Noninfectious complications in patients with pediatric-onset common variable immunodeficiency correlated with defects in somatic hypermutation but not in class-switch recombination
- Autores
- Almejún, María Belén; Campos, Bárbara Carolina; Patiño, Virginia; Galicchio, Miguel; Zelazko, Marta; Oleastro, Matías; Oppezzo, Pablo; Danielian, Silvia
- Año de publicación
- 2017
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Background Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production and usually presents with a normal quantity of peripheral B cells. Most attempts aiming to classify these patients have mainly been focused on T- or B-cell phenotypes and their ability to produce protective antibodies, but it is still a major challenge to find a suitable classification that includes the clinical and immunologic heterogeneity of these patients. Objective In this study we evaluated the late stages of B-cell differentiation in a heterogeneous population of patients with pediatric-onset CVID to clinically correlate and assess their ability to perform somatic hypermutation (SHM), class-switch recombination (CSR), or both. Methods We performed a previously reported assay, the restriction enzyme hotspot mutation assay (IgκREHMA), to evaluate in vivo SHM status. We amplified switch regions from genomic DNA to investigate the quality of the double-strand break repairs in the class-switch recombination process in vivo. We also tested the ability to generate immunoglobulin germline and circle transcripts and to upregulate the activation-induced cytidine deaminase gene through in vitro T-dependent and T-independent stimuli. Results Our results showed that patients could be classified into 2 groups according to their degree of SHM alteration. This stratification showed a significant association between patients of group A, severe alteration, and the presence of noninfectious complications. Additionally, 60% of patients presented with increased microhomology use at switched regions. In vitro activation revealed that patients with CVID behaved heterogeneously in terms of responsiveness to T-dependent stimuli. Conclusions The correlation between noninfectious complications and SHM could be an important tool for physicians to further characterize patients with CVID. This categorization would help to improve elucidation of the complex mechanisms involved in B-cell differentiation pathways.
Fil: Almejún, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Campos, Bárbara Carolina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Patiño, Virginia. Instituto Pasteur; Uruguay
Fil: Galicchio, Miguel. Hospital de Niños Víctor J. Vilela; Argentina
Fil: Zelazko, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Oleastro, Matías. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Oppezzo, Pablo. Instituto Pasteur; Uruguay
Fil: Danielian, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina - Materia
-
Class-Switch Recombination
Common Variable Immunodeficiency
Hypermutation
Pediatric
Somatic Hypermutation
Switch - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/52609
Ver los metadatos del registro completo
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Noninfectious complications in patients with pediatric-onset common variable immunodeficiency correlated with defects in somatic hypermutation but not in class-switch recombinationAlmejún, María BelénCampos, Bárbara CarolinaPatiño, VirginiaGalicchio, MiguelZelazko, MartaOleastro, MatíasOppezzo, PabloDanielian, SilviaClass-Switch RecombinationCommon Variable ImmunodeficiencyHypermutationPediatricSomatic HypermutationSwitchhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production and usually presents with a normal quantity of peripheral B cells. Most attempts aiming to classify these patients have mainly been focused on T- or B-cell phenotypes and their ability to produce protective antibodies, but it is still a major challenge to find a suitable classification that includes the clinical and immunologic heterogeneity of these patients. Objective In this study we evaluated the late stages of B-cell differentiation in a heterogeneous population of patients with pediatric-onset CVID to clinically correlate and assess their ability to perform somatic hypermutation (SHM), class-switch recombination (CSR), or both. Methods We performed a previously reported assay, the restriction enzyme hotspot mutation assay (IgκREHMA), to evaluate in vivo SHM status. We amplified switch regions from genomic DNA to investigate the quality of the double-strand break repairs in the class-switch recombination process in vivo. We also tested the ability to generate immunoglobulin germline and circle transcripts and to upregulate the activation-induced cytidine deaminase gene through in vitro T-dependent and T-independent stimuli. Results Our results showed that patients could be classified into 2 groups according to their degree of SHM alteration. This stratification showed a significant association between patients of group A, severe alteration, and the presence of noninfectious complications. Additionally, 60% of patients presented with increased microhomology use at switched regions. In vitro activation revealed that patients with CVID behaved heterogeneously in terms of responsiveness to T-dependent stimuli. Conclusions The correlation between noninfectious complications and SHM could be an important tool for physicians to further characterize patients with CVID. This categorization would help to improve elucidation of the complex mechanisms involved in B-cell differentiation pathways.Fil: Almejún, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Campos, Bárbara Carolina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Patiño, Virginia. Instituto Pasteur; UruguayFil: Galicchio, Miguel. Hospital de Niños Víctor J. Vilela; ArgentinaFil: Zelazko, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Oleastro, Matías. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Oppezzo, Pablo. Instituto Pasteur; UruguayFil: Danielian, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaMosby-Elsevier2017-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/52609Almejún, María Belén; Campos, Bárbara Carolina; Patiño, Virginia; Galicchio, Miguel; Zelazko, Marta; et al.; Noninfectious complications in patients with pediatric-onset common variable immunodeficiency correlated with defects in somatic hypermutation but not in class-switch recombination; Mosby-Elsevier; Journal of Allergy and Clinical Immunology; 139; 3; 3-2017; 913-9220091-6749CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.jaci.2016.08.030info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0091674916310545info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:41:53Zoai:ri.conicet.gov.ar:11336/52609instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:41:53.265CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Noninfectious complications in patients with pediatric-onset common variable immunodeficiency correlated with defects in somatic hypermutation but not in class-switch recombination |
title |
Noninfectious complications in patients with pediatric-onset common variable immunodeficiency correlated with defects in somatic hypermutation but not in class-switch recombination |
spellingShingle |
Noninfectious complications in patients with pediatric-onset common variable immunodeficiency correlated with defects in somatic hypermutation but not in class-switch recombination Almejún, María Belén Class-Switch Recombination Common Variable Immunodeficiency Hypermutation Pediatric Somatic Hypermutation Switch |
title_short |
Noninfectious complications in patients with pediatric-onset common variable immunodeficiency correlated with defects in somatic hypermutation but not in class-switch recombination |
title_full |
Noninfectious complications in patients with pediatric-onset common variable immunodeficiency correlated with defects in somatic hypermutation but not in class-switch recombination |
title_fullStr |
Noninfectious complications in patients with pediatric-onset common variable immunodeficiency correlated with defects in somatic hypermutation but not in class-switch recombination |
title_full_unstemmed |
Noninfectious complications in patients with pediatric-onset common variable immunodeficiency correlated with defects in somatic hypermutation but not in class-switch recombination |
title_sort |
Noninfectious complications in patients with pediatric-onset common variable immunodeficiency correlated with defects in somatic hypermutation but not in class-switch recombination |
dc.creator.none.fl_str_mv |
Almejún, María Belén Campos, Bárbara Carolina Patiño, Virginia Galicchio, Miguel Zelazko, Marta Oleastro, Matías Oppezzo, Pablo Danielian, Silvia |
author |
Almejún, María Belén |
author_facet |
Almejún, María Belén Campos, Bárbara Carolina Patiño, Virginia Galicchio, Miguel Zelazko, Marta Oleastro, Matías Oppezzo, Pablo Danielian, Silvia |
author_role |
author |
author2 |
Campos, Bárbara Carolina Patiño, Virginia Galicchio, Miguel Zelazko, Marta Oleastro, Matías Oppezzo, Pablo Danielian, Silvia |
author2_role |
author author author author author author author |
dc.subject.none.fl_str_mv |
Class-Switch Recombination Common Variable Immunodeficiency Hypermutation Pediatric Somatic Hypermutation Switch |
topic |
Class-Switch Recombination Common Variable Immunodeficiency Hypermutation Pediatric Somatic Hypermutation Switch |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
Background Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production and usually presents with a normal quantity of peripheral B cells. Most attempts aiming to classify these patients have mainly been focused on T- or B-cell phenotypes and their ability to produce protective antibodies, but it is still a major challenge to find a suitable classification that includes the clinical and immunologic heterogeneity of these patients. Objective In this study we evaluated the late stages of B-cell differentiation in a heterogeneous population of patients with pediatric-onset CVID to clinically correlate and assess their ability to perform somatic hypermutation (SHM), class-switch recombination (CSR), or both. Methods We performed a previously reported assay, the restriction enzyme hotspot mutation assay (IgκREHMA), to evaluate in vivo SHM status. We amplified switch regions from genomic DNA to investigate the quality of the double-strand break repairs in the class-switch recombination process in vivo. We also tested the ability to generate immunoglobulin germline and circle transcripts and to upregulate the activation-induced cytidine deaminase gene through in vitro T-dependent and T-independent stimuli. Results Our results showed that patients could be classified into 2 groups according to their degree of SHM alteration. This stratification showed a significant association between patients of group A, severe alteration, and the presence of noninfectious complications. Additionally, 60% of patients presented with increased microhomology use at switched regions. In vitro activation revealed that patients with CVID behaved heterogeneously in terms of responsiveness to T-dependent stimuli. Conclusions The correlation between noninfectious complications and SHM could be an important tool for physicians to further characterize patients with CVID. This categorization would help to improve elucidation of the complex mechanisms involved in B-cell differentiation pathways. Fil: Almejún, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Campos, Bárbara Carolina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Patiño, Virginia. Instituto Pasteur; Uruguay Fil: Galicchio, Miguel. Hospital de Niños Víctor J. Vilela; Argentina Fil: Zelazko, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Oleastro, Matías. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Oppezzo, Pablo. Instituto Pasteur; Uruguay Fil: Danielian, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina |
description |
Background Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production and usually presents with a normal quantity of peripheral B cells. Most attempts aiming to classify these patients have mainly been focused on T- or B-cell phenotypes and their ability to produce protective antibodies, but it is still a major challenge to find a suitable classification that includes the clinical and immunologic heterogeneity of these patients. Objective In this study we evaluated the late stages of B-cell differentiation in a heterogeneous population of patients with pediatric-onset CVID to clinically correlate and assess their ability to perform somatic hypermutation (SHM), class-switch recombination (CSR), or both. Methods We performed a previously reported assay, the restriction enzyme hotspot mutation assay (IgκREHMA), to evaluate in vivo SHM status. We amplified switch regions from genomic DNA to investigate the quality of the double-strand break repairs in the class-switch recombination process in vivo. We also tested the ability to generate immunoglobulin germline and circle transcripts and to upregulate the activation-induced cytidine deaminase gene through in vitro T-dependent and T-independent stimuli. Results Our results showed that patients could be classified into 2 groups according to their degree of SHM alteration. This stratification showed a significant association between patients of group A, severe alteration, and the presence of noninfectious complications. Additionally, 60% of patients presented with increased microhomology use at switched regions. In vitro activation revealed that patients with CVID behaved heterogeneously in terms of responsiveness to T-dependent stimuli. Conclusions The correlation between noninfectious complications and SHM could be an important tool for physicians to further characterize patients with CVID. This categorization would help to improve elucidation of the complex mechanisms involved in B-cell differentiation pathways. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-03 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/52609 Almejún, María Belén; Campos, Bárbara Carolina; Patiño, Virginia; Galicchio, Miguel; Zelazko, Marta; et al.; Noninfectious complications in patients with pediatric-onset common variable immunodeficiency correlated with defects in somatic hypermutation but not in class-switch recombination; Mosby-Elsevier; Journal of Allergy and Clinical Immunology; 139; 3; 3-2017; 913-922 0091-6749 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/52609 |
identifier_str_mv |
Almejún, María Belén; Campos, Bárbara Carolina; Patiño, Virginia; Galicchio, Miguel; Zelazko, Marta; et al.; Noninfectious complications in patients with pediatric-onset common variable immunodeficiency correlated with defects in somatic hypermutation but not in class-switch recombination; Mosby-Elsevier; Journal of Allergy and Clinical Immunology; 139; 3; 3-2017; 913-922 0091-6749 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jaci.2016.08.030 info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0091674916310545 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
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application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Mosby-Elsevier |
publisher.none.fl_str_mv |
Mosby-Elsevier |
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reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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13.070432 |