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; Burg, Mirjam van der; Rolink, Antonius G.; Vezzoni, Paolo; Grassi, Fabio; Traggiai, Elisabetta; Villa, Anna

doi:10.1084/jem.20091928

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Journal article

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

Cassani, Barbara Fondazione Humanitas per la Ricerca, 20089 Rozzano, Italy
Poliani, Pietro Luigi Department of Pathology, University of Brescia, 25100 Brescia, Italy
Marrella, Veronica Italian National Research Council (CNR)-Istituto Tecnologie Biomediche, 20090 Milan, Italy - Istituto Clinico Humanitas, 20089 Rozzano, Italy
Schena, Francesca Laboratory of Immunology and Rheumatic Disease, IGG, 16147 Genoa, Italy
Sauer, Aisha V. San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy
Ravanini, Maria Department of Pathology, University of Brescia, 25100 Brescia, Italy
Strina, Dario Italian National Research Council (CNR)-Istituto Tecnologie Biomediche, 20090 Milan, Italy - Istituto Clinico Humanitas, 20089 Rozzano, Italy
Busse, Christian E. Max Planck Research Group Molecular Immunology, Max Planck Institute for Infection Biology, D-10117 Berlin, Germany
Regenass, Stephan Division of Clinical Immunology, University Hospital Zürich, Zürich CH 8091, Switzerland
Wardemann, Hedda Max Planck Research Group Molecular Immunology, Max Planck Institute for Infection Biology, D-10117 Berlin, Germany
Martini, Alberto Laboratory of Immunology and Rheumatic Disease, IGG, 16147 Genoa, Italy
Facchetti, Fabio Department of Pathology, University of Brescia, 25100 Brescia, Italy
Burg, Mirjam van der Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3015 GE Rotterdam, Netherlands
Rolink, Antonius G. Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
Vezzoni, Paolo Italian National Research Council (CNR)-Istituto Tecnologie Biomediche, 20090 Milan, Italy - Istituto Clinico Humanitas, 20089 Rozzano, Italy
Grassi, Fabio Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Dipartimento di Biologia e Genetica per le Scienze Mediche, Università’ degli Studi di Milano, 20133 Milan, Italy
Traggiai, Elisabetta Laboratory of Immunology and Rheumatic Disease, IGG, 16147 Genoa, Italy
Villa, Anna Italian National Research Council (CNR)-Istituto Tecnologie Biomediche, 20090 Milan, Italy - San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy

14.06.2010

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Journal of experimental medicine. - 2010, vol. 207, no. 7, p. 1525-1540

English 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 Rag2R229Q 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 Rag2R229Q 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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