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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
immunology and microbiology
Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency
Journal of Experimental Medicine, Volume 207, No. 7, Year 2010
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Description
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. © 2010 Walter et al.
Authors & Co-Authors
Walter, Jolán Eszter
United States, Boston
Boston Children's Hospital
Rucci, Francesca
United States, Boston
Boston Children's Hospital
Patrizi, Laura
United States, Boston
Boston Children's Hospital
Recher, Mike
United States, Boston
Boston Children's Hospital
Regenass, Stephan
Switzerland, Zurich
Universitatsspital Zurich
Paganini, Tiziana
Italy, Brescia
Università Degli Studi Di Brescia
Keszei, Marton
United States, Boston
Harvard Medical School
Pessach, Itai M.
United States, Boston
Boston Children's Hospital
Lang, Philipp Alexander
Canada, Toronto
University of Toronto
Poliani, Pietro Luigi
Italy, Brescia
Università Degli Studi Di Brescia
Giliani, S.
Italy, Brescia
Università Degli Studi Di Brescia
Al-Herz, Waleed
Kuwait
Al-sabah Hospital
Cowan, Morton J.
United States, San Francisco
Ucsf Benioff Children‘s Hospital
Puck, Jennifer M.
United States, San Francisco
Ucsf Benioff Children‘s Hospital
Bleesing, Jack Jan Hendrik
United States, Cincinnati
Cincinnati Children's Hospital Medical Center
Niehues, Tim
Germany, Dusseldorf
Heinrich-heine-universität Düsseldorf
Schuetz, Catharina
Germany, Ulm
Universitätsklinikum Ulm
Malech, Harry L.
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
DeRavin, Suk See
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Facchetti, Fabio
Italy, Brescia
Università Degli Studi Di Brescia
Gennery, Andrew R.
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Andersson, Emma
United States, Boston
Boston Children's Hospital
Kamani, Nayesh R.
United States, Washington, D.c.
Childrens National Health System
Sekiguchi, Jo Ann
United States, Ann Arbor
University of Michigan, Ann Arbor
Alenezi, Hamid M.
Kuwait
Al-sabah Hospital
Chinen, Javier
United States, Houston
Baylor College of Medicine
Dbaibo, Ghassan S.
Lebanon, Beirut
American University of Beirut
ElGhazali, Gehad Eltayeb B.
Saudi Arabia, Riyadh
Faculty of Medicine
Fontana, Adriano
Switzerland, Zurich
Universitatsspital Zurich
Pašić, Srdjan S.
Serbia, Belgrade
Mother and Child Health Institute, Belgrade, rs
Detre, Cynthia
United States, Boston
Harvard Medical School
Terhorst, Cox
United States, Boston
Harvard Medical School
Alt, Frederick W.
United States, Boston
Harvard Medical School
Notarangelo, Luigi Daniele
United States, Boston
Boston Children's Hospital
Statistics
Citations: 34
Authors: 34
Affiliations: 18
Identifiers
Doi:
10.1084/jem.20091927
ISSN:
00221007
e-ISSN:
15409538
Research Areas
Cancer