Ikaros prevents autoimmunity by controlling anergy and Toll-like receptor signaling in B cells
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作者:
Schwickert, Tanja A.
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Vienna Bioctr, Res Inst Mol Pathol, Vienna, AustriaVienna Bioctr, Res Inst Mol Pathol, Vienna, Austria
Schwickert, Tanja A.
[1
]
Tagoh, Hiromi
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Vienna Bioctr, Res Inst Mol Pathol, Vienna, Austria
Univ Oxford, Ludwig Inst Canc Res, Oxford, EnglandVienna Bioctr, Res Inst Mol Pathol, Vienna, Austria
Tagoh, Hiromi
[1
,2
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Schindler, Karina
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Vienna Bioctr, Res Inst Mol Pathol, Vienna, AustriaVienna Bioctr, Res Inst Mol Pathol, Vienna, Austria
Schindler, Karina
[1
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Fischer, Maria
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Vienna Bioctr, Res Inst Mol Pathol, Vienna, AustriaVienna Bioctr, Res Inst Mol Pathol, Vienna, Austria
Fischer, Maria
[1
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Jaritz, Markus
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Vienna Bioctr, Res Inst Mol Pathol, Vienna, AustriaVienna Bioctr, Res Inst Mol Pathol, Vienna, Austria
Jaritz, Markus
[1
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Busslinger, Meinrad
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Vienna Bioctr, Res Inst Mol Pathol, Vienna, AustriaVienna Bioctr, Res Inst Mol Pathol, Vienna, Austria
Busslinger, Meinrad
[1
]
机构:
[1] Vienna Bioctr, Res Inst Mol Pathol, Vienna, Austria
[2] Univ Oxford, Ludwig Inst Canc Res, Oxford, England
The establishment of a diverse B cell antigen receptor (BCR) repertoire by V(D)J recombination also generates autoreactive B cells. Anergy is one tolerance mechanism; it renders autoreactive B cells insensitive to stimulation by self-antigen, whereas Toll-like receptor (TLR) signaling can reactivate anergic B cells. Here, we describe a critical role of the transcription factor Ikaros in controlling BCR anergy and TLR signaling. Mice with specific deletion of Ikaros in mature B cells developed systemic autoimmunity. Ikaros regulated many anergy-associated genes, including Zfp318, which is implicated in the attenuation of BCR responsiveness by promoting immunoglobulin D expression in anergic B cells. TLR signaling was hyperactive in Ikaros-deficient B cells, which failed to upregulate feedback inhibitors of the MyD88-nuclear factor kappa B signaling pathway. Systemic inflammation was lost on expression of a non-self-reactive BCR or loss of MyD88 in Ikaros-deficient B cells. Thus, Ikaros acts as a guardian preventing autoimmunity by promoting BCR anergy and restraining TLR signaling.
机构:
Rensselaer Polytech Inst, Dept Elect Comp & Syst Engn, Troy, NY USABoston Univ, Program Bioinformat, Boston, MA 02215 USA
Julius, A. Agung
Amar, Salomon
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Boston Univ, Program Bioinformat, Boston, MA 02215 USA
Boston Univ, Ctr Antiinflammatory Therapeut, Goldman Sch Dent Med, Boston, MA 02215 USABoston Univ, Program Bioinformat, Boston, MA 02215 USA