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00925njm 22002777a 4500 dc Bakhtiar, Shahrzad author González Granado, Luis Ignacio author Huenecke, Sabine author 2022-09-13 BACKGROUND: Immune dysregulation as a result of an inborn error of immunity (IEI) leads to the complicated symptoms of refractory multi-organ immune dysregulation. B lymphocytes with immune regulatory capacity (Breg) are activated by environmental triggers and act as regulators of the immune response as observed in several autoimmune diseases. OBJECTIVE: We sought to investigate the Breg profile and the CD21 expressing B cells of patients with LRBA deficiency (N = 6) and non-LRBA deficiency IEI (N = 13) with overlapping clinical symptoms of immune dysregulation. Normal values for Breg subpopulations were obtained from patients age-matched healthy cohorts (N = 48). Furthermore, we investigated the impact of abatacept treatment in LRBA deficient patients receiving biweekly abatacept (N = 5). METHODS: Using a flow cytometric approach with a pre-formulated antibody panel in peripheral blood samples, Breg subsets including plasmablasts (CD27CD38), transitional B cells (CD24CD38), and B10 cells (CD24CD27), and additionally the CD21 B cells (CD21CD38) were analyzed. Breg function was assessed by the interleukin-10 expression within the CD19 population. Additionally, B cell cytokines were measured in cell culture supernatants. RESULTS: We observe significant alterations of B cell/Breg subpopulations in the LRBA deficient cohort including a severe lack of memory B cells (P = 0.031) and B10 cells (P = 0.031) as well as a tendency towards higher CD21 B cells (P = 0.063). Within the non-LRBA deficient cohort, we observe a significant expansion of the plasmablasts (P = 0.012), and a tendency towards elevated levels of CD21 expressing B cells (P = 0.063). The treatment with abatacept ameliorated disease symptoms in the LRBA deficient cohort and led to an effective decrease in CD21 B cells over time (P = 0.021). Furthermore, there was a significantly increased level of B cell-activating factor (BAFF; P = 0.02) and lower IL-12p70 secretion upon stimulation (P = 0.020) in the LRBA cohort. CONCLUSION: Aberrant maturation of Breg subsets and the pathological expansion of CD21 B cells in patients with IEI may have therapeutic implications. Patients suffering from LRBA deficiency show a lack of memory B cells, insufficient expansion of B10 cells, increased BAFF levels as well as an increase in circulating CD21 B cells. Abatacept treatment results in a steady decrease in CD21 B cells. This original article investigates regulatory B-cell abnormalities in patients with inborn errors of immunity and severe immune dysregulation. The study compared patients with LRBA deficiency, patients with non-LRBA inborn errors of immunity and overlapping immune-dysregulation phenotypes, and age-matched healthy controls. Using flow cytometry, the authors analyzed regulatory B-cell subsets including plasmablasts, transitional B cells, B10 cells and CD21low B cells, together with IL-10 expression and B-cell cytokine production. LRBA-deficient patients showed marked alterations in B-cell maturation, including reduced memory B cells and B10 cells, increased BAFF levels and expansion of CD21low B cells. Abatacept treatment was associated with clinical improvement and a progressive decrease in CD21low B cells, supporting the potential value of Breg and CD21low B-cell profiling as biomarkers and therapeutic readouts in immune dysregulation. Bakhtiar S, Kaffenberger C, Salzmann-Manrique E, Donhauser S, Lueck L, Edeer Karaca N, Gonzalez-Granado LI, Hazar E, Keles S, Seidel MG, Fekadu J, Königs C, Schubert R, Bader P, Huenecke S. Regulatory B cells in patients suffering from inborn errors of immunity with severe immune dysregulation. J Autoimmun. 2022;132:102891. doi: 10.1016/j.jaut.2022.102891. PMID: 36113303. 0896-8411 10.1016/j.jaut.2022.102891 https://hdl.handle.net/20.500.14352/138253 https://doi.org/10.1016/j.jaut.2022.102891 36113303 https://www.sciencedirect.com/science/article/pii/S0896841122000993?via%3Dihub Regulatory B cells in patients suffering from inborn errors of immunity with severe immune dysregulation.