title: TLR9 in peritoneal B-1b cells is essential for production of protective self-reactive IgM to control Th17 cells and severe autoimmunity.
abstract: The role of TLR9 in the development of the autoimmune disease systemic lupus erythematosus is controversial. In different mouse models of the disease, loss of TLR9 abolishes the generation of anti-nucleosome IgG autoantibodies but at the same time exacerbates lupus disease. However, the TLR9-dependent tolerance mechanism is unknown. In this study, we show that loss of TLR9 is associated with low peritoneal B-1b cell numbers and low levels of protective self-reactive IgM serum autoantibodies in lupus-prone FcγRIIB-deficient mice leading to the uncontrolled accumulation of proinflammatory CD4(+) cells and exacerbated autoimmunity. TLR7 signaling was not able to compensate for the loss of TLR9 signaling in peritoneal B-1b cells to induce IgM Abs. Transfer of TLR9-expressing peritoneal B-1b cells from FcγRIIB-deficient mice or of recombinant monoclonal self-reactive IgM Abs was sufficient to reduce the frequency of proinflammatory Th17 cells and lupus disease in FcγRIIB/TLR9 double-deficient mice. Taken together, these data provide evidence for a TLR9-dependent tolerance mechanism of peritoneal B-1b cells generating protective self-reactive IgM in lupus-prone mice to control Th17 cell development and severe autoimmunity.
authors.affiliation: Laboratory of Tolerance and Autoimmunity, German Rheumatism Research Center, Leibniz Institute, 10117 Berlin, Germany.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Stoehr
authors.forename: Carolin T
authors.initials: CT
authors.lastname: Schoen
authors.forename: Maria M M
authors.initials: MM
authors.lastname: Mertes
authors.forename: Susanne
authors.initials: S
authors.lastname: Eiglmeier
authors.forename: Vivien
authors.initials: V
authors.lastname: Holecska
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Lorenz
authors.forename: Tim
authors.initials: T
authors.lastname: Schommartz
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Schoen
authors.forename: Constanze
authors.initials: C
authors.lastname: Hess
authors.forename: André
authors.initials: A
authors.lastname: Winkler
authors.forename: Hedda
authors.initials: H
authors.lastname: Wardemann
authors.forename: Marc
authors.initials: M
authors.lastname: Ehlers
mesh_terms: D000818:Animals; D001202:Ascitic Fluid / Q000166:cytology / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D007075:Immunoglobulin M; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9