Disturbed canonical nuclear factor of κ light chain signaling in B cells of patients with common variable immunodeficiency

Keller, Baerbel; Cseresnyés, Zoltán; Stumpf, Ina; Wehr, Claudia; Fliegauf, Manfred; Bulashevska, Alla; Usadel, Susanne; Grimbacher, Bodo; Rizzi, Marta; Eibel, Hermann; Niesner, Raluca; Warnatz, Klaus

doi:10.1016/j.jaci.2016.04.043

Cited by 32 publications

(41 citation statements)

References 51 publications

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“…In this study, we also evaluated stimulation-induced levels of Bcl-2 family proteins in B cells after anti-BCR or anti-CD40 activation with or without IL-21. Keller et al previously reported impaired BCR-mediated Bcl-XL induction in naive B cells from CVID patients with expanded CD21 low cells 32 . Our present results demonstrate a broad CVID B cell defect regarding Bcl-2 and Bcl-XL upregulation as an apoptosis prevention mechanism.…”

Section: Discussionmentioning

confidence: 98%

IL-21 and anti-CD40 restore Bcl-2 family protein imbalance in vitro in low-survival CD27+ B cells from CVID patients

et al. 2018

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Common variable immunodeficiency (CVID) is characterized by an abnormal B cell differentiation to memory and antibody-secreting B cells. The defective functionality of CVID patients’ B cells could be the consequence of alterations in apoptosis regulation. We studied the balance of Bcl-2 family anti-/pro-apoptotic proteins to identify molecular mechanisms that could underlie B cell survival defects in CVID. We used flow cytometry to investigate Bcl-2, Bcl-XL, Bax, and Bim expression in B cells ex vivo and after anti-CD40 or anti-BCR activation with or without IL-21, besides to spontaneous and stimulation-induced Caspase-3 activation and viable/apoptotic B cell subpopulations. We found increased basal levels of Bax and Bim in CVID B cells that correlated with low viability and high Caspase-3 activation only in CD27+ B cells, particularly in a subgroup of apoptosis-prone CVID (AP-CVID) patients with low peripheral B cell counts and high autoimmunity prevalence (mostly cytopenias). We detected a broad B cell defect in CVID regarding Bcl-2 and Bcl-XL induction, irrespective of the stimulus used. Therefore, peripheral CVID memory B cells are prompted to die from apoptosis due to a constitutive Bcl-2 family protein imbalance and defective protection from activation-induced apoptosis. Interestingly, anti-CD40 and IL-21 induced normal and even higher levels of Bcl-XL, respectively, in CD27+ B cells from AP-CVID, which was accompanied by cell viability increase. Thus low-survival memory B cells from AP-CVID can overcome their cell death regulation defects through pro-survival signals provided by T cells. In conclusion, we identify apoptosis regulation defects as disease-contributing factors in CVID. B cell counts and case history of cytopenias might be useful to predict positive responses to therapeutic approaches targeting T-dependent signaling pathways.

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Section: Discussionmentioning

confidence: 98%

IL-21 and anti-CD40 restore Bcl-2 family protein imbalance in vitro in low-survival CD27+ B cells from CVID patients

et al. 2018

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“…Most genes identified in CVID patients so far are thus encoding molecules with cellular functions as receptors or signaling components in B-cell development, differentiation, activation, and homeostasis (1,38). More recent data have revealed a major role for disturbances in the NF-κB pathway in some CVID patients (39). Importantly, this more detailed molecular and immunological analysis has also revealed that some of the fractions within the population of "CVID patients" should be classified separately and be regarded rather as combined immunodeficiencies due to defects in interactions between T cells and B cells, for instance in the case of cytotoxic T lymphocyteassociated antigen (CTLA)4 deficiency and LPS-responsive and beige-like anchor protein (LRBA) deficiency (40,41).…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Genetic Variants in CVID Patients With Autoimmunity, Autoinflammation, or Malignancy

et al. 2020

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Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by recurrent bacterial infections and defined by reduced levels of IgG, IgA, and/or IgM, insufficient response to polysaccharide vaccination, and an abnormal B-cell immunophenotype with a significantly reduced fraction of isotype-switched memory B cells. In addition to this infectious phenotype, at least one third of the patients experience autoimmune, autoinflammatory, granulomatous, and/or malignant complications. The very heterogeneous presentation strongly suggests a collection of different disease entities with somewhat different pathogeneses and most likely diverse genetic etiologies. Major progress has been made during recent years with the advent and introduction of next-generation sequencing, initially for research purposes, but more recently in clinical practice. In the present study, we performed whole exome sequencing on 20 CVID patients with autoimmunity, autoinflammation, and/or malignancy from the Danish CVID cohort with the aim to identify gene variants with a certain, possible, or potential disease-causing role in CVID. Through bioinformatics analyses, we identified variants with possible/probable disease-causing potential in nine of the patients. Of these, three patients had four variants in three different genes classified as likely pathogenic (NFKB1, TNFAIP3, and TTC37), whereas in six patients, we identified seven variants of possible pathogenic potential classified as variants of unknown significance (STAT3, IL17F, IRAK4, DDX41, NLRC3, TNFRSF1A, and PLCG2). In the remaining 11 patients, we did not identify possible genetic causes. Genetic findings were correlated to clinical disease presentation, clinical immunological phenotype, and disease complications. We suggest that the variants identified in the present work should lay the ground for future studies to functionally validate their disease-causing potential and to investigate at the mechanistic and molecular level their precise role in CVID pathogenesis. Overall, we believe that the present work contributes important new insights into the genetic basis of CVID and particular in the subset of CVID patients with a complex phenotype involving not only infection, but also autoimmunity, autoinflammation, and malignancy.

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“…Still, other mutations introducing early stop codons have been identified in the RHD domain lacking an association with EBV infection ( 5 , 6 , 9 , 10 , 12 ). In addition, mutation p.R157* that has been reported with EBV reactivation episodes ( 13 ) has been identified in unrelated patients without apparent EBV infection ( 8 , 9 , 11 ). Similarly, other clinical manifestations such as autoinflammatory syndromes do not correlate with clustering of mutations on protein domains (Figure 2 ).…”

Section: Human Germline Mutations In Nfkb1 and Thementioning

confidence: 99%

“…NLS, nuclear localization sequence; RHD, Rel homology domain; GRR, glycine-rich region; DD, death domain. NF-κB1 mutations are referenced according to Roman numbering: (I) Kaustio et al ( 9 ); (II) Schipp et al ( 8 ); (III) Boztug et al ( 7 ); (IV) Fliegauf et al ( 5 ); (V) Lougaris, Moratto et al ( 6 ); (VI) Maffucci et al ( 10 ); (VII) Rae et al ( 12 ); (VIII) Lougaris, Patrizi et al ( 13 ) (IX) Keller et al ( 11 ). Clinical presentations are indicated by the following symbols: #, common variable immunodeficiencies (CVID) (incl.…”

Section: Human Germline Mutations In Nfkb1 and Thementioning

confidence: 99%

Human NF-κB1 Haploinsufficiency and Epstein–Barr Virus-Induced Disease—Molecular Mechanisms and Consequences

2018

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Nuclear factor kappa-light-chain-enhancer of activated B cells 1 (NF-κB1)-related human primary immune deficiencies have initially been characterized as defining a subgroup of common variable immunodeficiencies (CVIDs), representing intrinsic B-cell disorders with antibody deficiency and recurrent infections of various kind. Recent evidence indicates that NF-κB1 haploinsufficiency underlies a variable type of combined immunodeficiency (CID) affecting both B and T lymphocyte compartments, with a broadened spectrum of disease manifestations, including Epstein–Barr virus (EBV)-induced lymphoproliferative disease and immediate life-threatening consequences. As part of this review series focused on EBV-related primary immunodeficiencies, we discuss the current clinical and molecular understanding of monoallelic NFKB1 germline mutations with special focus on the emerging context of EBV-associated disease. We outline mechanistic implications of dysfunctional NF-κB1 in B and T cells and discuss the fatal relation of impaired T-cell function with the inability to clear EBV infections. Finally, we compare common and suggested treatment angles in the context of this complex disease.

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Disturbed canonical nuclear factor of κ light chain signaling in B cells of patients with common variable immunodeficiency

Cited by 32 publications

References 51 publications

IL-21 and anti-CD40 restore Bcl-2 family protein imbalance in vitro in low-survival CD27+ B cells from CVID patients

IL-21 and anti-CD40 restore Bcl-2 family protein imbalance in vitro in low-survival CD27+ B cells from CVID patients

Identification of Novel Genetic Variants in CVID Patients With Autoimmunity, Autoinflammation, or Malignancy

Human NF-κB1 Haploinsufficiency and Epstein–Barr Virus-Induced Disease—Molecular Mechanisms and Consequences

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