期刊
JOURNAL OF IMMUNOLOGY
卷 194, 期 6, 页码 2504-2512出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1402425
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资金
- National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health (NIH) Grant [AR050256]
- Department of the Army Grant [PR120610]
- NIH Training Grant [T32 AI-055428]
- NIH intramural program
- Grants-in-Aid for Scientific Research [25253032] Funding Source: KAKEN
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.
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