Abstract
Nucleic acid (NA)-sensing TLRs (NA-TLRs) promote the induction of anti-nuclear Abs in systemic lupus erythematosus. However, the extent to which other nonnuclear pathogenic autoantibody specificities that occur in lupus and independently in other autoimmune diseases depend on NA-TLRs, and which immune cells require NA-TLRs in systemic autoimmunity, remains to be determined. Using Unc93b1(3d) lupus-prone mice that lack NA-TLR signaling, we found that all pathogenic nonnuclear autoantibody specificities examined, even anti-RBC, required NA-TLRs. Furthermore, we document that NA-TLRs in B cells were required for the development of antichromatin and rheumatoid factor. These findings support a unifying NA-TLR-mediated mechanism of autoantibody production that has both pathophysiological and therapeutic implications for systemic lupus erythematosus and several other humoral-mediated autoimmune diseases. In particular, our findings suggest that targeting of NA-TLR signaling in B cells alone would be sufficient to specifically block production of a broad diversity of autoantibodies.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Antinuclear / immunology*
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Antibody-Producing Cells / immunology
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Autoantibodies / immunology
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B-Lymphocytes / immunology*
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Bone Marrow Cells / cytology
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CD4-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / immunology
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Chromatin / immunology
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Dendritic Cells
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Female
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Immunologic Deficiency Syndromes
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Lupus Erythematosus, Systemic / immunology
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Lymphocyte Activation / immunology
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Macrophages / immunology
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Membrane Glycoproteins / immunology*
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Membrane Transport Proteins / immunology
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Mice
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Mice, Inbred NZB
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Myeloid Differentiation Factor 88 / immunology
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Nucleic Acids / immunology*
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Primary Immunodeficiency Diseases
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Rheumatoid Factor / immunology
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Ribonucleoproteins / immunology
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Signal Transduction
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Toll-Like Receptor 7 / immunology*
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Toll-Like Receptor 9 / immunology*
Substances
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Antibodies, Antinuclear
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Autoantibodies
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Chromatin
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Membrane Glycoproteins
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Membrane Transport Proteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Nucleic Acids
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Ribonucleoproteins
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Tlr7 protein, mouse
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Tlr9 protein, mouse
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Toll-Like Receptor 7
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Toll-Like Receptor 9
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UNC93B1 protein, mouse
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Rheumatoid Factor