Censoring of self-reactive B cells with a range of receptor affinities in transgenic mice expressing heavy chains for a lysozyme-specific antibody.
Transgenic mice carrying a rearranged Ig gene encoding the H chain of a lysozyme-specific antibody were used to examine the effect of antigen binding affinity on elimination of self-reactive B cells. In H chain transgenic mice, B cells expressed surface IgM and IgD composed of lysozyme-specific H chains and many different possible L chains from endogenous L chain genes. Immunofluorescent staining and flow cytometry revealed a distinct subset comprising approximately 1% of spleen B cells that bound lysozyme with a high affinity comparable with the original lysozyme-specific antibody. Additional subsets accounting for a total of 5-6% of spleen B cells bound lysozyme more weakly, with the weakest requiring 10,000-fold higher concentrations of monomeric hen egg lysozyme to attain 50% receptor saturation. When the various B cell subpopulations were allowed to develop in animals expressing lysozyme as a membrane-bound antigen on autologous cells, both low and high affinity lysozyme-binding B cells were undetectable in peripheral lymphoid organs. These findings demonstrate the efficacy with which low affinity self-reactive B cells can be eliminated in vivo, consistent with the notion that this cellular mechanism accounts for the absence of natural IgM antibodies against self antigens on the surface of blood cells. The data also illustrate the potential use of Ig transgenic mice for analyzing and selecting novel receptor-ligand interactions.
Hartley
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SB
Howard Hughes Medical Institute, Stanford, CA.
Goodnow
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CC
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin; D007108:Immune Tolerance; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009113:Muramidase / Q000276:immunology*; D011828:Radiation Chimera; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*
D000906:Antibodies; D001324:Autoantigens; D007143:Immunoglobulin Heavy Chains; D011947:Receptors, Antigen, B-Cell; D009113:Muramidase