title: Role of nucleic acid-sensing TLRs in diverse autoantibody specificities and anti-nuclear antibody-producing B cells.
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.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Yi Ting
authors.initials: YT
authors.lastname: Koh
authors.forename: John C
authors.initials: JC
authors.lastname: Scatizzi
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Gahan
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lawson
authors.forename: Roberto
authors.initials: R
authors.lastname: Baccala
authors.forename: K Michael
authors.initials: KM
authors.lastname: Pollard
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Beutler
authors.forename: Argyrios N
authors.initials: AN
authors.lastname: Theofilopoulos
authors.forename: Dwight H
authors.initials: DH
authors.lastname: Kono
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D000921:Antibody-Producing Cells / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002843:Chromatin / Q000276:immunology; D003713:Dendritic Cells; D005260:Female; D007153:Immunologic Deficiency Syndromes; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D026901:Membrane Transport Proteins / Q000276:immunology; D051379:Mice; D008814:Mice, Inbred NZB; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D009696:Nucleic Acids / Q000276:immunology*; D000081207:Primary Immunodeficiency Diseases; D012217:Rheumatoid Factor / Q000276:immunology; D012261:Ribonucleoproteins / Q000276:immunology; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology*
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D002843:Chromatin; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009696:Nucleic Acids; D012261:Ribonucleoproteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C512254:UNC93B1 protein, mouse; D012217:Rheumatoid Factor