IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice

Thibault, Donna L; Chu, Alvina D.; Graham, Kareem; Balboni, Imelda; Lee, Lowen Y.; Kohlmoos, Cassidy; Landrigan, Angela; Higgins, John P.; Tibshirani, Robert; Utz, Paul J.

doi:10.1172/jci30065

Cited by 86 publications

(91 citation statements)

References 80 publications

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“…However, IRF9 is part of the interferon (IFN) stimulated gene factor 3 (ISGF3) heterotrimeric complex along with STAT1 (signal transducer and activator of transcription factor 1) and STAT2 (44). This complex regulates gene expression in response to IFN signaling.…”

Section: Discussionmentioning

confidence: 99%

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PU.1 Can Recruit BCL6 to DNA To Repress Gene Expression in Germinal Center B Cells

Wei

Zaprazna

Wang

et al. 2009

Molecular and Cellular Biology

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BCL6 is a transcriptional repressor crucial for germinal center formation. BCL6 represses transcription by a variety of mechanisms by binding to specific DNA sequences or by recruitment to DNA by protein interactions. We found that BCL6 can inhibit activities of the immunoglobulin kappa (Ig) intron and 3 enhancers. At the Ig 3 enhancer, BCL6 repressed enhancer activity through the PU.1 binding site. We found that BCL6 physically interacted with PU.1 in vivo and in vitro, and the results of sequential chromatin immunoprecipitation assays and transient-expression assays suggested that BCL6 recruitment to the Ig and Ig 3 enhancers occurred via PU.1 interaction. By computational studies, we identified genes that are repressed in germinal center cells and whose promoters contain conserved PU.1 binding sites in mouse and human. We found that many of these promoters bound to both PU.1 and BCL6 in vivo. In addition, BCL6 knockdown resulted in increased expression of a subset of these genes, demonstrating that BCL6 is involved in their repression. The recruitment of BCL6 to promoter regions by PU.1 represents a new regulatory mechanism that expands the number of genes regulated by this important transcriptional repressor.The B-cell lymphoma 6 (BCL6) gene was identified on the basis of its location at chromosomal breakpoints in nonHodgkin's disease B-cell lymphomas (7, 55). About 30% of diffuse large cell lymphoma cases contain translocations between the BCL6 locus at chromosome 3q27 and other genes (7,11,55). BCL6 belongs to the BTB-POZ zinc finger family of transcription factors and contains Kruppel-type zinc finger motifs at the carboxyl terminus and a POZ motif at the amino terminus. The six BCL6 zinc fingers bind to the consensus DNA sequence TTCCT(A/C)GAA (9, 39), and the BCL6 POZ domain physically interacts with corepressor proteins, including nuclear receptor corepressor (N-CoR), BCL-6-interacting corepressor (B-CoR), SMRT (silencing mediator of retinoid acid and thyroid hormone receptor)/mSIN3A (mammalian SIN3A), Mi-2/NURD (nucleosome remodeling and histone deacetylation), and histone deacetylase complexes to mediate its potent transrepressor activity (1,12,13,18,21,52,57).BCL6 plays crucial roles in germinal center biology. Knockout studies revealed that bcl6 Ϫ/Ϫ mice fail to develop germinal centers, lack affinity maturation, and mount reduced levels of antigen-specific antibody responses (10,14,54). In addition, inhibition of BCL6 function in B-cell lines initiates changes characteristic of plasma cell differentiation (40). BCL6 is thought to exert its effect on germinal center development by modulating the transcription of genes involved in cell cycle regulation, proliferation, activation, class switch recombination, and differentiation. BCL6 can repress a variety of genes, including Blimp-1, ATR (ataxia-telangiectasia and Rad3-related), CD80, p53, programmed cell death2, monocyte chemotactic peptide 1 (MCP-1), MCP-3, multidrug resistance-associated protein 1 (MRP1), and interleukin 18 (6,22,27,30,36,37,40,43...

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Section: Discussionmentioning

confidence: 99%

“…This complex regulates gene expression in response to IFN signaling. IRF9 is also involved in the germinal center reaction and plays a role in class switch recombination (44). Interestingly, IRF9 is required for immunoglobulin G (IgG) autoantibody production in an experimental model for systemic lupus erythematosus (44).…”

Section: Discussionmentioning

confidence: 99%

PU.1 Can Recruit BCL6 to DNA To Repress Gene Expression in Germinal Center B Cells

Wei

Zaprazna

Wang

et al. 2009

Molecular and Cellular Biology

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“…Although T-bet and Stat1 transcription factors are shown to regulate GLT of IgG2a, a detailed mechanism still remains unknown (14,15). Interestingly, both of these transcription factors are involved in the production of SLE-related autoantibodies (14,16).…”

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confidence: 99%

Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus

Savitsky

Yanai

Tamura

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Interferon regulatory factor (IRF) 5 is a key transcription factor for the activation of innate immune responses downstream of Tolllike receptor signaling. Based on recent genetic analyses, IRF5 is a focus for its potential involvement in systemic lupus erythematosus (SLE), although how IRF5 contributes to SLE is uncertain. In this study, we demonstrate a requirement for IRF5 in the development of murine SLE via its role in B lymphocytes. We show that antinuclear autoantibodies and Ig glomerular deposits, hallmarks of SLE, are absent in Irf5 −/− mice challenged to develop SLE by pristane injection. In particular, production of autoantibodies of the IgG2a subtype, the most prominent isotype in inducing autoimmunity, requires IRF5. Finally, we provide evidence for the critical role of this transcription factor in the secretion of pathogenic antibodies through its direct control of class switch recombination of the γ2a locus. By demonstrating a B-cell-intrinsic role, this study places IRF5 in a context that may have implications for understanding the pathogenesis of human SLE.autoimmunity | B lymphocytes | TLR signaling

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“…Hence, type I interferon, a consistent signature of viral infection, as well as of systemic lupus, may enhance Tlr7-dependent recognition of RNA autoantigens. When the effects of type I interferon are abrogated, Tlr7 expression in B cells, autoantibody production, and lupus disease manifestations are attenuated [17,18]. Vice versa, the absence of type I interferon signaling under normal conditions keeps Tlr7 expression below the required threshold for endogenous RNA recognition and autoreactive B (and T) cell expansion.…”

Section: See Accompanying Article By Fairhurst Et Almentioning

confidence: 99%

Molecular mimicry in innate immunity? The viral RNA recognition receptor TLR7 accelerates murine lupus

2008

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Toll-like receptors (TLR), such as TLR7, were first described as innate pathogen recognition receptors that trigger appropriate antimircrobial immune responses upon exposure to pathogen-associated molecules, e.g. viral ssRNA. In parallel to ongoing studies on TLRbiology, mounting experimental evidence suggests that endogenous RNA-related autoantigens may also activate dendritic cells (DC) and B cells through TLR7. TLR7-mediated DC activation, autoantibody secretion, lymphoproliferation, and autoimmune tissue injury, are frequently observed in various murine models of systemic lupus and lupus nephritis. A paper in the current issue of the European Journal of Immunology, provide striking experimental evidence for this concept; the authors show that the Y chromosome-linked autoimmune accelerating (Yaa) translocation from the X-chromosome, consisting of 16 genes including Tlr7, largely mediates the autoimmune phenotype via the duplication of Tlr7. This finding highlights the need to address the significance of TLR7 in human lupus in terms of both genetic risk and as a therapeutic option.

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IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice

Cited by 86 publications

References 80 publications

PU.1 Can Recruit BCL6 to DNA To Repress Gene Expression in Germinal Center B Cells

PU.1 Can Recruit BCL6 to DNA To Repress Gene Expression in Germinal Center B Cells

Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus

Molecular mimicry in innate immunity? The viral RNA recognition receptor TLR7 accelerates murine lupus

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