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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
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    14.06.2010
Published in:
  • 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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Medicine
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https://n2t.net/ark:/12658/srd1318995
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