Toll-like receptor 7 deficiency suppresses type 1 diabetes development by modulating B-cell differentiation and function

Hao, Juan; Peng, Jian; Pearson, James A.; Efthimiou, Georgios; Hu, Youjia; Tai, Ningwen; Xing, Yanpeng; Zhang, Luyao; Gu, Jianlei; Jiang, Jianping; Zhao, Hongyu; Zhang, Zhou; Wong, F. Susan; Li, Wen

doi:10.1038/s41423-020-00590-8

Cited by 17 publications

(27 citation statements)

References 48 publications

(21 reference statements)

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“…B cell receptor (BCR) signaling ( 32 , 49 ), is diminished in B cells from individuals with established type 1 diabetes ( 25 , 43 ). Signaling through TLR9 changes the frequency and function of IL-10 producing B cells in NOD mice; TLR9 deficiency specifically in B cells increased IL-10 producing cells and protected against diabetes ( 50 ). No direct study has demonstrated a mechanism that drives a Breg defect in type 1 diabetes in humans however, and this remains an outstanding question (see Discussion and Outstanding Questions ).…”

Section: Breg Induction and Type 1 Diabetesmentioning

confidence: 99%

Regulatory B Cells: Role in Type 1 Diabetes

Boldison

Wong

2021

Front. Immunol.

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Regulatory B cells (Bregs) have an anti-inflammatory role and can suppress autoimmunity, by employing both cytokine secretion and cell-contact mediated mechanisms. Numerous Breg subsets have been described and have overlapping phenotypes in terms of their immune expression markers or cytokine production. A hallmark feature of Bregs is the secretion of IL-10, although IL-35 and TGFβ−producing B cells have also been identified. To date, few reports have identified an impaired frequency or function of Bregs in individuals with type 1 diabetes; thus our understanding of the role played by these Breg subsets in the pathogenesis of this condition is limited. In this review we will focus on how regulatory B cells are altered in the development of type 1 diabetes, highlighting both frequency and function and discuss both human and animal studies.

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Section: Breg Induction and Type 1 Diabetesmentioning

confidence: 99%

Regulatory B Cells: Role in Type 1 Diabetes

Boldison

Wong

2021

Front. Immunol.

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“…Furthermore, in combination with IFNα, TLR7 activation augments IL-6 production and isotype switching in B cells [60]. In NOD mice, TLR7 deficiency delays and reduces the development of autoimmune diabetes and alters the functional responses of B cells [62]. Therefore, it is likely that the heightened expression of IFNα enhances TLR7 expression in B cells situated in the pancreas, and that this, in turn, synergistically amplifies IL-6 and pro-inflammatory cytokine production.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling reveals B cells are highly educated by the pancreatic environment during autoimmune diabetes

Boldison

Hopkinson

Davies

et al. 2022

Preprint

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B cells play an important role in driving the development of type 1 diabetes, however, it remains unclear how they contribute to local beta-cell destruction during disease progression. Using gene expression profiling of B cell subsets in the pancreas and pancreatic lymph nodes, we reveal that B cells are highly modified by the inflamed pancreatic tissue and can be distinguished by their transcriptional profile from those in the lymph node. We identified both a discrete and a core shared gene expression profile in islet CD19+CD138- and CD19+CD138+ B cell subsets, the latter known to have enriched autoreactivity during diabetes development. Upon localisation to pancreatic islets, CD138+ B cells overexpressed genes associated with adhesion molecules and growth factors compared to CD138- B cells. Their shared signature displayed gene expression changes related to the differentiation of antibody-secreting cells and gene regulatory networks associated with interferon signalling pathways, pro-inflammatory cytokines and toll-like receptor activation. Finally, abundant TLR7 expression was detected in islet B cells, and was enhanced specifically in CD138+ B cells. Our study, therefore, provides a detailed transcriptional analysis of islet B cells identifying specific gene signatures and interaction networks that point towards a functional role for B cells in driving autoimmune diabetes.

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“…The role of TLRs in immune regulation and T1D development has been uncovered by several studies. Deletion of Tlr7 protected NOD mice from T1D, which might be due to the altered differentiation and reduced antigen-presenting functions of B cells ( 21 ). Tlr9 deficient NOD mice exhibited a decreased incidence of T1D.…”

Section: Discussionmentioning

confidence: 99%

Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway

Ding

Luo

et al. 2021

Front. Immunol.

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Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-β-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-α and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-κB signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-α and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-α signaling pathway, which may provide novel insight into beta cell failure and T1D development.

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Toll-like receptor 7 deficiency suppresses type 1 diabetes development by modulating B-cell differentiation and function

Cited by 17 publications

References 48 publications

Regulatory B Cells: Role in Type 1 Diabetes

Regulatory B Cells: Role in Type 1 Diabetes

Gene expression profiling reveals B cells are highly educated by the pancreatic environment during autoimmune diabetes

Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway

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