Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthritis

ABSTRACT: Patients with rheumatoid arthritis (RA) may be classified as seropositive or seronegative according to the presence of autoantibodies. An abnormal B cell phenotype and function could be one of the main components of the immunopathology of seropositive patients; however, there is little inf...

Full description

Autores:
Rincón Arévalo, Héctor Julián
Rojas López, Mauricio
Vanegas García, Adriana Lucía
Muñoz Vahos, Carlos Horacio
Orejuela Erazo, Janine Andrea
Vásquez Duque, Gloria María
Castaño Monsalve, Diana María
Tipo de recurso:
Article of investigation
Fecha de publicación:
2021
Institución:
Universidad de Antioquia
Repositorio:
Repositorio UdeA
Idioma:
eng
OAI Identifier:
oai:bibliotecadigital.udea.edu.co:10495/40188
Acceso en línea:
https://hdl.handle.net/10495/40188
Palabra clave:
Artritis Reumatoide - inmunología
Arthritis, Rheumatoid - immunology
Autoanticuerpos - inmunología
Autoantibodies - immunology
Linfocitos B - inmunología
B-Lymphocytes - immunology
Diferenciación Celular - inmunología
Cell Differentiation - immunology
Citocinas - inmunología
Cytokines - immunology
Isotipos de Inmunoglobulinas - inmunología
Immunoglobulin Isotypes - immunology
Memoria Inmunológica - inmunología
Immunologic Memory - immunology
Activación de Linfocitos - inmunología
Lymphocyte Activation - immunology
Subgrupos de Linfocitos B
B-Lymphocyte Subsets
Receptores de Complemento 3d
Receptors, Complement 3d
Lectina 2 Similar a Ig de Unión al Ácido Siálico
Sialic Acid Binding Ig-like Lectin 2
https://id.nlm.nih.gov/mesh/D001172
https://id.nlm.nih.gov/mesh/D001323
https://id.nlm.nih.gov/mesh/D001402
https://id.nlm.nih.gov/mesh/D002454
https://id.nlm.nih.gov/mesh/D016207
https://id.nlm.nih.gov/mesh/D007132
https://id.nlm.nih.gov/mesh/D007156
https://id.nlm.nih.gov/mesh/D008213
https://id.nlm.nih.gov/mesh/D016175
https://id.nlm.nih.gov/mesh/D017464
https://id.nlm.nih.gov/mesh/D051918
Rights
openAccess
License
http://creativecommons.org/licenses/by-nc-nd/2.5/co/
id UDEA2_2a9f8f83b654f527e78b37ea8bd671ec
oai_identifier_str oai:bibliotecadigital.udea.edu.co:10495/40188
network_acronym_str UDEA2
network_name_str Repositorio UdeA
repository_id_str
dc.title.spa.fl_str_mv Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthritis
title Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthritis
spellingShingle Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthritis
Artritis Reumatoide - inmunología
Arthritis, Rheumatoid - immunology
Autoanticuerpos - inmunología
Autoantibodies - immunology
Linfocitos B - inmunología
B-Lymphocytes - immunology
Diferenciación Celular - inmunología
Cell Differentiation - immunology
Citocinas - inmunología
Cytokines - immunology
Isotipos de Inmunoglobulinas - inmunología
Immunoglobulin Isotypes - immunology
Memoria Inmunológica - inmunología
Immunologic Memory - immunology
Activación de Linfocitos - inmunología
Lymphocyte Activation - immunology
Subgrupos de Linfocitos B
B-Lymphocyte Subsets
Receptores de Complemento 3d
Receptors, Complement 3d
Lectina 2 Similar a Ig de Unión al Ácido Siálico
Sialic Acid Binding Ig-like Lectin 2
https://id.nlm.nih.gov/mesh/D001172
https://id.nlm.nih.gov/mesh/D001323
https://id.nlm.nih.gov/mesh/D001402
https://id.nlm.nih.gov/mesh/D002454
https://id.nlm.nih.gov/mesh/D016207
https://id.nlm.nih.gov/mesh/D007132
https://id.nlm.nih.gov/mesh/D007156
https://id.nlm.nih.gov/mesh/D008213
https://id.nlm.nih.gov/mesh/D016175
https://id.nlm.nih.gov/mesh/D017464
https://id.nlm.nih.gov/mesh/D051918
title_short Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthritis
title_full Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthritis
title_fullStr Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthritis
title_full_unstemmed Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthritis
title_sort Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthritis
dc.creator.fl_str_mv Rincón Arévalo, Héctor Julián
Rojas López, Mauricio
Vanegas García, Adriana Lucía
Muñoz Vahos, Carlos Horacio
Orejuela Erazo, Janine Andrea
Vásquez Duque, Gloria María
Castaño Monsalve, Diana María
dc.contributor.author.none.fl_str_mv Rincón Arévalo, Héctor Julián
Rojas López, Mauricio
Vanegas García, Adriana Lucía
Muñoz Vahos, Carlos Horacio
Orejuela Erazo, Janine Andrea
Vásquez Duque, Gloria María
Castaño Monsalve, Diana María
dc.contributor.researchgroup.spa.fl_str_mv Grupo de Inmunología Celular e Inmunogenética
dc.subject.decs.none.fl_str_mv Artritis Reumatoide - inmunología
Arthritis, Rheumatoid - immunology
Autoanticuerpos - inmunología
Autoantibodies - immunology
Linfocitos B - inmunología
B-Lymphocytes - immunology
Diferenciación Celular - inmunología
Cell Differentiation - immunology
Citocinas - inmunología
Cytokines - immunology
Isotipos de Inmunoglobulinas - inmunología
Immunoglobulin Isotypes - immunology
Memoria Inmunológica - inmunología
Immunologic Memory - immunology
Activación de Linfocitos - inmunología
Lymphocyte Activation - immunology
Subgrupos de Linfocitos B
B-Lymphocyte Subsets
Receptores de Complemento 3d
Receptors, Complement 3d
Lectina 2 Similar a Ig de Unión al Ácido Siálico
Sialic Acid Binding Ig-like Lectin 2
topic Artritis Reumatoide - inmunología
Arthritis, Rheumatoid - immunology
Autoanticuerpos - inmunología
Autoantibodies - immunology
Linfocitos B - inmunología
B-Lymphocytes - immunology
Diferenciación Celular - inmunología
Cell Differentiation - immunology
Citocinas - inmunología
Cytokines - immunology
Isotipos de Inmunoglobulinas - inmunología
Immunoglobulin Isotypes - immunology
Memoria Inmunológica - inmunología
Immunologic Memory - immunology
Activación de Linfocitos - inmunología
Lymphocyte Activation - immunology
Subgrupos de Linfocitos B
B-Lymphocyte Subsets
Receptores de Complemento 3d
Receptors, Complement 3d
Lectina 2 Similar a Ig de Unión al Ácido Siálico
Sialic Acid Binding Ig-like Lectin 2
https://id.nlm.nih.gov/mesh/D001172
https://id.nlm.nih.gov/mesh/D001323
https://id.nlm.nih.gov/mesh/D001402
https://id.nlm.nih.gov/mesh/D002454
https://id.nlm.nih.gov/mesh/D016207
https://id.nlm.nih.gov/mesh/D007132
https://id.nlm.nih.gov/mesh/D007156
https://id.nlm.nih.gov/mesh/D008213
https://id.nlm.nih.gov/mesh/D016175
https://id.nlm.nih.gov/mesh/D017464
https://id.nlm.nih.gov/mesh/D051918
dc.subject.meshuri.none.fl_str_mv https://id.nlm.nih.gov/mesh/D001172
https://id.nlm.nih.gov/mesh/D001323
https://id.nlm.nih.gov/mesh/D001402
https://id.nlm.nih.gov/mesh/D002454
https://id.nlm.nih.gov/mesh/D016207
https://id.nlm.nih.gov/mesh/D007132
https://id.nlm.nih.gov/mesh/D007156
https://id.nlm.nih.gov/mesh/D008213
https://id.nlm.nih.gov/mesh/D016175
https://id.nlm.nih.gov/mesh/D017464
https://id.nlm.nih.gov/mesh/D051918
description ABSTRACT: Patients with rheumatoid arthritis (RA) may be classified as seropositive or seronegative according to the presence of autoantibodies. An abnormal B cell phenotype and function could be one of the main components of the immunopathology of seropositive patients; however, there is little information regarding B cell defects in these patients. This study shows a broad characterization of the B cell phenotype and function in patients with seropositive RA. We focused mainly on the evaluation of subsets, the expression of modulatory molecules of cell activation (CD22, FcɣRIIb and FcµR), calcium mobilization, global tyrosine phosphorylation, expression of activation markers, cytokine and immunoglobulin (Ig) production, proliferation and the in-vitro generation of plasma cells. Increased frequency of CD27- IgM- IgD- and CD21- B cells was observed in patients with seropositive RA compared with healthy donors (HD). Decreased expression of CD22 was primarily found in memory B cells of patients with RA regardless of seropositivity. B cells from seropositive patients exhibited normal proliferation, calcium mobilization kinetics and global tyrosine phosphorylation, but showed an increased frequency of CD86+ B cells compared with HD. B cells of seropositive patients secrete less interleukin-10 after in-vitro activation and showed a decreased frequency of plasma cell differentiation and IgM production compared with HD. Our data indicate that patients with seropositive RA have an increased frequency of atypical B cell populations previously associated with chronic activation and antigen exposure. This may result in the observed low responsiveness of these cells in vitro.
publishDate 2021
dc.date.issued.none.fl_str_mv 2021
dc.date.accessioned.none.fl_str_mv 2024-06-21T16:53:26Z
dc.date.available.none.fl_str_mv 2024-06-21T16:53:26Z
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 Rincón-Arévalo H, Rojas M, Vanegas-García A, Muñoz-Vahos C, Orejuela-Erazo J, Vásquez G, Castaño D. Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthritis. Clin Exp Immunol. 2021 May;204(2):221-238. doi: 10.1111/cei.13576.
dc.identifier.issn.none.fl_str_mv 0009-9104
dc.identifier.uri.none.fl_str_mv https://hdl.handle.net/10495/40188
dc.identifier.doi.none.fl_str_mv 10.1111/cei.13576
dc.identifier.eissn.none.fl_str_mv 1365-2249
identifier_str_mv Rincón-Arévalo H, Rojas M, Vanegas-García A, Muñoz-Vahos C, Orejuela-Erazo J, Vásquez G, Castaño D. Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthritis. Clin Exp Immunol. 2021 May;204(2):221-238. doi: 10.1111/cei.13576.
0009-9104
10.1111/cei.13576
1365-2249
url https://hdl.handle.net/10495/40188
dc.language.iso.spa.fl_str_mv eng
language eng
dc.relation.ispartofjournalabbrev.spa.fl_str_mv Clin. Exp. Immunol.
dc.relation.citationendpage.spa.fl_str_mv 238
dc.relation.citationissue.spa.fl_str_mv 2
dc.relation.citationstartpage.spa.fl_str_mv 221
dc.relation.citationvolume.spa.fl_str_mv 204
dc.relation.ispartofjournal.spa.fl_str_mv Clinical and Experimental Immunology
dc.rights.uri.*.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/2.5/co/
dc.rights.uri.spa.fl_str_mv https://creativecommons.org/licenses/by-nc-nd/4.0/
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 http://creativecommons.org/licenses/by-nc-nd/2.5/co/
https://creativecommons.org/licenses/by-nc-nd/4.0/
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.extent.spa.fl_str_mv 18 páginas
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv Oxford University Press
dc.publisher.place.spa.fl_str_mv Oxford, Inglaterra
institution Universidad de Antioquia
bitstream.url.fl_str_mv https://bibliotecadigital.udea.edu.co/bitstreams/8b061181-60bf-4594-8531-293f95f0ad06/download
https://bibliotecadigital.udea.edu.co/bitstreams/d92c8ebc-2276-441b-8d7b-43b14a10b7cb/download
https://bibliotecadigital.udea.edu.co/bitstreams/54429cac-583d-486d-8b41-06435185b177/download
https://bibliotecadigital.udea.edu.co/bitstreams/ce7dde62-dc61-441b-bc15-1fe98adb020f/download
https://bibliotecadigital.udea.edu.co/bitstreams/29a50484-4c3a-4111-86f4-1b0948a3b233/download
bitstream.checksum.fl_str_mv 8a4605be74aa9ea9d79846c1fba20a33
5450aa2e29626c9b215633f97ee0fa8e
b88b088d9957e670ce3b3fbe2eedbc13
aeeadef6ccf59c243d2ca06395d5cb3c
2718d877fa4265218a0d1582c2f46366
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_ 1851052457134653440
spelling Rincón Arévalo, Héctor JuliánRojas López, MauricioVanegas García, Adriana LucíaMuñoz Vahos, Carlos HoracioOrejuela Erazo, Janine AndreaVásquez Duque, Gloria MaríaCastaño Monsalve, Diana MaríaGrupo de Inmunología Celular e Inmunogenética2024-06-21T16:53:26Z2024-06-21T16:53:26Z2021Rincón-Arévalo H, Rojas M, Vanegas-García A, Muñoz-Vahos C, Orejuela-Erazo J, Vásquez G, Castaño D. Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthritis. Clin Exp Immunol. 2021 May;204(2):221-238. doi: 10.1111/cei.13576.0009-9104https://hdl.handle.net/10495/4018810.1111/cei.135761365-2249ABSTRACT: Patients with rheumatoid arthritis (RA) may be classified as seropositive or seronegative according to the presence of autoantibodies. An abnormal B cell phenotype and function could be one of the main components of the immunopathology of seropositive patients; however, there is little information regarding B cell defects in these patients. This study shows a broad characterization of the B cell phenotype and function in patients with seropositive RA. We focused mainly on the evaluation of subsets, the expression of modulatory molecules of cell activation (CD22, FcɣRIIb and FcµR), calcium mobilization, global tyrosine phosphorylation, expression of activation markers, cytokine and immunoglobulin (Ig) production, proliferation and the in-vitro generation of plasma cells. Increased frequency of CD27- IgM- IgD- and CD21- B cells was observed in patients with seropositive RA compared with healthy donors (HD). Decreased expression of CD22 was primarily found in memory B cells of patients with RA regardless of seropositivity. B cells from seropositive patients exhibited normal proliferation, calcium mobilization kinetics and global tyrosine phosphorylation, but showed an increased frequency of CD86+ B cells compared with HD. B cells of seropositive patients secrete less interleukin-10 after in-vitro activation and showed a decreased frequency of plasma cell differentiation and IgM production compared with HD. Our data indicate that patients with seropositive RA have an increased frequency of atypical B cell populations previously associated with chronic activation and antigen exposure. This may result in the observed low responsiveness of these cells in vitro.Universidad de Antioquia. Vicerrectoría de investigación. Comité para el Desarrollo de la Investigación - CODIColombia. Ministerio de Ciencia, Tecnología e Innovación - MincienciasBanco de la República ColombiaCOL000863918 páginasapplication/pdfengOxford University PressOxford, Inglaterrahttp://creativecommons.org/licenses/by-nc-nd/2.5/co/https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthritisArtículo 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/publishedVersionArtritis Reumatoide - inmunologíaArthritis, Rheumatoid - immunologyAutoanticuerpos - inmunologíaAutoantibodies - immunologyLinfocitos B - inmunologíaB-Lymphocytes - immunologyDiferenciación Celular - inmunologíaCell Differentiation - immunologyCitocinas - inmunologíaCytokines - immunologyIsotipos de Inmunoglobulinas - inmunologíaImmunoglobulin Isotypes - immunologyMemoria Inmunológica - inmunologíaImmunologic Memory - immunologyActivación de Linfocitos - inmunologíaLymphocyte Activation - immunologySubgrupos de Linfocitos BB-Lymphocyte SubsetsReceptores de Complemento 3dReceptors, Complement 3dLectina 2 Similar a Ig de Unión al Ácido SiálicoSialic Acid Binding Ig-like Lectin 2https://id.nlm.nih.gov/mesh/D001172https://id.nlm.nih.gov/mesh/D001323https://id.nlm.nih.gov/mesh/D001402https://id.nlm.nih.gov/mesh/D002454https://id.nlm.nih.gov/mesh/D016207https://id.nlm.nih.gov/mesh/D007132https://id.nlm.nih.gov/mesh/D007156https://id.nlm.nih.gov/mesh/D008213https://id.nlm.nih.gov/mesh/D016175https://id.nlm.nih.gov/mesh/D017464https://id.nlm.nih.gov/mesh/D051918Clin. Exp. Immunol.2382221204Clinical and Experimental Immunology2015-7668727, 20153508, agreement 201511, 2015RoR:03bp5hc83RoR:03fd5ne08RoR:01shra089PublicationLICENSElicense.txtlicense.txttext/plain; charset=utf-81748https://bibliotecadigital.udea.edu.co/bitstreams/8b061181-60bf-4594-8531-293f95f0ad06/download8a4605be74aa9ea9d79846c1fba20a33MD53falseAnonymousREADORIGINALCastañoDiana_2021_Atypical_Phenotype_Response.pdfCastañoDiana_2021_Atypical_Phenotype_Response.pdfArtículo de investigaciónapplication/pdf2148724https://bibliotecadigital.udea.edu.co/bitstreams/d92c8ebc-2276-441b-8d7b-43b14a10b7cb/download5450aa2e29626c9b215633f97ee0fa8eMD51trueAnonymousREADCC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8823https://bibliotecadigital.udea.edu.co/bitstreams/54429cac-583d-486d-8b41-06435185b177/downloadb88b088d9957e670ce3b3fbe2eedbc13MD52falseAnonymousREADTEXTCastañoDiana_2021_Atypical_Phenotype_Response.pdf.txtCastañoDiana_2021_Atypical_Phenotype_Response.pdf.txtExtracted texttext/plain78206https://bibliotecadigital.udea.edu.co/bitstreams/ce7dde62-dc61-441b-bc15-1fe98adb020f/downloadaeeadef6ccf59c243d2ca06395d5cb3cMD54falseAnonymousREADTHUMBNAILCastañoDiana_2021_Atypical_Phenotype_Response.pdf.jpgCastañoDiana_2021_Atypical_Phenotype_Response.pdf.jpgGenerated Thumbnailimage/jpeg16225https://bibliotecadigital.udea.edu.co/bitstreams/29a50484-4c3a-4111-86f4-1b0948a3b233/download2718d877fa4265218a0d1582c2f46366MD55falseAnonymousREAD10495/40188oai:bibliotecadigital.udea.edu.co:10495/401882025-03-26 22:38:34.046http://creativecommons.org/licenses/by-nc-nd/2.5/co/open.accesshttps://bibliotecadigital.udea.edu.coRepositorio Institucional de la Universidad de Antioquiaaplicacionbibliotecadigitalbiblioteca@udea.edu.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