Regulatory B cells in patients suffering from inborn errors of immunity with severe immune dysregulation. Issue 132 (October 2022)

• Record Type: Journal Article
• Authors: Bakhtiar, Shahrzad; Kaffenberger, Celia; Salzmann-Manrique, Emilia; Donhauser, Sabine; Lueck, Leon; Karaca, Neslihan Edeer; Gonzalez-Granado, Luis I.; Hazar, Esra; Keles, Sevgi; Seidel, Markus G.; Fekadu, Julia; Königs, Christoph; Schubert, Ralf; Bader, Peter; Huenecke, Sabine
• Is Part Of: Journal of autoimmunity. Issue 132(2022)
• Publication Date: 2022-10
• Subjects: B regulatory cells -- Inborn error of immunity -- LRBA -- CD21 low B cell -- B10 cells -- Abatacept; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2022.102891
• Languages: English
• ISSNs: 0896-8411

Abstract

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 hi CD38 hi ), and B10 cells (CD24 hi CD27 + ), and additionally the CD21 low B cells (CD21 low CD38 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. Highlights: Breg profile of patients with severe symptoms of immune dysregulation due to inborn errors of immunity is presented. LRBA deficiency syndrome serves as a disease model and a prime example for IEI with severe immune dysregulation. The role of B10 cells and CD21 low B cell is highlighted in the setting of LRBA and non-LRBA IEI with immune dysregulation. Abatacept leads to an effective decrease in CD21 low B cells over time in LRBA deficient patients. Results add to the better understanding of immune dysregulation and might provide targets for future treatment possibilities.