Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition

Rodríguez-Cortez, Virginia C.; Molina, Lucía del Pino; Rodríguez-Ubreva, Javier; Ciudad, Laura; Green, David; Company, Carlos; Urquiza, José; Tegnér, Jesper; Rodríguez-Gallego, Carlos; López‐Granados, Eduardo; Ballestar, Esteban

doi:10.1038/ncomms8335

Cited by 90 publications

(82 citation statements)

References 45 publications

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“…By performing whole genome and RNA sequencing, interesting genes and pathways were found to be related to the CVID [52]. By examining genome-wide methylation sites, multiple genes were found to be hypermethylated in switched memory B cells of CVID patient, suggesting the potential role of defective demethylation in the development of CVID [58]. Though the latter two studies have the limitation of small sample size, they demonstrated the success of applying these novel high-throughput omics approaches to the study of the complex disease CVID.…”

Section: Discussionmentioning

confidence: 98%

“…Many of these genes were further validated by pyrosequencing. [58][59][60] In addition to the identification of hypermethylated genes with potential contributions to the development of CVID, this study also demonstrated how studying monozygotic twins could significantly impact our understanding of the etiology of immune disorders.…”

Section: High-throughput Epigenomic Approachmentioning

confidence: 94%

“…DNA methylation is one important epigenetic mechanism for regulating gene expression [57]. Using Infinium HumanMethylation450 BeadChips, Rodriguez-Cortez et al [58] profiled the epigenome of B cells derived from monozygotic twins discordant for CVID and observed a total of 311 CpG sites with differential DNA methylation. Interestingly, multiple genes identified were hypermethylated and appear to be involved in BCR signaling.…”

Section: High-throughput Epigenomic Approachmentioning

confidence: 98%

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Understanding the genetic and epigenetic basis of common variable immunodeficiency disorder through omics approaches

Jin

Wei

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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Section: Discussionmentioning

confidence: 98%

Section: High-throughput Epigenomic Approachmentioning

confidence: 94%

Section: High-throughput Epigenomic Approachmentioning

confidence: 98%

See 1 more Smart Citation

Understanding the genetic and epigenetic basis of common variable immunodeficiency disorder through omics approaches

Jin

Wei

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…The results presented support the notion of a complex basis of CVID and related milder PAD disorders, in which an accumulation of multiple genetic and/or environmental factors contributes to the final phenotype. 3,15,16 Monogenic defects have only been identified in a minority of cases with CVID. 14 Remarkably, some relatives with the same monogenic defect were found to be asymptomatic or suffer from a milder PAD phenotype such as IgGSD.…”

Section: Discussionmentioning

confidence: 99%

“…15 In addition, B cells in CVID patients have been shown to have DNA methylation alterations in genes critical for B-cell function, implicating a role for epigenetic factors in the pathogenesis of CVID. 16 While the immunological phenotype of CVID has been investigated in depth, there are only few reports on IPH and IgGSD and none on cohorts of asymptomatic PAD family members. We, therefore, performed a detailed immunophenotypic analysis of CVID, IPH and IgGSD patients as well as asymptomatic first-degree relatives of the PAD patients included in the study (asymptomatic family members, AFM) and unrelated healthy controls (HC).…”

mentioning

confidence: 99%

The immunophenotypic fingerprint of patients with primary antibody deficiencies is partially present in their asymptomatic first-degree relatives

et al. 2016

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T he etiology of primary antibody deficiencies is largely unknown. Beside rare monogenic forms, the majority of cases seem to have a more complex genetic basis. Whereas common variable immunodeficiency has been investigated in depth, there are only a few reports on milder primary antibody deficiencies such as idiopathic primary hypogammaglobulinemia and IgG subclass deficiency. We performed flow cytometric immunophenotyping in 33 patients with common variable immunodeficiency, 23 with idiopathic primary hypogammaglobulinemia and 21 with IgG subclass deficiency, as well as in 47 asymptomatic first-degree family members of patients and 101 unrelated healthy controls. All three groups of patients showed decreased memory B-and naïve T-cell subsets and decreased B-cell activating factor receptor expression. In contrast, circulating follicular helper T-cell frequency and expression of inducible T-cell costimulator and chemokine receptors were only significantly altered in patients with common variable immunodeficiency. Asymptomatic firstdegree family members of patients demonstrated similar, albeit intermediate, alterations in naïve and memory B-and T-cell subsets. About 13% of asymptomatic relatives had an abnormal peripheral B-cell composition. Furthermore, asymptomatic relatives showed decreased levels of CD4 + recent thymic emigrants and increased central memory T cells. Serum IgG and IgM levels were also significantly lower in asymptomatic relatives than in healthy controls. We conclude that, in our cohort, the immunophenotypic landscape of primary antibody deficiencies comprises a spectrum, in which some alterations are shared between all primary antibody deficiencies whereas others are only associated with common variable immunodeficiency. Importantly, asymptomatic first-degree family members of patients were found to have an intermediate phenotype for peripheral Band T-cell subsets.

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Molecular Genetics of Common Variable Immunodeficiency

Bogaert

Dullaers

Baere

et al. 2017

Encyclopedia of Life Sciences

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Common variable immunodeficiency (CVID) is one of the most frequently diagnosed primary immunodeficiencies (PIDs) characterised by antibody deficiency, poor responses to vaccination and an increased susceptibility to infections and complications due to immune dysregulation. The clinical diagnosis of CVID is an umbrella covering an immunologically and genetically heterogeneous group of diseases. To date, 22 disease‐causing genes have been associated with monogenic forms of CVID, encompassing 2–10% of reported cases. However, these genetic subtypes are now considered to account for distinct disease entities and have been removed from under the CVID umbrella. Furthermore, accumulating data suggest that the majority of CVID patients have a complex or multifactorial disorder, in which multiple genetic, epigenetic and/or environmental factors are involved. Genetic testing for monogenic causes should especially be performed in CVID patients with early onset of disease, noninfectious complications, a positive family history and/or consanguineous parents, since this could be important for genetic counselling, follow up and/or treatment decisions. Key Concepts CVID is a diagnosis of exclusion, encompassing a clinically, immunologically and genetically heterogeneous group of PID patients. Monogenic defects have so far been reported in 2–10% of CVID patients. The majority of CVID patients are believed to have a complex or multifactorial aetiology. Patients in whom a monogenic cause is identified are no longer classified under CVID, but under separate disease entities (IUIS classification). A monogenic cause of CVID is more probable in case of early onset of disease, complications of immune dysregulation, a positive family history and/or consanguinity. Especially in CVID patients with early onset of disease and/or noninfectious complications, genetic workup should be performed to identify or exclude an underlying monogenic cause since this could be important for patient management decisions.

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Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition

Cited by 90 publications

References 45 publications

Understanding the genetic and epigenetic basis of common variable immunodeficiency disorder through omics approaches

Understanding the genetic and epigenetic basis of common variable immunodeficiency disorder through omics approaches

The immunophenotypic fingerprint of patients with primary antibody deficiencies is partially present in their asymptomatic first-degree relatives

Molecular Genetics of Common Variable Immunodeficiency

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