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.
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