Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency

Jolan E. Walter, Francesca Rucci, Laura Patrizi, Mike Recher, Stephan Regenass, Tiziana Paganini, Marton Keszei, Itai Pessach, Philipp A. Lang, Pietro Luigi Poliani, Silvia Giliani, Waleed Al-Herz, Morton J. Cowan, Jennifer M. Puck, Jack Bleesing, Tim Niehues, Catharina Schuetz, Harry Malech, Suk See DeRavin, Fabio FacchettiAndrew R. Gennery, Emma Andersson, Naynesh R. Kamani, Jo Ann Sekiguchi, Hamid M. Alenezi, Javier Chinen, Ghassan Dbaibo, Gehad ElGhazali, Adriano Fontana, Srdjan Pasic, Cynthia Detre, Cox Terhorst, Frederick W. Alt, Luigi D. Notarangelo

Research output: Contribution to journalArticlepeer-review


The contribution of B cells to the pathology of Omenn syndrome and leaky severe combined immunodeficiency (SCID) has not been previously investigated. We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1 S723C mutation that impairs, but does not abrogate, V(D)J recombination activity. In spite of a severe block at the pro-B cell stage and profound B cell lymphopenia, significant serum levels of immunoglobulin (Ig) G, IgM, IgA, and IgE and a high proportion of Ig-secreting cells were detected in mut/mut mice. Antibody responses to trinitrophenyl (TNP)-Ficoll and production of high-affinity antibodies to TNP-keyhole limpet hemocyanin were severely impaired, even after adoptive transfer of wild-type CD4+ T cells. Mut/mut mice produced high amounts of low-affinity self-reactive antibodies and showed significant lymphocytic infiltrates in peripheral tissues. Autoantibody production was associated with impaired receptor editing and increased serum B cell-activating factor (BAFF) concentrations. Autoantibodies and elevated BAFF levels were also identified in patients with Omenn syndrome and leaky SCID as a result of hypomorphic RAG mutations. These data indicate that the stochastic generation of an autoreactive B cell repertoire, which is associated with defects in central and peripheral checkpoints of B cell tolerance, is an important, previously unrecognized, aspect of immunodeficiencies associated with hypomorphic RAG mutations.

Original languageEnglish
Pages (from-to)1541-1554
Number of pages14
JournalJournal of Experimental Medicine
Issue number7
StatePublished - 5 Jul 2010
Externally publishedYes


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