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 2010-06-14 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. application/pdf https://n2t.net/ark:/12658/srd1318995 https://susi.usi.ch/global/documents/318995 https://susi.usi.ch/documents/318995/files/Cassani_JEM_2010.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1084/jem.20091928 info:eu-repo/semantics/altIdentifier/ark/12658/srd1318995 info:eu-repo/semantics/openAccess CC BY-NC-SA Journal of experimental medicine. - 2010, vol. 207, no. 7, p. 1525-1540 info:eu-repo/classification/udc/61 Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome http://purl.org/coar/resource_type/c_6501