scholarly journals An HLA-Transgenic Mouse Model of Type 1 Diabetes That Incorporates the Reduced but Not Abolished Thymic Insulin Expression Seen in Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Jeffrey Babad ◽  
Riyasat Ali ◽  
Jennifer Schloss ◽  
Teresa P. DiLorenzo
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Beta Cells ◽  
Immune Cell ◽  
Regulatory Region ◽  
Islet Autoimmunity ◽  
Positive Type ◽  
Insulin Expression ◽  
Pancreatic Islet Beta Cells

Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of the pancreatic islet beta cells. Multiple genetic loci contribute to disease susceptibility in humans, with the most responsible locus being the major histocompatibility complex (MHC). Certain MHC alleles are predisposing, including the common HLA-A∗02:01. After the MHC, the locus conferring the strongest susceptibility to T1D is the regulatory region of the insulin gene, and alleles associated with reduced thymic insulin expression are predisposing. Mice express two insulin genes,Ins1andIns2. While both are expressed in beta cells, onlyIns2is expressed in the thymus. We have developed an HLA-A∗02:01-transgenic NOD-based T1D model that is heterozygous for a functionalIns2gene. These mice exhibit reduced thymic insulin expression and accelerated disease in both genders. Immune cell populations are not grossly altered, and the mice exhibit typical signs of islet autoimmunity, including CD8 T cell responses to beta cell peptides also targeted in HLA-A∗02:01-positive type 1 diabetes patients. This model should find utility as a tool to uncover the mechanisms underlying the association between reduced thymic insulin expression and T1D in humans and aid in preclinical studies to evaluate insulin-targeted immunotherapies for the disease.

scholarly journals Presumption of guilt for T cells in type 1 diabetes: lead culprits or partners in crime depending on age of onset?

Diabetologia ◽  
2020 ◽  
Vol 64 (1) ◽  
pp. 15-25 ◽  
Author(s):  
Alexia Carré ◽  
Sarah J. Richardson ◽  
Etienne Larger ◽  
Roberto Mallone
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Beta Cells ◽  
Disease Onset ◽  
Strong Support ◽  
Islet Autoimmunity ◽  
Relative Role ◽  
Age Related

AbstractAvailable evidence provides arguments both for and against a primary pathogenic role for T cells in human type 1 diabetes. Genetic susceptibility linked to HLA Class II lends strong support. Histopathology documents HLA Class I hyperexpression and islet infiltrates dominated by CD8+ T cells. While both hallmarks are near absent in autoantibody-positive donors, the variable insulitis and residual beta cells of recent-onset donors suggests the existence of a younger-onset endotype with more aggressive autoimmunity and an older-onset endotype with more vulnerable beta cells. Functional arguments from ex vivo and in vitro human studies and in vivo ‘humanised’ mouse models are instead neutral or against a T cell role. Clinical support is provided by the appearance of islet autoantibodies before disease onset. The faster C-peptide loss and superior benefits of immunotherapies in individuals with younger-onset type 1 diabetes reinforce the view of age-related endotypes. Clarifying the relative role of T cells will require technical advances in the identification of their target antigens, in their detection and phenotyping in the blood and pancreas, and in the study of the T cell/beta cell crosstalk. Critical steps toward this goal include the understanding of the link with environmental triggers, the description of T cell changes along the natural history of disease, and their relationship with age and the ‘benign’ islet autoimmunity of healthy individuals.

scholarly journals Common patterns of gene regulation associated with Cesarean section and the development of islet autoimmunity – indications of immune cell activation

2017 ◽  
Author(s):  
M. Laimighofer ◽  
R. Lickert ◽  
R. Fürst ◽  
F. J. Theis ◽  
C. Winkler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 1 Diabetes ◽  
T Lymphocytes ◽  
Cesarean Section ◽  
Cell Activation ◽  
Immune Cell ◽  
Islet Autoimmunity ◽  
Nucleotide Synthesis ◽  
Immune Cell Activation

AbstractBackgroundBirth by Cesarean section increases the risk of developing type 1 diabetes later in life; however, the underlying molecular mechanisms of this effect remain unclear. We aimed to elucidate common regulatory processes observed after Cesarean section and the development of islet autoimmunity, which precedes type 1 diabetes, by investigating the transcriptome of blood cells in the developing immune system.MethodsWe analyzed gene expression of peripheral blood mononuclear cells taken at several time points from children with increased familial and genetic risk for type 1 diabetes (n = 109). We investigated effects of Cesarean section on gene expression profiles of children in the first year of life using a generalized additive mixed model to account for the longitudinal data structure. To investigate the effect of islet autoimmunity, we compared gene expression differences between children after initiation of islet autoimmunity and age-matched children who did not develop islet autoantibodies. Finally, we compared both results to identify common regulatory patterns of Cesarean section and islet autoimmunity at the gene expression level.ResultsWe identified two differentially expressed pathways in children born by Cesarean section: the pentose phosphate pathway and pyrimidine metabolism, both involved in nucleotide synthesis and cell proliferation. Islet autoantibody analysis revealed multiple differentially expressed pathways generally involved in immune processes, including both of the above-mentioned nucleotide synthesis pathways. Comparison of global gene expression signatures showed that transcriptomic changes were systematically and significantly correlated between Cesarean section and islet autoimmunity. In addition, signatures of both Cesarean section and islet autoimmunity correlated with transcriptional changes observed during activation of isolated CD4+ T lymphocytes.ConclusionsWe identified coherent gene expression signatures for Cesarean section, an early risk factor for type 1 diabetes, and islet autoantibodies positivity, an obligatory stage of autoimmune response prior to the development of type 1 diabetes. Both transcriptional signatures were correlated with changes in gene expression during the activation of CD4+ T lymphocytes, reflecting common molecular changes in immune cell activation.

scholarly journals A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes

2018 ◽  
Vol 10 (422) ◽  
pp. eaag1782 ◽  
Author(s):  
Isabelle Serr ◽  
Martin G. Scherm ◽  
Adam M. Zahm ◽  
Jonathan Schug ◽  
Victoria K. Flynn ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Early Stage ◽  
Tolerance Induction ◽  
Islet Autoimmunity ◽  
Activated T Cells

Molecular checkpoints that trigger the onset of islet autoimmunity or progression to human type 1 diabetes (T1D) are incompletely understood. Using T cells from children at an early stage of islet autoimmunity without clinical T1D, we find that a microRNA181a (miRNA181a)–mediated increase in signal strength of stimulation and costimulation links nuclear factor of activated T cells 5 (NFAT5) with impaired tolerance induction and autoimmune activation. We show that enhancing miRNA181a activity increases NFAT5 expression while inhibiting FOXP3+ regulatory T cell (Treg) induction in vitro. Accordingly, Treg induction is improved using T cells from NFAT5 knockout (NFAT5ko) animals, whereas altering miRNA181a activity does not affect Treg induction in NFAT5ko T cells. Moreover, high costimulatory signals result in phosphoinositide 3-kinase (PI3K)–mediated NFAT5, which interferes with FoxP3+ Treg induction. Blocking miRNA181a or NFAT5 increases Treg induction in murine and humanized models and reduces murine islet autoimmunity in vivo. These findings suggest targeting miRNA181a and/or NFAT5 signaling for the development of innovative personalized medicines to limit islet autoimmunity.

PS17 - 85. How immune cell therapy modifies islet autoimmunity in type 1 diabetes

2011 ◽  
Vol 9 (3) ◽  
pp. 149-149
Author(s):  
Fleur Kleijwegt ◽  
Sandra laban ◽  
Antoinette Joosten ◽  
Tanja Nikolic ◽  
Bart Roep
Keyword(s):  
Type 1 Diabetes ◽  
Cell Therapy ◽  
Immune Cell ◽  
Islet Autoimmunity

scholarly journals Clinical and genetic correlates of islet-autoimmune signatures in juvenile-onset type 1 diabetes

Diabetologia ◽  
2019 ◽  
Vol 63 (2) ◽  
pp. 351-361 ◽  
Author(s):  
Laura A. Claessens ◽  
Joris Wesselius ◽  
Menno van Lummel ◽  
Sandra Laban ◽  
Flip Mulder ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Beta Cell ◽  
Genetic Risk Score ◽  
Islet Autoimmunity ◽  
Juvenile Onset ◽  
Disease Heterogeneity ◽  
Onset Type ◽  
High Responders

Abstract Aims/hypothesis Heterogeneity in individuals with type 1 diabetes has become more generally appreciated, but has not yet been extensively and systematically characterised. Here, we aimed to characterise type 1 diabetes heterogeneity by creating immunological, genetic and clinical profiles for individuals with juvenile-onset type 1 diabetes in a cross-sectional study. Methods Participants were HLA-genotyped to determine HLA-DR-DQ risk, and SNP-genotyped to generate a non-HLA genetic risk score (GRS) based on 93 type 1 diabetes-associated SNP variants outside the MHC region. Islet autoimmunity was assessed as T cell proliferation upon stimulation with the beta cell antigens GAD65, islet antigen-2 (IA-2), preproinsulin (PPI) and defective ribosomal product of the insulin gene (INS-DRIP). Clinical parameters were collected retrospectively. Results Of 80 individuals, 67 had proliferation responses to one or more islet antigens, with vast differences in the extent of proliferation. Based on the multitude and amplitude of the proliferation responses, individuals were clustered into non-, intermediate and high responders. High responders could not be characterised entirely by enrichment for the highest risk HLA-DR3-DQ2/DR4-DQ8 genotype. However, high responders did have a significantly higher non-HLA GRS. Clinically, high T cell responses to beta cell antigens did not reflect in worsened glycaemic control, increased complications, development of associated autoimmunity or younger age at disease onset. The number of beta cell antigens that an individual responded to increased with disease duration, pointing to chronic islet autoimmunity and epitope spreading. Conclusions/interpretation Collectively, these data provide new insights into type 1 diabetes disease heterogeneity and highlight the importance of stratifying patients on the basis of their genetic and autoimmune signatures for immunotherapy and personalised disease management.

scholarly journals Influence of Vitamin D on Islet Autoimmunity and Beta-Cell Function in Type 1 Diabetes

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2185 ◽  
Author(s):  
Marco Infante ◽  
Camillo Ricordi ◽  
Janine Sanchez ◽  
Michael J. Clare-Salzler ◽  
Nathalia Padilla ◽  
...  
Keyword(s):  
Vitamin D ◽  
Type 1 Diabetes ◽  
Vitamin D Deficiency ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Current Knowledge ◽  
Islet Autoimmunity ◽  
Immunomodulatory Effects

Type 1 diabetes (T1D) is a chronic autoimmune disease leading to immune-mediated destruction of pancreatic beta cells, resulting in the need for insulin therapy. The incidence of T1D is increasing worldwide, thus prompting researchers to investigate novel immunomodulatory strategies to halt autoimmunity and modify disease progression. T1D is considered as a multifactorial disease, in which genetic predisposition and environmental factors interact to promote the triggering of autoimmune responses against beta cells. Over the last decades, it has become clear that vitamin D exerts anti-inflammatory and immunomodulatory effects, apart from its well-established role in the regulation of calcium homeostasis and bone metabolism. Importantly, the global incidence of vitamin D deficiency is also dramatically increasing and epidemiologic evidence suggests an involvement of vitamin D deficiency in T1D pathogenesis. Polymorphisms in genes critical for vitamin D metabolism have also been shown to modulate the risk of T1D. Moreover, several studies have investigated the role of vitamin D (in different doses and formulations) as a potential adjuvant immunomodulatory therapy in patients with new-onset and established T1D. This review aims to present the current knowledge on the immunomodulatory effects of vitamin D and summarize the clinical interventional studies investigating its use for prevention or treatment of T1D.

scholarly journals Evolving Antibody Therapies for the Treatment of Type 1 Diabetes

2021 ◽  
Vol 11 ◽  
Author(s):  
Qi Ke ◽  
Charles J. Kroger ◽  
Matthew Clark ◽  
Roland M. Tisch
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Antigenic Specificity ◽  
Immune Effector ◽  
Effector Cells ◽  
Therapeutic Drugs ◽  
Self Tolerance

Type 1 diabetes (T1D) is widely considered to be a T cell driven autoimmune disease resulting in reduced insulin production due to dysfunction/destruction of pancreatic β cells. Currently, there continues to be a need for immunotherapies that selectively reestablish persistent β cell-specific self-tolerance for the prevention and remission of T1D in the clinic. The utilization of monoclonal antibodies (mAb) is one strategy to target specific immune cell populations inducing autoimmune-driven pathology. Several mAb have proven to be clinically safe and exhibit varying degrees of efficacy in modulating autoimmunity, including T1D. Traditionally, mAb therapies have been used to deplete a targeted cell population regardless of antigenic specificity. However, this treatment strategy can prove detrimental resulting in the loss of acquired protective immunity. Nondepleting mAb have also been applied to modulate the function of immune effector cells. Recent studies have begun to define novel mechanisms associated with mAb-based immunotherapy that alter the function of targeted effector cell pools. These results suggest short course mAb therapies may have persistent effects for regaining and maintaining self-tolerance. Furthermore, the flexibility to manipulate mAb properties permits the development of novel strategies to target multiple antigens and/or deliver therapeutic drugs by a single mAb molecule. Here, we discuss current and potential future therapeutic mAb treatment strategies for T1D, and T cell-mediated autoimmunity.

scholarly journals B Quiet: Autoantigen-Specific Strategies to Silence Raucous B Lymphocytes and Halt Cross-Talk with T Cells in Type 1 Diabetes

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 42
Author(s):  
Jamie L. Felton ◽  
Holly Conway ◽  
Rachel H. Bonami
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Beta Cell ◽  
B Lymphocytes ◽  
Cell Function ◽  
Immune Cell ◽  
Disease Risk ◽  
Significant Risk

Islet autoantibodies are the primary biomarkers used to predict type 1 diabetes (T1D) disease risk. They signal immune tolerance breach by islet autoantigen-specific B lymphocytes. T-B lymphocyte interactions that lead to expansion of pathogenic T cells underlie T1D development. Promising strategies to broadly prevent this T-B crosstalk include T cell elimination (anti-CD3, teplizumab), B cell elimination (anti-CD20, rituximab), and disruption of T cell costimulation/activation (CTLA-4/Fc fusion, abatacept). However, global disruption or depletion of immune cell subsets is associated with significant risk, particularly in children. Therefore, antigen-specific therapy is an area of active investigation for T1D prevention. We provide an overview of strategies to eliminate antigen-specific B lymphocytes as a means to limit pathogenic T cell expansion to prevent beta cell attack in T1D. Such approaches could be used to prevent T1D in at-risk individuals. Patients with established T1D would also benefit from such targeted therapies if endogenous beta cell function can be recovered or islet transplant becomes clinically feasible for T1D treatment.

scholarly journals Etiopathogenesis of Insulin Autoimmunity

2012 ◽  
Vol 2012 ◽  
pp. 1-20
Author(s):  
Norio Kanatsuna ◽  
George K. Papadopoulos ◽  
Antonis K. Moustakas ◽  
Åke Lenmark
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Age At Onset ◽  
Class I Mhc ◽  
Beta Cell Destruction ◽  
Hla Dr ◽  
Pancreatic Islet Beta Cells ◽  
Insulin Autoantibody ◽  
Cellular Immune

Autoimmunity against pancreatic islet beta cells is strongly associated with proinsulin, insulin, or both. The insulin autoreactivity is particularly pronounced in children with young age at onset of type 1 diabetes. Possible mechanisms for (pro)insulin autoimmunity may involve beta-cell destruction resulting in proinsulin peptide presentation on HLA-DR-DQ Class II molecules in pancreatic draining lymphnodes. Recent data on proinsulin peptide binding to type 1 diabetes-associated HLA-DQ2 and -DQ8 is reviewed and illustrated by molecular modeling. The importance of the cellular immune reaction involving cytotoxic CD8-positive T cells to kill beta cells through Class I MHC is discussed along with speculations of the possible role of B lymphocytes in presenting the proinsulin autoantigen over and over again through insulin-carrying insulin autoantibodies. In contrast to autoantibodies against other islet autoantigens such as GAD65, IA-2, and ZnT8 transporters, it has not been possible yet to standardize the insulin autoantibody test. As islet autoantibodies predict type 1 diabetes, it is imperative to clarify the mechanisms of insulin autoimmunity.

Regeneration of insulin-producing [beta]-cells during recovery from disease: a cure for Type 1 Diabetes

2018 ◽  
Author(s):  
◽  
Tobechukwu Kenneth Ukah
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Combination Therapy ◽  
Beta Cells ◽  
Th17 Cells ◽  
Nod Mice ◽  
I Cells

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Type 1 diabetes (T1D) is a chronic disease condition characterized by destruction of the insulin-producing [beta]-cells by self-reactive lymphocytes of the immune system. While some immunotherapeutic approaches against T1D directly target and modulate diabetogenic specific T cells or the entire T cell repertoire, other efforts utilize antigen presenting cells or T cell-regulating molecules to control the T cells. In chapter II, we set out to determine the role of regulatory cytokines, IL-4 and IL-13 in T1D progression. IL-4 and IL-13 are widely reported as anti-inflammatory cytokines, and both can signal via the IL-4R[alpha]/IL-13R[alpha]1 heteroreceptor (HR). To determine the role of these cytokines in T1D development, we generated NOD mice in which the IL-13R[alpha]1 arm of the HR is deleted, thereby rendering the HR nonfunctional. Surprisingly, the findings indicate that NOD mice lacking the HR (13R-/-) display resistance to T1D as the rise in blood glucose level (BGL) and islet inflammation were significantly delayed in these HR-deficient relative to HR-sufficient (13R+/+) mice. In fact, the frequency and spleen-to-pancreas dynamics of both Th1 and Th17 cells were affected in 13R-/- mice. This outcome is likely due to an increase in the frequency of mTGF[beta][subscript +]Foxp3[subscript int] regulatory T cells and persistence of CD206[subscript +] macrophage in the pancreas as both types of cells confer resistance to T1D upon transfer to 13R+/+ mice. These findings reveal new insights as to the role environmental IL-4/IL-13 and the HR play in peripheral tolerance and the development of T1D. In chapter III, we investigate the source of newly formed β-cells during recovery from overt T1D under a combination therapy that involves an immunoglobulin chimera, Ig-GAD2 and bone marrow cells transfer. This combination therapy proved effective in driving immune modulation of diabetogenic-specific T cells and repair of the islet vasculature leading to the formation of new endogenous [beta]-cells that were able to thrive and restore long-lasting normoglycemia. Our new findings reveal and suggest that the combination therapy leads to the formation of healthy islets by inducing division of residual β-cells and differentiation of precursor cells. Furthermore, while the pancreas is cleared of immune infiltration during recovery from disease, both the lymph nodes and spleen displayed a significant reduction in Th17 cells, and the disease did not rebound. These circumstances are relevant to humans as intervention could be made at early as well as late stages after diagnosis. Overall, these results provide insights on future immunotherapeutic measures of T1D using regulatory cytokines or intervention with an antigen-specific therapy.

Sign in / Sign up

Export Citation Format

Share Document