scholarly journals TLR9-deficiency in B cells Promotes Immune Tolerance via IL-10 in a Type 1 Diabetes Mouse Model

2020 ◽  
Author(s):  
Ada Admin ◽  
Sha Sha ◽  
James A Pearson ◽  
Jian Peng ◽  
Youjia Hu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
B Cells ◽  
B Cell ◽  
Nod Mice ◽  
Adaptive Immune ◽  
Immune Molecule ◽  
And Function ◽  
Intrinsic Effect ◽  
Specific Deletion

Toll-like receptor 9 (TLR9) is highly expressed in B cells and B cells are important in the pathogenesis of type 1 diabetes (T1D) development. However, the intrinsic effect of TLR9 in B cells on beta cell autoimmunity is not known. To fill this knowledge gap, we generated non-obese diabetic (NOD) mice with a B cell-specific deficiency of TLR9 (TLR9<sup>fl/fl</sup>/CD19-Cre+ NOD). The B cell-specific deletion of TLR9 resulted in near complete protection from T1D development. Diabetes protection was accompanied by an increased proportion of IL-10-producing B cells. We also found that TLR9-deficient B cells were hyporesponsive to both innate and adaptive immune-stimuli. This suggested that TLR9 in B cells modulates T1D susceptibility in NOD mice by changing the frequency and function of IL-10-producing B cells. Molecular analysis revealed a network of TLR9 with MMPs, TIMP1 and CD40, all of which are inter-connected with IL-10. Our study has highlighted an important connection of an innate immune molecule in B cells to the immuno-pathogenesis of T1D. Thus, targeting the TLR9 pathway, specifically in B cells, may provide a novel therapeutic strategy for T1D treatment.

scholarly journals TLR9-deficiency in B cells Promotes Immune Tolerance via IL-10 in a Type 1 Diabetes Mouse Model

2020 ◽  
Author(s):  
Ada Admin ◽  
Sha Sha ◽  
James A Pearson ◽  
Jian Peng ◽  
Youjia Hu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
B Cells ◽  
B Cell ◽  
Nod Mice ◽  
Adaptive Immune ◽  
Immune Molecule ◽  
And Function ◽  
Intrinsic Effect ◽  
Specific Deletion

Toll-like receptor 9 (TLR9) is highly expressed in B cells and B cells are important in the pathogenesis of type 1 diabetes (T1D) development. However, the intrinsic effect of TLR9 in B cells on beta cell autoimmunity is not known. To fill this knowledge gap, we generated non-obese diabetic (NOD) mice with a B cell-specific deficiency of TLR9 (TLR9<sup>fl/fl</sup>/CD19-Cre+ NOD). The B cell-specific deletion of TLR9 resulted in near complete protection from T1D development. Diabetes protection was accompanied by an increased proportion of IL-10-producing B cells. We also found that TLR9-deficient B cells were hyporesponsive to both innate and adaptive immune-stimuli. This suggested that TLR9 in B cells modulates T1D susceptibility in NOD mice by changing the frequency and function of IL-10-producing B cells. Molecular analysis revealed a network of TLR9 with MMPs, TIMP1 and CD40, all of which are inter-connected with IL-10. Our study has highlighted an important connection of an innate immune molecule in B cells to the immuno-pathogenesis of T1D. Thus, targeting the TLR9 pathway, specifically in B cells, may provide a novel therapeutic strategy for T1D treatment.

scholarly journals Regulatory B Cells: Role in Type 1 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Joanne Boldison ◽  
F. Susan Wong
Keyword(s):  
Type 1 Diabetes ◽  
B Cells ◽  
Animal Studies ◽  
Cytokine Production ◽  
Cytokine Secretion ◽  
Cell Contact ◽  
Regulatory B Cells ◽  
And Function ◽  
Hallmark Feature

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.

Regulation of B cell homeostasis by Ptpn22 contributes to type 1 diabetes in NOD mice

Endocrine ◽  
2019 ◽  
Vol 67 (3) ◽  
pp. 535-543
Author(s):  
Xiajie Shi ◽  
Feng Shao ◽  
Zhixia Li ◽  
Lin Kang ◽  
Junbin Liu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
B Cell ◽  
Nod Mice ◽  
Cell Homeostasis ◽  
B Cell Homeostasis

scholarly journals Altered Tim-1 and IL-10 Expression in Regulatory B Cell Subsets in Type 1 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Yikai Liu ◽  
Zhiying Chen ◽  
Junlin Qiu ◽  
Hongzhi Chen ◽  
Zhiguang Zhou
Keyword(s):  
Type 1 Diabetes ◽  
Blood Glucose ◽  
B Cells ◽  
B Cell ◽  
Fasting Blood Glucose ◽  
Healthy Controls ◽  
Regulatory B Cell ◽  
Significant Difference ◽  
B Cell Subsets

BackgroundType 1 diabetes (T1D) is an autoimmune disease with a complex aetiology. B cells play an important role in the pathogenesis of T1D. Regulatory B cells (Bregs) are a subset of B cells that produce and secrete the inhibitory factor interleukin-10 (IL-10), thereby exerting an anti-inflammatory effect. It was recently discovered that T-cell immunoglobulin mucin domain 1 (Tim-1) is essential for maintaining Bregs function related to immune tolerance. However, the detailed understanding of Tim-1+ Bregs and IL-10+ Bregs in T1D patients is lacking. This study aimed to characterize the profile of B cell subsets in T1D patients compared with that in controls and determine whether Tim-1+ Bregs and IL-10+ Bregs play roles in T1D.Materials and MethodsA total of 47 patients with T1D, 30 patients with type 2 diabetes (T2D) and 24 healthy controls were recruited in this study. Flow cytometry was used to measure the levels of different B cell subsets (including B cells, plasmablasts, and Bregs) in the peripheral blood. Radiobinding assays were performed to detect the antibody titres of T1D patients. In addition, the correlations between different B cell subsets and patient parameters were investigated.ResultsCompared with healthy controls, differences in frequency of Tim-1+ Bregs were significantly decreased in patients with T1D (36.53 ± 6.51 vs. 42.25 ± 6.83, P=0.02*), and frequency of IL-10+ Bregs were lower than healthy controls (17.64 ± 7.21vs. 24.52 ± 11.69, P=0.009**), the frequency of total Bregs in PBMC was also decreased in patients with T1D (1.42 ± 0.53vs. 1.99 ± 0.93, P=0.002.**). We analyzed whether these alterations in B cells subsets were associated with clinical features. The frequencies of Tim-1+ Bregs and IL-10+ Bregs were negatively related to fasting blood glucose (FBG) (r=-0.25 and -0.22; P=0.01* and 0.03*, respectively). The frequencies of Tim-1+ Bregs and IL-10+ Bregs are positively correlated with fast C-peptide (FCP) (r=0.23 and 0.37; P=0.02* and 0.0001***, respectively). In addition, the frequency of IL-10+ Breg was also negatively related to glycosylated haemoglobin (HbA1c) (r=-0.20, P=0.04*). The frequencies of Tim-1+ Bregs, IL-10+ Bregs and Bregs in T2D patients were reduced, but no statistically significant difference was found between other groups. Interestingly, there was positive correlation between the frequencies of Tim-1+ Bregs and IL-10+ Bregs in T1D (r=0.37, P=0.01*). Of note, it is worth noting that our study did not observe any correlations between B cell subsets and autoantibody titres.ConclusionsOur study showed altered Tim-1 and IL-10 expression in regulatory B cell in T1D patients. Tim-1, as suggested by the present study, is associated with islet function and blood glucose levels. These findings indicate that Tim-1+ Bregs and IL-10+ Bregs were involved in the pathogenesis of T1D.

scholarly journals High-Throughput Detection of Autoantigen-Specific B Cells Among Distinct Functional Subsets in Autoimmune Donors

2021 ◽  
Vol 12 ◽  
Author(s):  
Bryan A. Joosse ◽  
James H. Jackson ◽  
Alberto Cisneros ◽  
Austin B. Santhin ◽  
Scott A. Smith ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
B Cells ◽  
Autoimmune Diseases ◽  
B Cell ◽  
High Throughput ◽  
Cell Subset ◽  
Trna Synthetase ◽  
Antibody Secreting Cells

Antigen-specific B cells (ASBCs) can drive autoimmune disease by presenting autoantigen to cognate T cells to drive their activation, proliferation, and effector cell differentiation and/or by differentiating into autoantibody-secreting cells. Autoantibodies are frequently used to predict risk and diagnose several autoimmune diseases. ASBCs can drive type 1 diabetes even when immune tolerance mechanisms block their differentiation into antibody-secreting cells. Furthermore, anti-histidyl tRNA synthetase syndrome patients have expanded IgM+ Jo-1-binding B cells, which clinically diagnostic IgG Jo-1 autoantibodies may not fully reflect. Given the potential disconnect between the pathologic function of ASBCs and autoantibody secretion, direct study of ASBCs is a necessary step towards developing better therapies for autoimmune diseases, which often have no available cure. We therefore developed a high-throughput screening pipeline to 1) phenotypically identify specific B cell subsets, 2) expand them in vitro, 3) drive them to secrete BCRs as antibody, and 4) identify wells enriched for ASBCs through ELISA detection of antibody. We tested the capacity of several B cell subset(s) to differentiate into antibody-secreting cells following this robust stimulation. IgM+ and/or IgD+, CD27- memory, memory, switched memory, and BND B cells secreted B cell receptor (BCR) as antibody following in vitro stimulation, whereas few plasmablasts responded. Bimodal responses were observed across autoimmune donors for IgM+ CD21lo and IgM- CD21lo B cells, consistent with documented heterogeneity within the CD21lo subset. Using this approach, we detected insulin-binding B cell bias towards CD27- memory and CD27+ memory subsets in pre-symptomatic type 1 diabetes donors. We took advantage of routine detection of Jo-1-binding B cells in Jo-1+ anti-histidyl tRNA synthetase syndrome patients to show that Jo-1-binding B cells and total B cells expanded 20-30-fold using this culture system. Overall, these studies highlight technology that is amenable to small numbers of cryopreserved peripheral blood mononuclear cells that enables interrogation of phenotypic and repertoire attributes of ASBCs derived from autoimmune patients.

Construction of a novel vaccine by conjugating a B-cell epitope of DPP4 to peptide IA2(5)-P2-1 to significantly control type 1 diabetes in NOD mice

Vaccine ◽  
2017 ◽  
Vol 35 (51) ◽  
pp. 7187-7197 ◽  
Author(s):  
Ya Li ◽  
Huimin Cao ◽  
Yiping Li ◽  
Zhixin Li ◽  
Xiaomin Wei ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
B Cell ◽  
Cell Epitope ◽  
Nod Mice ◽  
B Cell Epitope

Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse

2013 ◽  
Vol 126 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Abhirup Jayasimhan ◽  
Kristy P. Mansour ◽  
Robyn M. Slattery
Keyword(s):  
Type 1 Diabetes ◽  
Cell Mass ◽  
Nod Mice ◽  
Diabetic Mouse ◽  
Nod Mouse ◽  
Β Cells ◽  
Autoimmune Destruction ◽  
Immune Mediated ◽  
And Function

T1D (Type 1 diabetes) is an autoimmune disease caused by the immune-mediated destruction of pancreatic β-cells. Studies in T1D patients have been limited by the availability of pancreatic samples, a protracted pre-diabetic phase and limitations in markers that reflect β-cell mass and function. The NOD (non-obese diabetic) mouse is currently the best available animal model of T1D, since it develops disease spontaneously and shares many genetic and immunopathogenic features with human T1D. Consequently, the NOD mouse has been extensively studied and has made a tremendous contribution to our understanding of human T1D. The present review summarizes the key lessons from NOD mouse studies concerning the genetic susceptibility, aetiology and immunopathogenic mechanisms that contribute to autoimmune destruction of β-cells. Finally, we summarize the potential and limitations of immunotherapeutic strategies, successful in NOD mice, now being trialled in T1D patients and individuals at risk of developing T1D.

scholarly journals Altered Regulatory B Cell Subsets in Children with Type 1 Diabetes Mellitus

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Mohamed A. El-Mokhtar ◽  
Nahla M. Elsherbiny ◽  
Douaa Sayed ◽  
Duaa M. Raafat ◽  
Eman Askar ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Blood Glucose ◽  
B Cells ◽  
B Cell ◽  
Fasting Blood Glucose ◽  
Interleukin 10 ◽  
Peripheral Tolerance ◽  
Regulatory B Cell ◽  
B Cell Subsets

B regulatory cells (Breg) refer to characteristic subsets of B cells that generally exert anti-inflammatory functions and maintain peripheral tolerance mainly through their ability to secrete interleukin-10 (IL10). Dysregulation in the function of Breg cells was reported in several autoimmune diseases. However, the relation between Breg and children with type 1 diabetes (T1D) is poorly understood. Thus, this study is aimed at determining whether Breg cells play a role in T1D in children or not, so we hypothesized that an altered phenotype of B cell subsets is associated with T1D in children. Children with T1D (n=29) and control children with normal blood glucose levels (n=14) were recruited. The percentages of different circulating IL10-producing Breg subsets, including B10, immature transitional, and plasmablasts were determined using flow cytometry analysis. Furthermore, the association between different IL10-producing B cells and patient parameters was investigated. The percentage of circulating IL10+CD24hiCD27+ (B10) and IL10+CD24hiCD38hi (immature transitional) subsets of Breg cells was significantly lower in T1D patients than in healthy controls. Moreover, these cells were also negatively correlated with fasting blood glucose and HbA1c levels. Breg cells did not correlate with autoantibody levels in the serum. These findings suggest that certain Breg subsets are numerically deficient in children with T1D. This alteration in frequency is associated with deficient islet function and glycemia. These findings suggest that Breg cells may be involved in the loss of auto-tolerance and consequent destruction of pancreatic cells and could, therefore, be a potential target for immunotherapy.

Sign in / Sign up

Export Citation Format

Share Document