B Cell Receptor-Mediated Calcium Signaling Is Impaired in B Lymphocytes of Type Ia Patients with Common Variable Immunodeficiency

Abstract

Several lines of evidence have demonstrated B cell intrinsic activation defects in patients with common variable immunodeficiency (CVID). The rapid increase of intracellular free calcium concentrations after engagement of the BCR represents one crucial element in this activation process. The analysis of 53 patients with CVID for BCR-induced calcium flux identified a subgroup of patients with significantly reduced Ca2+ signals in primary B cells. This subgroup strongly corresponded to the class Ia of the Freiburg classification. Comparison at the level of defined B cell subpopulations revealed reduced Ca2+ signals in all mature B cell populations of patients with CVID class Ia when compared with healthy individuals and other groups of patients with CVID but not in circulating transitional B cells. BCR-induced Ca2+ responses were the lowest in CD21low B cells in patients as well as healthy donors, indicating an additional cell-specific mechanism inhibiting the Ca2+ flux. Although proximal BCR signaling events are unperturbed in patients’ B cells, including normal phospholipase Cγ2 phosphorylation and Ca2+ release from intracellular stores, Ca2+ influx from the extracellular space is significantly impaired. CD22, a negative regulator of calcium signals in B cells, is highly expressed on CD21low B cells from patients with CVID Ia and might be involved in the attenuated Ca2+ response of this B cell subpopulation. These data from patients with CVID suggest that a defect leading to impaired BCR-induced calcium signaling is associated with the expansion of CD21low B cells, hypogammaglobulinemia, autoimmune dysregulation, and lymphadenopathy.

Telomere‐dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency

“…We further investigated the phenotype of CD21 low CD27 1 B cells, and found that they share with CD21 low CD27 À B cells the expression of a peculiar array of receptors ( Fig. 2) associated with anergy and homing [6,9], thus suggesting similar functional properties.Collectively, our findings are consistent with the concept [5,8] that multiple subsets of B and T cells are dysfunctional in CVID 1a patients. …”

“…A previous report described overall normal telomeres in T and B cells from CVID patients [21]; however, the mean telomere lengths varied greatly from patient to patient. Since patients were not classified according to the immunophenotype, the data reported in that study appear consistent, rather than contradictory, with distinct subgroups of CVID patients with different rates of telomere attrition.Shortening of telomeres in B cells as well as in T cells of CVID 1a patients is consistent with the notion that both cell types are dysfunctional in this subgroup of CVID [5][6][7][8]. The mean telomere length in whole B-and T-cell populations was independent on the relative predominance of specific subsets such as CD21 low B cells or memory T cells.…”

“…1B) The CD21 low B cells expanded in CVID 1a and in other conditions, such as HIV [6] or HCV [11,12] infection, are either naïve-like CD27 À or memory-like CD27 1 . However, only the phenotype and function of CD21 low CD27 À B cells has been investigated in detail [7][8][9], and the CD21 low CD27 1 B cells have been proposed as precursors of short-lived plasmablasts rather than exhausted cells as their CD27 À counterparts [13]. We further investigated the phenotype of CD21 low CD27 1 B cells, and found that they share with CD21 low CD27 À B cells the expression of a peculiar array of receptors ( Fig.…”

“…These cells are profoundly anergic to B-cell stimuli, and display an array of inhibitory molecules that are likely to induce their unresponsiveness [6,7]. However, defects of calcium influx upon BCR triggering have been described in all B-cell subsets of CVID 1a patients except in their transitional B cells [8]. We observed that the percentage of B cells entering proliferation (precursor cohort) after stimulation of TLR7 or TLR9 was reduced in CVID 1a patients compared with CVID non-1a patients and healthy donors (Fig.…”

“…However, this possibility is made unlikely by the fact that CVID 1a patients are characterized by idiopathic lymphoproliferation and autoimmunity, but not by a higher rate of infections than CVID non-1a patients [25]. Nevertheless, it is possible that still unrecognized defect(s) in the telomere maintenance machinery make CVID 1a patients more susceptible to the accelerated shortening of telomeres driven by chronic infection.An appealing clue to explain telomere attrition in CVID 1a may arise from the recent observation of defective BCR-induced Ca 21 influx in all mature B cells of these patients [8]. Ca 21 is a ubiquitous second messenger controlling several cellular functions including growth, differentiation and, as highlighted by recent studies, cell senescence [26].…”