title: Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome.
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.
authors.affiliation: Fondazione Humanitas per la Ricerca, 20089 Rozzano, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cassani
authors.forename: Pietro Luigi
authors.initials: PL
authors.lastname: Poliani
authors.forename: Veronica
authors.initials: V
authors.lastname: Marrella
authors.forename: Francesca
authors.initials: F
authors.lastname: Schena
authors.forename: Aisha V
authors.initials: AV
authors.lastname: Sauer
authors.forename: Maria
authors.initials: M
authors.lastname: Ravanini
authors.forename: Dario
authors.initials: D
authors.lastname: Strina
authors.forename: Christian E
authors.initials: CE
authors.lastname: Busse
authors.forename: Stephan
authors.initials: S
authors.lastname: Regenass
authors.forename: Hedda
authors.initials: H
authors.lastname: Wardemann
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.forename: Antonius G
authors.initials: AG
authors.lastname: Rolink
authors.forename: Paolo
authors.initials: P
authors.lastname: Vezzoni
authors.forename: Fabio
authors.initials: F
authors.lastname: Grassi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Traggiai
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D000921:Antibody-Producing Cells / Q000276:immunology* / Q000473:pathology*; D000941:Antigens / Q000276:immunology; D053264:B-Cell Activating Factor / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D002451:Cell Compartmentation; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D006706:Homeostasis / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D008208:Lymphatic System / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology; D016511:Severe Combined Immunodeficiency / Q000276:immunology* / Q000473:pathology*; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists
chemical_list: D000941:Antigens; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D004268:DNA-Binding Proteins; D000939:Epitopes; C499308:Rag2 protein, mouse; C505720:Tnfsf13b protein, mouse; D051193:Toll-Like Receptors