Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency.
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.
Walter
Jolan E
JE
Division of Immunology and The Manton Center for Orphan Disease Research, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Rucci
Francesca
F
Patrizi
Laura
L
Recher
Mike
M
Regenass
Stephan
S
Paganini
Tiziana
T
Keszei
Marton
M
Pessach
Itai
I
Lang
Philipp A
PA
Poliani
Pietro Luigi
PL
Giliani
Silvia
S
Al-Herz
Waleed
W
Cowan
Morton J
MJ
Puck
Jennifer M
JM
Bleesing
Jack
J
Niehues
Tim
T
Schuetz
Catharina
C
Malech
Harry
H
DeRavin
Suk See
SS
Facchetti
Fabio
F
Gennery
Andrew R
AR
Andersson
Emma
E
Kamani
Naynesh R
NR
Sekiguchi
JoAnn
J
Alenezi
Hamid M
HM
Chinen
Javier
J
Dbaibo
Ghassan
G
ElGhazali
Gehad
G
Fontana
Adriano
A
Pasic
Srdjan
S
Detre
Cynthia
C
Terhorst
Cox
C
Alt
Frederick W
FW
Notarangelo
Luigi D
LD
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
D001323:Autoantibodies; D053264:B-Cell Activating Factor; D018398:Homeodomain Proteins; C505720:Tnfsf13b protein, mouse; C064658:RAG-1 protein