B Cell TLR7 Expression Drives Anti-RNA Autoantibody Production and Exacerbates Disease in Systemic Lupus Erythematosus–Prone Mice

Hwang, Sun Hee; Lee, Huiyin; Yamamoto, Misa; Jones, Leigh Ann; Dayalan, Jivanaah; Hopkins, Richard A.; Zhou, Xin; Yarovinsky, Felix; Connolly, John E.; Lafaille, Maria A. Curotto de; Wakeland, Edward K.; Fairhurst, Anna‐Marie

doi:10.4049/jimmunol.1202195

Cited by 111 publications

(130 citation statements)

References 58 publications

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“…In this study, we found that there was only a minor increase in total B cell numbers, whereas myeloid cells and T cells increased significantly in the enlarged spleens in 8-wk-old mice. The similar phenomenon, which is that the expanded myeloid cells and T cells are induced in reaction to autoimmunity and inflammation, was found in mice lacking genes involved in NF-kB activation (45)(46)(47). Previously, NF-kB was also reported to be regulated by other PRMTs (48)(49)(50), suggesting that arginine methylation plays unique roles in NF-kB activation.…”

Section: Discussionmentioning

confidence: 63%

Histone Arginine Methylation by PRMT7 Controls Germinal Center Formation via Regulating Bcl6 Transcription

Ying

Mei

Zhang

et al. 2015

The Journal of Immunology

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B cells are the center of humoral immunity and produce Abs to protect against foreign Ags. B cell defects lead to diseases such as leukemia and lymphomas. Histone arginine methylation is important for regulating gene activation and silencing in cells. Although the process commonly exists in mammalian cells, its roles in B cells are unknown. To explore the effects of aberrant histone arginine methylation on B cells, we generated mice with a B cell–specific knockout of PRMT7, a member of the methyltransferases that mediate arginine methylation of histones. In this article, we showed that the loss of PRMT7 led to decreased mature marginal zone B cells and increased follicular B cells and promoted germinal center formation after immunization. Furthermore, mice lacking PRMT7 expression in B cells secreted low levels of IgG1 and IgA. Abnormal expression of germinal center genes (i.e., Bcl6, Prdm1, and Irf4) was detected in conditional knockout mice. By overexpressing PRMT7 in the Raji and A20 cell lines derived from B cell lymphomas, we validated the fact that PRMT7 negatively regulated Bcl6 expression. Using chromatin immunoprecipitation–PCR, we found that PRMT7 could recruit H4R3me1 and symmetric H4R3me2 to the Bcl6 promoter. These results provide evidence for the important roles played by PRMT7 in germinal center formation.

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Section: Discussionmentioning

confidence: 63%

Histone Arginine Methylation by PRMT7 Controls Germinal Center Formation via Regulating Bcl6 Transcription

Ying

Mei

Zhang

et al. 2015

The Journal of Immunology

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“…The yaa-associated increase in TLR7 expression and function was determined to be critical for the development of severe disease, independent of the SLE-model (15)(16)(17). More recently, we demonstrated that a twofold increase in TLR7 alone on the Sle1 background is sufficient to drive disease in an almost identical manner to the addition of the yaa susceptibility locus (18). Normalization of B-cell TLR7 did not affect GN, suggesting that the increase in other cells drives severe pathology.…”

mentioning

confidence: 73%

RNA sensing by conventional dendritic cells is central to the development of lupus nephritis

Celhar

Hopkins

Thornhill

et al. 2015

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

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Glomerulonephritis is a common and debilitating feature of systemic lupus erythematosus (SLE). The precise immune mechanisms that drive the progression from benign autoimmunity to glomerulonephritis are largely unknown. Previous investigations have shown that a moderate increase of the innate Toll-like receptor 7 (TLR7) is sufficient for the development of nephritis. In these systems normalization of B-cell TLR7 expression or temporal depletion of plasmacytoid dendritic cells (pDCs) slow progression; however, the critical cell that is responsible for driving full immunopathology remains unidentified. In this investigation we have shown that conventional DC expression of TLR7 is essential for severe autoimmunity in the Sle1Tg7 model of SLE. We show that a novel expanding CD11b+ conventional DC subpopulation dominates the infiltrating renal inflammatory milieu, localizing to the glomeruli. Moreover, exposure of human myeloid DCs to IFN-α or Flu increases TLR7 expression, suggesting they may have a role in self-RNA recognition pathways in clinical disease. To our knowledge, this study is the first to highlight the importance of conventional DC-TLR7 expression for kidney pathogenesis in a murine model of SLE.TLR7 | dendritic cells | SLE | nephritis | autoimmunity

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“…The nucleic acid components of SLE autoantigens have previously been shown to activate B cells through TLR7 and contribute to lupus disease (34). To investigate the contribution of B cells in the lupus phenotype that we observed in TLR8 −/− , TLR8/9 −/− , and TLR9 −/− mice, total splenocytes were stimulated with R848 and the activation status of B cells were assessed by FACS analysis.…”

Section: Resultsmentioning

confidence: 99%

TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice

Desnues

Macedo

Roussel‐Queval

et al. 2014

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

110

105

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Systemic lupus erythematosus (SLE) is a complex autoimmune disease with diverse clinical presentations characterized by the presence of autoantibodies to nuclear components. Toll-like receptor (TLR)7, TLR8, and TLR9 sense microbial or endogenous nucleic acids and are implicated in the development of SLE. In mice TLR7-deficiency ameliorates SLE, but TLR8-or TLR9-deficiency exacerbates the disease because of increased TLR7 response. Thus, both TLR8 and TLR9 control TLR7 function, but whether TLR8 and TLR9 act in parallel or in series in the same or different cell types in controlling TLR7-mediated lupus remains unknown. Here, we reveal that double TLR8/9-deficient (TLR8/9 −/− ) mice on the C57BL/6 background showed increased abnormalities characteristic of SLE, including splenomegaly, autoantibody production, frequencies of marginal zone and B1 B cells, and renal pathology compared with single TLR8 −/− or TLR9 −/− mice. On the cellular level, TLR8 −/− and TLR8/ 9 −/− dendritic cells were hyperesponsive to TLR7 ligand R848, but TLR9 −/− cells responded normally. Moreover, B cells from TLR9 −/− and TLR8/9 −/− mice were hyperesponsive to R848, but TLR8 −/− B cells were not. These results reveal that TLR8 and TLR9 have an additive effect on controlling TLR7 function and TLR7-mediated lupus; however, they act on different cell types. TLR8 controls TLR7 function on dendritic cells, and TLR9 restrains TLR7 response on B cells. knockout mice | innate immunity | endosomal TLRs

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B Cell TLR7 Expression Drives Anti-RNA Autoantibody Production and Exacerbates Disease in Systemic Lupus Erythematosus–Prone Mice

Cited by 111 publications

References 58 publications

Histone Arginine Methylation by PRMT7 Controls Germinal Center Formation via Regulating Bcl6 Transcription

Histone Arginine Methylation by PRMT7 Controls Germinal Center Formation via Regulating Bcl6 Transcription

RNA sensing by conventional dendritic cells is central to the development of lupus nephritis

TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice

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