Cellular and molecular mechanisms underlying immune tolerance against type 1 diabetes

2016 ◽  
Author(s):  
◽  
Weirong Chen
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Molecular Mechanisms ◽  
Antigen Presenting Cells ◽  
Insulin Dependent Diabetes Mellitus ◽  
The United States ◽  
Dependent Diabetes Mellitus ◽  
Glucose Levels ◽  
Antigen Presenting

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Type 1 diabetes (T1D), also known as insulin-dependent diabetes mellitus, is a chronic autoimmune disease caused by the destruction of insulin-producing beta-cells in the pancreatic islets by self-reactive immune cells. About three million Americans have T1D currently and each year there are more than 30,000 new T1D cases in the United States. Hyperglycemia in T1D patients may affect major organs and cause complications including cardiovascular diseases, nerve damage, kidney problems, blindness, and amputation. Unfortunately, there is no cure for T1D and T1D patients have to rely on life-long insulin replacement to maintain blood glucose levels in the normal range. Therefore, immunotherapies which target pathogenic T cells specifically while circumventing broad immune suppression are desired to treat T1D. Our lab has incorporated a mimotope p79 into an Ig molecule, and the resulting Ig-p79 chimera is able to prevent the adoptive transfer of T1D in NOD.scid mice by diabetogenic BDC2.5 T cells. Consequently, these T cells are retained in the spleen and cannot migrate to the pancreas due to diminished expression of the transcription factor T-bet and chemokine receptor CXCR3. Moreover, we found mTOR, a key serine/threonine protein kinase, is the major target of Ig-p79 and T cells undergoing antigen-induced tolerance have an impaired function of mTORC1, but not mTORC2. This mechanism is brought about by antigen presenting cells through upregulation of PD-L1 inhibitory molecules. Under this circumstance, PDL1 on antigen presenting cells interacts specifically with PD-1 on T cells, leading to recruitment of SHP-2 phosphatase to the cytoplasmic tail of PD-1. Active SHP-2 then induces dephosphorylation of phosphatidylinositol-3-kinase protein, which in turn results in the defective activity of mTORC1, diminished expression of CXCR3 and suppression of T1D development. Thus, our findings suggest that drugs that target mTORC1 in diabetogenic T cells would provide an approach to prevent and treat T1D. Moreover, this study also opens a new avenue for antigen presenting cells that express high levels of PD-L1 as means to induce tolerance of pathogenic T cells in T1D patients.

scholarly journals Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type-1 diabetes

2020 ◽  
Author(s):  
Heejoo Kim ◽  
Jelena Perovanovic ◽  
Arvind Shakya ◽  
Zuolian Shen ◽  
Cody N. German ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Target Genes ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Glucose Levels ◽  
Transcriptional Coregulator

AbstractThe transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present, but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice, but diminished in monoclonal models specific to artificial or neoantigens. Rationally-designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels, and reduced T cell infiltration and proinflammatory cytokine expression in newly-diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.~40-word summary statement for the online JEM table of contents and alertsKim and colleagues show that OCA-B in T cells is essential for the generation of type-1 diabetes. OCA-B loss leaves the pancreatic lymph nodes largely undisturbed, but associates autoreactive CD4+ T cells in the pancreas with anergy while deleting potentially autoreactive CD8+ T cells.SummaryKim et al. show that loss or inhibition of OCA-B in T cells protects mice from type-1 diabetes.

scholarly journals Metallothionein expression in slow- vs. fast-twitch muscle fibers following 4 weeks of streptozotocin-induced type 1 diabetes

FACETS ◽  
2018 ◽  
Vol 3 (1) ◽  
pp. 315-325 ◽  
Author(s):  
Pamela Mondragon ◽  
Andreas Bergdahl
Keyword(s):  
Oxidative Stress ◽  
Type 1 Diabetes ◽  
Molecular Mechanisms ◽  
Protein Carbonyl ◽  
Glucose Levels ◽  
Significant Difference ◽  
Streptozotocin Induced Diabetes ◽  
Carbonyl Formation ◽  
Fast Twitch

Type 1 diabetes (T1DM) is known to cause an increase in reactive oxygen species (ROS) and elevated intracellular glucose levels. We investigated the metallothionein I and II (MT I+II) antioxidants expression in soleus (mainly slow-twitch) and plantaris (predominantly fast-twitch) skeletal muscle using a rodent model of streptozotocin-induced diabetes. The presence of oxidative stress was confirmed by the detection of increased levels of protein carbonyl formation in the diabetic tissues. DAB (3,3′-diaminobenzidine) immunostaining and Western blotting analyses demonstrated that MT I+II expression was significantly upregulated in the diabetic soleus and plantaris muscle tissues compared with their respective controls. Moreover, no significant difference was detected between the plantaris and soleus controls or between the plantaris and soleus diabetic tissues. These findings suggest that there is an increase in MT protein expression in the soleus and plantaris muscles associated with the induction of T1DM. A better understanding of the molecular mechanisms that allow MT to prevent the oxidative stress associated with diabetes could lead to a novel therapeutic strategy for this chronic disease and its associated complications.

Association of HLA-DRB1 and -DQ Alleles and Haplotypes with Type 1 Diabetes in Jordanians

2020 ◽  
Vol 20 (6) ◽  
pp. 895-902 ◽  
Author(s):  
Sawsan I. Khdair ◽  
Wassan Jarrar ◽  
Yazun Bashir Jarrar ◽  
Safa’a Bataineh ◽  
Omar Al-Khaldi
Keyword(s):  
Type 1 Diabetes ◽  
Human Leukocyte ◽  
Positive Association ◽  
Insulin Dependent Diabetes Mellitus ◽  
Class Ii ◽  
Protective Role ◽  
Hla Class Ii ◽  
Dependent Diabetes Mellitus ◽  
Risk Alleles

Background: The Human Leukocyte Antigen (HLA) class II genes, particularly the HLADR and -DQ loci, have been shown to play a crucial role in Type 1 Diabetes (T1D) development. Objective: This study is the first to examine the contribution of the HLA-DR/DQ alleles and haplotypes to T1D susceptibility in Jordanians. Methods: Polymerase chain reaction sequence-specific primers (PCR-SSP) were used to genotype 41 Jordanian healthy controls and 50 insulin-dependent diabetes mellitus (IDDM) patients. Results: The following alleles were found to be significant high risk alleles in T1D Jordanian patients: DRB1*04 (OR=3.95, p<0.001), DRB1*0301(OR=5.27, p<0.001), DQA1*0301 (OR=5.67, p<0.001), DQA1*0501(OR=3.18, p=0.002), DQB1*0201(OR=2.18, p=0.03), DQB1*0302 (OR=5.67, p<0.001). However, Jordanians harboring the DRB1*0701 (OR=0.37, p=0.01), DRB1*1101 (OR=0.2, p=0.01), DQA1*0505 (OR=0.31, p=0.02), DQA1*0103 (OR=0.33, p=0.04), DQA1*0201 (OR=0.45, p=0.04), DQB1*0301 (OR=0.23, p=0.001), DQB1*0501 (OR=0.18, p=0.009) alleles had a significantly lower risk of developing T1D. Conclusion: A strong positive association of DRB1*04-DQA1*0301-DQBl*0302 (OR=5.67, p<0.001) and DRB1*0301-DQA1*0501-DQB1*0201 (OR=6.24, p<0.001) putative haplotypes with IDDM was evident in Jordanian IDDM patients whereas DRB1*1101-DQA1*0505- DQB1*0301 (OR=0.23, p=0.03) was shown to have a protective role against T1D in Jordanians. Our findings show that specific HLA class II alleles and haplotypes are significantly associated with susceptibility to T1D in Jordanians.

Ikaros Deficiency Enhances Notch Signaling in Host Antigen Presenting Cells and Differentially Regulates Gvhd and GVL Responses After Experimental BMT.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 690-690
Author(s):  
Tomomi Toubai ◽  
Yaping Sun ◽  
Isao Tawara ◽  
Chelsea Malter ◽  
Kathleen Lowler ◽  
...  
Keyword(s):  
T Cells ◽  
Notch Signaling ◽  
Research Funding ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Antigen Presenting Cells ◽  
Lymphoid Cells ◽  
Clinical Severity ◽  
Comprehensive Cancer Center ◽  
Antigen Presenting

Abstract Abstract 690 Host antigen presenting cells (APCs) are necessary for induction of graft-versus-host (GVH) responses. But the APC autonomous molecular mechanisms that are critical for modulation of GVH are not known. Ikaros (Ik) is a zinc-finger DNA binding protein that is essential for the development of lymphoid cells and hematological malignancies. Because Ik is known to negatively regulate certain dendritic cell (DC), the most potent APCs, functions (Wu et al, Immunity, 1997) we hypothesized that its deficiency in host APCs will reduce GVHD. We generated [B6→B6] and [Ik-/-B6→B6] chimeras and utilized them as recipients in well characterized MHC matched, minor mismatched C3H.SW B6 model of acute GVHD. [B6→B6] and [Ik/-B6 → B6] animals received 9 Gy and were transplanted with 3 × 106 T cells and 5 × 106 BM from either syngeneic B6 or allogeneic C3H.SW donors. Contrary to our hypothesis, [Ik-/-B6 < 0.001). The increase in mortality was associated with a significant increase in GVHD specific clinical severity, histopathological damage of the liver and GI tract, donor T cell expansion, serum levels TNF-αa, IFNγ and IL-17 on days +7 and +14 after BMT. Similar results were obtained in a second, BALB/c→B6 model of GVHD and also in recipient chimeras generated from dominant negative Ikaros (IkDN) mice, demonstrating a role for Ik in a strain independent manner. We next performed systematic analyses of DCs to uncover the mechanisms underpinning our surprising results. Phenotypic analysis of spleen and BM derived DCs demonstrated similar numbers of CD8+ and CD8-CD11c+DCs but a reduced number of pDCs were present in Ik-/- animals when compared with WT animals. Ik-/-DCs demonstrated an immature phenotype as determined by the expression of CD40/80. By contrast, functional analyses of Ik-/- DCs, when stimulated with LPS showed significantly greater secretion of proinflammatory cytokines TNF-αa and IL-6 and greater stimulation of allo-T cells in MLRs when compared with WT B6 DCs. CFSE, annexin and CD107a labeling studies demonstrated that Ik-/-DCs caused greater proliferation without altering the rate of apoptosis or the cytotoxic function of the allo-T cells. To characterize the molecular mechanisms we evaluated the role of putative molecular targets of Ikaros, the Notch signaling pathway because Ikaros and Notch antagonistically regulate target genes (Chari et al. J Immunol 2008 and Bugeon, et al. J Immunol 2008). Both Ik-/- and IkDN DCs, at steady state, showed an increase in the expression of several Notch target genes such as Hes-1, Hex-1, Deltex1, Notch3, Jagged-1 and Jagged-2. Blockade of Notch signaling with γ-secretase inhibitor (DAPT) in MLR mitigated the enhanced allo-stimulatory capacity of the Ik-/- DCs, thus demonstrating a functional relevance for enhanced notch signaling in the absence of Ikaros. We next hypothesized that given the enhanced GVHD response that was associated with increased proliferation and preserved cytotoxicity of allo-T cells, the GVL response will also be enhanced in the recipients with Ik-/- APCs. Unexpectedly, the [B6→ B6] and [Ik-/-B6 → B6] chimeras when transplanted with allogeneic T cells from C3H.SW cells along with two different doses of syngeneic 0.5 or 1×104 MBL-2 tumor cells demonstrated equivalent GVL responses despite greater severity of GVHD. Together our data demonstrate (a) for the first time, to our knowledge, suggest differential regulation of GVHD and GVL at the level of host APCs and (b) show a role for a novel molecular pathway, the Ik-Notch axis, in the host APCs as an important modulator of GVH responses. Disclosures: Maillard: University of Michigan Comprehensive Cancer Center: Research Funding; Damon Runyon Cancer Foundation: Research Funding; ASH Scholar Awards : Research Funding.

Insulin-Dependent Diabetes Mellitus, Myasthenia Gravis, Pernicious Anaemia, Autoimmune Thyroiditis and Autoimmune Adrenalitis in a Single Patient

1988 ◽  
Vol 33 (1) ◽  
pp. 213-214 ◽  
Author(s):  
S. T. Green ◽  
J. P. Ng ◽  
D. Chan-Lam
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Myasthenia Gravis ◽  
Type 1 Diabetes Mellitus ◽  
Pernicious Anaemia ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Autoimmune Conditions

Two classical autoimmune polyendocrine deficiency syndromes with heritable tendencies are described, Type 1 diabetes mellitus being associated with the Type 2 polyendocrine deficiency syndrome (Schmidt's syndrome). A man with Type 1 diabetes mellitus is described who developed an unusual combination of five autoimmune conditions (myasthenia gravis, Addisonian pernicious anaemia, adrenalitis and thyroiditis) which did not fit into the Type 1 or Type 2 classical polyendocrine deficiency syndromes. This suggests that the autoantibody, biochemical and haematological screening of affected individuals and their relatives should be extended to anticipate a wider range of potential autoimmune conditions.

Review of Biguanide (Metformin) Toxicity

2018 ◽  
Vol 34 (11-12) ◽  
pp. 863-876 ◽  
Author(s):  
George Sam Wang ◽  
Christopher Hoyte
Keyword(s):  
Metabolic Acidosis ◽  
Atp Hydrolysis ◽  
Body Burden ◽  
Insulin Dependent Diabetes Mellitus ◽  
The United States ◽  
The Body ◽  
Dependent Diabetes Mellitus ◽  
Glucose Levels ◽  
Galega Officinalis ◽  
Lower Glucose

In the 1920s, guanidine, the active component of Galega officinalis, was shown to lower glucose levels and used to synthesize several antidiabetic compounds. Metformin (1,1 dimethylbiguanide) is the most well-known and currently the only marketed biguanide in the United States, United Kingdom, Canada, and Australia for the treatment of non-insulin-dependent diabetes mellitus. Although phenformin was removed from the US market in the 1970s, it is still available around the world and can be found in unregulated herbal supplements. Adverse events associated with therapeutic use of biguanides include gastrointestinal upset, vitamin B12 deficiency, and hemolytic anemia. Although the incidence is low, metformin toxicity can lead to hyperlactatemia and metabolic acidosis. Since metformin is predominantly eliminated from the body by the kidneys, toxicity can occur when metformin accumulates due to poor clearance from renal insufficiency or in the overdose setting. The dominant source of metabolic acidosis associated with hyperlactatemia in metformin toxicity is the rapid cytosolic adenosine triphosphate (ATP) turnover when complex I is inhibited and oxidative phosphorylation cannot adequately recycle the vast quantity of H+ from ATP hydrolysis. Although metabolic acidosis and hyperlactatemia are markers of metformin toxicity, the degree of hyperlactatemia and severity of acidemia have not been shown to be of prognostic value. Regardless of the etiology of toxicity, treatment should include supportive care and consideration for adjunct therapies such as gastrointestinal decontamination, glucose and insulin, alkalinization, extracorporeal techniques to reduce metformin body burden, and metabolic rescue.

scholarly journals Species-Specific Autoantibodies in Type 1 Diabetes1

1999 ◽  
Vol 84 (2) ◽  
pp. 643-648
Author(s):  
C. S. Hampe ◽  
E. Örtqvist ◽  
O. Rolandsson ◽  
M. Landin-Olsson ◽  
C. Törn ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Age At Onset ◽  
Insulin Dependent Diabetes Mellitus ◽  
Positive Control ◽  
Dependent Diabetes Mellitus ◽  
Diabetic Patients ◽  
Insulin Dependent ◽  
Species Specific ◽  
Type 1 Diabetic Patients

GAD65 autoantibodies (GAD65Ab) are important markers for type 1 (insulin-dependent) diabetes mellitus. Although most patients have GAD65Ab at the time of clinical diagnosis, there are also GAD65Ab-positive individuals in the population at low risk of developing type 1 diabetes. The aim of this study was to test the hypothesis that the GAD65Ab reactivity to GAD65 cloned from human, mouse, and rat in newly diagnosed type 1 diabetic patients differ from antibody-positive healthy individuals. Sera from 254 new-onset 0- to 34-yr-old type 1 diabetic patients and 270 controls were assayed for their reactivity to human, mouse, and rat GAD65. Among the type 1 diabetic patients there was a significant better binding of human GAD65 compared to either mouse (P = 0.03) or rat GAD65 (P = 0.0005). The preference for human GAD65 increased with increasing age at onset (P = 0.0002). This differentiation was not observed in 88 GAD65Ab-positive control subjects. Our data indicate that recognition of epitopes by GAD65Ab in type 1 diabetes is different from that in nontype 1 diabetes, GAD65Ab-positive individuals.

scholarly journals Genetic susceptibility to type 1 diabetes mellitus in humans

2007 ◽  
pp. 255-266
Author(s):  
D Kantárová ◽  
M Buc
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Current Knowledge ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Immune Mediated ◽  
Insulin Dependent ◽  
Genetically Determined

Type 1 diabetes mellitus (DM 1A) is an autoimmune disease belonging to the most frequent chronic diseases of the childhood and young adults. DM 1A results from immune-mediated destruction of the insulin-producing beta cells of the pancreas. It is a genetically determined disease and many genes or genetic regions were found to be associated with its induction. In addition to the insulin-dependent diabetes mellitus 1 (IDDM1) gene, which marks the HLA region, and IDDM2 which marks the insulin gene, significant associations of DM 1A to other IDMM genes or genetic regions we reported. We shortly review recent achievements in the field, and the state of current knowledge.

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