300 results on '"Wong, FS"'
Search Results
2. Hyperglycemia does not affect antigen specific activation and cytolytic killing by CD8+ T cells in vivo
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Recino, A, Barkan, K, Ladds, G, Cooke, A, Wong, FS, Wallberg, M, Ladds, Graham [0000-0001-7320-9612], Cooke, Anne [0000-0003-3327-6081], and Apollo - University of Cambridge Repository
- Subjects
diabetes ,T-cells ,immunometabolism ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Diabetes Mellitus, Experimental ,Interferon-gamma ,Mice ,Oxygen Consumption ,Hyperglycemia ,Animals ,mouse models ,Antigens ,health care economics and organizations ,hyperglycaemia - Abstract
Metabolism is of central importance to T cell survival and differentiation. It is well known that T cells cannot function in the absence of glucose, but it is less clear how they respond to excessive levels of glucose. In this study we investigated how increasing levels of glucose affect T cell-mediated immune responses. We examined the effects of increased levels of glucose on CD8⁺ T cell behaviour in vitro by assessing activation and cytokine production, as well as oxygen consumption rate, extracellular acidification rate and intracellular signalling. In addition, we assessed in vivo proliferation, cytokine production and cytolytic activity of cells in chemically induced diabetic C57BL6 mice. Elevated levels of glucose in in vitro cultures had modest effects on proliferation and cytokine production, while in vivo hyperglycemia had no effect on CD8⁺ T cell proliferation, interferon gamma production or cytolytic killing., This work was supported by the NC3Rs [grant number NC/M001083/1]; the BBSRC [grant number BB/M00015X/2]; the Leverhulme Trust [grant number EM-2015-030]; the Medical Research Council [grant number G0901155]; the Diabetes U.K. [grant number BDA 09/0003840]; the BBSRC-funded Midlands Integrative Biosciences Training Partnership (MIBTP) (K.B.); and the Lollipop Foundation (M.W. as the main grant applicant and A.R. as a co-applicant).
- Published
- 2017
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3. Arsenic removal by solvent extraction from copper tankhouse electrolyte
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Chemeca 84 (12th : 1984 : Melbourne, Vic.), Royston, D, Sheehan, GJ, Winborne, DA, Wong, FS, Armstrong, RW, and Hall, PG
- Published
- 1984
4. Targeted suppression of autoreactive CD8(+) T-cell activation using blocking anti-CD8 antibodies
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Clement, M, Pearson, JA, Gras, S, van den Berg, HA, Lissina, A, Llewellyn-Lacey, S, Willis, MD, Dockree, T, McLaren, JE, Ekeruche-Makinde, J, Gostick, E, Robertson, NP, Rossjohn, J, Burrows, SR, Price, DA, Wong, FS, Peakman, M, Skowera, A, Wooldridge, L, Clement, M, Pearson, JA, Gras, S, van den Berg, HA, Lissina, A, Llewellyn-Lacey, S, Willis, MD, Dockree, T, McLaren, JE, Ekeruche-Makinde, J, Gostick, E, Robertson, NP, Rossjohn, J, Burrows, SR, Price, DA, Wong, FS, Peakman, M, Skowera, A, and Wooldridge, L
- Abstract
CD8+ T-cells play a role in the pathogenesis of autoimmune diseases such as multiple sclerosis and type 1 diabetes. However, drugs that target the entire CD8+ T-cell population are not desirable because the associated lack of specificity can lead to unwanted consequences, most notably an enhanced susceptibility to infection. Here, we show that autoreactive CD8+ T-cells are highly dependent on CD8 for ligand-induced activation via the T-cell receptor (TCR). In contrast, pathogen-specific CD8+ T-cells are relatively CD8-independent. These generic differences relate to an intrinsic dichotomy that segregates self-derived and exogenous antigen-specific TCRs according to the monomeric interaction affinity with cognate peptide-major histocompatibility complex class I (pMHCI). As a consequence, "blocking" anti-CD8 antibodies can suppress autoreactive CD8+ T-cell activation in a relatively selective manner. These findings provide a rational basis for the development and in vivo assessment of novel therapeutic strategies that preferentially target disease-relevant autoimmune responses within the CD8+ T-cell compartment.
- Published
- 2016
5. The Study of HLA Class II and Autoimmune Diabetes
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Wong Fs and Li Wen
- Subjects
Models, Molecular ,Genetically modified mouse ,Transgene ,Autoimmunity ,Mice, Transgenic ,Peptide binding ,Human leukocyte antigen ,Biology ,Major histocompatibility complex ,Biochemistry ,Mice ,Structure-Activity Relationship ,Antigen ,Animals ,Humans ,Allele ,Molecular Biology ,Histocompatibility Antigens Class II ,General Medicine ,Diabetes Mellitus, Type 1 ,Immunology ,biology.protein ,Molecular Medicine ,Peptides ,Forecasting ,Peptide/MHC Complex - Abstract
Many autoimmune diseases have genetic associations with the Major Histocompatibility Complex (MHC) class II loci. Susceptibility to Type 1 diabetes mellitus (TIDM) is particularly associated with Human Leucocyte Antigen (HLA) DR3, 4 and associated DQ2, 8 alleles and this is well documented in genetic association studies. These molecules play an important role in presentation of peptide antigens after intracellular processing to CD4 T lymphocytes. During the last decade, a number of approaches have been used to elucidate the molecular basis for the association of particular alleles with susceptibility to or protection from TIDM. These studies have focused on investigating the structure of the antigen presenting molecules, together with their peptides. Through binding studies, peptide elution, molecular modelling and crystallization of the peptide MHC complex, it has been possible to define the peptide binding regions and examine the stability of binding of peptides from putative autoantigens. This knowledge has also facilitated the development of reagents such as multimeric MHC-peptide complexes that will help to track the low frequency, potentially pathogenic antigen specific cells. Recently, HLA transgenic mice have been generated and used to study T cell epitopes. In addition, although it is clear that the presence of HLA molecules alone does not by itself cause disease, these transgenic mice will develop diabetes when there is an islet "insult", even if the islet "insult" is, itself, not sufficient to precipitate disease in the absence of the HLA class II transgene. These mice will allow further study of the role of these HLA molecules in vivo. We now have a much greater general understanding of the possible reasons why particular molecules may encode susceptibility to or protection from disease. All these studies will provide information to ultimately define a rational basis for the development of targeted immunotherapy.
- Published
- 2003
6. The Role of CD4 . CD8 T Cells in IDDM
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Janeway Ca and Wong Fs
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CD4-Positive T-Lymphocytes ,business.industry ,Immunology ,CD8-Positive T-Lymphocytes ,Mice ,Interleukin 21 ,Diabetes Mellitus, Type 1 ,Text mining ,Mice, Inbred NOD ,Cancer research ,Animals ,Humans ,Immunology and Allergy ,Medicine ,Cytotoxic T cell ,business - Published
- 1999
7. Augmentin‐induced jaundice
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Wong Fs, Sewell Rb, Dabkowski P, Richard A. Smallwood, Francis J. Dudley, and Ryan J
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Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Time Factors ,medicine.drug_class ,Advisory committee ,Antibiotics ,Jaundice ,Amoxicillin-Potassium Clavulanate Combination ,Clavulanic Acids ,Drug Hypersensitivity ,Drug treatment ,Clavulanic acid ,medicine ,Humans ,Drug reaction ,Aged ,business.industry ,Amoxicillin ,General Medicine ,Middle Aged ,medicine.disease ,Surgery ,Hypersensitivity reaction ,Drug Therapy, Combination ,Female ,medicine.symptom ,business ,Progressive disease ,medicine.drug - Abstract
OBJECTIVE To alert clinicians to the hepatotoxic potential of Augmentin (amoxycillin and clavulanic acid), a widely prescribed antibiotic, in susceptible patients, and to point out that the hepatic illness may be delayed but serious and protracted. DESIGN AND SETTING Case reports of patients with Augmentin-induced jaundice referred to the gastroenterology departments in three major teaching hospitals, and a review of cases reported to the Australian Adverse Drug Reactions Advisory Committee (ADRAC). PATIENTS Eight patients with nine episodes of Augmentin-induced jaundice personally treated by the authors from March 1988 to February 1990 are described. A further 19 patients reported to ADRAC from May 1987 to November 1989 are discussed. All patient histories were carefully reviewed to ensure that there was a temporal relationship between the course of Augmentin and the onset of the hepatitic illness and that other causes of jaundice were reasonably excluded. RESULTS Jaundice developed in some of these patients several weeks after drug treatment was completed. The illness may be protracted over many weeks. As yet, there has been no case of progressive disease leading to the liver failure. CONCLUSIONS The data suggest that a hypersensitivity reaction to clavulanic acid is the likely cause of the jaundice. Therefore, Augmentin, although an important antibiotic, should be reserved for severe infections for which amoxycillin is unsuitable.
- Published
- 1991
8. Inhibition of AMP-activated protein kinase protects pancreatic beta-cells from cytokine-mediated apoptosis and CD8+ T-cell-induced cytotoxicity.
- Author
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Riboulet-Chavey A, Diraison F, Siew LK, Wong FS, Rutter GA, Riboulet-Chavey, Audrey, Diraison, Frédérique, Siew, L Khai, Wong, F Susan, and Rutter, Guy A
- Abstract
Objective: Apoptotic destruction of insulin-producing pancreatic beta-cells is involved in the etiology of both type 1 and type 2 diabetes. AMP-activated protein kinase (AMPK) is a sensor of cellular energy charge whose sustained activation has recently been implicated in pancreatic beta-cell apoptosis and in islet cell death posttransplantation. Here, we examine the importance of beta-cell AMPK in cytokine-induced apoptosis and in the cytotoxic action of CD8(+) T-cells.Research Design and Methods: Clonal MIN6 beta-cells or CD1 mouse pancreatic islets were infected with recombinant adenoviruses encoding enhanced green fluorescent protein (eGFP/null), constitutively active AMPK (AMPK-CA), or dominant-negative AMPK (AMPK-DN) and exposed or not to tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma. Apoptosis was detected by monitoring the cleavage of caspase-3 and DNA fragmentation. The cytotoxic effect of CD8(+) purified T-cells was examined against pancreatic islets from NOD mice infected with either null or the AMPK-DN-expressing adenoviruses.Results: Exposure to cytokines, or expression of AMPK-CA, induced apoptosis in clonal MIN6 beta-cells and CD1 mouse pancreatic islets. By contrast, overexpression of AMPK-DN protected against the proapoptotic effect of these agents, in part by preventing decreases in cellular ATP, and lowered the cytotoxic effect of CD8(+) T-cells toward NOD mouse islets.Conclusions: Inhibition of AMPK activity enhances islet survival in the face of assault by either cytokines or T-cells. AMPK may therefore represent an interesting therapeutic target to suppress immune-mediated beta-cell destruction and may increase the efficacy of islet allografts in type 1 diabetes. [ABSTRACT FROM AUTHOR]- Published
- 2008
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9. Dentinal carious lesion in three dimensions.
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Wong FS, Willmott NS, and Davis GR
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- 2006
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10. Ramipril-associated hepatotoxicity.
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Yeung E, Wong FS, Wanless IR, Shiota K, Guindi M, Joshi S, and Gardiner G
- Abstract
Context.--Angiotensin-converting enzyme inhibitors are prescribed for many cardiovascular and renal diseases. Adverse hepatic events, especially cholestasis, have rarely been reported with captopril, enalapril, lisinopril, and fosinopril. To date, hepatic injury associated with ramipril has not been reported. Objective.--To describe 3 patients who developed hepatitis, with or without jaundice, after receiving ramipril. Design.--Medical records and liver biopsies of the 3 patients were reviewed. Clinical, laboratory, and histologic findings were compared with findings in other cases of angiotensin-converting enzyme inhibitor-induced liver injury reported in the literature. Results.--The 3 patients were middle-aged men. In 2 patients, jaundice appeared 4 and 8 weeks after starting ramipril. Bilirubin levels peaked at 15.5 and 5 mg/dL, and alkaline phosphatase values peaked at 957 and 507 U/L. Aminotransferase levels were mildly elevated. Endoscopic retrograde cholangiopancreatography and ultrasonography showed no bile duct obstruction. Liver biopsies from the jaundiced patients were similar, with cholestasis, duct necrosis, and extravasation of bile, ductular proliferation, and portal inflammation. Cholestasis improved in 1 patient 6 weeks after stopping ramipril and was prolonged for 14 months in the other, in whom biliary cirrhosis was present on biopsy. The third patient developed hepatitis without jaundice 3 weeks after starting ramipril; symptoms resolved after stopping the drug. Ramipril-associated liver injury is similar to that seen with other angiotensin-converting enzyme inhibitors, but liver biopsy findings of duct necrosis and extravasation of bile have not been reported previously. Conclusion.--Prolonged cholestatic hepatitis and biliary cirrhosis may result from the use of ramipril. Monitoring of liver enzymes is advisable for patients starting on ramipril. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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11. A novel organ preservation protocol for advanced carcinoma of the larynx and pharynx.
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Robbins KT, Fontanesi J, Wong FS, Vicario D, Seagren S, Kumar P, Weisman R, Pellitteri P, Thomas JR, Flick P, Palmer R, Weir A 3rd, Kerber C, Murry T, Ferguson R, Los G, Orloff L, and Howell SB
- Published
- 1996
12. Cyclopentadienyl-ruthenium and -osmium chemistry. XIX. Some complexes containing η2-olefin, η2-allene and η2-alkyne ligands
- Author
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Bruce, MI, Hambley, TW, Rodgers, JR, Snow, MR, and Wong, FS
- Abstract
Reactions between RuCl(Pme3)2(η-C5H5) and unsaturated hydrocarbons in the presence of NH4PF6 have given [Ru(η2-un)(PMe3)2(η-C5H5)] PF6[un = C2H4, (E)-CH(CN)=CH(CN),CH2=CHCH=CH2, CH2=C=CH2, CH2=C=CMe2, C2Ph2, PhC2C2Ph, PhC2CO2Et, C2(CO2Me)2 and C2(CF3)2]. The molecular structures of the buta-1,3-diene (3) and allene (4) complexes have been determined. In both compounds, the unsaturated hydrocarbon is bonded to ruthenium in an asymmetric η2 mode: Ru-C 2.185, 2.242(5) [for (3)], 2.084, 2.172(6) [for (4)l; coordinated C=C 1.386(8), 1.394(8) A, respectively. The allene skeleton is bent by 35 at the central carbon. Crystal data: (3) monoclinic, P21/n, a 17.343(2), b 13.692(4), c 17.997(3) , β 94.91(1), Z 8; (4) orthorhombic, Pca21, a 18.999(3), b 9.253(3), c 23.016(6) , Z 8. The structures were refined to residuals of R 0.026, R, 0.028 for 4076 data with 1 > 2.5σ(I) [for (3)], and R 0.022, Rw 0.024 for 3054 data [for (4)].
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- 1982
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13. Anti-CD3 treatment up-regulates programmed cell death protein-1 expression on activated effector T cells and severely impairs their inflammatory capacity
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Wallberg, M, Recino, A, Phillips, J, Howie, D, Vienne, M, Paluch, C, Azuma, M, Wong, FS, Waldmann, H, and Cooke, A
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transgenic/knockout mouse ,diabetes ,tolerance/suppression/anergy ,antibodies ,3. Good health - Abstract
T cells play a key role in the pathogenesis of type 1 diabetes, and targeting the CD3 component of the T-cell receptor complex provides one therapeutic approach. Anti-CD3 treatment can reverse overt disease in spontaneously diabetic non-obese diabetic mice, an effect proposed to, at least in part, be caused by a selective depletion of pathogenic cells. We have used a transfer model to further investigate the effects of anti-CD3 treatment on green fluorescent protein (GFP)+ islet-specific effector T cells in vivo. The GFP expression allowed us to isolate the known effectors at different time-points during treatment to assess cell presence in various organs as well as gene expression and cytokine production. We find, in this model, that anti-CD3 treatment does not preferentially deplete the transferred effector cells, but instead inhibits their metabolic function and their production of interferon-γ. Programmed cell death protein 1 (PD-1) expression was up-regulated on the effector cells from anti-CD3-treated mice, and diabetes induced through anti-PD-L1 antibody could only be reversed with anti-CD3 antibody if the anti-CD3 treatment lasted beyond the point when the anti-PD-L1 antibody was washed out of the system. This suggests that PD-1/PD-L1 interaction plays an important role in the anti-CD3 antibody mediated protection. Our data demonstrate an additional mechanism by which anti-CD3 therapy can reverse diabetogenesis.
14. Regulatory CD4 + T cells redirected against pathogenic CD8 + T cells protect NOD mice from development of autoimmune diabetes.
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Kakabadse D, Chen D, Fishman S, Weinstein-Marom H, Davies J, Wen L, Gross G, and Wong FS
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- Animals, Mice, Humans, Female, Mice, SCID, Insulin immunology, Adoptive Transfer, Mice, Transgenic, Glucose-6-Phosphatase immunology, Glucose-6-Phosphatase genetics, beta 2-Microglobulin genetics, beta 2-Microglobulin immunology, Mice, Inbred NOD, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 prevention & control, CD8-Positive T-Lymphocytes immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Introduction: In this study, we report a novel therapeutic approach redirecting antigen-specific CD4
+ T cells recognizing a hybrid insulin peptide (BDC2.5 T cell receptor (TCR) transgenic CD4+ T cells) to attract and suppress islet-specific CD8+ T cells T cells in the non-obese diabetic (NOD) mouse model, and prevent the development of autoimmune diabetes., Methods: Purified BDC2.5 CD4+ T cells were induced to differentiate into regulatory T cells (Tregs). The Tregs were then electroporated with mRNA encoding chimeric human β2 microglobulin (hβ2 m) covalently linked to insulin B chain amino acids 15-23 (designated INS-eTreg) or islet-specific glucose-6-phosphatase related protein (IGRP) peptide 206-214 (designated IGRP-eTreg). Immunoregulatory functions of these engineered regulatory T cells (eTregs) were tested by in vitro assays and in vivo co-transfer experiments with β-cell-antigen-specific CD8+ T cells in NOD.Scid mice or by adoptive transfer into young, pre-diabetic NOD mice., Results: These eTregs were phenotyped by flow cytometry, and shown to have high expression of FoxP3, as well as other markers of Treg function, including IL-10. They suppressed polyclonal CD4+ T cells and antigen-specific CD8+ T cells (recognizing insulin or IGRP), decreasing proliferation and increasing exhaustion and regulatory markers in vitro . In vivo , eTregs reduced diabetes development in co-transfer experiments with pathogenic antigen-specific CD8+ T cells (INS-CD8+ or IGRP-CD8+ cells) into NOD.Scid mice. Finally, when the eTreg were injected into young NOD mice, they reduced insulitis and prevented spontaneous diabetes in the recipient mice., Conclusion: Our results suggest a novel therapeutic strategy to protect NOD mice by targeting antigen-specific cytotoxic CD8+ T cells, using redirected antigen-specific CD4+ Treg cells, to suppress autoimmune diabetes. This may suggest an innovative therapy for protection of people at risk of development of type 1 diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kakabadse, Chen, Fishman, Weinstein-Marom, Davies, Wen, Gross and Wong.)- Published
- 2024
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15. The Role of B Lymphocytes in Type 1 Diabetes.
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Smith MJ, Boldison J, and Wong FS
- Abstract
While autoreactive T cells are known to induce β-cell death in type 1 diabetes (T1D), self-reactive B cells also play an important role in the pathogenesis of T1D. Studies have shown that individuals living with T1D have an increased frequency of self-reactive B cells that escape from the bone marrow and populate peripheral organs, become activated, and participate in disease. These failed tolerance mechanisms may be attributed to genetic risk alleles that are associated with the development of T1D. Once in the periphery, these self-reactive B cells act as important antigen-presenting cells to autoreactive T cells and produce autoantibodies that are used to predict individuals at risk for or diagnosed with T1D. Here, we discuss the evidence that B cells are important in the pathogenesis of T1D, how these cells escape normal tolerance mechanisms, their role in disease progression, and how targeting these cells and/or monitoring them as biomarkers for response to therapy will be of clinical benefit., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)
- Published
- 2024
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16. Gut microbiota from B-cell-specific TLR9-deficient NOD mice promote IL-10 + Breg cells and protect against T1D.
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Yang X, Huang J, Peng J, Wang P, Wong FS, Wang R, Wang D, and Wen L
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- Animals, Mice, Mice, Knockout, B-Lymphocytes, Regulatory immunology, Female, B-Lymphocytes immunology, B-Lymphocytes metabolism, Toll-Like Receptor 9 deficiency, Toll-Like Receptor 9 genetics, Toll-Like Receptor 9 metabolism, Gastrointestinal Microbiome immunology, Mice, Inbred NOD, Interleukin-10 metabolism, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 microbiology
- Abstract
Introduction: Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β cells. Toll-like receptor 9 (TLR9) plays a role in autoimmune diseases, and B cell-specific TLR9 deficiency delays T1D development. Gut microbiota are implicated in T1D, although the relationship is complex. However, the impact of B cell-specific deficiency of TLR9 on intestinal microbiota and the impact of altered intestinal microbiota on the development of T1D are unclear., Objectives: This study investigated how gut microbiota and the intestinal barrier contribute to T1D development in B cell-specific TLR9-deficient NOD mice. Additionally, this study explored the role of microbiota in immune regulation and T1D onset., Methods: The study assessed gut permeability, gene expression related to gut barrier integrity, and gut microbiota composition. Antibiotics depleted gut microbiota, and fecal samples were transferred to germ-free mice. The study also examined IL-10 production, Breg cell differentiation, and their impact on T1D development., Results: B cell-specific TLR9-deficient NOD mice exhibited increased gut permeability and downregulated gut barrier-related gene expression. Antibiotics restored gut permeability, suggesting microbiota influence. Altered microbiota were enriched in Lachnospiraceae, known for mucin degradation. Transferring this microbiota to germ-free mice increased gut permeability and promoted IL-10-expressing Breg cells. Rag
-/- mice transplanted with fecal samples from Tlr9fl/fl Cd19 -Cre+ mice showed delayed diabetes onset, indicating microbiota's impact., Conclusion: B cell-specific TLR9 deficiency alters gut microbiota, increasing gut permeability and promoting IL-10-expressing Breg cells, which delay T1D. This study uncovers a link between TLR9, gut microbiota, and immune regulation in T1D, with implications for microbiota-targeted T1D therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Huang, Peng, Wang, Wong, Wang, Wang and Wen.)- Published
- 2024
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17. Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis.
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Wang P, Yang X, Zhang L, Sha S, Huang J, Peng J, Gu J, Pearson JA, Hu Y, Zhao H, Wong FS, Wang Q, and Wen L
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- Animals, Mice, Male, Mice, Inbred C57BL, Disease Models, Animal, Interferon Regulatory Factors, Obesity immunology, Obesity microbiology, Obesity metabolism, Gastrointestinal Microbiome, Dysbiosis immunology, Dysbiosis microbiology, Toll-Like Receptor 9 metabolism, Toll-Like Receptor 9 genetics, B-Lymphocytes immunology, B-Lymphocytes metabolism, Mice, Knockout, Inflammation metabolism, Diet, High-Fat adverse effects, Interleukin-10 metabolism
- Abstract
Toll-like receptor 9 (TLR9) recognizes bacterial, viral and self DNA and play an important role in immunity and inflammation. However, the role of TLR9 in obesity is less well-studied. Here, we generate B-cell-specific Tlr9-deficient (Tlr9
fl/fl /Cd19Cre+/- , KO) B6 mice and model obesity using a high-fat diet. Compared with control mice, B-cell-specific-Tlr9-deficient mice exhibited increased fat tissue inflammation, weight gain, and impaired glucose and insulin tolerance. Furthermore, the frequencies of IL-10-producing-B cells and marginal zone B cells were reduced, and those of follicular and germinal center B cells were increased. This was associated with increased frequencies of IFNγ-producing-T cells and increased follicular helper cells. In addition, gut microbiota from the KO mice induced a pro-inflammatory state leading to immunological and metabolic dysregulation when transferred to germ-free mice. Using 16 S rRNA gene sequencing, we identify altered gut microbial communities including reduced Lachnospiraceae, which may play a role in altered metabolism in KO mice. We identify an important network involving Tlr9, Irf4 and Il-10 interconnecting metabolic homeostasis, with the function of B and T cells, and gut microbiota in obesity., (© 2024. The Author(s).)- Published
- 2024
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18. Gut microbiota and therapy for obesity and type 2 diabetes.
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Zhang L, Wang P, Huang J, Xing Y, Wong FS, Suo J, and Wen L
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- Humans, Adolescent, Quality of Life, Obesity metabolism, Diabetes Mellitus, Type 2 therapy, Diabetes Mellitus, Type 2 complications, Gastrointestinal Microbiome, Bariatric Surgery
- Abstract
There has been a major increase in Type 2 diabetes and obesity in many countries, and this will lead to a global public health crisis, which not only impacts on the quality of life of individuals well but also places a substantial burden on healthcare systems and economies. Obesity is linked to not only to type 2 diabetes but also cardiovascular diseases, musculoskeletal disorders, and certain cancers, also resulting in increased medical costs and diminished quality of life. A number of studies have linked changes in gut in obesity development. Dysbiosis, a deleterious change in gut microbiota composition, leads to altered intestinal permeability, associated with obesity and Type 2 diabetes. Many factors affect the homeostasis of gut microbiota, including diet, genetics, circadian rhythms, medication, probiotics, and antibiotics. In addition, bariatric surgery induces changes in gut microbiota that contributes to the metabolic benefits observed post-surgery. Current obesity management strategies encompass dietary interventions, exercise, pharmacotherapy, and bariatric surgery, with emerging treatments including microbiota-altering approaches showing promising efficacy. While pharmacotherapy has demonstrated significant advancements in recent years, bariatric surgery remains one of the most effective treatments for sustainable weight loss. However, access to this is generally limited to those living with severe obesity. This underscores the need for non-surgical interventions, particularly for adolescents and mildly obese patients. In this comprehensive review, we assess longitudinal alterations in gut microbiota composition and functionality resulting from the two currently most effective anti-obesity treatments: pharmacotherapy and bariatric surgery. Additionally, we highlight the functions of gut microbiota, focusing on specific bacteria, their metabolites, and strategies for modulating gut microbiota to prevent and treat obesity. This review aims to provide insights into the evolving landscape of obesity management and the potential of microbiota-based approaches in addressing this pressing global health challenge., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Wang, Huang, Xing, Wong, Suo and Wen.)
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- 2024
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19. TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model.
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Pearson JA, Hu Y, Peng J, Wong FS, and Wen L
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- Animals, Humans, Mice, Cytokines metabolism, Dendritic Cells, Disease Susceptibility metabolism, Mice, Inbred NOD, Toll-Like Receptor 5 metabolism, Diabetes Mellitus, Type 1
- Abstract
Introduction: The incidence of the autoimmune disease, type 1 diabetes (T1D), has been increasing worldwide and recent studies have shown that the gut microbiota are associated with modulating susceptibility to T1D. Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and is widely expressed on many cells, including dendritic cells (DCs), which are potent antigen-presenting cells (APCs). TLR5 modulates susceptibility to obesity and alters metabolism through gut microbiota; however, little is known about the role TLR5 plays in autoimmunity, especially in T1D., Methods: To fill this knowledge gap, we generated a TLR5-deficient non-obese diabetic (NOD) mouse, an animal model of human T1D, for study., Results: We found that TLR5-deficiency led to a reduction in CD11c
+ DC development in utero , prior to microbial colonization, which was maintained into adulthood. This was associated with a bias in the DC populations expressing CD103, with or without CD8α co-expression, and hyper-secretion of different cytokines, both in vitro (after stimulation) and directly ex vivo . We also found that TLR5-deficient DCs were able to promote polyclonal and islet antigen-specific CD4+ T cell proliferation and proinflammatory cytokine secretion. Interestingly, only older TLR5-deficient NOD mice had a greater risk of developing spontaneous T1D compared to wild-type mice., Discussion: In summary, our data show that TLR5 modulates DC development and enhances cytokine secretion and diabetogenic CD4+ T cell responses. Further investigation into the role of TLR5 in DC development and autoimmune diabetes may give additional insights into the pathogenesis of Type 1 diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pearson, Hu, Peng, Wong and Wen.)- Published
- 2024
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20. Single-cell RNAseq identifies clonally expanded antigen-specific T-cells following intradermal injection of gold nanoparticles loaded with diabetes autoantigen in humans.
- Author
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Hanna SJ, Thayer TC, Robinson EJS, Vinh NN, Williams N, Landry LG, Andrews R, Siah QZ, Leete P, Wyatt R, McAteer MA, Nakayama M, Wong FS, Yang JHM, Tree TIM, Ludvigsson J, Dayan CM, and Tatovic D
- Subjects
- Humans, Autoantigens, Proinsulin genetics, Gold, Injections, Intradermal, Single-Cell Gene Expression Analysis, Peptides genetics, Receptors, Antigen, T-Cell genetics, Metal Nanoparticles, Diabetes Mellitus, Type 1
- Abstract
Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8
+ , whilst proinsulin-specific clones were both CD8+ and CD4+ . Proinsulin-specific CD8+ clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remained in situ for months to years, with a spectrum of tissue resident memory and effector memory phenotypes. As the T-cell response is divided between targeting the gold core and the antigenic cargo, this offers a route to improving resident memory T-cells formation in response to vaccines. In addition, our scRNAseq data indicate that focusing on clonally expanded skin infiltrating T-cells recruited to intradermally injected antigen is a highly efficient method to enrich and identify antigen-specific cells. This approach has the potential to be used to monitor the intradermal delivery of antigens and nanoparticles for immune modulation in humans., Competing Interests: CD has lectured for or been involved as an advisor to the following companies: Novonordisk, Sanofi-genzyme, Janssen, Servier, Lilly, Astrazeneca, Provention Bio, UCB, MSD, Vielo Bio, Avotres, Worg, Novartis. CD holds a patent jointly with Midatech plc and Provention Bio/Sanofi. DT is a Trustee for NovoNordisk UK Research Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hanna, Thayer, Robinson, Vinh, Williams, Landry, Andrews, Siah, Leete, Wyatt, McAteer, Nakayama, Wong, Yang, Tree, Ludvigsson, Dayan and Tatovic.)- Published
- 2023
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21. NMDA Receptors in the Basolateral Amygdala Complex Are Engaged for Pavlovian Fear Conditioning When an Animal's Predictions about Danger Are in Error.
- Author
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Keidar T, Williams-Spooner MJ, Wong FS, Westbrook RF, and Holmes NM
- Subjects
- Male, Rats, Animals, Receptors, N-Methyl-D-Aspartate metabolism, Amygdala physiology, Extinction, Psychological physiology, Fear physiology, Basolateral Nuclear Complex physiology
- Abstract
It is widely accepted that Pavlovian fear conditioning requires activation of NMDA receptors (NMDARs) in the basolateral amygdala complex (BLA). However, it was recently shown that activation of NMDAR in the BLA is only required for fear conditioning when danger occurs unexpectedly; it is not required for fear conditioning when danger occurs as expected. This study tested the hypothesis that NMDARs in the BLA are engaged for Pavlovian fear conditioning when an animal's predictions regarding danger are in error. In each experiment, rats (females in Experiment 1 and males in Experiments 2-5) were conditioned to fear one stimulus, S1, when it was paired with foot-shock (S1→shock), and 48 h later, a second stimulus, S2, when it was presented in sequence with the already-conditioned S1 and foot-shock (S2→S1→shock). Conditioning to S2 occurred under a BLA infusion of the NMDAR antagonist, D-AP5 or vehicle. The subsequent tests of freezing to S2 alone and S1 alone revealed that the antagonist had no effect on conditioning to S2 when the shock occurred exactly as predicted by the S1, but disrupted this conditioning when the shock occurred earlier/later than predicted by S1, or at a stronger/weaker intensity. These results imply that errors in the timing or intensity of a predicted foot-shock engage NMDARs in the BLA for Pavlovian fear conditioning. They are discussed in relation to theories which propose a role for prediction error in determining how experiences are organized in memory and how activation of NMDAR in the BLA might contribute to this organization. SIGNIFICANCE STATEMENT This study is significant in showing that prediction error determines how a new experience is encoded with respect to a past experience and, thereby, whether NMDA receptors (NMDARs) in the basolateral amygdala complex (BLA) encode the new experience. When prediction error is small (e.g., danger occurs as and when expected), the new experience is encoded together with a past experience as part of the same "mental model," and NMDAR activation in the BLA is not needed for this encoding. By contrast, when prediction error is large (e.g., danger occurs at an unexpected intensity or time), the new experience is encoded separately from the past experience as part of a new mental model, and NMDAR activation in the BLA is needed for this encoding., (Copyright © 2023 the authors.)
- Published
- 2023
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22. Novel engineered B lymphocytes targeting islet-specific T cells inhibit the development of type 1 diabetes in non-obese diabetic Scid mice.
- Author
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Chen D, Kakabadse D, Fishman S, Weinstein-Marom H, Davies J, Boldison J, Thayer TC, Wen L, Gross G, and Wong FS
- Subjects
- Mice, Animals, Mice, Inbred NOD, Mice, SCID, Histocompatibility Antigens Class II, Diabetes Mellitus, Type 1 prevention & control, Islets of Langerhans, Severe Combined Immunodeficiency, B-Lymphocytes, Regulatory
- Abstract
Introduction: In this study, we report a novel therapeutic approach using B lymphocytes to attract islet-specific T cells in the non-obese diabetic (NOD) mouse model and prevent the development of autoimmune diabetes. Rather than using the antibody receptor of B cells, this approach utilizes their properties as antigen-presenting cells to T cells., Methods: Purified splenic B cells were treated with lipopolysaccharide, which increases regulatory B (Breg) cell function, then electroporated with mRNA encoding either chimeric MHC-I or MHC-II molecules covalently linked to antigenic peptides. Immunoregulatory functions of these engineered B cells (e-B cells) were tested by in vitro assays and in vivo co-transfer experiments with beta-cell-antigen-specific CD8
+ or CD4+ T cells in NOD.Scid mice, respectively., Results: The e-B cells expressing chimeric MHC-I-peptide inhibited antigen-specific CD8+ T-cell cytotoxicity in vitro . The e-B cells expressing chimeric MHC-II-peptide induced antigen-specific CD4+ T cells to express the regulatory markers, PD-1, ICOS, CTLA-4, Lag3, and Nrp1. Furthermore, e-B cells encoding the chimeric MHC-I and MHC-II peptide constructs protected NOD.Scid mice from autoimmune diabetes induced by transfer of antigen-specific CD8+ and CD4+ T cells., Discussion: MHC-peptide chimeric e-B cells interacted with pathogenic T cells, and protected the host from autoimmune diabetes, in a mouse model. Thus, we have successfully expressed MHC-peptide constructs in B cells that selectively targeted antigen-specific cells, raising the possibility that this strategy could be used to endow different protective cell types to specifically regulate/remove pathogenic cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Kakabadse, Fishman, Weinstein-Marom, Davies, Boldison, Thayer, Wen, Gross and Wong.)- Published
- 2023
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23. Gene expression profiling in NOD mice reveals that B cells are highly educated by the pancreatic environment during autoimmune diabetes.
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Boldison J, Hopkinson JR, Davies J, Pearson JA, Leete P, Richardson S, Morgan NG, and Wong FS
- Subjects
- Mice, Animals, Mice, Inbred NOD, Pancreas metabolism, Gene Expression Profiling, Diabetes Mellitus, Type 1 metabolism, Islets of Langerhans metabolism
- Abstract
Aims/hypothesis: 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. Here, we use gene expression profiling of B cell subsets identified in inflamed pancreatic tissue to explore their primary functional role during the progression of autoimmune diabetes., Methods: Transcriptional profiling was performed on FACS-sorted B cell subsets isolated from pancreatic islets and the pancreatic lymph nodes of NOD mice., Results: B cells are highly modified by the inflamed pancreatic tissue and can be distinguished by their transcriptional profile from those in the lymph nodes. We identified both a discrete and a core shared gene expression profile in islet CD19
+ CD138- and CD19+ CD138+ B cell subsets, the latter of which is known to have enriched autoreactivity during diabetes development. On localisation to pancreatic islets, compared with CD138- B cells, CD138+ B cells overexpress genes associated with adhesion molecules and growth factors. Their shared signature consists of gene expression changes related to the differentiation of antibody-secreting cells and gene regulatory networks associated with IFN signalling pathways, proinflammatory cytokines and Toll-like receptor (TLR) activation. Finally, abundant TLR7 expression was detected in islet B cells and was enhanced specifically in CD138+ B cells., Conclusions/interpretation: Our study provides a detailed transcriptional analysis of islet B cells. Specific gene signatures and interaction networks have been identified that point towards a functional role for B cells in driving autoimmune diabetes., (© 2022. The Author(s).)- Published
- 2023
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24. NLRP6 deficiency expands a novel CD103 + B cell population that confers immune tolerance in NOD mice.
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Pearson JA, Peng J, Huang J, Yu X, Tai N, Hu Y, Sha S, Flavell RA, Zhao H, Wong FS, and Wen L
- Subjects
- Animals, Mice, Immune Tolerance, Inflammasomes metabolism, Lipopolysaccharides, Mice, Inbred NOD, Diabetes Mellitus, Type 1, Interleukin-10
- Abstract
Introduction: Gut microbiota have been linked to modulating susceptibility to Type 1 diabetes; however, there are many ways in which the microbiota interact with host cells, including through microbial ligand binding to intracellular inflammasomes (large multi-subunit proteins) to initiate immune responses. NLRP6, a microbe-recognizing inflammasome protein, is highly expressed by intestinal epithelial cells and can alter susceptibility to cancer, obesity and Crohn's disease; however, the role of NLRP6 in modulating susceptibility to autoimmune diabetes, was previously unknown., Methods: We generated NLRP6-deficient Non-obese diabetic (NOD) mice to study the effect of NLRP6-deficiency on the immune cells and susceptibility to Type 1 diabetes development., Results: NLRP6-deficient mice exhibited an expansion of CD103
+ B cells and were protected from type 1 diabetes. Moreover, NLRP6-deficient CD103+ B cells express regulatory markers, secreted higher concentrations of IL-10 and TGFb1 cytokines and suppressed diabetogenic T cell proliferation, compared to NLRP6-sufficient CD103+ B cells. Microarray analysis of NLRP6-sufficient and -deficient CD103+ B cells identified 79 significantly different genes including genes regulated by lipopolysaccharide (LPS), tretinoin, IL-10 and TGFb, which was confirmed in vitro following LPS stimulation. Furthermore, microbiota from NLRP6-deficient mice induced CD103+ B cells in colonized NLRP6-sufficient germ-free mice; however, the long-term maintenance of the CD103+ B cells required the absence of NLRP6 in the hosts, or continued exposure to microbiota from NLRP6-deficient mice., Discussion: Together, our data indicate that NLRP6 deficiency promotes expansion and maintenance of a novel TGF -dependent CD103+ Breg population. Thus, targeting NLRP6 therapeutically may prove clinically useful., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pearson, Peng, Huang, Yu, Tai, Hu, Sha, Flavell, Zhao, Wong and Wen.)- Published
- 2023
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25. Islet-specific CD8 + T cells gain effector function in the gut lymphoid tissues via bystander activation not molecular mimicry.
- Author
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Okada M, Zhang V, Loaiza Naranjo JD, Tillett BJ, Wong FS, Steptoe RJ, Bergot AS, and Hamilton-Williams EE
- Subjects
- Mice, Animals, CD8-Positive T-Lymphocytes, Peptides metabolism, Lymph Nodes, Epitopes metabolism, Diabetes Mellitus, Type 1 genetics, Islets of Langerhans metabolism, Islets of Langerhans pathology
- Abstract
Type 1 diabetes (T1D) is caused by aberrant activation of autoreactive T cells specific for the islet beta cells. How islet-specific T cells evade tolerance to become effector T cells is unknown, but it is believed that an altered gut microbiota plays a role. Possible mechanisms include bystander activation of autoreactive T cells in the gut or "molecular mimicry" from cross-reactivity between gut microbiota-derived peptides and islet-derived epitopes. To investigate these mechanisms, we use two islet-specific CD8
+ T cell clones and the non-obese diabetic mouse model of type 1 diabetes. Both insulin-specific G9C8 cells and IGRP-specific 8.3 cells underwent early activation and proliferation in the pancreatic draining lymph nodes but not in the Peyer's patches or mesenteric lymph nodes. Mutation of the endogenous epitope for G9C8 cells abolished their CD69 upregulation and proliferation, ruling out G9C8 cell activation by a gut microbiota derived peptide and molecular mimicry. However, previously activated islet-specific effector memory cells but not naïve cells migrated into the Peyer's patches where they increased their cytotoxic function. Oral delivery of butyrate, a microbiota derived anti-inflammatory metabolite, reduced IGRP-specific cytotoxic function. Thus, while initial activation of islet-specific CD8+ T cells occurred in the pancreatic lymph nodes, activated cells trafficked through the gut lymphoid tissues where they gained additional effector function via non-specific bystander activation influenced by the gut microbiota., (© 2022 The Authors. Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)- Published
- 2023
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26. Disruption of the glucagon receptor increases glucagon expression beyond α-cell hyperplasia in zebrafish.
- Author
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Kang Q, Zheng J, Jia J, Xu Y, Bai X, Chen X, Zhang XK, Wong FS, Zhang C, and Li M
- Subjects
- Animals, Zebrafish genetics, Zebrafish metabolism, Hyperplasia, RNA, Messenger, Glucagon, Receptors, Glucagon genetics, Receptors, Glucagon metabolism
- Abstract
The glucagon receptor (GCGR) is a potential target for diabetes therapy. Several emerging GCGR antagonism-based therapies are under preclinical and clinical development. However, GCGR antagonism, as well as genetically engineered GCGR deficiency in animal models, are accompanied by α-cell hyperplasia and hyperglucagonemia, which may limit the application of GCGR antagonism. To better understand the physiological changes in α cells following GCGR disruption, we performed single cell sequencing of α cells isolated from control and gcgr
-/- (glucagon receptor deficient) zebrafish. Interestingly, beyond the α-cell hyperplasia, we also found that the expression of gcga, gcgb, pnoca, and several glucagon-regulatory transcription factors were dramatically increased in one cluster of gcgr-/- α cells. We further confirmed that glucagon mRNA was upregulated in gcgr-/- animals by in situ hybridization and that glucagon promoter activity was increased in gcgr-/- ;Tg(gcga:GFP) reporter zebrafish. We also demonstrated that gcgr-/- α cells had increased glucagon protein levels and increased granules after GCGR disruption. Intriguingly, the increased mRNA and protein levels could be suppressed by treatment with high-level glucose or knockdown of the pnoca gene. In conclusion, these data demonstrated that GCGR deficiency not only induced α-cell hyperplasia but also increased glucagon expression in α cells, findings which provide more information about physiological changes in α-cells when the GCGR is disrupted., Competing Interests: Conflict of interest The authors declare that they have no conflicts interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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27. Adult-onset autoimmune diabetes.
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Buzzetti R, Maddaloni E, Gaglia J, Leslie RD, Wong FS, and Boehm BO
- Subjects
- Adult, Biomarkers, Child, Humans, Insulin therapeutic use, Quality of Life, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 1 diagnosis, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 drug therapy
- Abstract
Adult-onset autoimmune (AOA) diabetes pathophysiology starts with immune changes, followed by dysglycaemia and overt disease. AOA diabetes can occur as classic type 1 diabetes when associated with severe loss of insulin secretion. More frequently, it is diagnosed as latent autoimmune diabetes in adults, a slowly progressing form with late onset, a long period not requiring insulin, and it is often misdiagnosed as type 2 diabetes. As its clinical presentation varies remarkably and immune markers often lack specificity, it is challenging to classify each case ad hoc, especially when insulin treatment is not required at diagnosis. Proper care of AOA diabetes aims to prevent complications and to improve quality of life and life expectancy. To achieve these goals, attention should be paid to lifestyle factors, with the aid of pharmacological therapies properly tailored to each individual clinical setting. Given the heterogeneity of the disease, choosing the right therapy for AOA diabetes is challenging. Most of the trials testing disease-modifying therapies for autoimmune diabetes are conducted in people with childhood onset, whereas non-insulin diabetes therapies have mostly been studied in the larger population with type 2 diabetes. More randomized controlled trials of therapeutic agents in AOA diabetes are needed., (© 2022. Springer Nature Limited.)
- Published
- 2022
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28. Circadian rhythms and pancreas physiology: A review.
- Author
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Chan K, Wong FS, and Pearson JA
- Subjects
- Animals, Circadian Rhythm, Humans, Obesity, Pancreas, Diabetes Mellitus, Type 2, Metabolic Diseases
- Abstract
Type 2 diabetes mellitus, obesity and metabolic syndrome are becoming more prevalent worldwide and will present an increasingly challenging burden on healthcare systems. These interlinked metabolic abnormalities predispose affected individuals to a plethora of complications and comorbidities. Furthermore, diabetes is estimated by the World Health Organization to have caused 1.5 million deaths in 2019, with this figure projected to rise in coming years. This highlights the need for further research into the management of metabolic diseases and their complications. Studies on circadian rhythms, referring to physiological and behavioral changes which repeat approximately every 24 hours, may provide important insight into managing metabolic disease. Epidemiological studies show that populations who are at risk of circadian disruption such as night shift workers and regular long-haul flyers are also at an elevated risk of metabolic abnormalities such as insulin resistance and obesity. Aberrant expression of circadian genes appears to contribute to the dysregulation of metabolic functions such as insulin secretion, glucose homeostasis and energy expenditure. The potential clinical implications of these findings have been highlighted in animal studies and pilot studies in humans giving rise to the development of circadian interventions strategies including chronotherapy (time-specific therapy), time-restricted feeding, and circadian molecule stabilizers/analogues. Research into these areas will provide insights into the future of circadian medicine in metabolic diseases. In this review, we discuss the physiology of metabolism and the role of circadian timing in regulating these metabolic functions. Also, we review the clinical aspects of circadian physiology and the impact that ongoing and future research may have on the management of metabolic disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chan, Wong and Pearson.)
- Published
- 2022
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29. IgM-associated gut bacteria in obesity and type 2 diabetes in C57BL/6 mice and humans.
- Author
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Pearson JA, Ding H, Hu C, Peng J, Galuppo B, Wong FS, Caprio S, Santoro N, and Wen L
- Subjects
- Adolescent, Animals, Bacteria genetics, Child, Diet, High-Fat, Humans, Immunoglobulin M, Mice, Mice, Inbred C57BL, Obesity microbiology, RNA, Ribosomal, 16S genetics, Weight Gain, Diabetes Mellitus, Type 2
- Abstract
Aims/hypothesis: IgM is the primary antibody produced by B cells and we hypothesise that IgM antibodies to gut microbiota may play a role in immunometabolism in obesity and type 2 diabetes. To test our hypothesis, we used B6 mice deficient in activation-induced cytidine deaminase (Aid
-/- [also known as Aicda-/- ]) which secrete only IgM antibodies, and human faecal samples., Methods: We studied the immunometabolic effects and gut microbial changes in high-fat-diet-induced obesity (HFDIO) in Aid-/- B6 mice compared with wild-type mice. To determine similarities between mice and humans, human stool samples were collected from children and adolescents who were obese with normal glucose tolerance (NGT), obese with glucose intolerance (IGT), or obese and newly diagnosed with type 2 diabetes, for faecal microbiota transplant (FMT) into germ-free (GF) B6 mice and we assessed IgM-bound bacteria and immune responses., Results: Compared with wild-type mice, Aid-/- B6 mice developed exacerbated HFDIO due to abundant levels of IgM. FMT from Aid-/- B6 to GF B6 mice promoted greater weight gain in recipient mice compared with FMT using wild-type mouse faecal microbiota. Obese youth with type 2 diabetes had more IgM-bound gut bacteria. Using the stools from the obese youth with type 2 diabetes for FMT to GF B6 mice, we observed that the gut microbiota promoted body weight gain and impaired glucose tolerance in the recipient GF B6 mice. Importantly, some clinical features of these obese young individuals were mirrored in the GF B6 mice following FMT., Conclusions/interpretation: Our results suggest that IgM-bound gut microbiota may play an important role in the immuno-pathogenesis of obesity and type 2 diabetes, and provide a novel link between IgM in obesity and type 2 diabetes in both mice and humans., Data Availability: The 16s rRNA sequencing datasets supporting the current study have been deposited in the NCBI SRA public repository ( https://www.ncbi.nlm.nih.gov/sra ; accession no. SAMN18796639)., (© 2022. The Author(s).)- Published
- 2022
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30. Obesity aggravates contact hypersensitivity reaction in mice.
- Author
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Majewska-Szczepanik M, Kowalczyk P, Marcińska K, Strzępa A, Lis GJ, Wong FS, Szczepanik M, and Wen L
- Subjects
- Animals, CD4-Positive T-Lymphocytes, Humans, Inflammation, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity, Dermatitis, Allergic Contact, Interleukin-17
- Abstract
Background: Obesity is associated with chronic, low-grade inflammation in tissues and predisposes to various complications, including inflammatory skin diseases. However, the link between obesity and contact hypersensitivity (CHS) is not fully understood., Objectives: We sought to determine the influence of obesity on T helper 1 (Th1)-mediated CHS., Methods: The activity/phenotype/cytokine profile of the immune cells was tested in vivo and in vitro. Using quantitative polymerase chain reaction (qPCR) and fecal microbiota transplantation (FMT), we tested the role of a high-fat diet (HFD)-induced gut microbiota (GM) dysbiosis in increasing the effects of CHS., Results: Exacerbated CHS correlates with an increased inflammation-inducing GM in obese mice. We showed a proinflammatory milieu in the subcutaneous adipose tissue of obese mice, accompanied by proinflammatory CD4+ T cells and dendritic cells in skin draining lymph nodes and spleen. Obese interleukin (IL)-17A-/-B6 mice are protected from CHS aggravation, suggesting the importance of IL-17A in CHS aggravation in obesity., Conclusions: Obesity creates a milieu that induces more potent CHS-effector cells but does not have effects on already activated CHS-effector cells. IL-17A is essential for the pathogenesis of enhanced CHS during obesity. Our study provides novel knowledge about antigen-specific responses in obesity, which may help with the improvement of existing treatment and/or in designing novel treatment for obesity-associated skin disorders., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2022
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31. Artemether and aspterric acid induce pancreatic alpha cells to transdifferentiate into beta cells in zebrafish.
- Author
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Jia J, Kang Q, Liu S, Song Y, Wong FS, Qiu Y, and Li M
- Subjects
- Animals, Artemether metabolism, Heterocyclic Compounds, 3-Ring, Zebrafish, Glucagon-Secreting Cells metabolism, Insulin-Secreting Cells metabolism
- Abstract
Background and Purpose: Recently, the antimalarial drug, artemether and the neurotransmitter GABA were identified to convert alpha cells into beta-like cells in vivo. However, some of these observations were challenged by other studies. To help address the controversy, we took advantage of zebrafish as a model to perform this study., Experimental Approach: First, we performed a small-molecule screening for artemether and its skeleton analogues. Second, we used the Cre-LoxP system for lineage tracing to indicate the conversion of alpha cells into beta cells in vivo. The stable transgenic ins2:eGFP αTC1-6-cell line was used for evaluation of alpha-cell transdifferentiation in vitro. We further used multiple zebrafish transgenic and mutation lines to demonstrate beta-cell differentiation, beta-cell ablation and alpha-cell hyperplasia in this study., Key Results: We showed that artemether and another sesquiterpene, aspterric acid, induced alpha-cell transdifferentiation into beta cells, both in zebrafish as well as using αTC1-6 cells. Furthermore, these two compounds also converted alpha cells into beta cells when beta cells were lost or alpha cells were hyperplastic in zebrafish. Unlike the previous report, the conversion of alpha cells to beta cells was mediated by increasing Pax4 expression, but not suppression of Arx expression., Conclusion and Implications: Our data suggest that in zebrafish and αTC1-6 cells, both artemether and aspterric acid induce alpha-cell transdifferentiation. Our data, along with those of Li et al. (2017), suggested that artemether and aspterric acid were able to induce alpha-cell transdifferentiation, at least in zebrafish and αTC1-6 cells., (© 2021 The British Pharmacological Society.)
- Published
- 2022
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32. Editorial: Immunopathology of Type 1 Diabetes.
- Author
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Green EA, Cooke AC, Piganelli JD, Richardson SJ, Wen L, and Wong FS
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2022
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33. Activated but functionally impaired memory Tregs are expanded in slow progressors to type 1 diabetes.
- Author
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Boldison J, Long AE, Aitken RJ, Wilson IV, Megson C, Hanna SJ, Wong FS, and Gillespie KM
- Subjects
- Adult, Aged, Female, Flow Cytometry, Follow-Up Studies, Glucocorticoid-Induced TNFR-Related Protein metabolism, Humans, Lymphocyte Count, Male, Middle Aged, CD4-Positive T-Lymphocytes immunology, Diabetes Mellitus, Type 1 immunology, Memory T Cells immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Aims/hypothesis: Slow progressors to type 1 diabetes are individuals positive for multiple pancreatic islet autoantibodies who have remained diabetes-free for at least 10 years; regulation of the autoimmune response is understudied in this group. Here, we profile CD4
+ regulatory T cells (Tregs) in a small but well-characterised cohort of extreme slow progressors with a median age 43 (range 31-72 years), followed up for 18-32 years., Methods: Peripheral blood samples were obtained from slow progressors (n = 8), age- and sex-matched to healthy donors. One participant in this study was identified with a raised HbA1c at the time of assessment and subsequently diagnosed with diabetes; this donor was individually evaluated in the analysis of the data. Peripheral blood mononuclear cells (PBMCs) were isolated, and to assess frequency, phenotype and function of Tregs in donors, multi-parameter flow cytometry and T cell suppression assays were performed. Unsupervised clustering analysis, using FlowSOM and CITRUS (cluster identification, characterization, and regression), was used to evaluate Treg phenotypes., Results: Unsupervised clustering on memory CD4+ T cells from slow progressors showed an increased frequency of activated memory CD4+ Tregs, associated with increased expression of glucocorticoid-induced TNFR-related protein (GITR), compared with matched healthy donors. One participant with a raised HbA1c at the time of assessment had a different Treg profile compared with both slow progressors and matched controls. Functional assays demonstrated that Treg-mediated suppression of CD4+ effector T cells from slow progressors was significantly impaired, compared with healthy donors. However, effector CD4+ T cells from slow progressors were more responsive to Treg suppression compared with healthy donors, demonstrated by increased suppression of CD25 and CD134 expression on effector CD4+ T cells., Conclusions/interpretations: We conclude that activated memory CD4+ Tregs from slow progressors are expanded and enriched for GITR expression, highlighting the need for further study of Treg heterogeneity in individuals at risk of developing type 1 diabetes., (© 2021. The Author(s).)- Published
- 2022
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34. Safety of the use of gold nanoparticles conjugated with proinsulin peptide and administered by hollow microneedles as an immunotherapy in type 1 diabetes.
- Author
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Tatovic D, McAteer MA, Barry J, Barrientos A, Rodríguez Terradillos K, Perera I, Kochba E, Levin Y, Dul M, Coulman SA, Birchall JC, von Ruhland C, Howell A, Stenson R, Alhadj Ali M, Luzio SD, Dunseath G, Cheung WY, Holland G, May K, Ingram JR, Chowdhury MMU, Wong FS, Casas R, Dayan C, and Ludvigsson J
- Abstract
Antigen-specific immunotherapy is an immunomodulatory strategy for autoimmune diseases, such as type 1 diabetes, in which patients are treated with autoantigens to promote immune tolerance, stop autoimmune β-cell destruction and prevent permanent dependence on exogenous insulin. In this study, human proinsulin peptide C19-A3 (known for its positive safety profile) was conjugated to ultrasmall gold nanoparticles (GNPs), an attractive drug delivery platform due to the potential anti-inflammatory properties of gold. We hypothesised that microneedle intradermal delivery of C19-A3 GNP may improve peptide pharmacokinetics and induce tolerogenic immunomodulation and proceeded to evaluate its safety and feasibility in a first-in-human trial. Allowing for the limitation of the small number of participants, intradermal administration of C19-A3 GNP appears safe and well tolerated in participants with type 1 diabetes. The associated prolonged skin retention of C19-A3 GNP after intradermal administration offers a number of possibilities to enhance its tolerogenic potential, which should be explored in future studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology.)
- Published
- 2022
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35. Innate immunity in latent autoimmune diabetes in adults.
- Author
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Huang J, Pearson JA, Wong FS, Wen L, and Zhou Z
- Subjects
- Animals, Autoantibodies, CD8-Positive T-Lymphocytes pathology, Humans, Immunity, Innate, Rats, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2 pathology, Latent Autoimmune Diabetes in Adults
- Abstract
Latent autoimmune diabetes in adults (LADA) is an autoimmune disease that shares some genetic, immunological and clinical features with both type 1 diabetes and type 2 diabetes. Immune cells including CD4
+ T cells, CD8+ T cells, B cells, macrophages and dendritic cells (DCs) have been detected in the pancreas of patients with LADA and a rat model of LADA. Therefore, similar to type 1 diabetes, the pathogenesis of LADA may be caused by interactions between islet β-cells and innate and adaptive immune cells. However, the role of the immunity in the initiation and progression of LADA remains largely unknown. In this review, we have summarized the potential roles of innate immunity and immune-modulators in LADA development. Furthermore, we have examined the evidence and discussed potential innate immunological reasons for the slower development of LADA compared with type 1 diabetes. More in-depth mechanistic studies are needed to fully elucidate the roles of innate immune-associated genes, molecules and cells in their contributions to LADA pathogenesis. Undertaking these studies will greatly enhance the development of new strategies and optimization of current strategies for the diagnosis and treatment of the disease., (© 2021 John Wiley & Sons Ltd.)- Published
- 2022
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36. Not "either-or" but "which-when": A review of the evidence for integration in sensory preconditioning.
- Author
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Holmes NM, Wong FS, Bouchekioua Y, and Westbrook RF
- Subjects
- Animals, Mice, Rabbits, Rats, Conditioning, Psychological physiology
- Abstract
Sensory preconditioning protocols can be used to assess how the brain integrates memories that share common features. In these protocols, animals are first exposed to pairings of two relatively innocuous stimuli, S2 and S1 (stage 1), and then to pairings of one of these stimuli, S1, with an event of motivational significance (stage 2). Following this training, test presentations of S2 elicit responses appropriate to the motivationally significant event, and these responses are taken to indicate formation of distinct S2-S1 and S1-event memories that are integrated in some way to generate that responding. This paper reviews studies of sensory preconditioning in rats, mice, rabbits and people to determine whether S2-S1 and S1-event memories are integrated through a chaining process at the time of their retrieval (i.e., test presentations of S2 trigger retrieval of S1, and thereby, responses appropriate to the event); or "online" at the time of memory formation (i.e., in stage 2, S1 activates a representation of S2 such that both stimuli associate with the motivationally significant event). It finds that the type of integration is determined by the manner in which stimuli are presented in preconditioning as well as their familiarity. When the stimuli in preconditioning are presented repeatedly and/or serially (i.e., one after the other), the S2-S1 and S1-event memories are chained at the time of retrieval/testing. In contrast, when the stimuli in preconditioning are relatively novel and/or presented simultaneously, the S2-S1 and S1-event memories are integrated online. These statements are related to prior claims regarding the circumstances that promote different types of memory integration and, more generally, mechanisms of information processing in the mammalian brain., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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37. Incidence of diabetic retinopathy in newly diagnosed subjects with type 2 diabetes mellitus over 5 years: Contribution of Β-cell function.
- Author
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Roy Chowdhury S, Thomas RL, Dunseath GJ, Luzio SD, Wong FS, and Owens DR
- Subjects
- Glycated Hemoglobin metabolism, Humans, Incidence, Risk Factors, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 epidemiology, Diabetic Retinopathy diagnosis, Diabetic Retinopathy epidemiology, Diabetic Retinopathy etiology, Insulin-Secreting Cells metabolism
- Abstract
Aims: Identifying and modulating risk factors is essential to prevent visual impairment due to diabetic retinopathy (DR). This study examines incident DR with metabolic and hormonal factors in newly-diagnosed, treatment naïve, individuals with Type2 Diabetes Mellitus (T2DM), over a 5 year period from diagnosis., Methods: 233 T2DM subjects underwent serial DR screening using digital photography and standardised Meal Tolerance Tests at diagnosis and after 1, 2 and 5 years. Subjects (179) with no DR throughout the 5-year study period were compared with those who developed DR (54)., Results: Of 233 subjects, 54(23.2%) developed DR by 5 years, background DR in 50(93%) and exudative maculopathy in 4(7%) individuals. Of these subjects, 12(22%) developed DR after 1 year, 15(28%) after 2 years and 27(50%) after 5 years. At baseline, those with DR at 5 years had higher HbA
1c (p = 0.017), higher fasting plasma glucose (PG) (p = 0.031) and postprandial PG (p = 0.009). They were associated with reduced basal β-cell secretory function (M0 ) (p = 0.025), lower (p = 0.000) postprandial β-cell responsiveness (M1 ) and β-cell function (HOMA-B) (p = 0.044)., Conclusions: There is an independent association between glycaemic control and β-cell dysfunction at the time of diagnosis of T2DM, with incident DR over a follow-up period of 5 years., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
38. Environmental Determinants of Type 1 Diabetes: From Association to Proving Causality.
- Author
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Quinn LM, Wong FS, and Narendran P
- Subjects
- Communicable Diseases epidemiology, Diabetes Mellitus, Type 1 diagnosis, Gastrointestinal Microbiome, Humans, Incidence, Life Style, Obesity epidemiology, Risk Assessment, Risk Factors, Vaccines adverse effects, Diabetes Mellitus, Type 1 epidemiology, Environment, Environmental Exposure adverse effects
- Abstract
The rising incidence of type 1 diabetes (T1D) cannot be ascribed to genetics alone, and causative environmental triggers and drivers must also be contributing. The prospective TEDDY study has provided the greatest contributions in modern time, by addressing misconceptions and refining the search strategy for the future. This review outlines the evidence to date to support the pathways from association to causality, across all stages of T1D (seroconversion to beta cell failure). We focus on infections and vaccinations; infant growth and childhood obesity; the gut microbiome and the lifestyle factors which cultivate it. Of these, the environmental determinants which have the most supporting evidence are enterovirus infection, rapid weight gain in early life, and the microbiome. We provide an infographic illustrating the key environmental determinants in T1D and their likelihood of effect. The next steps are to investigate these environmental triggers, ideally though gold-standard randomised controlled trials and further prospective studies, to help explore public health prevention strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Quinn, Wong and Narendran.)
- Published
- 2021
- Full Text
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39. Regulatory B Cells: Role in Type 1 Diabetes.
- Author
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Boldison J and Wong FS
- Subjects
- Adolescent, Adult, Animals, Autoimmunity, Female, Humans, Immunophenotyping, Interleukin-10 biosynthesis, Interleukins biosynthesis, Islets of Langerhans immunology, Male, Mice, Transforming Growth Factor beta biosynthesis, Young Adult, B-Lymphocytes, Regulatory immunology, Diabetes Mellitus, Type 1 immunology
- Abstract
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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Boldison and Wong.)
- Published
- 2021
- Full Text
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40. Circadian Rhythm Modulation of Microbes During Health and Infection.
- Author
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Pearson JA, Voisey AC, Boest-Bjerg K, Wong FS, and Wen L
- Abstract
Circadian rhythms, referring to 24-h daily oscillations in biological and physiological processes, can significantly regulate host immunity to pathogens, as well as commensals, resulting in altered susceptibility to disease development. Furthermore, vaccination responses to microbes have also shown time-of-day-dependent changes in the magnitude of protective immune responses elicited in the host. Thus, understanding host circadian rhythm effects on both gut bacteria and viruses during infection is important to minimize adverse effects on health and identify optimal times for therapeutic administration to maximize therapeutic success. In this review, we summarize the circadian modulations of gut bacteria, viruses and their interactions, both in health and during infection. We also discuss the importance of chronotherapy (i.e., time-specific therapy) as a plausible therapeutic administration strategy to enhance beneficial therapeutic responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pearson, Voisey, Boest-Bjerg, Wong and Wen.)
- Published
- 2021
- Full Text
- View/download PDF
41. IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice.
- Author
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Huang J, Tan Q, Tai N, Pearson JA, Li Y, Chao C, Zhang L, Peng J, Xing Y, Zhang L, Hu Y, Zhou Z, Wong FS, and Wen L
- Subjects
- Animals, Diabetes Mellitus, Type 1 genetics, Interleukin-10 immunology, Mice, Mice, Inbred NOD, Mice, Knockout, Adaptive Immunity, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 microbiology, Gastrointestinal Microbiome immunology, Immunity, Innate, Interleukin-10 deficiency, T-Lymphocytes, Regulatory immunology
- Abstract
Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells. BDC2.5 T cells in BDC2.5 CD4
+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice ( BDC2.5+ NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progresses rapidly but rarely leads to spontaneous diabetes. This prevention of diabetes is mediated by T regulatory (Treg) cells in these mice. In this study, we investigated the role of interleukin 10 (IL-10) in the inhibition of diabetes in BDC2.5+ NOD mice by generating Il-10 -deficient BDC2.5+ NOD mice ( BDC2.5+ Il-10-/- NOD mice). Our results showed that BDC2.5+ Il-10-/- NOD mice displayed robust and accelerated diabetes development. Il-10 deficiency in BDC2.5+ NOD mice promoted the generation of neutrophils in the bone marrow and increased the proportions of neutrophils in the periphery (blood, spleen, and islets), accompanied by altered intestinal immunity and gut microbiota composition. In vitro studies showed that the gut microbiota from BDC2.5+ Il-10-/- NOD mice can expand neutrophil populations. Moreover, in vivo studies demonstrated that the depletion of endogenous gut microbiota by antibiotic treatment decreased the proportion of neutrophils. Although Il-10 deficiency in BDC2.5+ NOD mice had no obvious effects on the proportion and function of Treg cells, it affected the immune response and activation of CD4+ T cells. Moreover, the pathogenicity of CD4+ T cells was much increased, and this significantly accelerated the development of diabetes when these CD4+ T cells were transferred into immune-deficient NOD mice. Our study provides novel insights into the role of IL-10 in the modulation of neutrophils and CD4+ T cells in BDC2.5+ NOD mice, and suggests important crosstalk between gut microbiota and neutrophils in type 1 diabetes development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Huang, Tan, Tai, Pearson, Li, Chao, Zhang, Peng, Xing, Zhang, Hu, Zhou, Wong and Wen.)- Published
- 2021
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42. Inflammasomes and Type 1 Diabetes.
- Author
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Pearson JA, Wong FS, and Wen L
- Subjects
- Animals, Bacteria pathogenicity, Diabetes Mellitus, Type 1 microbiology, Disease Models, Animal, Disease Susceptibility, Humans, Immunity, Innate, Microbiota immunology, Signal Transduction, Diabetes Mellitus, Type 1 immunology, Inflammasomes immunology
- Abstract
Microbiota have been identified as an important modulator of susceptibility in the development of Type 1 diabetes in both animal models and humans. Collectively these studies highlight the association of the microbiota composition with genetic risk, islet autoantibody development and modulation of the immune responses. However, the signaling pathways involved in mediating these changes are less well investigated, particularly in humans. Importantly, understanding the activation of signaling pathways in response to microbial stimulation is vital to enable further development of immunotherapeutics, which may enable enhanced tolerance to the microbiota or prevent the initiation of the autoimmune process. One such signaling pathway that has been poorly studied in the context of Type 1 diabetes is the role of the inflammasomes, which are multiprotein complexes that can initiate immune responses following detection of their microbial ligands. In this review, we discuss the roles of the inflammasomes in modulating Type 1 diabetes susceptibility, from genetic associations to the priming and activation of the inflammasomes. In addition, we also summarize the available inhibitors for therapeutically targeting the inflammasomes, which may be of future use in Type 1 diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pearson, Wong and Wen.)
- Published
- 2021
- Full Text
- View/download PDF
43. Referral rates of patients with diabetes to secondary care are inversely related to the prevalence of diabetes in each primary care practice and confidence in treatment, not to HbA1c level.
- Author
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Siah QZ, Ubeysekara NH, Taylor PN, Davies SJ, Wong FS, Dayan CM, and Ali MA
- Subjects
- Glycated Hemoglobin, Humans, Prevalence, Primary Health Care, Referral and Consultation, Diabetes Mellitus, Secondary Care
- Abstract
Aims: To determine the factors affecting the referral rates of patients with diabetes from primary care to secondary care., Methods: A study based on 66 GP surgeries in the Cardiff and Vale University Health Board (population: 515,581) was conducted. We included patients who had an established clinical diagnosis of diabetes (type 1 and type 2) from September 2017 to September 2018. HbA1c outcome data of GP surgeries were obtained from the Quality and Outcomes Framework (QOF) database published for 2018. Referral rates were obtained from the electronic referral database of Cardiff and Vale University Health Board over the same period, and this was adjusted according to the number of patients with diabetes in each GP surgery. Confidence level on the treatment of diabetes among GPs was assessed as a sub-study conducted in nine GP surgeries in the same area, using a self-administered questionnaire. Linear regression was undertaken to assess the relationship between adjusted referral rate and key factors which might influence prescribing rate., Results: The average adjusted referral rate to secondary care in one year was 4.23% of patients with diabetes in each GP surgery, with a wide variation of 1.24% to 16.28%. The average percentage of patients with diabetes with HbA1c<59mmol/mol was 63.17% (range: 43.19-76.23%). The average confidence score of GPs in treating diabetes was 67% and ranged from 50-85% in the sub-study. Referral rates correlated inversely with the numbers of patients with diabetes in each practice β=-0.32; (95% CI -0.57, -0.08) p=0.01, but there was no significant correlation with the HbA1c outcome β=-0.13; (95% CI -0.39, 0.12); p=0.30. Borderline significant negative correlation was observed between referral rates and overall practice size β=-0.23; (95% CI -0.48, 0.02) p=0.07., Conclusions: Referral rates of patients with diabetes to secondary care are determined by the number of patients with diabetes in each practice and confidence level in treatment, not by the overall practice size or HbA1c level. Ensuring quality training in diabetes care for primary care teams as well as the development of integrated diabetes care may be the best way to optimise the volume and appropriateness of referrals to secondary care., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
44. Identifying the 'Achilles heel' of type 1 diabetes.
- Author
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Battaglia M, Buckner JH, Levings MK, Richardson SJ, Wong FS, and Tree TI
- Subjects
- B-Lymphocytes immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Humans, Neutrophils immunology, Diabetes Mellitus, Type 1 immunology
- Abstract
When Thetis dipped her son Achilles into the River Styx to make him immortal, she held him by the heel, which was not submerged, and thus created a weak spot that proved deadly for Achilles. Millennia later, Achilles heel is part of today's lexicon meaning an area of weakness or a vulnerable spot that causes failure. Also implied is that an Achilles heel is often missed, forgotten or under-appreciated until it is under attack, and then failure is fatal. Paris killed Achilles with an arrow 'guided by the Gods'. Understanding the pathogenesis of type 1 diabetes (T1D) in order to direct therapy for prevention and treatment is a major goal of research into T1D. At the International Congress of the Immunology of Diabetes Society, 2018, five leading experts were asked to present the case for a particular cell/element that could represent 'the Achilles heel of T1D'. These included neutrophils, B cells, CD8
+ T cells, regulatory CD4+ T cells, and enteroviruses, all of which have been proposed to play an important role in the pathogenesis of type 1 diabetes. Did a single entity emerge as 'the' Achilles heel of T1D? The arguments are summarized here, to make this case., (© 2021 British Society for Immunology.)- Published
- 2021
- Full Text
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45. Historical and new insights into pathogenesis of type 1 diabetes (2).
- Author
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Wong FS and Tree TI
- Subjects
- Autoantigens immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Humans, Diabetes Mellitus, Type 1 immunology
- Abstract
In this second and final part of the collection of articles for the Immunology of Diabetes Society review series on insights into pathogenesis of type 1 diabetes, we present two articles. The first of these covers a debate that took place in the Immunology of Diabetes Society meeting in London 2018, in which five investigators presented a case for specific immune cells/targets to be the 'Achilles Heel of type 1 diabetes'. The second article presents further insights into the generation of post-translationally modified peptides. It focuses upon mechanisms and processes that lead to new potentially autoantigenic targets for CD8
+ T cells, and complements the review of new hybrid peptide targets for CD4+ T cells in the first part of our series., (© 2021 British Society for Immunology.)- Published
- 2021
- Full Text
- View/download PDF
46. Natural Protection From Type 1 Diabetes in NOD Mice Is Characterized by a Unique Pancreatic Islet Phenotype.
- Author
-
Boldison J, Thayer TC, Davies J, and Wong FS
- Subjects
- Animals, Antigens, CD metabolism, CD4-Positive T-Lymphocytes metabolism, CTLA-4 Antigen genetics, CTLA-4 Antigen metabolism, Diabetes Mellitus, Type 1 genetics, Female, Flow Cytometry, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Integrin alpha Chains metabolism, Mice, Diabetes Mellitus, Type 1 metabolism, Islets of Langerhans metabolism
- Abstract
The NOD mouse develops spontaneous type 1 diabetes, with some features of disease that are very similar to the human disease. However, a proportion of NOD mice are naturally protected from developing diabetes, and currently, studies characterizing this cohort are very limited. Here, using both immunofluorescence and multiparameter flow cytometry, we focus on the pancreatic islet morphology and immune infiltrate observed in naturally protected NOD mice. We show that naturally protected NOD mice are characterized by an increased frequency of insulin-containing, smaller-sized, pancreatic islets. Although mice remain diabetes free, florid immune infiltrate remains. However, this immune infiltrate is skewed toward a regulatory phenotype in both T- and B-cell compartments. Pancreatic islets have an increased frequency of IL-10-producing B cells and associated cell surface markers. Resident memory CD69
+ CD8+ T cells show a significant shift toward reduced CD103 expression, while CD4+ T cells have increased FoxP3+ CTLA4+ expression. These data indicate that naturally protected NOD mice have a unique islet signature and provide new insight into regulatory mechanisms within pancreatic islets., (© 2021 by the American Diabetes Association.)- Published
- 2021
- Full Text
- View/download PDF
47. Differentiating MHC-Dependent and -Independent Mechanisms of Lymph Node Stromal Cell Regulation of Proinsulin-Specific CD8 + T Cells in Type 1 Diabetes.
- Author
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Thayer TC, Davies J, Pearson JA, Hanna SJ, Wen L, and Wong FS
- Subjects
- Animals, Dendritic Cells metabolism, Mice, Mice, Inbred NOD, CD8-Positive T-Lymphocytes metabolism, Diabetes Mellitus, Type 1 metabolism, Histocompatibility Antigens Class II metabolism, Lymph Nodes metabolism, Proinsulin metabolism, Stromal Cells metabolism
- Abstract
Lymph node stromal cells (LNSC) are essential for providing and maintaining peripheral self-tolerance of potentially autoreactive cells. In type 1 diabetes, proinsulin-specific CD8
+ T cells, escaping central and peripheral tolerance, contribute to β-cell destruction. Using G9Cα-/- CD8+ T cells specific for proinsulin, we studied the mechanisms by which LNSC regulate low-avidity autoreactive cells in the NOD mouse model of type 1 diabetes. Whereas MHC-matched NOD-LNSC significantly reduced G9Cα-/- CD8+ T-cell cytotoxicity and dendritic cell-induced proliferation, they failed to sufficiently regulate T cells stimulated by anti-CD3/CD28. In contrast, non-MHC-matched, control C57BL/6 mouse LNSC suppressed T-cell receptor engagement by anti-CD3/CD28 via MHC-independent mechanisms. This C57BL/6-LNSC suppression was maintained even after removal of the LNSC, demonstrating a direct effect of LNSC on T cells, modifying antigen sensitivity and effector function. Thus, our results suggest that a loss of NOD-LNSC MHC-independent suppressive mechanisms may contribute to diabetes development., (© 2020 by the American Diabetes Association.)- Published
- 2021
- Full Text
- View/download PDF
48. Toll-like receptor 7 deficiency suppresses type 1 diabetes development by modulating B-cell differentiation and function.
- Author
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Huang J, Peng J, Pearson JA, Efthimiou G, Hu Y, Tai N, Xing Y, Zhang L, Gu J, Jiang J, Zhao H, Zhou Z, Wong FS, and Wen L
- Subjects
- Animals, Diabetes Mellitus, Type 1 etiology, Diabetes Mellitus, Type 1 metabolism, Diabetes Mellitus, Type 1 pathology, Female, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Antigen Presentation immunology, B-Lymphocytes immunology, Cell Differentiation, Diabetes Mellitus, Type 1 prevention & control, Immunity, Innate, Membrane Glycoproteins physiology, T-Lymphocytes, Cytotoxic immunology, Toll-Like Receptor 7 physiology
- Abstract
Innate immunity mediated by Toll-like receptors (TLRs), which can recognize pathogen molecular patterns, plays a critical role in type 1 diabetes development. TLR7 is a pattern recognition receptor that senses single-stranded RNAs from viruses and host tissue cells; however, its role in type 1 diabetes development remains unclear. In our study, we discovered that Tlr7-deficient (Tlr7
-/- ) nonobese diabetic (NOD) mice, a model of human type 1 diabetes, exhibited a significantly delayed onset and reduced incidence of type 1 diabetes compared with Tlr7-sufficient (Tlr7+/+ ) NOD mice. Mechanistic investigations showed that Tlr7 deficiency significantly altered B-cell differentiation and immunoglobulin production. Moreover, Tlr7-/- NOD B cells were found to suppress diabetogenic CD4+ T-cell responses and protect immunodeficient NOD mice from developing diabetes induced by diabetogenic T cells. In addition, we found that Tlr7 deficiency suppressed the antigen-presenting functions of B cells and inhibited cytotoxic CD8+ T-cell activation by downregulating the expression of both nonclassical and classical MHC class I (MHC-I) molecules on B cells. Our data suggest that TLR7 contributes to type 1 diabetes development by regulating B-cell functions and subsequent interactions with T cells. Therefore, therapeutically targeting TLR7 may prove beneficial for disease protection.- Published
- 2021
- Full Text
- View/download PDF
49. TLR9 Deficiency in B Cells Promotes Immune Tolerance via Interleukin-10 in a Type 1 Diabetes Mouse Model.
- Author
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Sha S, Pearson JA, Peng J, Hu Y, Huang J, Xing Y, Zhang L, Zhu Y, Zhao H, Wong FS, Chen L, and Wen L
- Subjects
- Animals, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 immunology, Disease Models, Animal, Insulin-Secreting Cells immunology, Mice, Mice, Inbred NOD, Signal Transduction, Toll-Like Receptor 9 genetics, Diabetes Mellitus, Type 1 metabolism, Immune Tolerance genetics, Insulin-Secreting Cells metabolism, Interleukin-10 metabolism, Toll-Like Receptor 9 metabolism
- Abstract
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 β-cell autoimmunity is not known. To fill this knowledge gap, we generated NOD mice with a B-cell-specific deficiency of TLR9 (TLR9
fl/fl /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 interleukin-10 (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 matrix metalloproteinases, tissue inhibitor of metalloproteinase-1, and CD40, all of which are interconnected with IL-10. Our study has highlighted an important connection of an innate immune molecule in B cells to the immunopathogenesis of T1D. Thus, targeting the TLR9 pathway, specifically in B cells, may provide a novel therapeutic strategy for T1D treatment., (© 2020 by the American Diabetes Association.)- Published
- 2021
- Full Text
- View/download PDF
50. Using gold nanoparticles for enhanced intradermal delivery of poorly soluble auto-antigenic peptides.
- Author
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Singh RK, Malosse C, Davies J, Malissen B, Kochba E, Levin Y, Birchall JC, Coulman SA, Mous J, McAteer MA, Dayan CM, Henri S, and Wong FS
- Subjects
- Amino Acid Sequence, Animals, Cell Proliferation, Dendritic Cells drug effects, Injections, Intradermal, Mice, Inbred C57BL, Mice, Transgenic, Needles, Peptides chemistry, Peptides pharmacokinetics, Phenotype, Skin drug effects, Solubility, T-Lymphocytes drug effects, T-Lymphocytes immunology, Mice, Antigens metabolism, Gold chemistry, Metal Nanoparticles chemistry, Peptides pharmacology
- Abstract
Ultra-small 1-2 nm gold nanoparticles (NP) were conjugated with a poorly-soluble peptide auto-antigen, associated with type 1 diabetes, to modify the peptide pharmacokinetics, following its intradermal delivery. Peptide distribution was characterized, in vivo, after delivery using either conventional intradermal injection or a hollow microneedle device. The poorly-soluble peptide was effectively presented in distant lymph nodes (LN), spleen and draining LN when conjugated to the nanoparticles, whereas peptide alone was only presented in the draining LN. By contrast, nanoparticle conjugation to a highly-soluble peptide did not enhance in vivo distribution. Transfer of both free peptide and peptide-NPs from the skin to LN was reduced in mice lacking lymphoid homing receptor CCR7, suggesting that both are actively transported by migrating dendritic cells to LN. Collectively, these data demonstrate that intradermally administered ultra-small gold nanoparticles can widen the distribution of poorly-soluble auto-antigenic peptides to multiple lymphoid organs, thus enhancing their use as potential therapeutics., (Copyright © 2020. Published by Elsevier Inc.)
- Published
- 2021
- Full Text
- View/download PDF
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