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  Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome

Cassani, B., Poliani, P. L., Marrella, V., Schena, F., Sauer, A. V., Ravanini, M., et al. (2010). Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome. Journal of Experimental Medicine, 207(7), 1525-1540.

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Genre: Journal Article
Alternative Title : J. Exp. Med.

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J_Exp_Med_2010_207_1525.pdf (Publisher version), 7MB
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© 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/).
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 Creators:
Cassani, Barbara, Author
Poliani, Pietro Luigi, Author
Marrella, Veronica, Author
Schena, Francesca, Author
Sauer, Aisha V., Author
Ravanini, Maria, Author
Strina, Dario, Author
Busse, Christian E.1, Author              
Regenass, Stephan, Author
Wardemann, Hedda1, Author              
Martini, Alberto, Author
Facchetti, Fabio, Author
van der Burg, Mirjam, Author
Rolink, Antonius G., Author
Vezzoni, Paolo, Author
Grassi, Fabio, Author
Traggiai, Elisabetta, Author
Villa, Anna, Author
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1Max-Planck Research Group Molecular Immunology, Max Planck Institute for Infection Biology, Max Planck Society, ou_1664149              

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 Abstract: 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.

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Language(s): eng - English
 Dates: 2010-07-05
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: eDoc: 532570
ISI: 000279464700016
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Title: Journal of Experimental Medicine
  Alternative Title : J. Exp. Med.
Source Genre: Journal
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Pages: - Volume / Issue: 207 (7) Sequence Number: - Start / End Page: 1525 - 1540 Identifier: ISSN: 0022-1007