Receptor editing : an approach by autoreactive B cells to escape tolerance

• Published in: The Journal of experimental medicine Vol. 177; no. 4; pp. 999 - 1008
• Main Authors: GAY, D, SAUNDERS, T, CAMPER, S, WEIGERT, M
• Format: Journal Article
• Language: English
• Published: New York, NY Rockefeller University Press 01.04.1993; The Rockefeller University Press
• Subjects: Animals; Autoantibodies - genetics; Autoantibodies - immunology; Autoimmunity (experimental aspects and models); B-Lymphocytes - immunology; Base Sequence; Biological and medical sciences; Blotting, Southern; Cell Line; DNA - immunology; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Hybridomas; Immune Tolerance; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Heavy Chains - immunology; Immunoglobulin Heavy Chains - metabolism; Immunoglobulin Light Chains - genetics; Immunoglobulin Light Chains - immunology; Immunoglobulin Light Chains - metabolism; Mice; Mice, Inbred BALB C; Mice, Transgenic; Molecular Sequence Data; Receptors, Antigen, B-Cell - immunology; Receptors, Antigen, B-Cell - metabolism; Restriction Mapping; Autoimmunity; Immunoglobulins; heavy-Peptide chain; Rodentia; Transgenic animal; Autoantibody; light-Peptide chain; B-Lymphocyte; Vertebrata; Double stranded DNA; Specificity; Mammalia; Gene; Mouse; Immune tolerance; Biological receptor
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.177.4.999

To determine the fate of anti-DNA antibody-bearing B cells in normal mice, we generated transgenic mice bearing the heavy (H) and light (L) chain genes of a well-characterized anti-double-stranded DNA antibody. This antibody was originally isolated from a diseased MRL/lpr mouse and has characteristics common to spontaneously arising anti-DNA antibodies. Results show that the H/L transgene (tg) immunoglobulin receptor is not expressed by animals bearing both tgs, although single tg animals (H or L) express their transgenes. Young H/L tg animals express few B cells, whereas adult H/L tg animals maintain almost normal B cell numbers. Analysis of the immunoglobulin receptors used by adult B cells shows that all contain the tg H chain in association with endogenous L chains. These B cells transcribe the L tg as well as the rearranged endogenous L chain gene, and loss of endogenous L chain gene transcription results in resurrection of the 3H9 H/L tg product. Examination of the endogenous L chains used by these cells shows that they represent a highly restricted subset of V genes. Taken together, these data suggest that autoreactive transgenic B cells can rearrange endogenous L chain genes to alter surface receptors. Those L chains that compete successfully with the L tg for H chain binding, and that create a nonautoreactive receptor, allow the B cell to escape deletion. We suggest that this receptor editing is a mechanism used by immature autoreactive B cells to escape tolerance.