title: BCR and co-receptor crosstalk facilitate the positive selection of self-reactive transitional B cells.
abstract: The establishment of a diverse B cell repertoire requires fine-tuning of antigen receptor selection during development in order to permit sufficient diversity while reducing the potential for autoimmunity. In this review, we highlight recent studies demonstrating the central role of the B cell antigen receptor (BCR), in coordination with other key pro-survival signals mediated by CD40, BAFF-R, TACI and/or TLRs, in regulating both negative and positive selection of autoreactive B cells. In particular, we show how altered antigen or co-stimulatory signaling can facilitate positive selection of transitional B cells with self-reactive BCRs, ultimately leading to their entry into the mature, naive B cell compartment. We propose a model wherein altered receptor signals (due to inherited genetic changes) leads: first, to enhanced positive selection of autoreactive cells into the naïve B cell repertoire; subsequently, to an increased probability of pathogenic germinal center responses in individuals with a broad range of autoimmune disorders.
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA, United States; Seattle Children's Research Institute, Seattle, WA, United States.
authors.forename: Genita
authors.initials: G
authors.lastname: Metzler
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA, United States; Seattle Children's Research Institute, Seattle, WA, United States.
authors.forename: Nikita S
authors.initials: NS
authors.lastname: Kolhatkar
authors.affiliation: Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States; Department of Immunology, University of Washington School of Medicine, Seattle, WA, United States; Seattle Children's Research Institute, Seattle, WA, United States. Electronic address: drawling@u.washington.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics; D060966:Clonal Selection, Antigen-Mediated; D018858:Germinal Center / Q000502:physiology*; D006801:Humans; D009154:Mutation / Q000235:genetics; D020239:Receptor Cross-Talk; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D001324:Autoantigens; D011947:Receptors, Antigen, B-Cell