The Journal of allergy and clinical immunology · 2025
B-cell lymphocytosis and reprogramming due to biallelic CARD11 mutations.
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Bhattad Sagar, Gil Hwi M, Ruchinskas Allison, Stinson Jeffrey R, Staines Boone Aidé Tamara, Mohite Rachna Shanbhag, Janardhanan Jyothi, Singh Neha, Mariskanish Christine, Choi Joseph M, Basaria Shamel, Ye Xiang, Snow Andrew L, Markle Janet G
Аннотация
BACKGROUND: Adaptive immune responses are tightly controlled by proteins including CARD11 that regulate signaling events downstream of the T- and B-cell receptors. Germline mutations in CARD11 cause several distinct monogenic inborn errors of immunity with early childhood onset and potentially fatal prognoses. Somatic CARD11 gain-of-function mutations are associated with B-cell malignancies. Precisely how various CARD11 mutations culminate in unique clinical entities, and the mechanisms of CARD11-driven B-cell proliferation, is not fully understood.
OBJECTIVE: We sought to identify the genetic basis of disease and characterize immune-cell phenotypes and functions in a patient with apparent BENTA (B-cell expansion with nuclear factor-κB [NF-κB] and T-cell anergy) disease and a history of sibling death in early childhood.
METHODS: We used whole-exome sequencing, flow and mass cytometry, whole blood mRNA analyses, in vitro T-cell proliferation and B-cell differentiation assays, and single-cell RNA sequencing of patient-derived samples to identify the genetic basis of disease and define its molecular and cellular mechanisms. We also ectopically expressed wild-type and mutant forms of CARD11 in T and B cells and assessed their functional impacts on NF-κB-dependent responses.
RESULTS: We report a surprising new genetic basis of BENTA caused by homozygosity for the novel CARD11 mutation R331P and characterized by massive expansion of B cells with a naive surface phenotype and aberrant transcriptional program. This autosomal-recessive form of BENTA features exaggerated B-cell lymphocytosis relative to monoallelic BENTA. Furthermore, we have identified patterns of gene expression that distinguish B cells of patients with the autosomal-recessive form of BENTA from those of healthy controls and from monoallelic BENTA. We found that ectopic CARD11 R331P expression induced constitutive NF-κB activity in T and B cells. These data suggest that R331P is a gain-of-function mutation and causes BENTA in homozygosity.
CONCLUSIONS: These results define a novel autosomal-recessive form of BENTA disease. Additional analysis of mutation-driven changes in B-cell function may shed light on the mechanisms of B lymphomagenesis in patients with germline or somatic CARD11 variants.
OBJECTIVE: We sought to identify the genetic basis of disease and characterize immune-cell phenotypes and functions in a patient with apparent BENTA (B-cell expansion with nuclear factor-κB [NF-κB] and T-cell anergy) disease and a history of sibling death in early childhood.
METHODS: We used whole-exome sequencing, flow and mass cytometry, whole blood mRNA analyses, in vitro T-cell proliferation and B-cell differentiation assays, and single-cell RNA sequencing of patient-derived samples to identify the genetic basis of disease and define its molecular and cellular mechanisms. We also ectopically expressed wild-type and mutant forms of CARD11 in T and B cells and assessed their functional impacts on NF-κB-dependent responses.
RESULTS: We report a surprising new genetic basis of BENTA caused by homozygosity for the novel CARD11 mutation R331P and characterized by massive expansion of B cells with a naive surface phenotype and aberrant transcriptional program. This autosomal-recessive form of BENTA features exaggerated B-cell lymphocytosis relative to monoallelic BENTA. Furthermore, we have identified patterns of gene expression that distinguish B cells of patients with the autosomal-recessive form of BENTA from those of healthy controls and from monoallelic BENTA. We found that ectopic CARD11 R331P expression induced constitutive NF-κB activity in T and B cells. These data suggest that R331P is a gain-of-function mutation and causes BENTA in homozygosity.
CONCLUSIONS: These results define a novel autosomal-recessive form of BENTA disease. Additional analysis of mutation-driven changes in B-cell function may shed light on the mechanisms of B lymphomagenesis in patients with germline or somatic CARD11 variants.