Activation of Autoreactive B Cells by Endogenous TLR7 and TLR3 RNA Ligands |
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Authors: | Nathaniel M. Green Krishna-Sulayman Moody Michelle Debatis Ann Marshak-Rothstein |
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Affiliation: | From the ‡Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118 and ;the §Department of Medicine, Rheumatology Division, University of Massachusetts Medical School, Worcester, Massachusetts 01605 |
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Abstract: | The key step in the activation of autoreactive B cells is the internalization of nucleic acid containing ligands and delivery of these ligands to the Toll-like Receptor (TLR) containing endolysosomal compartment. Ribonucleoproteins represent a large fraction of autoantigens in systemic autoimmune diseases. Here we demonstrate that many uridine-rich mammalian RNA sequences associated with common autoantigens effectively activate autoreactive B cells. Priming with type I IFN increased the magnitude of activation, and the range of which RNAs were stimulatory. A subset of RNAs that contain a high degree of self-complementarity also activated B cells through TLR3. For the RNA sequences that activated predominantly through TLR7, the activation is proportional to uridine-content, and more precisely defined by the frequency of specific uridine-containing motifs. These results identify parameters that define specific mammalian RNAs as ligands for TLRs. |
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Keywords: | Antibodies Autoimmune Diseases Autoimmunity Immunology RNA Toll-like Receptors (TLR) B Cell |
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