TLR7 Signaling in Lupus B Cells: New Insights into Synergizing Factors and Downstream Signals

Satterthwaite, Anne B.

doi:10.1007/s11926-021-01047-1

Cited by 19 publications

(15 citation statements)

References 97 publications

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“…TLR7 synergistically promotes the differentiation of ABC/DN2 B-cell subsets with the help of cytokines such as IFN-γ and IL-21. Type I IFN and TLR7 enhance autoantibody production from transitional B cells [32]. These IFN interactions help coordinate the specific functions of SLE immunopathogenesis [33] and self-reactivity with DNA or RNA immune complexes was enhanced [29].…”

Section: Discussionmentioning

confidence: 98%

DNA Nanoflowers’ Amelioration of Lupus Symptoms in Mice via Blockade of TLR7/9’s Signal

Wang

Gan

2022

IJMS

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Inhibitory oligodeoxynucleotides (INH-ODN) can exert an immunomodulatory effect to specifically block TLR7 and TLR9 signaling in systemic lupus erythematosus (SLE). To extend the half-life of INH-ODN in vivo, the phosphorothioate backbone, instead of the native phosphodiester, is preferred due to its strong resistance against nuclease degradation. However, its incomplete degradation in vivo may lead to potential risk. To solve these problems and enhance the blockage of TLR7 and TLR9, we prepared highly compressed DNA nanoflowers with prolonged native DNA backbones and repeated INH-ODN motifs. Three therapeutic types of nanoflower, incorporating INH-ODN sequences, including IRS 661, IRS 869, and IRS 954, were prepared by rolling circle amplification and were subcutaneously injected into MRL/lpr mice. The TLR7 blocker of the IRS 661 nanoflower and the TLR9 antagonist of the IRS 869 nanoflower could decrease autoantibodies, reduce cytokine secretion, and alleviate lupus nephritis in mice. However, the IRS 954 nanoflower, the TLR7 and TLR9 dual antagonist, did not have additive or opposing effects on lupus nephritis but only showed a decrease in serum IFNα, suggesting that the TLR7 and TLR9 antagonist may have a competition mechanism or signal-dependent switching relationship. INH-ODN nanoflowers were proposed as a novel and potential therapeutic nucleic acids for SLE.

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Section: Discussionmentioning

confidence: 98%

DNA Nanoflowers’ Amelioration of Lupus Symptoms in Mice via Blockade of TLR7/9’s Signal

Wang

Gan

2022

IJMS

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“…Activation of distinct B cell subsets by TLR7 ligands is integral to autoimmunity, and elegant studies conducted over the past decade have revealed an important role for ABCs in mouse models of lupus pathogenesis ( 17 , 56 – 59 ). Of direct relevance to the current study, TLR7 is required for ABC expansion in the context of lupus ( 57 , 58 ), and B cells that express T-bet drive lupus-like disease in mice ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

“…Although TLR7 is expressed by diverse cells types, there is considerable evidence that the activation of TLR7-expressing B cells, in particular, is a central disease mechanism that drives SLE in mice and humans (17)(18)(19)(20). TLR7 plays an integral role in host defense, as it elicits a protective response upon recognition of single-stranded viral RNA (21).…”

Section: Introductionmentioning

confidence: 99%

TLR7 agonism accelerates disease in a mouse model of primary Sjögren’s syndrome and drives expansion of T-bet+ B cells

et al. 2022

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Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by chronic inflammation of exocrine tissue, resulting in loss of tears and saliva. Patients also experience many extra-glandular disease manifestations. Treatment for pSS is palliative, and there are currently no treatments available that target disease etiology. Previous studies in our lab demonstrated that MyD88 is crucial for pSS pathogenesis in the NOD.B10Sn-H2b (NOD.B10) pSS mouse model, although the way in which MyD88-dependent pathways become activated in disease remains unknown. Based on its importance in other autoimmune diseases, we hypothesized that TLR7 activation accelerates pSS pathogenesis. We administered the TLR7 agonist Imiquimod (Imq) or sham treatment to pre-disease NOD.B10 females for 6 weeks. Parallel experiments were performed in age and sex-matched C57BL/10 controls. Imq-treated pSS animals exhibited cervical lymphadenopathy, splenomegaly, and expansion of TLR7-expressing B cells. Robust lymphocytic infiltration of exocrine tissues, kidney and lung was observed in pSS mice following treatment with Imq. TLR7 agonism also induced salivary hypofunction in pSS mice, which is a hallmark of disease. Anti-nuclear autoantibodies, including Ro (SSA) and La (SSB) were increased in pSS mice following Imq administration. Cervical lymph nodes from Imq-treated NOD.B10 animals demonstrated an increase in the percentage of activated/memory CD4+ T cells. Finally, T-bet+ B cells were expanded in the spleens of Imq-treated pSS mice. Thus, activation of TLR7 accelerates local and systemic disease and promotes expansion of T-bet-expressing B cells in pSS.

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“…The histone protease E (Cathepsin E, CTSE), an intracellular hydrolytic aspartate protease, is expressed in immune and gastrointestinal system cells, lymphoid tissue, erythrocytes, and cancer cells, and is involved in protein conversion, regulation of immune responses, and apoptosis [26]. TLR7 promotes or suppresses B-cellmediated autoimmune responses, and the TLR7-speci c protein molecular chaperone -UNC93B1 is essential for maintaining TLR stability and signaling activity after synthesis [27]. The chemotactic protein CCL17 binds speci cally to CCR4 and has a role in attracting immune cells to speci c sites and inducing chemotaxis [28].…”

Section: Discussionmentioning

confidence: 99%

Identification of SNHG16 and Its Derived Tumor Immune Gene Signatures for Predicting Prognosis and Efficacy of Immunotherapy in Bladder Cancer

Zhu

et al. 2022

Preprint

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Background In the era of individualized therapy,there is a great need to incorporate lncRNAs into preclinical models to develop prognostic or therapeutic biomarkers.We sought to apply the tumor immune-associated lncRNA – SNHG16 to develop and validate a predictive model constructed from SNHG16 and associated immune gene signatures in BC patients obtained from independent public datasets and clinical internal cohorts, to assess the benefit of immune checkpoint inhibitors treatment and the prognosis in BC patients. Materials and methods A novel immune-related and independent predictive model was developed for prognosis and immunotherapeutic evaluation of bladder cancer, based on the identification and analysis of the immune-related SNHG16. Based on the training (TCGA-BLCA) and external validation datasets, the SNHG16-associated immune gene signature was applied to classify BC patients into low- and high-risk groups. Cell proliferation assay and Transwell assay were used to detect the function of related genes. Results There were significant differences in prognosis and response to immunotherapy among patients in the different risk groups. Univariate and multivariate analyses confirmed the SNHG16-associated immune gene signature to be an independent predictor of BC prognosis. In addition,in vitro functional assay data confirmed the cancer biological function of SNHG16 and its associated immune signature genes. Conclusions Immune-associated lncRNA-SNHG16 and its associated immune gene signatures are reliable tools for predicting BC prognosis and response to immunotherapy and may provide valuable insights for deciding the treatment for BC. Further, the model will provide useful guidance for clinical judgment and personalized regimen-selection for immunotherapy of bladder tumors.

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TLR7 Signaling in Lupus B Cells: New Insights into Synergizing Factors and Downstream Signals

Cited by 19 publications

References 97 publications

DNA Nanoflowers’ Amelioration of Lupus Symptoms in Mice via Blockade of TLR7/9’s Signal

DNA Nanoflowers’ Amelioration of Lupus Symptoms in Mice via Blockade of TLR7/9’s Signal

TLR7 agonism accelerates disease in a mouse model of primary Sjögren’s syndrome and drives expansion of T-bet+ B cells

Identification of SNHG16 and Its Derived Tumor Immune Gene Signatures for Predicting Prognosis and Efficacy of Immunotherapy in Bladder Cancer

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