title: B cell expression of the SH2-containing inositol 5-phosphatase (SHIP-1) is required to establish anergy to high affinity, proteinacious autoantigens.
abstract: Many self-reactive B cells exist in the periphery in a rapidly reversible state of unresponsiveness referred to as anergy. Reversibility of anergy indicates that chronically occupied BCR must transduce non-durable regulatory signals that maintain unresponsiveness. Consistent with such a mechanism, studies of immunoglobulin transgenic, as well as naturally occurring polyclonal autoreactive B cells demonstrate activation of the inositol 5-phosphatase SHIP-1 in anergic cells, and low affinity chromatin autoantigen-reactive B cells have been shown to require expression of this phosphatase to maintain anergy. However, it has been reported that anergy of B cells recognizing high affinity soluble antigen may not require SHIP-1, and is instead mediated by upregulation of the inositol 3-phosphatase PTEN. To further explore this apparent difference in mechanism we analyzed the effect of B cell-targeted SHIP-1 deletion on immune tolerance of high affinity anti-HEL B cells in mice expressing soluble HEL (MD4.ML-5). We report that SHIP-1 functions to dampen responses of naïve and low-dose antigen-primed B cells in vitro, and is required for induction of B cell tolerance. Thus, while anergy of B cells reactive with low affinity and likely polyvalent chromatin antigens is maintained by activation of inhibitory signaling circuitry involving SHIP-1, anergy of B cells recognizing soluble self antigen with high affinity also requires increased activity of SHIP-1.
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, USA.
authors.forename: Janie
authors.initials: J
authors.lastname: Akerlund
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Getahun
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, USA. Electronic address: John.Cambier@ucdenver.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Cambier
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D017635:Clonal Anergy; D007108:Immune Tolerance / Q000276:immunology; D007072:Immunoglobulin D / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D000072181:Inositol Polyphosphate 5-Phosphatases; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000235:genetics*; D011506:Proteins / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction; D018909:src Homology Domains / Q000235:genetics*
chemical_list: D001324:Autoantigens; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D011506:Proteins; D011947:Receptors, Antigen, B-Cell; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
keywords: Autoimmunity; B cells; MD4.ML-5; SHIP-1; Tolerance