Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses
Por:
Rodriguez-Ubreva, J, Arutyunyan, A, Bonder, MJ, Del Pino-Molina, L, Clark, SJ, de la Calle-Fabregat, C, Garcia-Alonso, L, Handfield, LF, Ciudad, L, Andres-Leon, E, Krueger, F, Catala-Moll, F, Rodriguez-Cortez, VC, Polanski, K, Mamanova, L, van Dongen, S, Kiselev, VY, Martinez-Saavedra, MT, Heyn, H, Martin, J, Warnatz, K, Lopez-Granados, E, Rodriguez-Gallego, C, Stegle, O, Kelsey, G, Vento-Tormo, R and Ballestar, E
Publicada:
1 abr 2022
Resumen:
Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency. Here the authors perform single-cell omics analyses in CVID-discordant monozygotic twins and show epigenetic and transcriptional alterations associated with activation in memory B cells.
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 naive-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 naive-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.
Filiaciones:
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Josep Carreras Res Inst IJC, Epigenet & Immune Dis Grp, Barcelona, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Programme PEBC, Chromatin & Dis Grp, Barcelona, Spain
Arutyunyan, A:
Wellcome Sanger Inst, Cellular Genet Dept, Wellcome Genome Campus, Hinxton, England
Univ Cambridge, Ctr Trophoblast Res, Cambridge, England
Bonder, MJ:
European Mol Biol Lab, European Bioinformat Inst EMBL EBI, Wellcome Genome Campus, Hinxton, Cambs, England
European Mol Biol Lab, Genome Biol Unit, Heidelberg, Germany
German Canc Res Ctr, Div Computat Genom & Syst Genet, Heidelberg, Germany
Del Pino-Molina, L:
La Paz Univ Hosp, Clin Immunol Dept, Madrid, Spain
La Paz Inst Hlth Res IdiPAZ, Ctr Biomed Network Res Rare Dis CIBERER U767, Lymphocyte Pathophysiol Immunodeficiencies Grp, Madrid, Spain
Clark, SJ:
Babraham Inst, Epigenet Programme, Cambridge, England
:
Josep Carreras Res Inst IJC, Epigenet & Immune Dis Grp, Barcelona, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Programme PEBC, Chromatin & Dis Grp, Barcelona, Spain
Garcia-Alonso, L:
Wellcome Sanger Inst, Cellular Genet Dept, Wellcome Genome Campus, Hinxton, England
Handfield, LF:
Wellcome Sanger Inst, Cellular Genet Dept, Wellcome Genome Campus, Hinxton, England
Ciudad, L:
Josep Carreras Res Inst IJC, Epigenet & Immune Dis Grp, Barcelona, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Programme PEBC, Chromatin & Dis Grp, Barcelona, Spain
Andres-Leon, E:
CSIC, Consejo Super Invest Cient IPBLN, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain
Krueger, F:
Babraham Inst, Bioinformat Unit, Cambridge, England
Catala-Moll, F:
Josep Carreras Res Inst IJC, Epigenet & Immune Dis Grp, Barcelona, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Programme PEBC, Chromatin & Dis Grp, Barcelona, Spain
Rodriguez-Cortez, VC:
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Programme PEBC, Chromatin & Dis Grp, Barcelona, Spain
Polanski, K:
Wellcome Sanger Inst, Cellular Genet Dept, Wellcome Genome Campus, Hinxton, England
Mamanova, L:
Wellcome Sanger Inst, Cellular Genet Dept, Wellcome Genome Campus, Hinxton, England
van Dongen, S:
Wellcome Sanger Inst, Cellular Genet Dept, Wellcome Genome Campus, Hinxton, England
Kiselev, VY:
Wellcome Sanger Inst, Cellular Genet Dept, Wellcome Genome Campus, Hinxton, England
Martinez-Saavedra, MT:
Hosp Univ Gran Canaria Dr Negrin, Dept Immunol, Las Palmas Gran Canaria, Spain
Heyn, H:
Barcelona Inst Sci & Technol BIST, Ctr Genom Regulat CRG, CNAG CRG, Barcelona, Spain
Univ Pompeu Fabra UPF, Barcelona, Spain
Martin, J:
CSIC, Consejo Super Invest Cient IPBLN, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain
Warnatz, K:
Univ Freiburg, Fac Med, Med Ctr, Dept Rheumatol & Clin Immunol, Freiburg, Germany
Univ Freiburg, Fac Med, Ctr Chron Immunodeficiency CCI, Med Ctr, Freiburg, Germany
Lopez-Granados, E:
La Paz Univ Hosp, Clin Immunol Dept, Madrid, Spain
La Paz Inst Hlth Res IdiPAZ, Ctr Biomed Network Res Rare Dis CIBERER U767, Lymphocyte Pathophysiol Immunodeficiencies Grp, Madrid, Spain
Rodriguez-Gallego, C:
Hosp Univ Gran Canaria Dr Negrin, Dept Immunol, Las Palmas Gran Canaria, Spain
Univ Fernando Pessoa, Dept Clin Sci, Las Palmas Gran Canaria, Spain
Stegle, O:
European Mol Biol Lab, European Bioinformat Inst EMBL EBI, Wellcome Genome Campus, Hinxton, Cambs, England
European Mol Biol Lab, Genome Biol Unit, Heidelberg, Germany
German Canc Res Ctr, Div Computat Genom & Syst Genet, Heidelberg, Germany
Wellcome Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England
Kelsey, G:
Univ Cambridge, Ctr Trophoblast Res, Cambridge, England
Babraham Inst, Epigenet Programme, Cambridge, England
Vento-Tormo, R:
Wellcome Sanger Inst, Cellular Genet Dept, Wellcome Genome Campus, Hinxton, England
Univ Cambridge, Ctr Trophoblast Res, Cambridge, England
:
Josep Carreras Res Inst IJC, Epigenet & Immune Dis Grp, Barcelona, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Programme PEBC, Chromatin & Dis Grp, Barcelona, Spain
East China Normal Univ ECNU, Hlth Sci Ctr HSC, Epigenet Inflammatory & Metab Dis Lab, Shanghai, Peoples R China
Green Published, gold, Green Submitted
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