title: B cell TLR7 expression drives anti-RNA autoantibody production and exacerbates disease in systemic lupus erythematosus-prone mice.
abstract: Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of antinuclear autoantibodies. Antinuclear autoantibody development is recognized as one of the initial stages of disease that often results in systemic inflammation, kidney disease, and death. The etiology is complex, but it is clear that innate pathways may play an important role in disease progression. Recent data have highlighted an important role for the TLR family, particularly TLR7, in both human disease and murine models. In this study, we have presented a low copy conditional TLR7 transgenic (Tg7) mouse strain that does not develop spontaneous autoimmunity. When we combine Tg7 with the Sle1 lupus susceptibility locus, the mice develop severe disease. Using the CD19(Cre) recombinase system, we normalized expression of TLR7 solely within the B cells. Using this method we demonstrated that overexpression of TLR7 within the B cell compartment reduces the marginal zone B cell compartment and increases B and T cell activation but not T follicular helper cell development. Moreover, this enhanced B cell TLR7 expression permits the specific development of Abs to RNA/protein complexes and exacerbates SLE disease.
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Huiyin
authors.initials: H
authors.lastname: Lee
authors.forename: Miwako
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Jones
authors.forename: Jivanaah
authors.initials: J
authors.lastname: Dayalan
authors.forename: Richard
authors.initials: R
authors.lastname: Hopkins
authors.forename: Xin J
authors.initials: XJ
authors.lastname: Zhou
authors.forename: Felix
authors.initials: F
authors.lastname: Yarovinsky
authors.forename: John E
authors.initials: JE
authors.lastname: Connolly
authors.forename: Maria A
authors.initials: MA
authors.lastname: Curotto de Lafaille
authors.forename: Edward K
authors.initials: EK
authors.lastname: Wakeland
authors.forename: Anna-Marie
authors.initials: AM
authors.lastname: Fairhurst
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000009:adverse effects / Q000096:biosynthesis*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D004843:Epistasis, Genetic / Q000276:immunology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D019076:Transgenes / Q000276:immunology
chemical_list: D001323:Autoantibodies; D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7