Regulatory B cells (Bregs) have been highlighted in very different pathology settings including autoimmune diseases, allergy, graft rejection, and cancer. Improving tools for the characterization of Bregs has become the main objective especially in humans. Transitional, mature B cells and plasma cells can differentiate into IL-10 producing Bregs in both mice and humans, suggesting that Bregs are not derived from unique precursors but may arise from different competent progenitors at unrestricted development stages. Moreover, in addition to IL-10 production, regulatory B cells used a broad range of suppressing mechanisms to modulate the immune response. Although Bregs have been consistently described in the literature, only a few reports described the molecular aspects that control the acquisition of the regulatory function. In this manuscript, we detailed the latest reports describing the control of IL-10, TGFβ, and GZMB production in different Breg subsets at the molecular level. We focused on the understanding of the role of the transcription factors STAT3 and c-MAF in controlling IL-10 production in murine and human B cells and how these factors may represent an important crossroad of several key drivers of the Breg response. Finally, we provided original data supporting the evidence that MAF is expressed in human IL-10- producing plasmablast and could be induced in vitro following different stimulation cocktails. At steady state, we reported that MAF is expressed in specific human B-cell tonsillar subsets including the IgD+ CD27+ unswitched population, germinal center cells and plasmablast.
Rheumatoid arthritis (RA) and periodontitis present many similar features. The benefits of anti-B lymphocyte therapy (rituximab) on reducing tissue resorption in RA prompted us to assess its potential efficacy on the periodontal status of patients with RA treated with rituximab.Periodontal status was assessed in 21 subjects with RA, divided into two groups: Group I consisted in 11 subjects assessed before their first infusion of rituximab and again 6 months later. Five of them were also assessed for up to 4 years after their first rituximab infusion. The 10 subjects in group II had received more than two courses of two rituximab infusions at the time of periodontal assessment.Pocket depth and attachment loss were significantly decreased 6 months after treatment with rituximab in group I. The periodontal status of the five subjects from group I followed for up to 48 months after rituximab treatment was improved irrespective of the clinical parameter observed. Patients from group II had a better periodontal status than patients from group I before treatment with rituximab.Anti-B lymphocyte therapy could be beneficial to improve periodontitis suggesting a major role of B cells in this disease.
Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
IntroductionCurrent therapeutic management of lupus nephritis (LN) fails to induce long-term remission in over 50% of patients, highlighting the urgent need for additional options.MethodsWe analysed differentially expressed genes in peripheral blood from active LN (n=41) and active non-renal lupus (n=62) patients versus healthy controls (n=497) from the European PRECISESADS project (NTC02890121), and dysregulated gene modules in a discovery (n=26) and a replication (n=15) set of active LN cases.ResultsReplicated gene modules qualified for correlation analyses with serological markers, and regulatory network and druggability analysis. Unsupervised co-expression network analysis revealed 20 dysregulated gene modules and stratified the active LN population into three distinct subgroups. These subgroups were characterised by low, intermediate, and high interferon (IFN) signatures, with differential dysregulation of the "B cell" and "plasma cells/immunoglobulins" modules. Drugs annotated to the IFN network included CC-motif chemokine receptor 1 inhibitors, programmed death-ligand 1 inhibitors, and irinotecan, while the anti-CD38 daratumumab and proteasome inhibitor bortezomib showed potential for counteracting the "plasma cells/immunoglobulins" transcriptomic signature. In silico analysis demonstrated the low-IFN subgroup to benefit from calcineurin inhibition and the intermediate-IFN subgroup from B cell targeted therapies. High-IFN patients exhibited greater anticipated response to anifrolumab while daratumumab appeared beneficial for the intermediate-IFN and high-IFN subgroups.ConclusionIn summary, IFN upregulation and B and plasma cell gene dysregulation patterns revealed three LN patient subgroups, which may not necessarily represent distinct disease phenotypes but rather phases of the inflammatory processes during a renal flare, providing a conceptual framework for precision medicine in LN.
