Cell intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses1
| Autor: | Nündel, Kerstin, Green, Nathaniel M., Shaffer, Arthur L., Moody, Krishna-Sulayman, Busto, Patricia, Eilat, Dan, Miyake, Kensuke, Oropallo, Michael A., Cancro, Michael P., Marshak-Rothstein, Ann |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Plasma Cells
Receptors Antigen B-Cell Autoimmunity Mice Transgenic Lymphocyte Activation Autoantigens Article immune system diseases Rheumatoid Factor Animals Cells Cultured Autoantibodies Cell Proliferation Oligonucleotide Array Sequence Analysis Mice Knockout B-Lymphocytes Mice Inbred BALB C Reverse Transcriptase Polymerase Chain Reaction virus diseases Cell Differentiation Flow Cytometry Toll-Like Receptor 7 Toll-Like Receptor 9 Interferon Regulatory Factors Syndecan-1 Transcriptome |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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