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.

B cell activating factor, B cell activating factor receptor, B lymphocyte, B lymphocyte induced maturation protein 1, B lymphocyte receptor, Omenn syndrome, Pneumococcus vaccine, RAG2 protein, T lymphocyte, T lymphocyte activation, X box binding protein 1, animal cell, animal experiment, animal model, animal tissue, article, autoantibody, bone marrow, cell expansion, cell maturation, clinical article, cytokine, cytokine production, disease model, effector cell, homeostasis, human, human cell, humoral immune deficiency, immunoglobulin, immunoglobulin blood level, immunoglobulin secreting cell, immunological tolerance, immunopathogenesis, lymphocyte proliferation, memory T lymphocyte mouse, nonhuman, plasma cell, priority journal, secretory cell, spleen, toll like receptor agonist
dx.doi.org/10.1084/jem.20091928, hdl.handle.net/1765/20635
The Journal of Experimental Medicine
Erasmus MC: University Medical Center Rotterdam

Cassani, B, Poliani, P.L, Marella, V, Schena, F, Sauer, A.V, Ravanini, M, … Villa, A. (2010). Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome. The Journal of Experimental Medicine, 207(7), 1525–1540. doi:10.1084/jem.20091928