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

[omenn syndrome]

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 Rag 2 (R 229 Q ) 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 Blimp 1 and Xbp 1 , 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 Rag 2 (R 229 Q ) 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 .