Regulatory B cells in patients suffering from inborn errors of immunity with severe immune dysregulation

Abstract

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^low 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 (CD27⁺CD38^hi), transitional B cells (CD24^hiCD38^hi), and B10 cells (CD24^hiCD27⁺), and additionally the CD21^low B cells (CD21^lowCD38^low) 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^low 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^low 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^low 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^low 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^low B cells. Abatacept treatment results in a steady decrease in CD21^low B cells.

Keywords: Abatacept; B regulatory cells; B10 cells; CD21 (low) B cell; Inborn error of immunity; LRBA.