Activated PIK3CD drives innate B cell expansion yet limits B cell–intrinsic immune responses

Abstract

Activated PI3K-delta syndrome (APDS) is an immunodeficiency caused by gain-of-function mutations in PIK3CD. This disease exhibits complex immune phenotypes including increased IgM, recurrent infection, and impaired vaccine responses. To better understand the impact of B cells in this disease, we generated an inducible model of the common APDS mutation (h-E1021K; referred to as aPIK3CD) and intercrossed these mice with B cell-specific Cre models. Mb1-aPIK3CD mice exhibited bone marrow B lymphopenia and, conversely, expansion of the peripheral innate B1a and MZ B cell compartments. aPIK3CD B cells manifest increased pS6 and increased survival at several stages, without alterations in cycling, and baseline increases in plasma cells, natural IgM, and IgG3. Finally, Mb1-aPIK3CD mice exhibited blunted T cell-independent immune responses, and both AID- and CD21-aPIK3CD mice displayed reduced class-switched antibodies following T cell-dependent immunization. Thus, aPIK3CD alters B cell development and function and is counter-productive during immune responses, providing insight into B cell-intrinsic contributions to the APDS phenotype.

Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production

“…3, B -D). This is consistent with previous observations of increased pro-and pre-B cells in the endogenous repertoire of Pik3cd GOF mice, as well as of pre-B and immature B cells in the BM of patients with PIK3CD GOF mutations (Avery et al, 2018;Preite et al, 2018;Stark et al, 2018;Wray-Dutra et al, 2018). As with WT cells, we observed dramatically reduced proportions of mature self-reactive Pik3cd GOF SW HEL B cells ( Fig.…”

“…6 C and Fig. S5), consistent with the decreased ability of Pik3cd GOF B cells to undergo class switch recombination (Avery et al, 2018;Preite et al, 2018;Wray-Dutra et al, 2018) and the paucity of IgG autoreactive antibodies in PIK3CD GOF patients (Fig. S1).…”

“…Interestingly, ∼40% of PIK3CD GOF patients also develop clinically relevant autoimmune disease, including autoimmune cytopenias, glomerulonephritis, and autoimmune thyroiditis (Coulter et al, 2017;Lucas et al, 2014;Maccari et al, 2018). Several recent studies have explored the pathogenesis of the immunodeficiency in these patients (Avery et al, 2018;Bier et al, 2019;Cannons et al, 2018;Cura Daball et al, 2018;Edwards et al, 2019;Preite et al, 2018;Preite et al, 2019;Ruiz-García et al, 2018;Stark et al, 2018;Wentink et al, 2017;Wentink et al, 2018;Wray-Dutra et al, 2018). These studies have revealed defects in B cells and CD4 + T cells, thereby elucidating mechanisms for poor antibody responses and susceptibility to respiratory infections, and altered natural killer and CD8 + T cell function, which provide an explanation for the viral susceptibility and possibly malignancy.…”

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

“…In line with the human data, Pik3cd E1020K/+ mice showed a partial B‐cell developmental block in the BM and expansion of transitional B cells in the periphery, although, one study did not observe increased transitional B cells, possibly because of different gating strategies or the use of a conditional mouse model that expressed mutant PI3Kδ at later stages in mature B cells . These changes were accompanied by outgrowth of marginal zone B cells at the expense of mature follicular B cells.…”

“…Recently, four independent groups, including ours, generated heterozygous mice expressing the E1020K mutant of PI3Kδ, equivalent to the most common APDS mutation . Pik3cd E1020K/+ mice recapitulate many phenotypes of APDS, including peripheral blood lymphopenia yet expansion of lymphocytes in the spleen, peripheral lymph nodes (LN), and gut‐associated lymphoid tissues (GALT), lymphoid nodules in lung and gut, elevated IgM, and autoimmune manifestations .…”