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Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency
The contribution of B cells to the pathology of Omenn syndrome and leaky severe combined immunodeficiency (SCID) has not been previously investigated. We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1 S723C mutation that impairs, but does not abrogate, V(D)J recombination ac...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901061/ https://www.ncbi.nlm.nih.gov/pubmed/20547827 http://dx.doi.org/10.1084/jem.20091927 |
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author | Walter, Jolan E. Rucci, Francesca Patrizi, Laura Recher, Mike Regenass, Stephan Paganini, Tiziana Keszei, Marton Pessach, Itai Lang, Philipp A. Poliani, Pietro Luigi Giliani, Silvia Al-Herz, Waleed Cowan, Morton J. Puck, Jennifer M. Bleesing, Jack Niehues, Tim Schuetz, Catharina Malech, Harry DeRavin, Suk See Facchetti, Fabio Gennery, Andrew R. Andersson, Emma Kamani, Naynesh R. Sekiguchi, JoAnn Alenezi, Hamid M. Chinen, Javier Dbaibo, Ghassan ElGhazali, Gehad Fontana, Adriano Pasic, Srdjan Detre, Cynthia Terhorst, Cox Alt, Frederick W. Notarangelo, Luigi D. |
author_facet | Walter, Jolan E. Rucci, Francesca Patrizi, Laura Recher, Mike Regenass, Stephan Paganini, Tiziana Keszei, Marton Pessach, Itai Lang, Philipp A. Poliani, Pietro Luigi Giliani, Silvia Al-Herz, Waleed Cowan, Morton J. Puck, Jennifer M. Bleesing, Jack Niehues, Tim Schuetz, Catharina Malech, Harry DeRavin, Suk See Facchetti, Fabio Gennery, Andrew R. Andersson, Emma Kamani, Naynesh R. Sekiguchi, JoAnn Alenezi, Hamid M. Chinen, Javier Dbaibo, Ghassan ElGhazali, Gehad Fontana, Adriano Pasic, Srdjan Detre, Cynthia Terhorst, Cox Alt, Frederick W. Notarangelo, Luigi D. |
author_sort | Walter, Jolan E. |
collection | PubMed |
description | The contribution of B cells to the pathology of Omenn syndrome and leaky severe combined immunodeficiency (SCID) has not been previously investigated. We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1 S723C mutation that impairs, but does not abrogate, V(D)J recombination activity. In spite of a severe block at the pro–B cell stage and profound B cell lymphopenia, significant serum levels of immunoglobulin (Ig) G, IgM, IgA, and IgE and a high proportion of Ig-secreting cells were detected in mut/mut mice. Antibody responses to trinitrophenyl (TNP)-Ficoll and production of high-affinity antibodies to TNP–keyhole limpet hemocyanin were severely impaired, even after adoptive transfer of wild-type CD4(+) T cells. Mut/mut mice produced high amounts of low-affinity self-reactive antibodies and showed significant lymphocytic infiltrates in peripheral tissues. Autoantibody production was associated with impaired receptor editing and increased serum B cell–activating factor (BAFF) concentrations. Autoantibodies and elevated BAFF levels were also identified in patients with Omenn syndrome and leaky SCID as a result of hypomorphic RAG mutations. These data indicate that the stochastic generation of an autoreactive B cell repertoire, which is associated with defects in central and peripheral checkpoints of B cell tolerance, is an important, previously unrecognized, aspect of immunodeficiencies associated with hypomorphic RAG mutations. |
format | Text |
id | pubmed-2901061 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-29010612011-01-05 Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency Walter, Jolan E. Rucci, Francesca Patrizi, Laura Recher, Mike Regenass, Stephan Paganini, Tiziana Keszei, Marton Pessach, Itai Lang, Philipp A. Poliani, Pietro Luigi Giliani, Silvia Al-Herz, Waleed Cowan, Morton J. Puck, Jennifer M. Bleesing, Jack Niehues, Tim Schuetz, Catharina Malech, Harry DeRavin, Suk See Facchetti, Fabio Gennery, Andrew R. Andersson, Emma Kamani, Naynesh R. Sekiguchi, JoAnn Alenezi, Hamid M. Chinen, Javier Dbaibo, Ghassan ElGhazali, Gehad Fontana, Adriano Pasic, Srdjan Detre, Cynthia Terhorst, Cox Alt, Frederick W. Notarangelo, Luigi D. J Exp Med Article The contribution of B cells to the pathology of Omenn syndrome and leaky severe combined immunodeficiency (SCID) has not been previously investigated. We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1 S723C mutation that impairs, but does not abrogate, V(D)J recombination activity. In spite of a severe block at the pro–B cell stage and profound B cell lymphopenia, significant serum levels of immunoglobulin (Ig) G, IgM, IgA, and IgE and a high proportion of Ig-secreting cells were detected in mut/mut mice. Antibody responses to trinitrophenyl (TNP)-Ficoll and production of high-affinity antibodies to TNP–keyhole limpet hemocyanin were severely impaired, even after adoptive transfer of wild-type CD4(+) T cells. Mut/mut mice produced high amounts of low-affinity self-reactive antibodies and showed significant lymphocytic infiltrates in peripheral tissues. Autoantibody production was associated with impaired receptor editing and increased serum B cell–activating factor (BAFF) concentrations. Autoantibodies and elevated BAFF levels were also identified in patients with Omenn syndrome and leaky SCID as a result of hypomorphic RAG mutations. These data indicate that the stochastic generation of an autoreactive B cell repertoire, which is associated with defects in central and peripheral checkpoints of B cell tolerance, is an important, previously unrecognized, aspect of immunodeficiencies associated with hypomorphic RAG mutations. The Rockefeller University Press 2010-07-05 /pmc/articles/PMC2901061/ /pubmed/20547827 http://dx.doi.org/10.1084/jem.20091927 Text en © 2010 Walter et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Article Walter, Jolan E. Rucci, Francesca Patrizi, Laura Recher, Mike Regenass, Stephan Paganini, Tiziana Keszei, Marton Pessach, Itai Lang, Philipp A. Poliani, Pietro Luigi Giliani, Silvia Al-Herz, Waleed Cowan, Morton J. Puck, Jennifer M. Bleesing, Jack Niehues, Tim Schuetz, Catharina Malech, Harry DeRavin, Suk See Facchetti, Fabio Gennery, Andrew R. Andersson, Emma Kamani, Naynesh R. Sekiguchi, JoAnn Alenezi, Hamid M. Chinen, Javier Dbaibo, Ghassan ElGhazali, Gehad Fontana, Adriano Pasic, Srdjan Detre, Cynthia Terhorst, Cox Alt, Frederick W. Notarangelo, Luigi D. Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency |
title | Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency |
title_full | Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency |
title_fullStr | Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency |
title_full_unstemmed | Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency |
title_short | Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency |
title_sort | expansion of immunoglobulin-secreting cells and defects in b cell tolerance in rag-dependent immunodeficiency |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901061/ https://www.ncbi.nlm.nih.gov/pubmed/20547827 http://dx.doi.org/10.1084/jem.20091927 |
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