii) positively correlated with basal Ca 2+ concentrations; (iii) independent from the BCR-PLCγ2-InsP 3 R (SOCE) Ca 2+ signaling pathway; (iv) supported by Orai1 and TRPC1 channels; (v) regulated by the pool of STIM1 located in the plasma membrane (STIM1 PM ); and (vi) blocked when using a mAb targeting STIM1 PM . Next, we further established an association between an elevated expression of STIM1 PM and clinical outcome. In addition, combining an anti-STIM1 mAb with rituximab significantly reduced in vitro CLL B cell viability within the high STIM1 PM CLL subgroup. Conclusions These data establish the critical role of a newly discovered BCR independent Ca 2+ entry in CLL evolution, provide new insights into CLL pathophysiology, and support innovative therapeutic perspectives such as targeting STIM1 located at the plasma membrane. Electronic supplementary material The online version of this article (10.1186/s40425-019-0591-3) contains supplementary material, which is available to authorized users.

Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease of autoimmune nature. The ethiopathogenic mechanisms involved are complex and include gut dysbiosis. 1 RA is characterized by autoantibodies production (rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA)). RA can lead to accumulating joint damage and irreversible disability. 2 Antiphospholipid antibodies (aPL) are a heterogeneous group of antibodies that have been associated with thrombotic or obstetrical events in patients with antiphospholipid syndrome (APS). 3 These antibodies can occur not only in APS but also in a