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TLR8 deficiency leads to autoimmunity in mice
Olivier Demaria, … , Richard A. Flavell, Lena Alexopoulou
Olivier Demaria, … , Richard A. Flavell, Lena Alexopoulou
Published September 1, 2010
Citation Information: J Clin Invest. 2010;120(10):3651-3662. https://doi.org/10.1172/JCI42081.
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Research Article Autoimmunity Article has an altmetric score of 7

TLR8 deficiency leads to autoimmunity in mice

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Abstract

TLRs play an essential role in the induction of immune responses by detecting conserved molecular products of microorganisms. However, the function of TLR8 is largely unknown. In the current study, we investigated the role of TLR8 signaling in immunity in mice. We found that Tlr8–/– DCs overexpressed TLR7, were hyperresponsive to various TLR7 ligands, and showed stronger and faster NF-κB activation upon stimulation with the TLR7 ligand R848. Tlr8–/– mice showed splenomegaly, defective development of marginal zone (MZ) and B1 B cells, and increased serum levels of IgM and IgG2a. Furthermore, Tlr8–/– mice exhibited increased serum levels of autoantibodies against small nuclear ribonucleoproteins, ribonucleoprotein, and dsDNA and developed glomerulonephritis, whereas neither Tlr7–/– nor Tlr8–/–Tlr7–/– mice showed any of the phenotypes observed in Tlr8–/– mice. These data provide evidence for a pivotal role for mouse TLR8 in the regulation of mouse TLR7 expression and prevention of spontaneous autoimmunity.

Authors

Olivier Demaria, Philippe P. Pagni, Stephanie Traub, Aude de Gassart, Nora Branzk, Andrew J. Murphy, David M. Valenzuela, George D. Yancopoulos, Richard A. Flavell, Lena Alexopoulou

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Figure 4

Defect of MZ B cells in Tlr8–/– mice.

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Defect of MZ B cells in Tlr8–/– mice.
   
(A) Spleen weight and size of ...
(A) Spleen weight and size of 8-week-old male WT and Tlr8–/– mice. Each point represents the value obtained from 1 mouse; horizontal bars denote mean values. ***P < 0.001. (B) Erythrocyte-depleted splenocytes from 6-month-old WT, Tlr8–/–, and Tlr8–/–Tlr7–/– mice were analyzed by flow cytometry for the expression of CD19, CD21, and CD23. Profiles using anti-CD21 and anti-CD23 were performed on CD19+ gated cells. Numbers denote the percentage of immature B cells (CD21–CD23–), follicular B cells (CD21intCD23hi) and MZ B cells (CD21hiCD23lo/–) in the indicated circles. (C) Spleen sections from WT or Tlr8–/– mice stained for MOMA1 (red) and B220 (green), or for B220 (red) and CD3 (blue). Scale bars: 200 μm. (D) BM cells (2 × 106 cells) from WT or Tlr8–/– mice were transferred i.v. into lethally irradiated WT or Tlr8–/– mice. After 6–8 weeks, splenocytes were analyzed by flow cytometry for the presence of MZ B cells. (A) Data are representative of 3 independent experiments with 5–9 mice per group. (B) Data are representative of 5 independent experiments with 3–4 mice per group. (C and D) Data are representative of 2 independent experiments with 3 mice per group.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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