Heterogeneous CD21low B Cell Subsets and Their Functional Impact in Common Variable Immunodeficiency

Atypical CD21low B lymphocytes are a naturally occurring transient subset that has been increasingly recognized in chronic diseases, such as infections and immune dysregulation, where they may persist for long. Their fate and functional role among inborn errors of immunity, such as common variable immunodeficiency (CVID), is yet to be fully understood. In this work, we provide a new perspective on atypical CD21low B cells by subdividing them into functionally relevant subsets that may differentially contribute to immune system dysregulation—namely naïve-like (IgD+ CD27−), double-negative-like (IgD− CD27−), and class-switch-like cells (IgD− CD27+). Our cohort included 30 adult patients with CVID (age range: 23–67 years) followed at the Institute of Immunology, 2nd Faculty of Medicine, Charles University, and Motol University Hospital. CD21low B lymphocytes were assessed in peripheral blood. We noted an increased number of total CD21low B lymphocytes and significant higher amount of naïve-like CD21low B cells compared to age-matched healthy controls (HC). Furthermore, to describe the involvement of individual CD21low B cell subpopulations in immune system dysregulation in CVID, we stimulated peripheral blood cells/isolated B cells from patients with TLR9 (CpG oligodeoxynucleotides [ODN]), TLR7/8 (R848—resiquimod), and B cell receptor ligands (anti-IgM and anti-CD40). We observed increased expression of costimulatory markers CD80/86, CD40, HLA-DR, and chemokine receptor CCR7 on the surface of CD21low B lymphocytes and their subpopulations in these patients after their stimulation. In addition, we also found changes in the relative representation of CD21low B lymphocyte subpopulations after in vitro stimulation via BCR and TLR. All of the above findings indicate that individual subpopulations of CD21low B lymphocytes contribute to immune system dysregulation in CVID patients, and further research is necessary to understand the exact mechanisms of CD21low B lymphocytes leading to the development of autoimmune or malignant diseases in these patients.