title: Receptor editing and genetic variability in human autoreactive B cells.
abstract: The mechanisms by which B cells undergo tolerance, such as receptor editing, clonal deletion, and anergy, have been established in mice. However, corroborating these mechanisms in humans remains challenging. To study how autoreactive human B cells undergo tolerance, we developed a novel humanized mouse model. Mice expressing an anti-human Igκ membrane protein to serve as a ubiquitous neo self-antigen (Ag) were transplanted with a human immune system. By following the fate of self-reactive human κ(+) B cells relative to nonautoreactive λ(+) cells, we show that tolerance of human B cells occurs at the first site of self-Ag encounter, the bone marrow, via a combination of receptor editing and clonal deletion. Moreover, the amount of available self-Ag and the genetics of the cord blood donor dictate the levels of central tolerance and autoreactive B cells in the periphery. Thus, this model can be useful for studying specific mechanisms of human B cell tolerance and to reveal differences in the extent of this process among human populations.
authors.affiliation: Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045 Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
authors.forename: Julie
authors.initials: J
authors.lastname: Lang
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ota
authors.affiliation: Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045 Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
authors.forename: Margot
authors.initials: M
authors.lastname: Kelly
authors.affiliation: Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045 Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
authors.forename: Pamela
authors.initials: P
authors.lastname: Strauch
authors.affiliation: Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045 Division of Allergy and Clinical Immunology, University of Colorado Denver School of Medicine, Aurora, CO 80045.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Freed
authors.affiliation: Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045 Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
authors.forename: Raul M
authors.initials: RM
authors.lastname: Torres
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: David
authors.initials: D
authors.lastname: Nemazee
authors.affiliation: Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045 Department of Biomedical Research, National Jewish Health, Denver, CO 80206 Roberta.Pelanda@ucdenver.edu.
authors.forename: Roberta
authors.initials: R
authors.lastname: Pelanda
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics*; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014644:Genetic Variation; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000378:metabolism; D007146:Immunoglobulin lambda-Chains / Q000235:genetics / Q000378:metabolism; D016130:Immunophenotyping; D051379:Mice; D008822:Mice, Transgenic; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism
chemical_list: D018941:Antigens, CD19; D001324:Autoantigens; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D011947:Receptors, Antigen, B-Cell