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

Abstract

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.

• Authors: 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 Facchetti, Andrew R Gennery, Emma Andersson, Naynesh R Kamani, JoAnn Sekiguchi, Hamid M Alenezi, Javier Chinen, Ghassan Dbaibo, Gehad ElGhazali, Adriano Fontana, Srdjan Pasic, Cynthia Detre, Cox Terhorst, Frederick W Alt, Luigi D Notarangelo
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 207 Issue 7 Pg. 1541-54 (Jul 05 2010) ISSN: 1540-9538 [Electronic] United States
• PMID: 20547827 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• B-Cell Activating Factor
• Homeodomain Proteins
• Tnfsf13b protein, mouse
• RAG-1 protein

Topics

• Animals
• Antibody Formation (immunology)
• Antibody-Producing Cells (immunology, pathology)
• Autoantibodies (blood)
• B-Cell Activating Factor (blood)
• B-Lymphocytes (immunology, pathology)
• Cell Proliferation
• Homeodomain Proteins (genetics, immunology)
• Humans
• Immune Tolerance (immunology)
• Immunity (immunology)
• Immunization
• Immunologic Deficiency Syndromes (blood, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Mutation (genetics)
• Spleen (immunology, pathology)