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1
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Tang CL, Lian Z, Ding FR, Liang J, Li XY. Schistosoma-related molecules as a new strategy to combat type 1 diabetes through immune regulation. Parasitol Int 2024; 98:102818. [PMID: 37848126 DOI: 10.1016/j.parint.2023.102818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 09/08/2023] [Accepted: 10/12/2023] [Indexed: 10/19/2023]
Abstract
The study of immune regulation mechanisms induced by parasites may help develop new treatment methods for inflammatory diseases including type 1 diabetes, which is related to type 1 immune responses. The negative correlation between schistosomiasis infection and type 1 diabetes has been confirmed, and the mechanism of Schistosoma-mediated prevention of type 1 diabetes may be related to the adaptive and innate immune systems. Schistosoma-related molecules affect immune cell composition and macrophage polarization and stimulate an increase in natural killer T cells. Furthermore, Schistosoma-related molecules can regulate the adaptive immune responses related to the prevention of type 1 diabetes and change the Th1/Th2 and Th17/Treg axis. Our previous review showed the role of regulatory T cells in the protective of type 1 diabetes mediated by Schistosoma. Here, we aim to review the other mechanisms of schistosomiasis infection and Schistosoma-related products in regulating the immune response associated with the treatment of type 1 diabetes.
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Affiliation(s)
- Chun-Lian Tang
- Wuchang Hospital, Wuhan University of Science and Technology, Wuhan 430063, China
| | - Zhan Lian
- Wuhan Pulmonary Hospital, Wuhan Institute for Tuberculosis Control, Wuhan 430030, China
| | - Fan-Rong Ding
- Wuchang Hospital, Wuhan University of Science and Technology, Wuhan 430063, China
| | - Jun Liang
- Wuhan Pulmonary Hospital, Wuhan Institute for Tuberculosis Control, Wuhan 430030, China.
| | - Xiang-You Li
- Wuchang Hospital, Wuhan University of Science and Technology, Wuhan 430063, China.
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2
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Saini A, Dalal P, Sharma D. Deciphering the Interdependent Labyrinth between Gut Microbiota and the Immune System. Lett Appl Microbiol 2022; 75:1122-1135. [PMID: 35730958 DOI: 10.1111/lam.13775] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 05/18/2022] [Accepted: 06/15/2022] [Indexed: 11/29/2022]
Abstract
The human gut microbiome interacts with each other and the host, which has significant effects on health and disease development. Intestinal homeostasis and inflammation are maintained by the dynamic interactions between gut microbiota and the innate and adaptive immune systems. Numerous metabolic products produced by the gut microbiota play a role in mediating cross-talk between gut epithelial and immune cells. In the event of an imbalance between the immune system and microbiota, the body becomes susceptible to infections, and homeostasis is compromised. This review mainly focuses on the interplay between microbes and the immune system, such as, T-cell and B-cell mediated adaptive responses to microbiota and signaling pathways for effective communication between the two. We have also highlighted the role of microbes in the activation of the immune response, the development of memory cells, and how the immune system determines the diversity of human gut microbiota. The review also explains the relationship of commensal microbiota and their relation in the production of immunoglobulins.
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Affiliation(s)
- Anamika Saini
- Institute of Nano Science and Technology, Knowledge City, Sector 81, Mohali, Punjab, -140306, India.,Amity Institute of Biotechnology, Amity University Jaipur, Rajasthan, 302006
| | - Priyanka Dalal
- Institute of Nano Science and Technology, Knowledge City, Sector 81, Mohali, Punjab, -140306, India
| | - Deepika Sharma
- Institute of Nano Science and Technology, Knowledge City, Sector 81, Mohali, Punjab, -140306, India
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Zipris D. Visceral Adipose Tissue: A New Target Organ in Virus-Induced Type 1 Diabetes. Front Immunol 2021; 12:702506. [PMID: 34421908 PMCID: PMC8371384 DOI: 10.3389/fimmu.2021.702506] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/19/2021] [Indexed: 12/14/2022] Open
Abstract
Type 1 diabetes (T1D) is a proinflammatory pathology that leads to the specific destruction of insulin producing β-cells and hyperglycaemia. Much of the knowledge about type 1 diabetes (T1D) has focused on mechanisms of disease progression such as adaptive immune cells and the cytokines that control their function, whereas mechanisms linked with the initiation of the disease remain unknown. It has been hypothesized that in addition to genetics, environmental factors play a pivotal role in triggering β-cell autoimmunity. The BioBreeding Diabetes Resistant (BBDR) and LEW1.WR1 rats have been used to decipher the mechanisms that lead to virus-induced T1D. Both animals develop β-cell inflammation and hyperglycemia upon infection with the parvovirus Kilham Rat Virus (KRV). Our earlier in vitro and in vivo studies indicated that KRV-induced innate immune upregulation early in the disease course plays a causal role in triggering β-cell inflammation and destruction. Furthermore, we recently found for the first time that infection with KRV induces inflammation in visceral adipose tissue (VAT) detectable as early as day 1 post-infection prior to insulitis and hyperglycemia. The proinflammatory response in VAT is associated with macrophage recruitment, proinflammatory cytokine and chemokine upregulation, endoplasmic reticulum (ER) and oxidative stress responses, apoptosis, and downregulation of adipokines and molecules that mediate insulin signaling. Downregulation of inflammation suppresses VAT inflammation and T1D development. These observations are strikingly reminiscent of data from obesity and type 2 diabetes (T2D) in which VAT inflammation is believed to play a causal role in disease mechanisms. We propose that VAT inflammation and dysfunction may be linked with the mechanism of T1D progression.
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Affiliation(s)
- Danny Zipris
- Innate Biotechnologies LLC, Denver, CO, United States
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4
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Bergamin CS, Pérez-Hurtado E, Oliveira L, Gabbay M, Piveta V, Bittencourt C, Russo D, Carmona RDC, Sato M, Dib SA. Enterovirus Neutralizing Antibodies, Monocyte Toll Like Receptors Expression and Interleukin Profiles Are Similar Between Non-affected and Affected Siblings From Long-Term Discordant Type 1 Diabetes Multiplex-Sib Families: The Importance of HLA Background. Front Endocrinol (Lausanne) 2020; 11:555685. [PMID: 33071971 PMCID: PMC7538605 DOI: 10.3389/fendo.2020.555685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 08/14/2020] [Indexed: 12/15/2022] Open
Abstract
Enteroviruses are main candidates among environmental agents in the development of type 1 diabetes (T1D). However, the relationship between virus and the immune system response during T1D pathogenesis is heterogeneous. This is an interesting paradigm and the search for answers would help to highlight the role of viral infection in the etiology of T1D. The current data is a cross-sectional study of affected and non-affected siblings from T1D multiplex-sib families to analyze associations among T1D, genetic, islet autoantibodies and markers of innate immunity. We evaluated the prevalence of anti-virus antibodies (Coxsackie B and Echo) and its relationships with human leukocyte antigen (HLA) class II alleles, TLR expression (monocytes), serum cytokine profile and islet β cell autoantibodies in 51 individuals (40 T1D and 11 non-affected siblings) from 20 T1D multiplex-sib families and 54 healthy control subjects. The viral antibody profiles were similar among all groups, except for antibodies against CVB2, which were more prevalent in the non-affected siblings. TLR4 expression was higher in the T1D multiplex-sib family's members than in the control subjects. TLR4 expression showed a positive correlation with CBV2 antibody prevalence (rS: 0.45; P = 0.03), CXCL8 (rS: 0.65, P = 0.002) and TNF-α (rS: 0.5, P = 0.01) serum levels in both groups of T1D multiplex-sib family. Furthermore, within these families, there was a positive correlation between HLA class II alleles associated with high risk for T1D and insulinoma-associated protein 2 autoantibody (IA-2A) positivity (odds ratio: 38.8; P = 0.021). However, the HLA protective haplotypes against T1D prevalence was higher in the non-affected than the affected siblings. This study shows that although the prevalence of viral infection is similar among healthy individuals and members from the T1D multiplex-sib families, the innate immune response is higher in the affected and in the non-affected siblings from these families than in the healthy controls. However, autoimmunity against β-islet cells and an absence of protective HLA alleles were only observed in the T1D multiplex-sib members with clinical disease, supporting the importance of the genetic background in the development of T1D and heterogeneity of the interaction between environmental factors and disease pathogenesis despite the high genetic diversity of the Brazilian population.
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Affiliation(s)
- Carla Sanchez Bergamin
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
- *Correspondence: Carla Sanchez Bergamin
| | - Elizabeth Pérez-Hurtado
- Immunology Division, Microbiology, Immunology and Parasitological Department, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
| | - Luanda Oliveira
- Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology and Tropical Medicine Institute of São Paulo, Faculdade de Medicina - Universidade de São Paulo, São Paulo, Brazil
| | - Monica Gabbay
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
| | - Valdecira Piveta
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
| | - Célia Bittencourt
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
| | - Denise Russo
- Enteric Diseases Laboratory, Virology Center From Instituto Adolfo Lutz, São Paulo, Brazil
| | - Rita de Cássia Carmona
- Enteric Diseases Laboratory, Virology Center From Instituto Adolfo Lutz, São Paulo, Brazil
| | - Maria Sato
- Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology and Tropical Medicine Institute of São Paulo, Faculdade de Medicina - Universidade de São Paulo, São Paulo, Brazil
| | - Sergio A. Dib
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
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Pei J, Wei S, Pei Y, Wu H, Wang D. Role of Dietary Gluten in Development of Celiac Disease and Type I Diabetes: Management Beyond Gluten-Free Diet. Curr Med Chem 2019; 27:3555-3576. [PMID: 30963964 DOI: 10.2174/0929867326666190409120716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 03/25/2019] [Accepted: 04/03/2019] [Indexed: 11/22/2022]
Abstract
Gluten triggers Celiac Disease (CD) and type I diabetes in genetically predisposed population of human leukocyte antigen DQ2/DQ8+ and associates with disorders such as schizophrenia and autism. Application of a strict gluten-free diet is the only well-established treatment for patients with CD, whereas the treatment for patients with celiac type I diabetes may be depend on the timing and frequency of the diet. The application of a gluten-free diet in patients with CD may contribute to the development of metabolic syndrome and nonalcoholic fatty liver disease and may also lead to a high glycemic index, low fiber diet and micronutrient deficiencies. The alteration of copper bioavailability (deficient, excess or aberrant coordination) may contribute to the onset and progress of related pathologies. Therefore, nutrient intake of patients on a gluten-free diet should be the focus of future researches. Other gluten-based therapies have been rising with interest such as enzymatic pretreatment of gluten, oral enzyme supplements to digest dietary gluten, gluten removal by breeding wheat varieties with reduced or deleted gluten toxicity, the development of polymeric binders to suppress gluten induced pathology.
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Affiliation(s)
- Jinli Pei
- Hainan Province Key Laboratory for Sustainable Utilization of Tropical Bioresources, Hainan University, Hainan, 570228, China.,Laboratory of Biotechnology and Molecular Pharmacology, School of Life and Pharmaceutical Sciences, Hainan University, Hainan 570228, China
| | - Shuangshuang Wei
- Hainan Province Key Laboratory for Sustainable Utilization of Tropical Bioresources, Hainan University, Hainan, 570228, China.,Laboratory of Biotechnology and Molecular Pharmacology, School of Life and Pharmaceutical Sciences, Hainan University, Hainan 570228, China
| | - Yechun Pei
- Hainan Province Key Laboratory for Sustainable Utilization of Tropical Bioresources, Hainan University, Hainan, 570228, China.,Laboratory of Biotechnology and Molecular Pharmacology, School of Life and Pharmaceutical Sciences, Hainan University, Hainan 570228, China
| | - Hao Wu
- Hainan Province Key Laboratory for Sustainable Utilization of Tropical Bioresources, Hainan University, Hainan, 570228, China.,Laboratory of Biotechnology and Molecular Pharmacology, School of Life and Pharmaceutical Sciences, Hainan University, Hainan 570228, China
| | - Dayong Wang
- Hainan Province Key Laboratory for Sustainable Utilization of Tropical Bioresources, Hainan University, Hainan, 570228, China.,Laboratory of Biotechnology and Molecular Pharmacology, School of Life and Pharmaceutical Sciences, Hainan University, Hainan 570228, China
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6
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Needell JC, Brown MN, Zipris D. Involvement of adipose tissue inflammation and dysfunction in virus-induced type 1 diabetes. J Endocrinol 2018; 238:61-75. [PMID: 29743341 DOI: 10.1530/joe-18-0131] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 05/08/2018] [Indexed: 12/16/2022]
Abstract
The etiopathogenesis of type 1 diabetes (T1D) remains poorly understood. We used the LEW1.WR1 rat model of Kilham rat virus (KRV)-induced T1D to better understand the role of the innate immune system in the mechanism of virus-induced disease. We observed that infection with KRV results in cell influx into visceral adipose tissue soon following infection prior to insulitis and hyperglycemia. In sharp contrast, subcutaneous adipose tissue is free of cellular infiltration, whereas β cell inflammation and diabetes are observed beginning on day 14 post infection. Immunofluorescence studies further demonstrate that KRV triggers CD68+ macrophage recruitment and the expression of KRV transcripts and proinflammatory cytokines and chemokines in visceral adipose tissue. Adipocytes from naive rats cultured in the presence of KRV express virus transcripts and upregulate cytokine and chemokine gene expression. KRV induces apoptosis in visceral adipose tissue in vivo, which is reflected by positive TUNEL staining and the expression of cleaved caspase-3. Moreover, KRV leads to an oxidative stress response and downregulates the expression of adipokines and genes associated with mediating insulin signaling. Activation of innate immunity with Poly I:C in the absence of KRV leads to CD68+ macrophage recruitment to visceral adipose tissue and a decrease in adipokine expression detected 5 days following Poly (I:C) treatment. Finally, proof-of-principle studies show that brief anti-inflammatory steroid therapy suppresses visceral adipose tissue inflammation and protects from virus-induced disease. Our studies provide evidence raising the hypothesis that visceral adipose tissue inflammation and dysfunction may be involved in early mechanisms triggering β cell autoimmunity.
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Affiliation(s)
- James C Needell
- Barbara Davis Center for Childhood DiabetesUniversity of Colorado Denver, Aurora, Colorado, USA
| | - Madalyn N Brown
- Barbara Davis Center for Childhood DiabetesUniversity of Colorado Denver, Aurora, Colorado, USA
| | - Danny Zipris
- Barbara Davis Center for Childhood DiabetesUniversity of Colorado Denver, Aurora, Colorado, USA
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7
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Becher PM, Hinrichs S, Fluschnik N, Hennigs JK, Klingel K, Blankenberg S, Westermann D, Lindner D. Role of Toll-like receptors and interferon regulatory factors in different experimental heart failure models of diverse etiology: IRF7 as novel cardiovascular stress-inducible factor. PLoS One 2018. [PMID: 29538462 PMCID: PMC5851607 DOI: 10.1371/journal.pone.0193844] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Heart failure (HF) is a leading cause of morbidity and mortality in the western world. Although optimal medical care and treatment is widely available, the prognosis of patients with HF is still poor. Toll-like receptors (TLRs) are important compartments of the innate immunity. Current studies have identified TLRs as critical mediators in cardiovascular diseases. In the present study, we investigated the involvement of TLRs and interferon (IFN) regulatory factors (IRFs) in different experimental HF models including viral myocarditis, myocardial ischemia, diabetes mellitus, and cardiac hypertrophy. In addition, we investigated for the first time comprehensive TLR and IRF gene and protein expression under basal conditions in murine and human cardiac tissue. We found that Tlr4, Tlr9 and Irf7 displayed highest gene expression under basal conditions, indicating their significant role in first-line defense in the murine and human heart. Moreover, induction of TLRs and IRFs clearly differs between the various experimental HF models of diverse etiology and the concomitant inflammatory status. In the HF model of acute viral-induced myocarditis, TLR and IRF activation displayed the uppermost gene expression in comparison to the remaining experimental HF models, indicating the highest amount of myocardial inflammation in myocarditis. In detail, Irf7 displayed by far the highest gene expression during acute viral infection. Interestingly, post myocardial infarction TLR and IRF gene expression was almost exclusively increased in the infarct zone after myocardial ischemia (Tlr2, Tlr3, Tlr6, Tlr7, Tlr9, Irf3, Irf7). With one exception, Irf3 showed a decreased gene expression in the remote zone post infarction. Finally, we identified Irf7 as novel cardiovascular stress-inducible factor in the pathologically stressed heart. These findings on TLR and IRF function in the inflamed heart highlight the complexity of inflammatory immune response and raise more interesting questions for future investigation.
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Affiliation(s)
- Peter Moritz Becher
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
- * E-mail:
| | - Svenja Hinrichs
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
- DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Nina Fluschnik
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
| | - Jan K. Hennigs
- Section Pneumology, Department of Medicine II, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Karin Klingel
- Cardiopathology, Institute for Pathology and Neuropathology, Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Stefan Blankenberg
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
- DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Dirk Westermann
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
- DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Diana Lindner
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
- DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
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Abstract
PURPOSE OF REVIEW Despite immense research efforts, type 1 diabetes (T1D) remains an autoimmune disease without a known trigger or approved intervention. Over the last three decades, studies have primarily focused on delineating the role of the adaptive immune system in the mechanism of T1D. The discovery of Toll-like receptors in the 1990s has advanced the knowledge on the role of the innate immune system in host defense as well as mechanisms that regulate adaptive immunity including the function of autoreactive T cells. RECENT FINDINGS Recent investigations suggest that inflammation plays a key role in promoting a large number of autoimmune disorders including T1D. Data from the LEW1.WR1 rat model of virus-induced disease and the RIP-B7.1 mouse model of diabetes suggest that innate immune signaling plays a key role in triggering disease progression. There is also evidence that innate immunity may be involved in the course of T1D in humans; however, a small number of clinical trials have shown that interfering with the function of the innate immune system following disease onset exerts only a modest effect on β-cell function. The data implying that innate immune pathways are linked with mechanisms of islet autoimmunity hold great promise for the identification of novel disease pathways that may be harnessed for clinical intervention. Nevertheless, more work needs to be done to better understand mechanisms by which innate immunity triggers β-cell destruction and assess the therapeutic value in blocking innate immunity for diabetes prevention.
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Affiliation(s)
- James C Needell
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, 80045, USA
| | - Danny Zipris
- Innate Biotechnologies LLC, Denver, CO, 80231, USA.
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Roberts FR, Hupple C, Norowski E, Walsh NC, Przewozniak N, Aryee KE, Van Dessel FM, Jurczyk A, Harlan DM, Greiner DL, Bortell R, Yang C. Possible type 1 diabetes risk prediction: Using ultrasound imaging to assess pancreas inflammation in the inducible autoimmune diabetes BBDR model. PLoS One 2017; 12:e0178641. [PMID: 28605395 PMCID: PMC5468055 DOI: 10.1371/journal.pone.0178641] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 05/16/2017] [Indexed: 11/26/2022] Open
Abstract
Background/Aims Studies of human cadaveric pancreas specimens indicate that pancreas inflammation plays an important role in type 1 diabetes pathogenesis. Due to the inaccessibility of pancreas in living patients, imaging technology to visualize pancreas inflammation is much in need. In this study, we investigated the feasibility of utilizing ultrasound imaging to assess pancreas inflammation longitudinally in living rats during the progression leading to type 1 diabetes onset. Methods The virus-inducible BBDR type 1 diabetes rat model was used to systematically investigate pancreas changes that occur prior to and during development of autoimmunity. The nearly 100% diabetes incidence upon virus induction and the highly consistent time course of this rat model make longitudinal imaging examination possible. A combination of histology, immunoblotting, flow cytometry, and ultrasound imaging technology was used to identify stage-specific pancreas changes. Results Our histology data indicated that exocrine pancreas tissue of the diabetes-induced rats underwent dramatic changes, including blood vessel dilation and increased CD8+ cell infiltration, at a very early stage of disease initiation. Ultrasound imaging data revealed significant acute and persistent pancreas inflammation in the diabetes-induced rats. The pancreas micro-vasculature was significantly dilated one day after diabetes induction, and large blood vessel (superior mesenteric artery in this study) dilation and inflammation occurred several days later, but still prior to any observable autoimmune cell infiltration of the pancreatic islets. Conclusions Our data demonstrate that ultrasound imaging technology can detect pancreas inflammation in living rats during the development of type 1 diabetes. Due to ultrasound’s established use as a non-invasive diagnostic tool, it may prove useful in a clinical setting for type 1 diabetes risk prediction prior to autoimmunity and to assess the effectiveness of potential therapeutics.
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Affiliation(s)
| | | | - Elaine Norowski
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Nicole C. Walsh
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Natalia Przewozniak
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Ken-Edwin Aryee
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Filia M. Van Dessel
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Agata Jurczyk
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - David M. Harlan
- Department of Medicine, University of Massachusetts Medical School, Massachusetts, United States of America
| | - Dale L. Greiner
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Rita Bortell
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Chaoxing Yang
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
- * E-mail:
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10
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Cabrera SM, Henschel AM, Hessner MJ. Innate inflammation in type 1 diabetes. Transl Res 2016; 167:214-27. [PMID: 25980926 PMCID: PMC4626442 DOI: 10.1016/j.trsl.2015.04.011] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Revised: 04/02/2015] [Accepted: 04/21/2015] [Indexed: 02/06/2023]
Abstract
Type 1 diabetes mellitus (T1D) is an autoimmune disease often diagnosed in childhood that results in pancreatic β-cell destruction and life-long insulin dependence. T1D susceptibility involves a complex interplay between genetic and environmental factors and has historically been attributed to adaptive immunity, although there is now increasing evidence for a role of innate inflammation. Here, we review studies that define a heightened age-dependent innate inflammatory state in T1D families that is paralleled with high fidelity by the T1D-susceptible biobreeding rat. Innate inflammation may be driven by changes in interactions between the host and environment, such as through an altered microbiome, intestinal hyperpermeability, or viral exposures. Special focus is put on the temporal measurement of plasma-induced transcriptional signatures of recent-onset T1D patients and their siblings as well as in the biobreeding rat as it defines the natural history of innate inflammation. These sensitive and comprehensive analyses have also revealed that those who successfully managed T1D risk develop an age-dependent immunoregulatory state, providing a possible mechanism for the juvenile nature of T1D. Therapeutic targeting of innate inflammation has been proven effective in preventing and delaying T1D in rat models. Clinical trials of agents that suppress innate inflammation have had more modest success, but efficacy may be improved by the addition of combinatorial approaches that target other aspects of T1D pathogenesis. An understanding of innate inflammation and mechanisms by which this susceptibility is both potentiated and mitigated offers important insight into T1D progression and avenues for therapeutic intervention.
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Affiliation(s)
- Susanne M. Cabrera
- The Max McGee National Research Center for Juvenile Diabetes, Children’s Research Institute of Children’s Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Angela M. Henschel
- The Max McGee National Research Center for Juvenile Diabetes, Children’s Research Institute of Children’s Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Martin J. Hessner
- The Max McGee National Research Center for Juvenile Diabetes, Children’s Research Institute of Children’s Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
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11
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Bergamin CS, Dib SA. Enterovirus and type 1 diabetes: What is the matter? World J Diabetes 2015; 6:828-839. [PMID: 26131324 PMCID: PMC4478578 DOI: 10.4239/wjd.v6.i6.828] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 01/30/2015] [Accepted: 04/09/2015] [Indexed: 02/05/2023] Open
Abstract
A complex interaction of genetic and environmental factors can trigger the immune-mediated mechanism responsible for type 1 diabetes mellitus (T1DM) establishment. Environmental factors may initiate and possibly sustain, accelerate, or retard damage to β-cells. The role of environmental factors in this process has been exhaustive studied and viruses are among the most probable ones, especially enteroviruses. Improvements in enterovirus detection methods and randomized studies with patient follow-up have confirmed the importance of human enterovirus in the pathogenesis of T1DM. The genetic risk of T1DM and particular innate and acquired immune responses to enterovirus infection contribute to a tolerance to T1DM-related autoantigens. However, the frequency, mechanisms, and pathways of virally induced autoimmunity and β-cell destruction in T1DM remain to be determined. It is difficult to investigate the role of enterovirus infection in T1DM because of several concomitant mechanisms by which the virus damages pancreatic β-cells, which, consequently, may lead to T1DM establishment. Advances in molecular and genomic studies may facilitate the identification of pathways at earlier stages of autoimmunity when preventive and therapeutic approaches may be more effective.
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12
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Gottlieb PA, Alkanani AK, Michels AW, Lewis EC, Shapiro L, Dinarello CA, Zipris D. α1-Antitrypsin therapy downregulates toll-like receptor-induced IL-1β responses in monocytes and myeloid dendritic cells and may improve islet function in recently diagnosed patients with type 1 diabetes. J Clin Endocrinol Metab 2014; 99:E1418-26. [PMID: 24527714 PMCID: PMC4121034 DOI: 10.1210/jc.2013-3864] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Recent studies have implicated proinflammatory responses in the mechanism of type 1 diabetes (T1D). OBJECTIVE Our objective was to evaluate the safety and effects of therapy with the anti-inflammatory serum protein α1-antitrypsin (AAT) on islet function and innate immunity in recent-onset patients. DESIGN AND SETTING This was an open-label phase I trial at the Barbara Davis Center for Childhood Diabetes, University of Colorado Denver. PATIENTS Twelve recently diagnosed subjects with T1D with detectable C-peptides were included in the study. INTERVENTION Eight consecutive weekly infusions of 80 mg/kg of AAT were given. MAIN OUTCOME MEASURES PATIENTS were monitored for adverse effects of AAT therapy, C-peptide responses to a mixed-meal tolerance test, and toll-like receptor (TLR)-induced cellular IL-1β in monocytes and myeloid dendritic cells (mDCs). RESULTS No adverse effects were detected. AAT led to increased, unchanged, or moderately reduced levels of C-peptide responses compared with baseline in 5 patients. The total content of TLR4-induced cellular IL-1β in monocytes at 12 months after AAT therapy was 3-fold reduced compared with baseline (P < .05). Furthermore, at baseline, 82% of monocytes produced IL-1β, but at 12 months after therapy, the level decreased to 42%. Similar reductions were observed using TLR7/8 and TLR3 agonists in monocytes and mDCs. Unexpectedly, the reduction in cellular IL-1β was observed only 9 and 12 months after treatment but not in untreated diabetics. Improved β-cell function in the 5 AAT-treated individuals correlated with lower frequencies of monocytes and mDCs producing IL-1β compared with subjects without improvement of islet function (P < .04 and P < .02, respectively). CONCLUSIONS We hypothesize that AAT may have a beneficial effect on T1D in recently diagnosed patients that is associated with downmodulation of IL-1β.
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Affiliation(s)
- Peter A Gottlieb
- Barbara Davis Center for Childhood Diabetes (P.A.G., A.K.A., A.W.M., D.Z.) and Division of Infectious Diseases (C.A.D.), University of Colorado Denver, Aurora, Colorado 80045; Department of Clinical Biochemistry and Pharmacology (E.C.L.), Faculty of Health Sciences, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel; and Department of Medicine (L.S.), Division of Infectious Diseases, Veterans Affairs Medical Center and University of Colorado Denver, Denver, Colorado 80202
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Alkanani AK, Hara N, Lien E, Ir D, Kotter CV, Robertson CE, Wagner BD, Frank DN, Zipris D. Induction of diabetes in the RIP-B7.1 mouse model is critically dependent on TLR3 and MyD88 pathways and is associated with alterations in the intestinal microbiome. Diabetes 2014; 63:619-31. [PMID: 24353176 DOI: 10.2337/db13-1007] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
RIP-B7.1 transgenic mice express B7.1 costimulatory molecules in pancreatic islets and develop diabetes after treatment with polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA and agonist of Toll-like receptor (TLR) 3 and retinoic acid-inducible protein I. We used this model to investigate the role of TLR pathways and intestinal microbiota in disease progression. RIP-B7.1 mice homozygous for targeted disruption of TLR9, TLR3, and myeloid differentiation factor-88 (MyD88), and most of the wild-type RIP-B7.1 mice housed under normal conditions remained diabetes-free after poly I:C administration. However, the majority of TLR9-deficient mice and wild-type animals treated with poly I:C and an antibiotic developed disease. In sharp contrast, TLR3- and MyD88-deficient mice were protected from diabetes following the same treatment regimen. High-throughput DNA sequencing demonstrated that TLR9-deficient mice treated with antibiotics plus poly I:C had higher bacterial diversity compared with disease-resistant mice. Furthermore, principal component analysis suggested that TLR9-deficient mice had distinct gut microbiome compared with the diabetes-resistant mice. Finally, the administration of sulfatrim plus poly I:C to TLR9-deficient mice resulted in alterations in the abundance of gut bacterial communities at the phylum and genus levels. These data imply that the induction of diabetes in the RIP-B7.1 model is critically dependent on TLR3 and MyD88 pathways, and involves modulation of the intestinal microbiota.
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Affiliation(s)
- Aimon K Alkanani
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
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Bouças AP, Oliveira FDSD, Canani LH, Crispim D. The role of interferon induced with helicase C domain 1 (IFIH1) in the development of type 1 diabetes mellitus. ACTA ACUST UNITED AC 2013; 57:667-76. [DOI: 10.1590/s0004-27302013000900001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 09/10/2013] [Indexed: 12/12/2022]
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic, progressive, autoimmune disease characterized by metabolic decompensation frequently leading to dehydration and ketoacidosis. Viral pathogens seem to play a major role in triggering the autoimmune destruction that leads to the development of T1DM. Among several viral strains investigated so far, enteroviruses have been consistently associated with T1DM in humans. One of the mediators of viral damage is the double-stranded RNA (dsRNA) generated during replication and transcription of viral RNA and DNA. The IFIH1 gene encodes a cytoplasmic receptor of the pattern-recognition receptors (PRRs) family that recognizes dsRNA, playing a role in the innate immune response triggered by viral infection. Binding of dsRNA to this PRR triggers the release of proinflammatory cytokines, such as interferons (IFNs), which exhibit potent antiviral activity, protecting uninfected cells and inducing apoptosis of infected cells. The IFIH1 gene appears to play a major role in the development of some autoimmune diseases, and it is, therefore, a candidate gene for T1DM. Within this context, the objective of the present review was to address the role of IFIH1 in the development of T1DM.
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Affiliation(s)
- Ana Paula Bouças
- Universidade Federal do Rio Grande do Sul, Brazil; UFRGS, Brazil
| | | | | | - Daisy Crispim
- Universidade Federal do Rio Grande do Sul, Brazil; UFRGS, Brazil
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Yang C, diIorio P, Jurczyk A, O'Sullivan-Murphy B, Urano F, Bortell R. Pathological endoplasmic reticulum stress mediated by the IRE1 pathway contributes to pre-insulitic beta cell apoptosis in a virus-induced rat model of type 1 diabetes. Diabetologia 2013; 56:2638-46. [PMID: 24121653 PMCID: PMC4845659 DOI: 10.1007/s00125-013-3044-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 08/15/2013] [Indexed: 01/06/2023]
Abstract
AIMS/HYPOTHESIS We hypothesised that pathological endoplasmic reticulum (ER) stress contributes to beta cell death during development of type 1 diabetes. In this study, we investigated the occurrence of beta cell ER stress and the signalling pathways involved during discrete stages of autoimmune diabetes progression. The virus-inducible BBDR rat model was used to systematically interrogate the three main ER stress signalling pathways (IRE1 [inositol-requiring protein-1], PERK [double-stranded RNA-dependent protein kinase (PKR)-like ER kinase] and ATF6 [activating transcription factor 6]) in pancreatic beta cells during type 1 diabetes development. METHODS ER stress and apoptotic markers were assessed by immunoblot analyses of isolated pancreatic islets and immunofluorescence staining of pancreas sections from control and virus-induced rats. Various time points were analysed: (1) early stages preceding the development of insulitis and (2) a late stage during onset and progression of insulitis, which precedes overt hyperglycaemia. RESULTS The IRE1 pathway, including its downstream component X-box-binding protein 1, was specifically activated in pancreatic beta cells of virus-induced rats at early stages preceding the development of insulitis. Furthermore, ER stress-specific pro-apoptotic caspase 12 and effector caspase 3 were also activated at this stage. Activation of PERK and its downstream effector pro-apoptotic CHOP (CCAAT/-enhancer-binding-protein homologous protein), only occurred during late stages of diabetes induction concurrent with insulitis, whereas ATF6 activation in pancreatic beta cells was similar in control and virus-induced rats. CONCLUSIONS/INTERPRETATION Activation of the IRE1 pathway and ER stress-specific pro-apoptotic caspase 12, before the development of insulitis, are indicative of ER stress-mediated beta cell damage. The early occurrence of pathological ER stress and death in pancreatic beta cells may contribute to the initiation and/or progression of virus-induced autoimmune diabetes.
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Affiliation(s)
- Chaoxing Yang
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
- Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA
| | - Philip diIorio
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
- Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA
| | - Agata Jurczyk
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
- Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA
| | - Bryan O'Sullivan-Murphy
- Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA
| | - Fumihiko Urano
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO
- Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Rita Bortell
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
- Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA
- Correspondence should be addressed to Rita Bortell, PhD, Program in Molecular Medicine, 368 Plantation Street, AS7-2055, Worcester, MA 01605. Phone: 508-856-3788, Fax: 508-856-4093,
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Histone deacetylase inhibitor suppresses virus-induced proinflammatory responses and type 1 diabetes. J Mol Med (Berl) 2013; 92:93-102. [PMID: 23982318 DOI: 10.1007/s00109-013-1078-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Revised: 07/02/2013] [Accepted: 08/14/2013] [Indexed: 01/04/2023]
Abstract
UNLABELLED Microbial infections are hypothesized to play a key role in the mechanism leading to type 1 diabetes (T1D). We used the LEW1.WR1 rat model of Kilham rat virus (KRV)-induced islet destruction to better understand how virus infection triggers T1D. Inoculation of the LEW1.WR1 rat with KRV results in systemic inflammation followed by insulitis and islet destruction 2-4 weeks post-infection. In this study, we evaluated the effect of treatment with the anti-inflammatory histone deacetylase inhibitor (HDACi) ITF-2357 on KRV-induced immunity and disease progression. Administering LEW1.WR1 rats with KRV plus ITF-2357 on 14 consecutive days beginning on the day of infection protected animals from islet infiltration and T1D. ITF-2357 reversed KRV-induced T and B cell accumulation in the spleen or pancreatic lymph nodes on day 5 following infection. Moreover, ITF-2357 reduced the expression level of KRV-induced p40 subunit of IL-12/IL-23 in spleen cells in vitro and in the peripheral blood in vivo. ITF-2357 suppressed the KRV-induced expression of transcripts for IRF-7 in the rat INS-1 beta cell line. ITF-2357 increased the virus-induced IL-6 gene expression in the spleen, but did not alter the ability of LEW1.WR1 rats to develop normal KRV-specific humoral and cellular immune responses and clear the virus from the pancreatic lymph nodes, spleen, and serum. Finally, ITF-2357 reversed virus-induced modulation of bacterial communities in the intestine early following infection. The data suggest that targeting innate immune pathways with inhibitors of HDAC might represent an efficient therapeutic strategy for preventing T1D. KEY MESSAGE Microbial infections have been implicated in triggering type 1 diabetes in humans and animal models. The LEW1.WR1 rat develops inflammation and T1D following infection with Kilham rat virus. The histone deacetylase inhibitor ITF-2357 suppresses virus-induced inflammation and prevents diabetes. ITF-2357 prevents T1D without altering virus-specific adaptive immunity or virus clearance. ITF-2357 therapy may be an efficient approach to prevent T1D in genetically susceptible individuals.
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Zipris D. The interplay between the gut microbiota and the immune system in the mechanism of type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 2013; 20:265-70. [PMID: 23743644 DOI: 10.1097/med.0b013e3283628569] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW Discuss recent data linking the intestinal microbiome with mechanisms of inflammation and islet destruction. RECENT FINDINGS Type 1 diabetes (T1D) is a proinflammatory disease that results in the loss of insulin-producing beta cells. How T1D is triggered is unclear; however, both genetic and environmental factors were implicated in disease mechanisms. Emerging evidence supports the notion that there is a complex interaction between the intestinal microbiome and the immune system and this cross-talk is involved in maintaining normal immune homeostasis in the gut and periphery. Under some circumstances the gut microbiota could lead to pathogenic immune responses resulting in inflammation in the intestine as well as other organs. Indeed, recent data from genetically susceptible individuals suggested that alterations in gut bacterial communities may be involved in the mechanism of islet destruction. Studies performed in animal models of T1D indicated that manipulating the gut microbiome can protect from islet destruction via mechanisms that may involve down-regulating both the adaptive and innate immune systems. SUMMARY Further work is required to identify specific bacterial communities and mechanisms involved in triggering T1D. A better knowledge of the role of the gut microbiome in islet destruction could lead to new clinical interventions to restore healthy homeostasis and prevent disease development.
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Affiliation(s)
- Danny Zipris
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado 80045–6511 , USA.
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Current world literature. Curr Opin Endocrinol Diabetes Obes 2013; 20:156-60. [PMID: 23434800 DOI: 10.1097/med.0b013e32835f8a71] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Hara N, Alkanani AK, Ir D, Robertson CE, Wagner BD, Frank DN, Zipris D. The role of the intestinal microbiota in type 1 diabetes. Clin Immunol 2012; 146:112-9. [PMID: 23314185 DOI: 10.1016/j.clim.2012.12.001] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Revised: 11/30/2012] [Accepted: 12/01/2012] [Indexed: 02/07/2023]
Abstract
The digestive tract hosts trillions of bacteria that interact with the immune system and can influence the balance between pro-inflammatory and regulatory immune responses. Recent studies suggest that alterations in the composition of the intestinal microbiota may be linked with the development of type 1 diabetes (T1D). Data from the biobreeding diabetes prone (BBDP) and the LEW1.WR1 models of T1D support the hypothesis that intestinal bacteria may be involved in early disease mechanisms. The data indicate that cross-talk between the gut microbiota and the innate immune system may be involved in islet destruction. Whether a causal link between intestinal microbiota and T1D exists, the identity of the bacteria and the mechanism whereby they promote the disease remain to be examined. A better understanding of the interplay between microbes and innate immune pathways in early disease stages holds promise for the design of immune interventions and disease prevention in genetically susceptible individuals.
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Affiliation(s)
- Naoko Hara
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO 80045, USA
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Hara N, Alkanani AK, Ir D, Robertson CE, Wagner BD, Frank DN, Zipris D. Prevention of virus-induced type 1 diabetes with antibiotic therapy. THE JOURNAL OF IMMUNOLOGY 2012; 189:3805-14. [PMID: 22988033 DOI: 10.4049/jimmunol.1201257] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Microbes were hypothesized to play a key role in the progression of type 1 diabetes (T1D). We used the LEW1.WR1 rat model of Kilham rat virus (KRV)-induced T1D to test the hypothesis that the intestinal microbiota is involved in the mechanism leading to islet destruction. Treating LEW1.WR1 rats with KRV and a combination of trimethoprim and sulfamethoxazole (Sulfatrim) beginning on the day of infection protected the rats from insulitis and T1D. Pyrosequencing of bacterial 16S rRNA and quantitative RT-PCR indicated that KRV infection resulted in a transient increase in the abundance of Bifidobacterium spp. and Clostridium spp. in fecal samples from day 5- but not day 12-infected versus uninfected animals. Similar alterations in the gut microbiome were observed in the jejunum of infected animals on day 5. Treatment with Sulfatrim restored the level of intestinal Bifidobacterium spp. and Clostridium spp. We also observed that virus infection induced the expression of KRV transcripts and the rapid upregulation of innate immune responses in Peyer's patches and pancreatic lymph nodes. However, antibiotic therapy reduced the virus-induced inflammation as reflected by the presence of lower amounts of proinflammatory molecules in both the Peyer's patches and pancreatic lymph nodes. Finally, Sulfatrim treatment reduced the number of B cells in Peyer's patches and downmodulated adaptive immune responses to KRV, but did not interfere with antiviral Ab responses or viral clearance from the spleen, pancreatic lymph nodes, and serum. The data suggest that gut microbiota may be involved in promoting virus-induced T1D in the LEW1.WR1 rat model.
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Affiliation(s)
- Naoko Hara
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO 80045, USA
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