Intrinsic Plasma Cell Differentiation Defects in B Cell Expansion with NF-κB and T Cell Anergy Patient B Cells

Abstract

B cell Expansion with NF-κB and T cell Anergy (BENTA) disease is a novel B cell lymphoproliferative disorder caused by germline, gain-of-function mutations in the lymphocyte scaffolding protein CARD11, which drives constitutive NF-κB signaling. Despite dramatic polyclonal expansion of naive and immature B cells, BENTA patients also present with signs of primary immunodeficiency, including markedly reduced percentages of class-switched/memory B cells and poor humoral responses to certain vaccines. Using purified naive B cells from our BENTA patient cohort, here we show that BENTA B cells exhibit intrinsic defects in B cell differentiation. Despite a profound in vitro survival advantage relative to normal donor B cells, BENTA patient B cells were severely impaired in their ability to differentiate into short-lived IgDloCD38hi plasmablasts or CD138+ long-lived plasma cells in response to various stimuli. These defects corresponded with diminished IgG antibody production and correlated with poor induction of specific genes required for plasma cell commitment. These findings provide important mechanistic clues that help explain both B cell lymphocytosis and humoral immunodeficiency in BENTA disease.

The CBM-opathies—A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex

“…Low serum IgM and IgA levels are noted in some patients, with IgG being variable. In vitro studies of naïve patient B cells demonstrated impaired B cell differentiation into plasmablasts and long-lived plasma cells, consistent with poor IgG secretion in culture ( 106 ). These defects could be explained in part by a failed induction of specific factors required for plasma cell commitment, including BLIMP-1 and XBP-1.…”

A Regulatory Circuit Controlling the Dynamics of NFκB cRel Transitions B Cells from Proliferation to Plasma Cell Differentiation

“…Thus, both cRel and RelA are indispensable for humoral immunity but for different functional reasons. However, a recent study showed that in the genetic disease B cell expansion with NFkB and T cell anergy (BENTA), constitutively active NFkB results in reduced ASC generation (Arjunaraja et al, 2017), suggesting that precise regulation of each NFkB dimer is required for healthy ASC generation.…”

Impaired Control of Epstein–Barr Virus Infection in B-Cell Expansion with NF-κB and T-Cell Anergy Disease

“…Poor humoral immune responses in these patients are also reflected in very low frequencies of circulating class-switched and memory B cells, as well as low levels of IgM and IgA in the serum. Impaired humoral immunity in BENTA is evidenced by intrinsic defects in plasma cell differentiation and antibody secretion upon stimulation of naïve patient B cells in vitro , despite normal proliferation and enhanced survival ( 41 ). The hyporesponsiveness of BENTA patient T cells to in vitro stimulation, including poor proliferation and reduced IL-2 secretion, may also contribute to defective class-switched Ab responses ( 23 , 35 ).…”

“…The authors connected some of these defects to enhanced expression of the transcriptional repressor Blimp-1, which has been shown to promote T cell exhaustion. Although we have not measured Blimp-1 in BENTA T cells, we recently characterized a profound, intrinsic defect in patient B cell differentiation linked to failed induction of Blimp-1 ( 41 ). Clearly much more work is required to understand how elevated NF-κB activation perturbs seemingly independent pathways downstream of TCR signaling.…”