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

Cassani, Barbara and Poliani, Pietro Luigi and Marrella, Veronica and Schena, Francesca and Sauer, Aisha V. and Ravanini, Maria and Strina, Dario and Busse, Christian E. and Regenass, Stephan and Wardemann, Hedda and Martini, Alberto and Facchetti, Fabio and van der Burg, Mirjam and Rolink, Antonius G. and Vezzoni, Paolo and Grassi, Fabio and Traggiai, Elisabetta and Villa, Anna. (2010) Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome. Journal of experimental medicine, Vol. 207, H. 7. pp. 1525-1540.

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Official URL: http://edoc.unibas.ch/dok/A6007207

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Developmental and Molecular Immunology (Rolink)
UniBasel Contributors:Rolink, Antonius G.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Rockefeller University Press
ISSN:0022-1007
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:31 Dec 2015 10:52
Deposited On:24 May 2013 09:14

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