The expressions of Toll-like receptor 9 and T-bet in circulating B and T cells in newly diagnosed, untreated systemic lupus erythematosus and correlations with disease activity and laboratory data in a Chinese population

Wu, Ou; Chen, Guo Ping; Hong, Chang Seop; Li, Xiang Pei; Xu, Jian; Zhao, Shu Shan; Sawada, Jun; Jin, Feng; Jin, Cai; Fang, Xue Hui; Zhang, Wen Hui; Li, Lian Hong; Zhang, Ning; Li, Jing; Li, Jia Jia; Pan, Fa Ming; Wang, Chang Zhong; Ye, Dong‐Qing

doi:10.1016/j.imbio.2008.10.004

Cited by 27 publications

(19 citation statements)

References 30 publications

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“…However, the discovery of TLRs in humans opened a new field in the studies of lupus [2], and our study of TLR3, TLR7, and TLR9 confirms their potential influence on the disease. TLR expression has been studied on the molecular level (mRNA), as well as the protein level, and involves many subsets of peripheral blood cells [15–20]. Higher expression of TLR9 has been shown in SLE patients, compared to healthy individuals, which is consistent with our findings.…”

Section: Discussionsupporting

confidence: 91%

Expression of Toll-Like Receptors 3, 7, and 9 in Peripheral Blood Mononuclear Cells from Patients with Systemic Lupus Erythematosus

Klonowska-Szymczyk

Wolska

Robak

et al. 2014

Mediators of Inflammation

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Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology. The results of experimental studies point to the involvement of innate immunity receptors—toll-like receptors (TLR)—in the pathogenesis of the disease. The aim of the study was to assess the expression of TLR3, 7, and 9 in the population of peripheral blood mononuclear cells (PBMC) and in B lymphocytes (CD19+), T lymphocytes (CD4+ and CD8+) using flow cytometry. The study group included 35 patients with SLE and 15 healthy controls. The patient group presented a significantly higher percentage of TLR3- and TLR9-positive cells among all PBMCs and their subpopulations (CD3+, CD4+, CD8+, and CD19+ lymphocytes) as well as TLR7 in CD19+ B-lymphocytes, compared to the control group. There was no correlation between the expression of all studied TLRs and the disease activity according to the SLAM scale, and the degree of organ damage according to the SLICC/ACR Damage Index. However, a correlation was observed between the percentage of various TLR-positive cells and some clinical (joint lesions) and laboratory (lymphopenia, hypogammaglobulinemia, anaemia, and higher ESR) features and menopause in women. The results of the study suggest that TLR3, 7, and 9 play a role in the pathogenesis of SLE and have an impact on organ involvement in SLE.

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Section: Discussionsupporting

confidence: 91%

Expression of Toll-Like Receptors 3, 7, and 9 in Peripheral Blood Mononuclear Cells from Patients with Systemic Lupus Erythematosus

Klonowska-Szymczyk

Wolska

Robak

et al. 2014

Mediators of Inflammation

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“…Increased levels of TLR7 and TLR9 expression have been repeatedly documented in peripheral B cells from SLE patients [30], [31], [32], [33], [34]. We sought to determine whether the enhanced receptor expression was associated with alterations in cell responses to the cognate ligands.…”

Section: Resultsmentioning

confidence: 99%

“…Given the reported upregulation of TLR7 and TLR9 expression in B cells from SLE patients [30], [31], [32], [33], [34], it was surprising to see that these cells mounted virtually normal, and sometimes even reduced responses to the stimulation of the corresponding ligands. These seemingly contradictory findings prompted us to examine the expression of negative regulators for TLR signaling.…”

Section: Resultsmentioning

confidence: 99%

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The Largely Normal Response to Toll-Like Receptor 7 and 9 Stimulation and the Enhanced Expression of SIGIRR by B Cells in Systemic Lupus Erythematosus

Zhu

2012

PLoS ONE

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BackgroundAltered Toll-like receptor (TLR) signaling has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The present study was undertaken to characterize responses of B cells from SLE patients to TLR7 and TLR9 stimulation and to explore the potential role of single immunoglobulin interleukin-1 receptor related molecule (SIGIRR) in the regulation of TLR-mediated responses of SLE B cells.Methodology/Principal FindingsPeripheral blood mononuclear cells (PBMC) were isolated from 64 patients with SLE and 37 healthy donors. CD19+ B cells purified using microbeads were cultured with TLR7 or TLR9 agonists. Cell proliferation was measured by thymine incorporation and the frequency of antibody-secreting cells was determined by ELISPOT assay. SIGIRR expression in PBMCs and B cells was analyzed using flow cytometry analysis. In contrast to the enhanced proliferation following B cell receptor (BCR) engagement, B cells from SLE patients exhibited a virtually normal proliferative response to TLR7 or TLR9 stimulation. Moreover, B cells from SLE patients and healthy donors were almost equally competent to differentiate into antibody-secreting cells upon TLR engagement except for a reduction in the generation of IgG-secreting cells by TLR9-stimulated lupus B cells. In line with these somehow unexpected observations, SLE B cells were found to express a significantly higher level of SIGIRR than normal B cells.Conclusions/SignificanceDespite the reported upregulation of TLR7 and TLR9 expression in B cell from SLE patients, their responses to TLR stimulation were largely normal. The increased expression of the negative regulator SIGIRR may be partly responsible for the “balance of terror”.

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“…NOD mice spontaneously develop autoimmune responses in a variety of tissues, including salivary, lacrimal, thyroid, parathyroid, adrenal, testis, large bowel, and red blood cells, in addition to diabetes [28,53]. NOD mice can also be used as models to experimentally induce autoimmune diseases, such as experimental autoimmune thyroiditis, encephalomyelitis, and systemic lupus erythematosus [54]. Therefore, further research with NODiPSCs should provide a way to examine the onset and progression of autoimmune diseases in vitro or in reconstituted animal models.…”

Section: Discussionmentioning

confidence: 99%

Differentiation and Transplantation of Functional Pancreatic Beta Cells Generated from Induced Pluripotent Stem Cells Derived from a Type 1 Diabetes Mouse Model

Jeon

Lim

Kim

et al. 2012

Stem Cells and Development

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The nonobese diabetic (NOD) mouse is a classical animal model for autoimmune type 1 diabetes (T1D), closely mimicking features of human T1D. Thus, the NOD mouse presents an opportunity to test the effectiveness of induced pluripotent stem cells (iPSCs) as a therapeutic modality for T1D. Here, we demonstrate a proof of concept for cellular therapy using NOD mouse-derived iPSCs (NOD-iPSCs). We generated iPSCs from NOD mouse embryonic fibroblasts or NOD mouse pancreas-derived epithelial cells (NPEs), and applied directed differentiation protocols to differentiate the NOD-iPSCs toward functional pancreatic beta cells. Finally, we investigated whether the NPE-iPSC-derived insulin-producing cells could normalize hyperglycemia in transplanted diabetic mice. The NOD-iPSCs showed typical embryonic stem cell-like characteristics such as expression of markers for pluripotency, in vitro differentiation, teratoma formation, and generation of chimeric mice. We developed a method for stepwise differentiation of NOD-iPSCs into insulin-producing cells, and found that NPE-iPSCs differentiate more readily into insulin-producing cells. The differentiated NPE-iPSCs expressed diverse pancreatic beta cell markers and released insulin in response to glucose and KCl stimulation. Transplantation of the differentiated NPE-iPSCs into diabetic mice resulted in kidney engraftment. The engrafted cells responded to glucose by secreting insulin, thereby normalizing blood glucose levels. We propose that NODiPSCs will provide a useful tool for investigating genetic susceptibility to autoimmune diseases and generating a cellular interaction model of T1D, paving the way for the potential application of patient-derived iPSCs in autologous beta cell transplantation for treating diabetes.

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The expressions of Toll-like receptor 9 and T-bet in circulating B and T cells in newly diagnosed, untreated systemic lupus erythematosus and correlations with disease activity and laboratory data in a Chinese population

Cited by 27 publications

References 30 publications

Expression of Toll-Like Receptors 3, 7, and 9 in Peripheral Blood Mononuclear Cells from Patients with Systemic Lupus Erythematosus

Expression of Toll-Like Receptors 3, 7, and 9 in Peripheral Blood Mononuclear Cells from Patients with Systemic Lupus Erythematosus

The Largely Normal Response to Toll-Like Receptor 7 and 9 Stimulation and the Enhanced Expression of SIGIRR by B Cells in Systemic Lupus Erythematosus

Differentiation and Transplantation of Functional Pancreatic Beta Cells Generated from Induced Pluripotent Stem Cells Derived from a Type 1 Diabetes Mouse Model

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