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

B Cassani, PL Poliani, V Marrella, F Schena… - Journal of experimental …, 2010 - rupress.org
B Cassani, PL Poliani, V Marrella, F Schena, AV Sauer, M Ravanini, D Strina, CE Busse…
Journal of experimental medicine, 2010rupress.org
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 …
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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