B cell deletion, anergy, and receptor editing in "knock in" mice targeted with a germline-encoded or somatically mutated anti-DNA heavy chain.
To study the relative contributions of clonal deletion, clonal anergy, and receptor editing to tolerance induction in autoreactive B cells and their dependence on B cell receptor affinity, we have constructed "knock in" mice in which germline encoded or somatically mutated, rearranged anti-DNA heavy (H) chains were targeted to the H chain locus of the mouse. The targeted H chains were expressed on the vast majority of bone marrow (BM) and splenic B cells and were capable of Ig class switching and the acquisition of somatic mutations. A quantitative analysis of B cell populations in the BM as well as of Jkappa utilization and DNA binding of hybridoma Abs suggested that immature B cell deletion and light (L) chain editing were the major mechanisms affecting tolerance. Unexpectedly, these mechanisms were less effective in targeted mice expressing the somatically mutated, anti-DNA H chain than in mice expressing the germline-encoded H chain, possibly due to the greater abundance of high affinity, anti-DNA immature B cells in the BM. Consequently, autoreactive B cells that showed features of clonal anergy could be recovered in the periphery of these mice. Our results suggest that clonal deletion and receptor editing are interrelated mechanisms that act in concert to eliminate autoreactive B cells from the immune system. Clonal anergy may serve as a back-up mechanism for central tolerance, or it may represent an intermediate step in clonal deletion.
Pewzner-Jung
Y
Y
Division of Medicine, Hadassah University Hospital, Faculty of Medicine of the Hebrew University, Jerusalem, Israel.
Friedmann
D
D
Sonoda
E
E
Jung
S
S
Rajewsky
K
K
Eilat
D
D
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics*; D000956:Antigens, Viral / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000276:immunology; D017635:Clonal Anergy; D017637:Clonal Deletion; D004247:DNA / Q000276:immunology*; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D018390:Gene Targeting; D005803:Genes, Immunoglobulin; D006825:Hybridomas / Q000276:immunology; D007114:Immunization; D017578:Immunoglobulin Class Switching; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007144:Immunoglobulin J-Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D009980:Influenza A virus / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D016415:Sequence Alignment; D017385:Sequence Homology; D013154:Spleen / Q000276:immunology
D000974:Antibodies, Antinuclear; D000956:Antigens, Viral; D001324:Autoantigens; D007143:Immunoglobulin Heavy Chains; D007144:Immunoglobulin J-Chains; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D008070:Lipopolysaccharides; D011947:Receptors, Antigen, B-Cell; D004247:DNA