Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses

Javier Rodríguez-Ubreva, Anna Arutyunyan, Marc Jan Bonder, Lucía Del Pino-Molina, Stephen J. Clark, Carlos de la Calle-Fabregat, Luz Garcia-Alonso, Louis-François Handfield, Laura Ciudad, Eduardo Andrés-León, Felix Krueger, Francesc Català-Moll, Virginia C. Rodríguez-Cortez, Krzysztof Polanski, Lira Mamanova, Stijn van Dongen, Vladimir Yu. Kiselev, María T. Martínez-Saavedra, Holger Heyn, Javier Martín, Klaus Warnatz, Eduardo López-Granados, Carlos Rodríguez-Gallego, Oliver Stegle, Gavin Kelsey, Roser Vento-Tormo, Esteban Ballestar

Abstract

Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients.

Datasets

1. Activated PBMCs - Expanded cohort CITE-seq
Metadata
batch
sample
stimulation
prelim_annot
celltype_predictions
phase
louvain
Age of disease onset
Autoimmunity
Gastrointestinal disease
Lung disease (bronchiectasis)
Lymphoadenopathy
Splenomegaly
History of hypogammaglobulinemia, IgA deficiency or immunodeficiency in other family members
GC_celltype_predictions_all_genes
CVID_class_Freiburg
CVID_class_Euroclass
assay_ontology_term_id
author_cell_type
cell_type_ontology_term_id
development_stage_ontology_term_id
disease_ontology_term_id
donor_id
organism_ontology_term_id
self_reported_ethnicity_ontology_term_id
sex_ontology_term_id
suspension_type
tissue_ontology_term_id
tissue_type
cell_type
assay
disease
organism
sex
tissue
self_reported_ethnicity
development_stage
815442 cells
614879 cells
713380 cells
111691 cells
010869 cells
49328 cells
59058 cells
25413 cells
35004 cells
Preview
Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses
2. Activated PBMCs - Twins scRNA-seq
Metadata
activation
batch
sample
celltype_predictions
phase
cell_type_corrected_final
assay_ontology_term_id
cell_type_ontology_term_id
development_stage_ontology_term_id
disease_ontology_term_id
donor_id
organism_ontology_term_id
self_reported_ethnicity_ontology_term_id
sex_ontology_term_id
suspension_type
tissue_ontology_term_id
tissue_type
cell_type
assay
disease
organism
sex
tissue
self_reported_ethnicity
development_stage
CD39111 cells
CD40L3968 cells
CTRL3822 cells
Preview
Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses
3. Steady-state B cells - scRNA-seq
Metadata
batchcode
lane
batch
assay_ontology_term_id
cell_type_ontology_term_id
development_stage_ontology_term_id
disease_ontology_term_id
donor_id
organism_ontology_term_id
self_reported_ethnicity_ontology_term_id
sex_ontology_term_id
suspension_type
tissue_ontology_term_id
author_cell_type
tissue_type
cell_type
assay
disease
organism
sex
tissue
self_reported_ethnicity
development_stage
BATCH2354 cells
BATCH3342 cells
BATCH1316 cells
BATCH4312 cells
Preview
Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses

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Source data

https://cellxgene.cziscience.com/collections/bf325905-5e8e-42e3-933d-9a9053e9af80

Alias names

EGAD00001008575, PRJEB50820, PMID35365635, PMC8975885

Cite this study

Rodríguez-Ubreva, J., Arutyunyan, A., Bonder, M.J., Del Pino-Molina, L., Clark, S.J., de la Calle-Fabregat, C., Garcia-Alonso, L., Handfield, L.F., Ciudad, L., Andres-Leon, E. and Krueger, F., 2022. Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses. Nature communications, 13(1), p.1779. https://doi.org/10.1038/s41467-022-29450-x