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

Lookup NU author(s): Professor Andrew GenneryORCiD

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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.


Publication metadata

Author(s): Walter JE, Rucci F, Patrizi L, Recher M, Regenass S, Paganini T, Keszei M, Pessach I, Lang PA, Poliani PL, Giliani S, Al-Herz W, Cowan MJ, Puck JM, Bleesing J, Niehues T, Schuetz C, Malech H, DeRavin SS, Facchetti F, Gennery AR, Andersson E, Kamani NR, Sekiguchi J, Alenezi HM, Chinen J, Dbaibo G, ElGhazali G, Fontana A, Pasic S, Detre C, Terhorst C, Alt FW, Notarangelo LD

Publication type: Article

Publication status: Published

Journal: Journal of Experimental Medicine

Year: 2010

Volume: 207

Issue: 7

Pages: 1541-1554

Print publication date: 01/07/2010

ISSN (print): 0022-1007

ISSN (electronic): 1540-9538

Publisher: Rockefeller University Press

URL: http://dx.doi.org/10.1084/jem.20091927

DOI: 10.1084/jem.20091927


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Funding

Funder referenceFunder name
American Academy of Allergy, Asthma and Immunology, American Thoracic Society
Dubai Harvard Foundation for Medical Research
GlaxoSmithKline
Jeffrey Model Diagnostic Center for Primary Immunodeficiencies at Children's Hospital Boston, Fondazione CARIPLO
Manton Foundation
San Francisco Jeffrey Model Diagnostic Center for Primary Immunodeficiencies
University of California
AI063058National Institutes of Health
P01 AI076210-01A1National Institutes of Health
PASMP3-127678/1Swiss National Science Foundation (SNF/SSMBS)
U54AI082973-01National Institutes of Health

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