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Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome
Hypomorphic RAG mutations, leading to limited V(D)J rearrangements, cause Omenn syndrome (OS), a peculiar severe combined immunodeficiency associated with autoimmune-like manifestations. Whether B cells play a role in OS pathogenesis is so far unexplored. Here we report the detection of plasma cells...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901059/ https://www.ncbi.nlm.nih.gov/pubmed/20547828 http://dx.doi.org/10.1084/jem.20091928 |
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author | Cassani, Barbara Poliani, Pietro Luigi Marrella, Veronica Schena, Francesca Sauer, Aisha V. Ravanini, Maria Strina, Dario Busse, Christian E. Regenass, Stephan Wardemann, Hedda Martini, Alberto Facchetti, Fabio van der Burg, Mirjam Rolink, Antonius G. Vezzoni, Paolo Grassi, Fabio Traggiai, Elisabetta Villa, Anna |
author_facet | Cassani, Barbara Poliani, Pietro Luigi Marrella, Veronica Schena, Francesca Sauer, Aisha V. Ravanini, Maria Strina, Dario Busse, Christian E. Regenass, Stephan Wardemann, Hedda Martini, Alberto Facchetti, Fabio van der Burg, Mirjam Rolink, Antonius G. Vezzoni, Paolo Grassi, Fabio Traggiai, Elisabetta Villa, Anna |
author_sort | Cassani, Barbara |
collection | PubMed |
description | Hypomorphic RAG mutations, leading to limited V(D)J rearrangements, cause Omenn syndrome (OS), a peculiar severe combined immunodeficiency associated with autoimmune-like manifestations. Whether B cells play a role in OS pathogenesis is so far unexplored. Here we report the detection of plasma cells in lymphoid organs of OS patients, in which circulating B cells are undetectable. Hypomorphic Rag2(R229Q) knock-in mice, which recapitulate OS, revealed, beyond severe B cell developmental arrest, a normal or even enlarged compartment of immunoglobulin-secreting cells (ISC). The size of this ISC compartment correlated with increased expression of Blimp1 and Xbp1, and these ISC were sustained by elevated levels of T cell derived homeostatic and effector cytokines. The detection of high affinity pathogenic autoantibodies toward target organs indicated defaults in B cell selection and tolerance induction. We hypothesize that impaired B cell receptor (BCR) editing and a serum B cell activating factor (BAFF) abundance might contribute toward the development of a pathogenic B cell repertoire in hypomorphic Rag2(R229Q) knock-in mice. BAFF-R blockade reduced serum levels of nucleic acid-specific autoantibodies and significantly ameliorated inflammatory tissue damage. These findings highlight a role for B cells in OS pathogenesis. |
format | Text |
id | pubmed-2901059 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-29010592011-01-05 Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome Cassani, Barbara Poliani, Pietro Luigi Marrella, Veronica Schena, Francesca Sauer, Aisha V. Ravanini, Maria Strina, Dario Busse, Christian E. Regenass, Stephan Wardemann, Hedda Martini, Alberto Facchetti, Fabio van der Burg, Mirjam Rolink, Antonius G. Vezzoni, Paolo Grassi, Fabio Traggiai, Elisabetta Villa, Anna J Exp Med Article Hypomorphic RAG mutations, leading to limited V(D)J rearrangements, cause Omenn syndrome (OS), a peculiar severe combined immunodeficiency associated with autoimmune-like manifestations. Whether B cells play a role in OS pathogenesis is so far unexplored. Here we report the detection of plasma cells in lymphoid organs of OS patients, in which circulating B cells are undetectable. Hypomorphic Rag2(R229Q) knock-in mice, which recapitulate OS, revealed, beyond severe B cell developmental arrest, a normal or even enlarged compartment of immunoglobulin-secreting cells (ISC). The size of this ISC compartment correlated with increased expression of Blimp1 and Xbp1, and these ISC were sustained by elevated levels of T cell derived homeostatic and effector cytokines. The detection of high affinity pathogenic autoantibodies toward target organs indicated defaults in B cell selection and tolerance induction. We hypothesize that impaired B cell receptor (BCR) editing and a serum B cell activating factor (BAFF) abundance might contribute toward the development of a pathogenic B cell repertoire in hypomorphic Rag2(R229Q) knock-in mice. BAFF-R blockade reduced serum levels of nucleic acid-specific autoantibodies and significantly ameliorated inflammatory tissue damage. These findings highlight a role for B cells in OS pathogenesis. The Rockefeller University Press 2010-07-05 /pmc/articles/PMC2901059/ /pubmed/20547828 http://dx.doi.org/10.1084/jem.20091928 Text en © 2010 Cassani 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 Cassani, Barbara Poliani, Pietro Luigi Marrella, Veronica Schena, Francesca Sauer, Aisha V. Ravanini, Maria Strina, Dario Busse, Christian E. Regenass, Stephan Wardemann, Hedda Martini, Alberto Facchetti, Fabio van der Burg, Mirjam Rolink, Antonius G. Vezzoni, Paolo Grassi, Fabio Traggiai, Elisabetta Villa, Anna Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome |
title | Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome |
title_full | Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome |
title_fullStr | Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome |
title_full_unstemmed | Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome |
title_short | Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome |
title_sort | homeostatic expansion of autoreactive immunoglobulin-secreting cells in the rag2 mouse model of omenn syndrome |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901059/ https://www.ncbi.nlm.nih.gov/pubmed/20547828 http://dx.doi.org/10.1084/jem.20091928 |
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