Impaired receptor editing in the primary B cell repertoire of BASH-deficient mice.
The editing of B cell Ag receptor (BCR) through successive rearrangements of Ig genes has been considered to be a major mechanism for the central B cell tolerance, which precludes appearance of self-reactive B cells, through studies using anti-self-Ig transgenic/knock-in mouse systems. However, contribution of the receptor editing in the development of the normal B cell repertoire remains unclear. In addition, the signaling pathway directing this event is unknown. In this study, we demonstrate that receptor editing in anti-DNA Ig knock-in mice is impaired in the absence of an adaptor protein BASH (BLNK/SLP-65) that is involved in BCR signaling. Remarkably, the supposed hallmarks of receptor editing such as Iglambda chain expression, recombination sequence rearrangements at Igkappa loci, and presence of in-frame VkappaJkappa joins in the Igkappa loci inactivated by the recombination sequence rearrangements, were all diminished in BASH-deficient mice with unmanipulated Ig loci. BCR ligation-induced Iglambda gene recombination in vitro was also impaired in BASH-deficient B cells. Furthermore, the BASH-deficient mice showed an excessive Ab response to a DNA carrier immunization, suggesting the presence of unedited DNA-reactive B cells in the periphery. These results not only define a signaling pathway required for receptor editing but indicate that the BCR-signaled receptor editing indeed operates in the development of normal B cell repertoire and contributes to establishing the B cell tolerance.
Hayashi
Katsuhiko
K
Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan.
Nojima
Takuya
T
Goitsuka
Ryo
R
Kitamura
Daisuke
D
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D017635:Clonal Anergy / Q000235:genetics; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005819:Genetic Markers / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D017393:RNA Editing / Q000235:genetics / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000974:Antibodies, Antinuclear; D001324:Autoantigens; C113939:B cell linker protein; D002352:Carrier Proteins; D005819:Genetic Markers; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell; D019444:Vaccines, DNA