Regulatory B Cells in Patients Suffering from Inborn Errors of Immunity with Severe Immune Dysregulation.

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 CD21low expressing B cells of patients with LRBA deficiency (N symbolscript 6) and non-LRBA deficiency IEI (N symbolscript 13) with overlapping clinical symptoms of immune dys-regulation. Normal values for Breg subpopulations were obtained from patients age-matched healthy cohorts (N symbolscript 48). Furthermore, we investigated the impact of abatacept treatment in LRBA deficient patients receiving biweekly abatacept (N symbolscript 5).Methods: Using a flow cytometric approach with a pre-formulated antibody panel in peripheral blood samples, Breg subsets including plasmablasts symbolscript transitional B cells (CD24hiCD38hi), and B10 cells symbolscript and additionally the CD21low B cells (CD21lowCD38low) were analyzed. Breg function was assessed by the interleukin-10 expression within the symbolscript 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 symbolscript 0.031) and B10 cells (P symbolscript 0.031) as well as a tendency towards higher CD21low B cells (P symbolscript 0.063). Within the non-LRBA deficient cohort, we observe a significant expansion of the plasmablasts (P symbolscript 0.012), and a tendency towards elevated levels of CD21low expressing B cells (P symbolscript 0.063). The treatment with abatacept ameliorated disease symptoms in the LRBA deficient cohort and led to an effective decrease in CD21low B cells over time (P symbolscript 0.021). Furthermore, there was a significantly increased level of B cell-activating factor (BAFF; P symbolscript 0.02) and lower IL-12p70 secretion upon stimulation (P symbolscript 0.020) in the LRBA cohort.Conclusion: Aberrant maturation of Breg subsets and the pathological expansion of CD21low 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 CD21low B cells. Abatacept treatment results in a steady decrease in CD21low B cells.