title: Receptor editing can lead to allelic inclusion and development of B cells that retain antibodies reacting with high avidity autoantigens.
abstract: Receptor editing is a major B cell tolerance mechanism that operates by secondary Ig gene rearrangements to change the specificity of autoreactive developing B cells. In the 3-83Igi mouse model, receptor editing operates in every autoreactive anti-H-2K(b) B cell, providing a novel receptor without additional cell loss. Despite the efficiency of receptor editing in generating nonautoreactive Ag receptors, we show in this study that this process does not inactivate the autoantibody-encoding gene(s) in every autoreactive B cell. In fact, receptor editing can generate allelically and isotypically included B cells that simultaneously express the original autoreactive and a novel nonautoreactive Ag receptors. Such dual Ab-expressing B cells differentiate into transitional and mature B cells retaining the expression of the autoantibody despite the high avidity interaction between the autoantibody and the self-Ag in this system. Moreover, we find that these high avidity autoreactive B cells retain the autoreactive Ag receptor within the cell as a consequence of autoantigen engagement and through a Src family kinase-dependent process. Finally, anti-H-2K(b) IgM autoantibodies are found in the sera of older 3-83Igi mice, indicating that dual Ab-expressing autoreactive B cells are potentially functional and capable of differentiating into IgM autoantibody-secreting plasma cells under certain circumstances. These results demonstrate that autoreactive B cells reacting with ubiquitous membrane bound autoantigens can bypass mechanisms of central tolerance by coexpressing nonautoreactive Abs. These dual Ab-expressing autoreactive B cells conceal their autoantibodies within the cell manifesting a superficially tolerant phenotype that can be partially overcome to secrete IgM autoantibodies.
authors.affiliation: Integrated Department of Immunology, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, CO 80206, USA.
authors.forename: Sucai
authors.initials: S
authors.lastname: Liu
authors.forename: Maria-Gabriela
authors.initials: MG
authors.lastname: Velez
authors.forename: Jessica
authors.initials: J
authors.lastname: Humann
authors.forename: Sarah
authors.initials: S
authors.lastname: Rowland
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Conrad
authors.forename: Regina
authors.initials: R
authors.lastname: Halverson
authors.forename: Raul M
authors.initials: RM
authors.lastname: Torres
authors.forename: Roberta
authors.initials: R
authors.lastname: Pelanda
mesh_terms: D000367:Age Factors; D000483:Alleles; D000818:Animals; D001323:Autoantibodies / Q000502:physiology*; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D001666:Binding Sites, Antibody / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D015322:Gene Rearrangement, B-Lymphocyte / Q000276:immunology*; D006825:Hybridomas; D007108:Immune Tolerance / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D017393:RNA Editing / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D011947:Receptors, Antigen, B-Cell; D019061:src-Family Kinases