1. Role of nucleic acid-sensing TLRs in diverse autoantibody specificities and anti-nuclear antibody-producing B cells.
- Author
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Koh YT, Scatizzi JC, Gahan JD, Lawson BR, Baccala R, Pollard KM, Beutler BA, Theofilopoulos AN, and Kono DH
- Subjects
- Animals, Antibody-Producing Cells immunology, Autoantibodies immunology, Bone Marrow Cells cytology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Chromatin immunology, Dendritic Cells, Female, Immunologic Deficiency Syndromes, Lupus Erythematosus, Systemic immunology, Lymphocyte Activation immunology, Macrophages immunology, Membrane Transport Proteins immunology, Mice, Mice, Inbred NZB, Myeloid Differentiation Factor 88 immunology, Primary Immunodeficiency Diseases, Rheumatoid Factor immunology, Ribonucleoproteins immunology, Signal Transduction, Antibodies, Antinuclear immunology, B-Lymphocytes immunology, Membrane Glycoproteins immunology, Nucleic Acids immunology, Toll-Like Receptor 7 immunology, Toll-Like Receptor 9 immunology
- 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.
- Published
- 2013
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