title: Spontaneous loss of tolerance of autoreactive B cells in Act1-deficient rheumatoid factor transgenic mice.
abstract: Self-reactive B cells in BALB/c AM14 transgenic (Tg) rheumatoid factor mice are not subject to central or peripheral tolerization. Instead, they remain at a stage of "clonal ignorance"; that is, they do not proliferate and differentiate into Ab-forming cells. However, the immunoregulatory mechanisms that prevent autoantibody production in these mice remain unclear. In this study, we show that crossing AM14 Tg mice to a mouse strain deficient in Act1, a molecule involved in the regulation of BAFF-R and CD40-signaling in B cells, results in spontaneous activation of AM14 Tg B cells and production of AM14-specific Abs. Three- to 5-mo-old AM14 Tg Act1(-/-) mice showed significant expansion of AM14 Tg B cells, including a 2- to 3-fold increase in the spleen and cervical lymph nodes compared with AM14 Tg Act1(+/+) mice. Furthermore, in the presence of endogenous self-Ag (IgH(a) congenic background), AM14 Tg Act1(-/-) B cells were spontaneously activated and differentiated into Ab-forming cells. In contrast with previous studies using AM14 Tg MLR.Fas(lpr) mice, we found that a significant number of AM14 Tg cells AM14 Tg Act1(-/-) mice displayed phenotypic characteristics of germinal center B cells. Anti-CD40L treatment significantly limited the expansion and activation of AM14 Tg Act1(-/-) B cells, suggesting that CD40L-mediated signals are required for the retention of these cells. Our results support the important role of Act1 in the regulation of self-reactive B cells and reveal how Act1 functions to prevent the production of autoantibodies.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Giltiay
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Cullen
authors.forename: Trine N
authors.initials: TN
authors.lastname: Jørgensen
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000276:immunology*; D000818:Animals; D000917:Antibody Formation; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D012217:Rheumatoid Factor / Q000235:genetics / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001323:Autoantibodies; D053264:B-Cell Activating Factor; C515963:Traf3ip2 protein, mouse; D012217:Rheumatoid Factor
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