TLR8 deficiency leads to autoimmunity in mice

被引：160

作者：

Demaria, Olivier ^{[1
,2
,3
]}

Pagni, Philippe P. ^{[1
,2
,3
]}

Traub, Stephanie ^{[1
,2
,3
]}

de Gassart, Aude ^{[1
,2
,3
]}

Branzk, Nora ^{[1
,2
,3
]}

Murphy, Andrew J. ^{[4
]}

Valenzuela, David M. ^{[4
]}

Yancopoulos, George D. ^{[4
]}

Flavell, Richard A. ^{[5
,6
]}

Alexopoulou, Lena ^{[1
,2
,3
]}

机构：

[1] Univ Aix Marseille 2, Ctr Immunol Marseille Luminy, F-13288 Marseille 9, France

[2] INSERM, U631, F-13258 Marseille, France

[3] CNRS, UMR6102, Marseille, France

[4] Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA

[5] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA

[6] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2010年 / 120卷 / 10期

关键词：

TOLL-LIKE RECEPTORS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; B-CELL SUBSETS; IMMUNE-COMPLEX GLOMERULONEPHRITIS; DOUBLE-STRANDED-RNA; DENDRITIC CELLS; CUTTING EDGE; RESPONSES; EXPRESSION; RECOGNITION;

D O I：

10.1172/JCI42081

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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-kappa B 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(-1-)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.

引用

页码：3651 / 3662

页数：12

共 43 条

[21] Toll-like receptor control of the adaptive immune responses [J].

Iwasaki, A ;

Medzhitov, R .

NATURE IMMUNOLOGY, 2004, 5 (10) :987-995

[22] TLR9 signaling in B cells determines class switch recombination to IgG2a [J].

Jegerlehner, Andrea ;

Maurer, Patrik ;

Bessa, Juliana ;

Hinton, Heather J. ;

Kopf, Manfred ;

Bachmann, Martin F. .

JOURNAL OF IMMUNOLOGY, 2007, 178 (04) :2415-2420

[23] Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848 [J].

Jurk, M ;

Heil, F ;

Vollmer, J ;

Schetter, C ;

Krieg, AM ;

Wagner, H ;

Lipford, G ;

Bauer, S .

NATURE IMMUNOLOGY, 2002, 3 (06) :499-499

[24] Toll-like Receptor and RIG-1-like Receptor Signaling [J].

Kawai, Taro ;

Akira, Shizuo .

YEAR IN IMMUNOLOGY 2008, 2008, 1143 :1-20

[25] Innate-like B cells [J].

Kearney, JF .

SPRINGER SEMINARS IN IMMUNOPATHOLOGY, 2005, 26 (04) :377-383

[26] RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement [J].

Lau, CM ;

Broughton, C ;

Tabor, AS ;

Akira, S ;

Flavell, RA ;

Mamula, MJ ;

Christensen, SR ;

Shlomchik, MJ ;

Viglianti, GA ;

Rifkin, IR ;

Marshak-Rothstein, A .

JOURNAL OF EXPERIMENTAL MEDICINE, 2005, 202 (09) :1171-1177

[27] Recognition of single-stranded RNA viruses by Toll-like receptor 7 [J].

Lund, JM ;

Alexopoulou, L ;

Sato, A ;

Karow, M ;

Adams, NC ;

Gale, NW ;

Iwasaki, A ;

Flavell, RA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (15) :5598-5603

[28] Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis [J].

Ma, Yinghua ;

Li, Jianxue ;

Chiu, Isaac ;

Wang, Yawen ;

Sloane, Jacob A. ;

Lu, Jining ;

Kosaras, Bela ;

Sidman, Richard L. ;

Volpe, Joseph J. ;

Vartanian, Timothy .

JOURNAL OF CELL BIOLOGY, 2006, 175 (02) :209-215

[29] B1 cells: similarities and differences with other B cell subsets [J].

Martin, F ;

Kearney, JF .

CURRENT OPINION IN IMMUNOLOGY, 2001, 13 (02) :195-201

[30] Toll-like receptors and antibody responses [J].

Nemazee, D ;

Gavin, A ;

Hoebe, K ;

Beutler, B .

NATURE, 2006, 441 (7091) :E4-E4

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