title: Apoptotic marginal zone deletion of anti-Sm/ribonucleoprotein B cells.
abstract: CD40L is excessively produced in both human and murine lupus and plays a role in lupus pathogenesis. To address how excess CD40L induces autoantibody production, we crossed CD40L-transgenic mice with the anti-DNA H-chain transgenic mouse lines 3H9 and 56R, well-characterized models for studying B-cell tolerance to nuclear antigens. Excess CD40L did not induce autoantibody production in 3H9 mice in which anergy maintains self-tolerance, nor did it perturb central tolerance, including deletion and receptor editing, of anti-DNA B cells in 56R mice. In contrast, CD40L/56R mice restored a large number of marginal zone (MZ) B cells reactive to Sm/ribonucleoprotein (RNP) and produced autoantibody, whereas these B cells were deleted by apoptosis in MZ of 56R mice. Thus, excess CD40L efficiently blocked tolerance of Sm/RNP-reactive MZ B cells, leading to production of anti-Sm/RNP antibody implicated in the pathogenesis of lupus. These results suggest that self-reactive B cells such as anti-Sm/RNP B cells, which somehow escape tolerance in the bone marrow and migrate to MZ, are tolerized by apoptotic deletion in MZ and that a break in this tolerance may play a role in the pathogenesis of lupus.
authors.affiliation: Laboratory of Immunology, Graduate School of Biomedical Sciences, and Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kishi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Higuchi
authors.forename: Shirly
authors.initials: S
authors.lastname: Phoon
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sakamaki
authors.forename: Koki
authors.initials: K
authors.lastname: Kamiya
authors.forename: Gabriela
authors.initials: G
authors.lastname: Riemekasten
authors.forename: Kazunari
authors.initials: K
authors.lastname: Akiyoshi
authors.forename: Martin G
authors.initials: MG
authors.lastname: Weigert
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tsubata
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D004002:Clodronic Acid; D003433:Crosses, Genetic; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology*; D007150:Immunohistochemistry; D007211:Indoles; D008081:Liposomes; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D007211:Indoles; D008081:Liposomes; D004002:Clodronic Acid; D023201:CD40 Ligand; C007293:DAPI