Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-35592
Walter, J E; Rucci, F; Patrizi, L; Recher, M; Regenass, S; Paganini, T; Keszei, M; Pessach, I; Lang, P A; Poliani, P L; Giliani, S; Al-Herz, W; Cowan, M J; Puck, J M; Bleesing, J; Niehues, T; Schuetz, C; Malech, H; DeRavin, S S; Facchetti, F; Gennery, A R; Andersson, E; Kamani, N R; Sekiguchi, J; Alenezi, H M; Chinen, J; Dbaibo, G; ElGhazali, G; Fontana, A; Pasic, S; Detre, C; Terhorst, C; Alt, F W; Notarangelo, L D (2010). Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency. Journal of Experimental Medicine, 207(7):1541-1554.
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.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Clinic for Immunology|
|DDC:||610 Medicine & health|
|Deposited On:||05 Nov 2010 10:55|
|Last Modified:||28 Nov 2013 01:21|
|Publisher:||Rockefeller University Press|
|Citations:||Web of Science®. Times Cited: 21|
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