Abstract
The altered wiring of signaling pathways downstream of antigen receptors of T and B cells contributes to the dysregulation of the adaptive immune system, potentially causing immunodeficiency and autoimmunity. In humans, the investigation of such complex systems benefits from nature’s experiments in patients with genetically defined primary immunodeficiencies. Disturbed B-cell receptor (BCR) signaling in a subgroup of common variable immunodeficiency (CVID) patients with immune dysregulation and expanded T-bethighCD21low B cells in peripheral blood has been previously reported. Here, we investigate PI3K signaling and its targets as crucial regulators of survival, proliferation and metabolism by intracellular flow cytometry, imaging flow cytometry and RNAseq. We observed increased basal but disturbed BCR-induced PI3K signaling, especially in T-bethighCD21low B cells from CVID patients, translating into impaired activation of crucial downstream molecules and affecting proliferation, survival and the metabolic profile. In contrast to CVID, increased basal activity of PI3K in patients with a gain-of-function mutation in PIK3CD and activated PI3K delta syndrome (APDS) did not result in impaired BCR-induced AKT-mTOR-S6 phosphorylation, highlighting that signaling defects in B cells in CVID and APDS patients are fundamentally different and that assessing responses to BCR stimulation is an appropriate confirmative diagnostic test for APDS. The active PI3K signaling in vivo may render autoreactive T-bethighCD21low B cells in CVID at the same time to be more sensitive to mTOR or PI3K inhibition.
Highlights
Common variable immunodeficiency (CVID) comprises a heterologous group of patients with primary antibody deficiency
To visualize the PI3K signaling pathway, phosphorylation of AKT and the downstream effector molecules mTOR and ribosomal protein S6 were analyzed in B cells of common variable immunodeficiency (CVID) patients and healthy donors (HD) in the unstimulated situation and after B-cell receptor (BCR)
CD21low and CD21pos B cells refer to the respective naïve B-cell subsets (Figure 1A and see Supplementary Figure S1A for the full gating strategy)
Summary
Common variable immunodeficiency (CVID) comprises a heterologous group of patients with primary antibody deficiency. CVID is defined by low serum IgG and IgA with or without IgM and a poor vaccination response or differentiation of class-switched memory B cells [1]. Especially of the respiratory and the gastrointestinal tract, nearly half of CVID patients present with a variety of non-infectious manifestations of immune dysregulation. These comprise autoimmune cytopenias, granulomatous disease, interstitial lung disease, splenomegaly, lymphadenopathy and chronic enteropathy [2,3,4]. CVID patients with immune dysregulation often display a more severe reduction of switched memory B cells and an accumulation of T-bethigh CD21low B cells in peripheral blood [5,6,7]. The underlying mechanism of B-cell dysfunction and immune dysregulation varies and frequently remains elusive
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