The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA . Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s disease and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

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 adaptive immune response relies on specific apoptotic programs to maintain homeostasis. Conventional effector T cell (Tcon) expansion is constrained by both forkhead box P3 (FOXP3) +-regulatory T cells (Tregs) and restimulation-induced cell death (RICD), a propriocidal apoptosis pathway triggered by repeated stimulation through the T-cell receptor (TCR). Constitutive FOXP3 expression protects Tregs from RICD by suppressing SLAM-associated protein (SAP), a key adaptor protein that amplifies TCR signaling strength. The role of transient FOXP3 induction in activated human CD4 and CD8 Tcons remains unresolved, but its expression is inversely correlated with acquired RICD sensitivity. Here, we describe a novel role for FOXP3 in protecting human Tcons from premature RICD during expansion. Unlike FOXP3-mediated protection from RICD in Tregs, FOXP3 protects Tcons through a distinct mechanism requiring de novo transcription that does not require SAP suppression. Transcriptome profiling and functional analyses of expanding Tcons revealed that FOXP3 enhances expression of the SLAM family receptor CD48, which in turn sustains basal autophagy and suppresses pro-apoptotic p53 signaling. Both CD48 and FOXP3 expression reduced p53 accumulation upon TCR restimulation. Furthermore, silencing FOXP3 expression or blocking CD48 decreased the mitochondrial membrane potential in expanding Tcons with a concomitant reduction in basal autophagy. Our findings suggest that FOXP3 governs a distinct transcriptional program in early-stage effector Tcons that maintains RICD resistance via CD48-dependent protective autophagy and p53 suppression.

No abstract

BENTA (B cell Expansion with NF-κB and T cell Anergy) disease is a rare, selective B cell lymphoproliferative disorder caused by gain-of-function (GOF) mutations in the lymphocyte scaffolding molecule CARD11. CARD11 is required for downstream activation of NF-κB following antigen receptor engagement, which normally triggers recruitment of BCL10 and MALT1. MALT1 serves both scaffolding and proteolytic functions that initiate and amplify canonical NF-κB signaling. It still remains unclear how continuous CARD11 signaling ultimately drives massive B cell accumulation in BENTA patients. Here we show that in contrast to normal human B cells, BENTA patient B cells exhibited a striking resistance to apoptosis in cell culture, particularly after stimulation. Enhanced survival of patient cells was dependent on MALT1 protease, which is activated constitutively by CARD11 GOF mutants. Treatment with a novel, specific low molecular weight inhibitor of MALT1 protease completely restored apoptosis sensitivity in BENTA patient B cells. RNA-Seq analyses revealed that MALT1 protease inhibition induced a specific subset of pro-apoptotic genes in activated patient B cells, and downregulated multiple genes associated with cell cycle progression and metabolism, in addition to several NF-κB target genes. Although not strictly required for CARD11-dependent NF-κB activation, our results imply that MALT1 protease function governs a pro-survival signaling program in BENTA B cells that likely contributes to the profound B cell lymphocytosis that distinguishes this disease. MALT1 protease thus represents an attractive therapeutic target for reducing B cell burden in these patients, thereby lowering the risk of B cell malignancy later in life.