title: 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.affiliation: Division of Immunology and The Manton Center for Orphan Disease Research, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jolan E
authors.initials: JE
authors.lastname: Walter
authors.forename: Francesca
authors.initials: F
authors.lastname: Rucci
authors.forename: Laura
authors.initials: L
authors.lastname: Patrizi
authors.forename: Mike
authors.initials: M
authors.lastname: Recher
authors.forename: Stephan
authors.initials: S
authors.lastname: Regenass
authors.forename: Tiziana
authors.initials: T
authors.lastname: Paganini
authors.forename: Marton
authors.initials: M
authors.lastname: Keszei
authors.forename: Itai
authors.initials: I
authors.lastname: Pessach
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Pietro Luigi
authors.initials: PL
authors.lastname: Poliani
authors.forename: Silvia
authors.initials: S
authors.lastname: Giliani
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.forename: Morton J
authors.initials: MJ
authors.lastname: Cowan
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Puck
authors.forename: Jack
authors.initials: J
authors.lastname: Bleesing
authors.forename: Tim
authors.initials: T
authors.lastname: Niehues
authors.forename: Catharina
authors.initials: C
authors.lastname: Schuetz
authors.forename: Harry
authors.initials: H
authors.lastname: Malech
authors.forename: Suk See
authors.initials: SS
authors.lastname: DeRavin
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Gennery
authors.forename: Emma
authors.initials: E
authors.lastname: Andersson
authors.forename: Naynesh R
authors.initials: NR
authors.lastname: Kamani
authors.forename: JoAnn
authors.initials: J
authors.lastname: Sekiguchi
authors.forename: Hamid M
authors.initials: HM
authors.lastname: Alenezi
authors.forename: Javier
authors.initials: J
authors.lastname: Chinen
authors.forename: Ghassan
authors.initials: G
authors.lastname: Dbaibo
authors.forename: Gehad
authors.initials: G
authors.lastname: ElGhazali
authors.forename: Adriano
authors.initials: A
authors.lastname: Fontana
authors.forename: Srdjan
authors.initials: S
authors.lastname: Pasic
authors.forename: Cynthia
authors.initials: C
authors.lastname: Detre
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D000921:Antibody-Producing Cells / Q000276:immunology* / Q000473:pathology*; D001323:Autoantibodies / Q000097:blood; D053264:B-Cell Activating Factor / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D049109:Cell Proliferation; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007109:Immunity / Q000276:immunology; D007114:Immunization; D007153:Immunologic Deficiency Syndromes / Q000097:blood / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D013154:Spleen / Q000276:immunology / Q000473:pathology
chemical_list: D001323:Autoantibodies; D053264:B-Cell Activating Factor; D018398:Homeodomain Proteins; C505720:Tnfsf13b protein, mouse; C064658:RAG-1 protein