Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow

ABSTRACT: Bone marrow plasma cells (BMPC) are the correlate of humoral immunity, consistently releasing antibodies into the bloodstream. It remains unclear if BMPC reflect different activation environments or maturation of their precursors. Here we define human BMPC heterogeneity and track the recru...

Full description

Autores:
Rincón Arévalo, Héctor Julián
Ferreira Gomes, Marta
Chen, Yidan
Durek, Pawel
Heinrich, Frederik
Bauer, Laura
Franziska, Szelinski
Guerra, Gabriela Maria
Stefanski, Ana Luisa
Niedobitek, Antonia
Wiedemann, Annika
Bondareva, Marina
Tipo de recurso:
Article of investigation
Fecha de publicación:
2024
Institución:
Universidad de Antioquia
Repositorio:
Repositorio UdeA
Idioma:
eng
OAI Identifier:
oai:bibliotecadigital.udea.edu.co:10495/42168
Acceso en línea:
https://hdl.handle.net/10495/42168
Palabra clave:
Células Productoras de Anticuerpos
Antibody-Producing Cells
Antígenos CD19
Antigens, CD19
Linfocitos B
B-Lymphocytes
Células de la Médula Ósea
Bone Marrow Cells
Médula Ósea
Bone Marrow
COVID-19
Vacuna contra Difteria, Tétanos y Tos Ferina
Diphtheria-Tetanus-Pertussis Vaccine
Inmunidad Humoral
Immunity, Humoral
Interleucinas
Interleukins
Células Plasmáticas
Plasma Cells
SARS-CoV-2
Análisis de la Célula Individual
Single-Cell Analysis
Vacunación
Vaccination
https://id.nlm.nih.gov/mesh/D000921
https://id.nlm.nih.gov/mesh/D018941
https://id.nlm.nih.gov/mesh/D001402
https://id.nlm.nih.gov/mesh/D001854
https://id.nlm.nih.gov/mesh/D001853
https://id.nlm.nih.gov/mesh/D000086382
https://id.nlm.nih.gov/mesh/D015721
https://id.nlm.nih.gov/mesh/D056724
https://id.nlm.nih.gov/mesh/D007378
https://id.nlm.nih.gov/mesh/D010950
https://id.nlm.nih.gov/mesh/D000086402
https://id.nlm.nih.gov/mesh/D059010
https://id.nlm.nih.gov/mesh/D014611
Rights
openAccess
License
https://creativecommons.org/licenses/by/4.0/
id UDEA2_4f30145cef4470d82498b756f6e45158
oai_identifier_str oai:bibliotecadigital.udea.edu.co:10495/42168
network_acronym_str UDEA2
network_name_str Repositorio UdeA
repository_id_str
dc.title.spa.fl_str_mv Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow
title Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow
spellingShingle Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow
Células Productoras de Anticuerpos
Antibody-Producing Cells
Antígenos CD19
Antigens, CD19
Linfocitos B
B-Lymphocytes
Células de la Médula Ósea
Bone Marrow Cells
Médula Ósea
Bone Marrow
COVID-19
Vacuna contra Difteria, Tétanos y Tos Ferina
Diphtheria-Tetanus-Pertussis Vaccine
Inmunidad Humoral
Immunity, Humoral
Interleucinas
Interleukins
Células Plasmáticas
Plasma Cells
SARS-CoV-2
Análisis de la Célula Individual
Single-Cell Analysis
Vacunación
Vaccination
https://id.nlm.nih.gov/mesh/D000921
https://id.nlm.nih.gov/mesh/D018941
https://id.nlm.nih.gov/mesh/D001402
https://id.nlm.nih.gov/mesh/D001854
https://id.nlm.nih.gov/mesh/D001853
https://id.nlm.nih.gov/mesh/D000086382
https://id.nlm.nih.gov/mesh/D015721
https://id.nlm.nih.gov/mesh/D056724
https://id.nlm.nih.gov/mesh/D007378
https://id.nlm.nih.gov/mesh/D010950
https://id.nlm.nih.gov/mesh/D000086402
https://id.nlm.nih.gov/mesh/D059010
https://id.nlm.nih.gov/mesh/D014611
title_short Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow
title_full Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow
title_fullStr Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow
title_full_unstemmed Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow
title_sort Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow
dc.creator.fl_str_mv Rincón Arévalo, Héctor Julián
Ferreira Gomes, Marta
Chen, Yidan
Durek, Pawel
Heinrich, Frederik
Bauer, Laura
Franziska, Szelinski
Guerra, Gabriela Maria
Stefanski, Ana Luisa
Niedobitek, Antonia
Wiedemann, Annika
Bondareva, Marina
dc.contributor.author.none.fl_str_mv Rincón Arévalo, Héctor Julián
Ferreira Gomes, Marta
Chen, Yidan
Durek, Pawel
Heinrich, Frederik
Bauer, Laura
Franziska, Szelinski
Guerra, Gabriela Maria
Stefanski, Ana Luisa
Niedobitek, Antonia
Wiedemann, Annika
Bondareva, Marina
dc.contributor.researchgroup.spa.fl_str_mv Grupo de Inmunología Celular e Inmunogenética
dc.subject.decs.none.fl_str_mv Células Productoras de Anticuerpos
Antibody-Producing Cells
Antígenos CD19
Antigens, CD19
Linfocitos B
B-Lymphocytes
Células de la Médula Ósea
Bone Marrow Cells
Médula Ósea
Bone Marrow
COVID-19
Vacuna contra Difteria, Tétanos y Tos Ferina
Diphtheria-Tetanus-Pertussis Vaccine
Inmunidad Humoral
Immunity, Humoral
Interleucinas
Interleukins
Células Plasmáticas
Plasma Cells
SARS-CoV-2
Análisis de la Célula Individual
Single-Cell Analysis
Vacunación
Vaccination
topic Células Productoras de Anticuerpos
Antibody-Producing Cells
Antígenos CD19
Antigens, CD19
Linfocitos B
B-Lymphocytes
Células de la Médula Ósea
Bone Marrow Cells
Médula Ósea
Bone Marrow
COVID-19
Vacuna contra Difteria, Tétanos y Tos Ferina
Diphtheria-Tetanus-Pertussis Vaccine
Inmunidad Humoral
Immunity, Humoral
Interleucinas
Interleukins
Células Plasmáticas
Plasma Cells
SARS-CoV-2
Análisis de la Célula Individual
Single-Cell Analysis
Vacunación
Vaccination
https://id.nlm.nih.gov/mesh/D000921
https://id.nlm.nih.gov/mesh/D018941
https://id.nlm.nih.gov/mesh/D001402
https://id.nlm.nih.gov/mesh/D001854
https://id.nlm.nih.gov/mesh/D001853
https://id.nlm.nih.gov/mesh/D000086382
https://id.nlm.nih.gov/mesh/D015721
https://id.nlm.nih.gov/mesh/D056724
https://id.nlm.nih.gov/mesh/D007378
https://id.nlm.nih.gov/mesh/D010950
https://id.nlm.nih.gov/mesh/D000086402
https://id.nlm.nih.gov/mesh/D059010
https://id.nlm.nih.gov/mesh/D014611
dc.subject.meshuri.none.fl_str_mv https://id.nlm.nih.gov/mesh/D000921
https://id.nlm.nih.gov/mesh/D018941
https://id.nlm.nih.gov/mesh/D001402
https://id.nlm.nih.gov/mesh/D001854
https://id.nlm.nih.gov/mesh/D001853
https://id.nlm.nih.gov/mesh/D000086382
https://id.nlm.nih.gov/mesh/D015721
https://id.nlm.nih.gov/mesh/D056724
https://id.nlm.nih.gov/mesh/D007378
https://id.nlm.nih.gov/mesh/D010950
https://id.nlm.nih.gov/mesh/D000086402
https://id.nlm.nih.gov/mesh/D059010
https://id.nlm.nih.gov/mesh/D014611
description ABSTRACT: Bone marrow plasma cells (BMPC) are the correlate of humoral immunity, consistently releasing antibodies into the bloodstream. It remains unclear if BMPC reflect different activation environments or maturation of their precursors. Here we define human BMPC heterogeneity and track the recruitment of antibody-secreting cells (ASC) from SARS-CoV-2 vaccine immune reactions to the bone marrow (BM). Trajectories based on single-cell transcriptomes and repertoires of peripheral and BM ASC reveal sequential colonisation of BMPC compartments. In activated B cells, IL-21 suppresses CD19 expression, indicating that CD19low-BMPC are derived from follicular, while CD19high-BMPC originate from extrafollicular immune reactions. In primary immune reactions, both CD19low- and CD19high-BMPC compartments are populated. In secondary immune reactions, most BMPC are recruited to CD19high-BMPC compartments, reflecting their origin from extrafollicular reactivations of memory B cells. A pattern also observable in vaccinated-convalescent individuals and upon diphtheria/tetanus/pertussis recall-vaccination. Thus, BMPC diversity reflects the evolution of a given humoral immune response.
publishDate 2024
dc.date.accessioned.none.fl_str_mv 2024-09-16T14:48:30Z
dc.date.available.none.fl_str_mv 2024-09-16T14:48:30Z
dc.date.issued.none.fl_str_mv 2024
dc.type.spa.fl_str_mv Artículo de investigación
dc.type.coar.spa.fl_str_mv http://purl.org/coar/resource_type/c_2df8fbb1
dc.type.redcol.spa.fl_str_mv https://purl.org/redcol/resource_type/ART
dc.type.coarversion.spa.fl_str_mv http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/article
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/publishedVersion
format http://purl.org/coar/resource_type/c_2df8fbb1
status_str publishedVersion
dc.identifier.citation.spa.fl_str_mv Ferreira-Gomes, M., Chen, Y., Durek, P. et al. Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow. Nat Commun 15, 4182 (2024). https://doi.org/10.1038/s41467-024-48570-0
dc.identifier.uri.none.fl_str_mv https://hdl.handle.net/10495/42168
dc.identifier.doi.none.fl_str_mv 10.1038/s41467-024-48570-0
dc.identifier.eissn.none.fl_str_mv 2041-1723
identifier_str_mv Ferreira-Gomes, M., Chen, Y., Durek, P. et al. Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow. Nat Commun 15, 4182 (2024). https://doi.org/10.1038/s41467-024-48570-0
10.1038/s41467-024-48570-0
2041-1723
url https://hdl.handle.net/10495/42168
dc.language.iso.spa.fl_str_mv eng
language eng
dc.relation.ispartofjournalabbrev.spa.fl_str_mv Nat. Commun.
dc.relation.citationendpage.spa.fl_str_mv 16
dc.relation.citationissue.spa.fl_str_mv 1
dc.relation.citationstartpage.spa.fl_str_mv 1
dc.relation.citationvolume.spa.fl_str_mv 15
dc.relation.ispartofjournal.spa.fl_str_mv Nature Communications
dc.rights.uri.spa.fl_str_mv https://creativecommons.org/licenses/by/4.0/
dc.rights.uri.*.fl_str_mv http://creativecommons.org/licenses/by/2.5/co/
dc.rights.accessrights.spa.fl_str_mv info:eu-repo/semantics/openAccess
dc.rights.coar.spa.fl_str_mv http://purl.org/coar/access_right/c_abf2
rights_invalid_str_mv https://creativecommons.org/licenses/by/4.0/
http://creativecommons.org/licenses/by/2.5/co/
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.extent.spa.fl_str_mv 16 páginas
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv Nature Research
dc.publisher.place.spa.fl_str_mv Londres, Inglaterra
institution Universidad de Antioquia
bitstream.url.fl_str_mv https://bibliotecadigital.udea.edu.co/bitstreams/882440e0-7442-4633-a561-4bf7fc08fd3e/download
https://bibliotecadigital.udea.edu.co/bitstreams/5c29a226-0e2f-433a-9aa4-cc8f9db56ec2/download
https://bibliotecadigital.udea.edu.co/bitstreams/1968b380-9e62-4422-9a96-70cdad5c43ea/download
https://bibliotecadigital.udea.edu.co/bitstreams/2dd81387-c445-4e1c-9bbd-cf9f8dec97af/download
https://bibliotecadigital.udea.edu.co/bitstreams/9b885c97-eb46-48e3-8bfe-317d5b36d0dd/download
bitstream.checksum.fl_str_mv 1646d1f6b96dbbbc38035efc9239ac9c
8a4605be74aa9ea9d79846c1fba20a33
5461ba6722db91618b0e0cba9b14de83
b3bda63712fdecaaffeb759354304c60
b6a4d3900941de8390bf281849384615
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
MD5
repository.name.fl_str_mv Repositorio Institucional de la Universidad de Antioquia
repository.mail.fl_str_mv aplicacionbibliotecadigitalbiblioteca@udea.edu.co
_version_ 1851052573653467136
spelling Rincón Arévalo, Héctor JuliánFerreira Gomes, MartaChen, YidanDurek, PawelHeinrich, FrederikBauer, LauraFranziska, SzelinskiGuerra, Gabriela MariaStefanski, Ana LuisaNiedobitek, AntoniaWiedemann, AnnikaBondareva, MarinaGrupo de Inmunología Celular e Inmunogenética2024-09-16T14:48:30Z2024-09-16T14:48:30Z2024Ferreira-Gomes, M., Chen, Y., Durek, P. et al. Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow. Nat Commun 15, 4182 (2024). https://doi.org/10.1038/s41467-024-48570-0https://hdl.handle.net/10495/4216810.1038/s41467-024-48570-02041-1723ABSTRACT: Bone marrow plasma cells (BMPC) are the correlate of humoral immunity, consistently releasing antibodies into the bloodstream. It remains unclear if BMPC reflect different activation environments or maturation of their precursors. Here we define human BMPC heterogeneity and track the recruitment of antibody-secreting cells (ASC) from SARS-CoV-2 vaccine immune reactions to the bone marrow (BM). Trajectories based on single-cell transcriptomes and repertoires of peripheral and BM ASC reveal sequential colonisation of BMPC compartments. In activated B cells, IL-21 suppresses CD19 expression, indicating that CD19low-BMPC are derived from follicular, while CD19high-BMPC originate from extrafollicular immune reactions. In primary immune reactions, both CD19low- and CD19high-BMPC compartments are populated. In secondary immune reactions, most BMPC are recruited to CD19high-BMPC compartments, reflecting their origin from extrafollicular reactivations of memory B cells. A pattern also observable in vaccinated-convalescent individuals and upon diphtheria/tetanus/pertussis recall-vaccination. Thus, BMPC diversity reflects the evolution of a given humoral immune response.COL000863916 páginasapplication/pdfengNature ResearchLondres, Inglaterrahttps://creativecommons.org/licenses/by/4.0/http://creativecommons.org/licenses/by/2.5/co/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrowArtículo de investigaciónhttp://purl.org/coar/resource_type/c_2df8fbb1https://purl.org/redcol/resource_type/ARThttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionCélulas Productoras de AnticuerposAntibody-Producing CellsAntígenos CD19Antigens, CD19Linfocitos BB-LymphocytesCélulas de la Médula ÓseaBone Marrow CellsMédula ÓseaBone MarrowCOVID-19Vacuna contra Difteria, Tétanos y Tos FerinaDiphtheria-Tetanus-Pertussis VaccineInmunidad HumoralImmunity, HumoralInterleucinasInterleukinsCélulas PlasmáticasPlasma CellsSARS-CoV-2Análisis de la Célula IndividualSingle-Cell AnalysisVacunaciónVaccinationhttps://id.nlm.nih.gov/mesh/D000921https://id.nlm.nih.gov/mesh/D018941https://id.nlm.nih.gov/mesh/D001402https://id.nlm.nih.gov/mesh/D001854https://id.nlm.nih.gov/mesh/D001853https://id.nlm.nih.gov/mesh/D000086382https://id.nlm.nih.gov/mesh/D015721https://id.nlm.nih.gov/mesh/D056724https://id.nlm.nih.gov/mesh/D007378https://id.nlm.nih.gov/mesh/D010950https://id.nlm.nih.gov/mesh/D000086402https://id.nlm.nih.gov/mesh/D059010https://id.nlm.nih.gov/mesh/D014611Nat. Commun.161115Nature CommunicationsPublicationCC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8927https://bibliotecadigital.udea.edu.co/bitstreams/882440e0-7442-4633-a561-4bf7fc08fd3e/download1646d1f6b96dbbbc38035efc9239ac9cMD52falseAnonymousREADLICENSElicense.txtlicense.txttext/plain; charset=utf-81748https://bibliotecadigital.udea.edu.co/bitstreams/5c29a226-0e2f-433a-9aa4-cc8f9db56ec2/download8a4605be74aa9ea9d79846c1fba20a33MD53falseAnonymousREADORIGINALRinconHector_2024_Recruitment_Plasma_Cells_From.pdfRinconHector_2024_Recruitment_Plasma_Cells_From.pdfArtículo de investigaciónapplication/pdf6203363https://bibliotecadigital.udea.edu.co/bitstreams/1968b380-9e62-4422-9a96-70cdad5c43ea/download5461ba6722db91618b0e0cba9b14de83MD51trueAnonymousREADTEXTRinconHector_2024_Recruitment_Plasma_Cells_From.pdf.txtRinconHector_2024_Recruitment_Plasma_Cells_From.pdf.txtExtracted texttext/plain100389https://bibliotecadigital.udea.edu.co/bitstreams/2dd81387-c445-4e1c-9bbd-cf9f8dec97af/downloadb3bda63712fdecaaffeb759354304c60MD54falseAnonymousREADTHUMBNAILRinconHector_2024_Recruitment_Plasma_Cells_From.pdf.jpgRinconHector_2024_Recruitment_Plasma_Cells_From.pdf.jpgGenerated Thumbnailimage/jpeg17494https://bibliotecadigital.udea.edu.co/bitstreams/9b885c97-eb46-48e3-8bfe-317d5b36d0dd/downloadb6a4d3900941de8390bf281849384615MD55falseAnonymousREAD10495/42168oai:bibliotecadigital.udea.edu.co:10495/421682025-03-27 00:30:48.645https://creativecommons.org/licenses/by/4.0/open.accesshttps://bibliotecadigital.udea.edu.coRepositorio Institucional de la Universidad de Antioquiaaplicacionbibliotecadigitalbiblioteca@udea.edu.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