title: Activation of rheumatoid factor-specific B cells is antigen dependent and occurs preferentially outside of germinal centers in the lupus-prone NZM2410 mouse model.
abstract: AM14 rheumatoid factor (RF) B cells in the MRL/lpr mice are activated by dual BCR and TLR7/9 ligation and differentiate into plasmablasts via an extrafollicular (EF) route. It was not known whether this mechanism of activation of RF B cells applied to other lupus-prone mouse models. We investigated the mechanisms by which RF B cells break tolerance in the NZM2410-derived B6.Sle1.Sle2.Sle3 (TC) strain in comparison with C57BL/6 (B6) controls, each expressing the AM14 H chain transgene in the presence or absence of the IgG2a(a) autoantigen. The TC, but not B6, genetic background promotes the differentiation of RF B cells into Ab-forming cells (AFCs) in the presence of the autoantigen. Activated RF B cells preferentially differentiated into plasmablasts in EF zones. Contrary to the MRL/lpr strain, TC RF B cells were also located within germinal centers, but only the formation of EF foci was positively correlated with the production of RF AFCs. Immunization of young TC.AM14 H chain transgenic mice with IgG2a(a) anti-chromatin immune complexes (ICs) activated RF B cells in a BCR- and TLR9-dependent manner. However, these IC immunizations did not result in the production of RF AFCs. These results show that RF B cells break tolerance with the same general mechanisms in the TC and the MRL/lpr lupus-prone genetic backgrounds, namely the dual activation of the BCR and TLR9 pathways. There are also distinct differences, such as the presence of RF B cells in GCs and the requirement of chronic IgG2a(a) anti-chromatin ICs for full differentiation of RF AFCs.
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Allison
authors.initials: A
authors.lastname: Sang
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Haitao
authors.initials: H
authors.lastname: Niu
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520; and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Jaime
authors.initials: J
authors.lastname: Cullen
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Seung Chul
authors.initials: SC
authors.lastname: Choi
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Ying Yi
authors.initials: YY
authors.lastname: Zheng
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520; and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Haowei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520; and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610; morel@ufl.edu.
authors.forename: Laurence
authors.initials: L
authors.lastname: Morel
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D002843:Chromatin / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D018858:Germinal Center / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*; D012217:Rheumatoid Factor / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D002843:Chromatin; D007074:Immunoglobulin G; D011947:Receptors, Antigen, B-Cell; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D012217:Rheumatoid Factor