title: Cell-intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses.
abstract: Endosomal TLRs play an important role in systemic autoimmune diseases, such as systemic erythematosus lupus, in which DNA- and RNA-associated autoantigens activate autoreactive B cells through TLR9- and TLR7-dependent pathways. Nevertheless, TLR9-deficient autoimmune-prone mice develop more severe clinical disease, whereas TLR7-deficient and TLR7/9-double deficient autoimmune-prone mice develop less severe disease. To determine whether the regulatory activity of TLR9 is B cell intrinsic, we directly compared the functional properties of autoantigen-activated wild-type, TLR9-deficient, and TLR7-deficient B cells in an experimental system in which proliferation depends on BCR/TLR coengagement. In vitro, TLR9-deficient cells are less dependent on survival factors for a sustained proliferative response than are either wild-type or TLR7-deficient cells. The TLR9-deficient cells also preferentially differentiate toward the plasma cell lineage, as indicated by expression of CD138, sustained expression of IRF4, and other molecular markers of plasma cells. In vivo, autoantigen-activated TLR9-deficient cells give rise to greater numbers of autoantibody-producing cells. Our results identify distinct roles for TLR7 and TLR9 in the differentiation of autoreactive B cells that explain the capacity of TLR9 to limit, as well as TLR7 to promote, the clinical features of systemic erythematosus lupus.
authors: Division of Rheumatology, Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA 01605;
authors: Kerstin
authors: K
authors: Nündel
authors: Division of Rheumatology, Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA 01605;
authors: Nathaniel M
authors: NM
authors: Green
authors: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Arthur L
authors: AL
authors: Shaffer
authors: Division of Rheumatology, Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA 01605;
authors: Krishna L
authors: KL
authors: Moody
authors: Division of Rheumatology, Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA 01605;
authors: Patricia
authors: P
authors: Busto
authors: Hadassah University Hospital, Jerusalem 91322, Israel;
authors: Dan
authors: D
authors: Eilat
authors: Department of Microbiology and Immunology, University of Tokyo, Tokyo 108-8639, Japan; and.
authors: Kensuke
authors: K
authors: Miyake
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104.
authors: Michael A
authors: MA
authors: Oropallo
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104.
authors: Michael P
authors: MP
authors: Cancro
authors: Division of Rheumatology, Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA 01605; ann.rothstein@umassmed.edu.
authors: Ann
authors: A
authors: Marshak-Rothstein
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D005434:Flow Cytometry; D050835:Interferon Regulatory Factors / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012217:Rheumatoid Factor / Q000276:immunology; D053668:Syndecan-1 / Q000276:immunology / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D059467:Transcriptome / Q000276:immunology; D000099218:Interferon Regulatory Factor-4
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D050835:Interferon Regulatory Factors; D011947:Receptors, Antigen, B-Cell; D012217:Rheumatoid Factor; D053668:Syndecan-1; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D000099218:Interferon Regulatory Factor-4