title: Anergic self-reactive B cells present self antigen and respond normally to CD40-dependent T-cell signals but are defective in antigen-receptor-mediated functions.
abstract: B-cell tolerance to soluble protein self antigens such as hen egg lysozyme (HEL) is mediated by clonal anergy. Anergic B cells fail to mount antibody responses even in the presence of carrier-primed T cells, suggesting an inability to activate or respond to T helper cells. To investigate the nature of this defect, B cells from tolerant HEL/anti-HEL double-transgenic mice were incubated with a membrane preparation from activated T-cell clones expressing the CD40 ligand. These membranes, together with interleukin 4 and 5 deliver the downstream antigen-independent CD40-dependent B-cell-activating signals required for productive T-B collaboration. Anergic B cells responded to this stimulus by proliferating and secreting antibody at levels comparable to or better than control B cells. Furthermore, anergic B cells presented HEL acquired in vivo and could present the unrelated antigen, conalbumin, targeted for processing via surface IgD. In contrast, the low immunoglobulin receptor levels on anergic B cells were associated with reduced de novo presentation of HEL and a failure to upregulate costimulatory ligands for CD28. These defects in immunoglobulin-receptor-mediated functions could be overcome in vivo, suggesting a number of mechanisms for induction of autoantibody responses.
authors.affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia.
authors.forename: J M
authors.initials: JM
authors.lastname: Eris
authors.forename: A
authors.initials: A
authors.lastname: Basten
authors.forename: R
authors.initials: R
authors.lastname: Brink
authors.forename: K
authors.initials: K
authors.lastname: Doherty
authors.forename: M R
authors.initials: MR
authors.lastname: Kehry
authors.forename: P D
authors.initials: PD
authors.lastname: Hodgkin
mesh_terms: D000818:Animals; D000917:Antibody Formation; D015703:Antigens, CD / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens; D002462:Cell Membrane / Q000276:immunology; D003207:Conalbumin / Q000276:immunology; D005434:Flow Cytometry; D007108:Immune Tolerance; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009113:Muramidase / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D011947:Receptors, Antigen, B-Cell; D003207:Conalbumin; D009113:Muramidase