An IFNγ-dependent immune-endocrine circuit lowers blood glucose to potentiate the innate antiviral immune response.

Viral infection makes us feel sick as the immune system alters systemic metabolism to better fight the pathogen. The extent of these changes is relative to the severity of disease. Whether blood glucose is subject to infection-induced modulation is mostly unknown. Here we show that strong, nonlethal infection restricts systemic glucose availability, which promotes the antiviral type I interferon (IFN-I) response. Following viral infection, we find that IFNγ produced by γδ T cells stimulates pancreatic ß cells to increase glucose-induced insulin release. Subsequently, hyperinsulinemia lessens hepatic glucose output. Glucose restriction enhances IFN-I production by curtailing lactate-mediated inhibition of IRF3 and NF-κB signaling. Induced hyperglycemia constrained IFN-I production and increased mortality upon infection. Our findings identify glucose restriction as a physiological mechanism to bring the body into a heightened state of responsiveness to viral pathogens. This immune-endocrine circuit is disrupted in hyperglycemia, possibly explaining why patients with diabetes are more susceptible to viral infection.

High Prevalence of A-ß+ Ketosis-Prone Diabetes in Children with Type 2 Diabetes and Diabetic Ketoacidosis at Diagnosis: Evidence from the Rare and Atypical Diabetes Network (RADIANT).

Background: A-ß+ ketosis-prone diabetes (KPD) in adults is characterized by presentation with diabetic ketoacidosis (DKA), negative islet autoantibodies, and preserved ß-cell function in persons with a phenotype of obesity-associated type 2 diabetes (T2D). The prevalence of KPD has not been evaluated in children. We investigated children with DKA at "T2D" onset and determined the prevalence and characteristics of pediatric A-ß+ KPD within this cohort. Methods: We reviewed the records of 716 children with T2D at a large academic hospital and compared clinical characteristics of those with and without DKA at onset. In the latter group, we identified patients with A-ß+ KPD using criteria of the Rare and Atypical Diabetes Network (RADIANT) and defined its prevalence and characteristics. Results: Mean age at diagnosis was 13.7 ± 2.4 years: 63% female; 59% Hispanic, 29% African American, 9% non-Hispanic White, and 3% other. Fifty-six (7.8%) presented with DKA at diagnosis and lacked islet autoantibodies. Children presenting with DKA were older and had lower C-peptide and higher glucose concentrations than those without DKA. Twenty-five children with DKA (45%) met RADIANT A-ß+ KPD criteria. They were predominantly male (64%), African American or Hispanic (96%), with substantial C-peptide (1.3 ± 0.7 ng/mL) at presentation with DKA and excellent long-term glycemic control (HbA1c 6.6% ± 1.9% at follow-up (median 1.3 years postdiagnosis)). Conclusions: In children with a clinical phenotype of T2D and DKA at diagnosis, approximately half meet criteria for A-ß+ KPD. They manifest the key characteristics of obesity, preserved ß-cell function, male predominance, and potential to discontinue insulin therapy, similar to adults with A-ß+ KPD.

Autoimmune CD8+ T cells in type 1 diabetes: from single-cell RNA sequencing to T-cell receptor redirection.

Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by pancreatic ß cell destruction and mediated primarily by autoreactive CD8+ T cells. It has been shown that only a small number of stem cell-like ß cell-specific CD8+ T cells are needed to convert normal mice into T1D mice; thus, it is likely that T1D can be cured or significantly improved by modulating or altering self-reactive CD8+ T cells. However, stem cell-type, effector and exhausted CD8+ T cells play intricate and important roles in T1D. The highly diverse T-cell receptors (TCRs) also make precise and stable targeted therapy more difficult. Therefore, this review will investigate the mechanisms of autoimmune CD8+ T cells and TCRs in T1D, as well as the related single-cell RNA sequencing (ScRNA-Seq), CRISPR/Cas9, chimeric antigen receptor T-cell (CAR-T) and T-cell receptor-gene engineered T cells (TCR-T), for a detailed and clear overview. This review highlights that targeting CD8+ T cells and their TCRs may be a potential strategy for predicting or treating T1D.

Proinsulin degradation and presentation of a proinsulin B-chain autoantigen involves ER-associated protein degradation (ERAD)-enzyme UBE2G2.

Type 1 diabetes (T1D) is characterized by HLA class I-mediated presentation of autoantigens on the surface of pancreatic ß-cells. Recognition of these autoantigens by CD8+ T cells results in the destruction of pancreatic ß-cells and, consequently, insulin deficiency. Most epitopes presented at the surface of ß-cells derive from the insulin precursor molecule proinsulin. The intracellular processing pathway(s) involved in the generation of these peptides are poorly defined. In this study, we show that a proinsulin B-chain antigen (PPIB5-14) originates from proinsulin molecules that are processed by ER-associated protein degradation (ERAD) and thus originate from ER-resident proteins. Furthermore, screening genes encoding for E2 ubiquitin conjugating enzymes, we identified UBE2G2 to be involved in proinsulin degradation and subsequent presentation of the PPIB10-18 autoantigen. These insights into the pathway involved in the generation of insulin-derived peptides emphasize the importance of proinsulin processing in the ER to T1D pathogenesis and identify novel targets for future T1D therapies.

Altering ß Cell Antigen Exposure to Exhausted CD8+ T Cells Prevents Autoimmune Diabetes in Mice.

Chronic destruction of insulin-producing pancreatic ß cells by T cells results in autoimmune diabetes. Similar to other chronic T cell-mediated pathologies, a role for T cell exhaustion has been identified in diabetes in humans and NOD mice. The development and differentiation of exhausted T cells depends on exposure to Ag. In this study, we manipulated ß cell Ag presentation to target exhausted autoreactive T cells by inhibiting IFN-γ-mediated MHC class I upregulation or by ectopically expressing the ß cell Ag IGRP under the MHC class II promotor in the NOD8.3 model. Islet PD-1+TIM3+CD8+ (terminally exhausted [TEX]) cells were primary producers of islet granzyme B and CD107a, suggestive of cells that have entered the exhaustion program yet maintained cytotoxic capacity. Loss of IFN-γ-mediated ß cell MHC class I upregulation correlated with a significant reduction in islet TEX cells and diabetes protection in NOD8.3 mice. In NOD.TII/8.3 mice with IGRP expression induced in APCs, IGRP-reactive T cells remained exposed to high levels of IGRP in the islets and periphery. Consequently, functionally exhausted TEX cells, with reduced granzyme B expression, were significantly increased in these mice and this correlated with diabetes protection. These results indicate that intermediate Ag exposure in wild-type NOD8.3 islets allows T cells to enter the exhaustion program without becoming functionally exhausted. Moreover, Ag exposure can be manipulated to target this key cytotoxic population either by limiting the generation of cytotoxic TIM3+ cells or by driving their functional exhaustion, with both resulting in diabetes protection.

Immunopeptidome mining reveals a novel ERS-induced target in T1D.

Autoreactive CD8+ T cells play a key role in type 1 diabetes (T1D), but the antigen spectrum that activates autoreactive CD8+ T cells remains unclear. Endoplasmic reticulum stress (ERS) has been implicated in ß-cell autoantigen generation. Here, we analyzed the major histocompatibility complex class I (MHC-I)-associated immunopeptidome (MIP) of islet ß-cells under steady and ERS conditions and found that ERS reshaped the MIP of ß-cells and promoted the MHC-I presentation of a panel of conventional self-peptides. Among them, OTUB258-66 showed immunodominance, and the corresponding autoreactive CD8+ T cells were diabetogenic in nonobese diabetic (NOD) mice. High glucose intake upregulated pancreatic OTUB2 expression and amplified the OTUB258-66-specific CD8+ T-cell response in NOD mice. Repeated OTUB258-66 administration significantly reduced the incidence of T1D in NOD mice. Interestingly, peripheral blood mononuclear cells (PBMCs) from patients with T1D, but not from healthy controls, showed a positive IFN-γ response to human OTUB2 peptides. This study provides not only a new explanation for the role of ERS in promoting ß-cell-targeted autoimmunity but also a potential target for the prevention and treatment of T1D. The data are available via ProteomeXchange with the identifier PXD041227.

Conveying the pathogenesis of type 1 diabetes to the blind, low-vision and diverse needs communities through sensory stimulation.

To educate members of the blind, low-vision and diverse needs communities on the pathogenesis of the chronic autoimmune disease, type 1 diabetes, members of our team with research expertise in immune-mediated diseases, participated in the 2023 Monash Sensory Science (MSS) Exhibition. Using QR code linked audio commentary, participants were guided through tactile displays demonstrating normal insulin action in the regulation of blood glucose levels and its vital role in providing energy to tissues, followed by displays describing the various stages of the immune system's aberrant attack and the eventual complete destruction of the insulin producing beta-cells of the pancreatic islets in type 1 diabetes. These models conveyed to the participants the huge effect that this autoimmune-mediated disease has on the quality of life of affected individuals including the subsequent lifelong reliance on insulin injections to maintain glucose homeostasis. This MSS Exhibition provided a unique opportunity for our researchers to engage with under-represented members of the community and to raise awareness about such a debilitating and common autoimmune disease.

The immunology of type 1 diabetes.

Following the seminal discovery of insulin a century ago, treatment of individuals with type 1 diabetes (T1D) has been largely restricted to efforts to monitor and treat metabolic glucose dysregulation. The recent regulatory approval of the first immunotherapy that targets T cells as a means to delay the autoimmune destruction of pancreatic ß-cells highlights the critical role of the immune system in disease pathogenesis and tends to pave the way for other immune-targeted interventions for T1D. Improving the efficacy of such interventions across the natural history of the disease will probably require a more detailed understanding of the immunobiology of T1D, as well as technologies to monitor residual ß-cell mass and function. Here we provide an overview of the immune mechanisms that underpin the pathogenesis of T1D, with a particular emphasis on T cells.

Teplizumab and ß-Cell Function in Newly Diagnosed Type 1 Diabetes.

BACKGROUND: Teplizumab, a humanized monoclonal antibody to CD3 on T cells, is approved by the Food and Drug Administration to delay the onset of clinical type 1 diabetes (stage 3) in patients 8 years of age or older with preclinical (stage 2) disease. Whether treatment with intravenous teplizumab in patients with newly diagnosed type 1 diabetes can prevent disease progression is unknown. METHODS: In this phase 3, randomized, placebo-controlled trial, we assessed ß-cell preservation, clinical end points, and safety in children and adolescents who were assigned to receive teplizumab or placebo for two 12-day courses. The primary end point was the change from baseline in ß-cell function, as measured by stimulated C-peptide levels at week 78. The key secondary end points were the insulin doses that were required to meet glycemic goals, glycated hemoglobin levels, time in the target glucose range, and clinically important hypoglycemic events. RESULTS: Patients treated with teplizumab (217 patients) had significantly higher stimulated C-peptide levels than patients receiving placebo (111 patients) at week 78 (least-squares mean difference, 0.13 pmol per milliliter; 95% confidence interval [CI], 0.09 to 0.17; P<0.001), and 94.9% (95% CI, 89.5 to 97.6) of patients treated with teplizumab maintained a clinically meaningful peak C-peptide level of 0.2 pmol per milliliter or greater, as compared with 79.2% (95% CI, 67.7 to 87.4) of those receiving placebo. The groups did not differ significantly with regard to the key secondary end points. Adverse events occurred primarily in association with administration of teplizumab or placebo and included headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome. CONCLUSIONS: Two 12-day courses of teplizumab in children and adolescents with newly diagnosed type 1 diabetes showed benefit with respect to the primary end point of preservation of ß-cell function, but no significant differences between the groups were observed with respect to the secondary end points. (Funded by Provention Bio and Sanofi; PROTECT ClinicalTrials.gov number, NCT03875729.).

Increased plasmablasts enhance T cell-mediated beta cell destruction and promote the development of type 1 diabetes.

BACKGROUND: Although type 1 diabetes (T1D) is typically described as a T cell-mediated autoimmune disease, increasing evidence for a role of B cells has emerged. However, the pivotal disease-relevant B cell subset and its contribution to islet autoimmunity remain elusive. METHODS: The frequencies and phenotypic characteristics of circulating B cell subsets were analyzed using flow cytometry in individuals with new-onset T1D, long-term T1D, type 2 diabetes, and nondiabetic controls, and also in a prospective cohort of patients receiving mesenchymal stromal cell (MSC) transplantation. NOD mice and adoptive transfer assay were used to dissect the role of the certain B cell subset in disease progression. An in-vitro coculture system of islets with immune cells was established to examine the response against islets and the underlying mechanisms. RESULTS: We identified that plasmablasts, a B cell subset at the antibody-secreting stage, were significantly increased and correlated with the deterioration of beta cell function in patients with new-onset T1D. Further, a fall of plasmablast number was associated with the preservation of beta cell function in patients who received MSC transplantation after 3 months of follow-up. Meanwhile, a gradual increase of plasmablasts in pancreatic lymph nodes during the natural progression of insulitis was observed in non-obese diabetic (NOD) mice; adoptive transfer of plasmablasts together with T cells from NOD mice accelerated diabetes onset in NOD/SCID recipients. CONCLUSIONS: Our study revealed that plasmablasts may function as antigen-presenting cells and promote the activation and proinflammatory response of CD4+ T cells, further contributing to the T cell-mediated beta cell destruction. Our results provide insights into the pathogenic role of plasmablasts in islet autoimmunity and may offer new translational strategies for inhibiting T1D development.

An autoimmune stem-like CD8 T cell population drives type 1 diabetes.

CD8 T cell-mediated autoimmune diseases result from the breakdown of self-tolerance mechanisms in autoreactive CD8 T cells1. How autoimmune T cell populations arise and are sustained, and the molecular programmes defining the autoimmune T cell state, are unknown. In type 1 diabetes, ß-cell-specific CD8 T cells destroy insulin-producing ß-cells. Here we followed the fate of ß-cell-specific CD8 T cells in non-obese diabetic mice throughout the course of type 1 diabetes. We identified a stem-like autoimmune progenitor population in the pancreatic draining lymph node (pLN), which self-renews and gives rise to pLN autoimmune mediators. pLN autoimmune mediators migrate to the pancreas, where they differentiate further and destroy ß-cells. Whereas transplantation of as few as 20 autoimmune progenitors induced type 1 diabetes, as many as 100,000 pancreatic autoimmune mediators did not. Pancreatic autoimmune mediators are short-lived, and stem-like autoimmune progenitors must continuously seed the pancreas to sustain ß-cell destruction. Single-cell RNA sequencing and clonal analysis revealed that autoimmune CD8 T cells represent unique T cell differentiation states and identified features driving the transition from autoimmune progenitor to autoimmune mediator. Strategies aimed at targeting the stem-like autoimmune progenitor pool could emerge as novel and powerful immunotherapeutic interventions for type 1 diabetes.

Vitamin D supplementation induces CatG-mediated CD4+ T cell inactivation and restores pancreatic ß-cell function in mice with type 1 diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease accompanied by the immune-mediated destruction of pancreatic ß-cells. In this study, we aimed to explore the regulatory effects of vitamin D (VD) supplementation on pancreatic ß-cell function by altering the expression of bioinformatically identified cathepsin G (CatG) in T1D mice. A T1D mouse model was established in nonobese diabetic (NOD) mice, and their islets were isolated and purified. Pancreatic mononuclear cells (MNCs) were collected, from which CD4+ T cells were isolated. The levels of interleukin (IL)-2, IL-10, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) in the supernatant of mouse pancreatic tissue homogenate were assessed using ELISA. Immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelin (TUNEL) staining were conducted to evaluate the effects of VD supplementation on pancreatic tissues of T1D mice. The pancreatic ß-cell line MIN6 was used for in vitro substantiation of findings in vivo. VD supplementation reduced glucose levels and improved glucose tolerance in T1D mice. Furthermore, VD supplementation improved pancreatic ß-cell function and suppressed immunological and inflammatory reactions in the T1D mice. We documented overexpression of CatG in diabetes tissue samples, and then showed that VD supplementation normalized the islet immune microenvironment through downregulating CatG expression in T1D mice. Experiments in vitro subsequently demonstrated that VD supplementation impeded CD4+ T activation by downregulating CatG expression and thereby enhanced pancreatic ß-cell function. Results of the present study elucidated that VD supplementation can downregulate the expression of CatG and inhibit CD4+ T cell activation, thereby improving ß-cell function in T1D.NEW & NOTEWORTHY We report that vitamin D (VD) supplementation downregulates CatG expression and inhibits CD4+ T cell activation, thereby improving ß-cell function in type 1 diabetes (T1D). This study deepens our understanding of the pathogenesis of T1D and clarifies molecular events underlying the alleviatory effect of VD for immunotherapy against T1D.

Single-cell analysis of the human pancreas in type 2 diabetes using multi-spectral imaging mass cytometry.

Type 2 diabetes mellitus (T2D) is a chronic age-related disorder characterized by hyperglycemia due to the failure of pancreatic beta cells to compensate for increased insulin demand. Despite decades of research, the pathogenic mechanisms underlying T2D remain poorly defined. Here, we use imaging mass cytometry (IMC) with a panel of 34 antibodies to simultaneously quantify markers of pancreatic exocrine, islet, and immune cells and stromal components. We analyze over 2 million cells from 16 pancreata obtained from donors with T2D and 13 pancreata from age-similar non-diabetic controls. In the T2D pancreata, we observe significant alterations in islet architecture, endocrine cell composition, and immune cell constituents. Thus, both HLA-DR-positive CD8 T cells and macrophages are enriched intra-islet in the T2D pancreas. These efforts demonstrate the utility of IMC for investigating complex events at the cellular level in order to provide insights into the pathophysiology of T2D.

Butyrate Protects Pancreatic Beta Cells from Cytokine-Induced Dysfunction.

Pancreatic beta cell dysfunction caused by metabolic and inflammatory stress contributes to the development of type 2 diabetes (T2D). Butyrate, produced by the gut microbiota, has shown beneficial effects on glucose metabolism in animals and humans and may directly affect beta cell function, but the mechanisms are poorly described. The aim of this study was to investigate the effect of butyrate on cytokine-induced beta cell dysfunction in vitro. Mouse islets, rat INS-1E, and human EndoC-ßH1 beta cells were exposed long-term to non-cytotoxic concentrations of cytokines and/or butyrate to resemble the slow onset of inflammation in T2D. Beta cell function was assessed by glucose-stimulated insulin secretion (GSIS), gene expression by qPCR and RNA-sequencing, and proliferation by incorporation of EdU into newly synthesized DNA. Butyrate protected beta cells from cytokine-induced impairment of GSIS and insulin content in the three beta cell models. Beta cell proliferation was reduced by both cytokines and butyrate. Expressions of the beta cell specific genes Ins, MafA, and Ucn3 reduced by the cytokine IL-1ß were not affected by butyrate. In contrast, butyrate upregulated the expression of secretion/transport-related genes and downregulated inflammatory genes induced by IL-1ß in mouse islets. In summary, butyrate prevents pro-inflammatory cytokine-induced beta cell dysfunction.

Partners in Crime: Beta-Cells and Autoimmune Responses Complicit in Type 1 Diabetes Pathogenesis.

Type 1 diabetes (T1D) is an autoimmune disease characterized by autoreactive T cell-mediated destruction of insulin-producing pancreatic beta-cells. Loss of beta-cells leads to insulin insufficiency and hyperglycemia, with patients eventually requiring lifelong insulin therapy to maintain normal glycemic control. Since T1D has been historically defined as a disease of immune system dysregulation, there has been little focus on the state and response of beta-cells and how they may also contribute to their own demise. Major hurdles to identifying a cure for T1D include a limited understanding of disease etiology and how functional and transcriptional beta-cell heterogeneity may be involved in disease progression. Recent studies indicate that the beta-cell response is not simply a passive aspect of T1D pathogenesis, but rather an interplay between the beta-cell and the immune system actively contributing to disease. Here, we comprehensively review the current literature describing beta-cell vulnerability, heterogeneity, and contributions to pathophysiology of T1D, how these responses are influenced by autoimmunity, and describe pathways that can potentially be exploited to delay T1D.

Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway.

Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-ß-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-α and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-κB signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-α and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-α signaling pathway, which may provide novel insight into beta cell failure and T1D development.

The Immunoregulatory Role of the Signal Regulatory Protein Family and CD47 Signaling Pathway in Type 1 Diabetes.

Background: The pathogenesis of type 1 diabetes (T1D) involves complex genetic susceptibility that impacts pathways regulating host immunity and the target of autoimmune attack, insulin-producing pancreatic ß-cells. Interactions between risk variants and environmental factors result in significant heterogeneity in clinical presentation among those who develop T1D. Although genetic risk is dominated by the human leukocyte antigen (HLA) class II and insulin (INS) gene loci, nearly 150 additional risk variants are significantly associated with the disease, including polymorphisms in immune checkpoint molecules, such as SIRPG. Scope of Review: In this review, we summarize the literature related to the T1D-associated risk variants in SIRPG, which include a protein-coding variant (rs6043409, G>A; A263V) and an intronic polymorphism (rs2281808, C>T), and their potential impacts on the immunoregulatory signal regulatory protein (SIRP) family:CD47 signaling axis. We discuss how dysregulated expression or function of SIRPs and CD47 in antigen-presenting cells (APCs), T cells, natural killer (NK) cells, and pancreatic ß-cells could potentially promote T1D development. Major Conclusions: We propose a hypothesis, supported by emerging genetic and functional immune studies, which states a loss of proper SIRP:CD47 signaling may result in increased lymphocyte activation and cytotoxicity and enhanced ß-cell destruction. Thus, we present several novel therapeutic strategies for modulation of SIRPs and CD47 to intervene in T1D.

Hybrid computational modeling demonstrates the utility of simulating complex cellular networks in type 1 diabetes.

Persistent destruction of pancreatic ß-cells in type 1 diabetes (T1D) results from multifaceted pancreatic cellular interactions in various phase progressions. Owing to the inherent heterogeneity of coupled nonlinear systems, computational modeling based on T1D etiology help achieve a systematic understanding of biological processes and T1D health outcomes. The main challenge is to design such a reliable framework to analyze the highly orchestrated biology of T1D based on the knowledge of cellular networks and biological parameters. We constructed a novel hybrid in-silico computational model to unravel T1D onset, progression, and prevention in a non-obese-diabetic mouse model. The computational approach that integrates mathematical modeling, agent-based modeling, and advanced statistical methods allows for modeling key biological parameters and time-dependent spatial networks of cell behaviors. By integrating interactions between multiple cell types, model results captured the individual-specific dynamics of T1D progression and were validated against experimental data for the number of infiltrating CD8+T-cells. Our simulation results uncovered the correlation between five auto-destructive mechanisms identifying a combination of potential therapeutic strategies: the average lifespan of cytotoxic CD8+T-cells in islets; the initial number of apoptotic ß-cells; recruitment rate of dendritic-cells (DCs); binding sites on DCs for naïve CD8+T-cells; and time required for DCs movement. Results from therapy-directed simulations further suggest the efficacy of proposed therapeutic strategies depends upon the type and time of administering therapy interventions and the administered amount of therapeutic dose. Our findings show modeling immunogenicity that underlies autoimmune T1D and identifying autoantigens that serve as potential biomarkers are two pressing parameters to predict disease onset and progression.

Therapeutic Strategies for Diabetes: Immune Modulation in Pancreatic ß Cells.

Increased incidence of type I and type II diabetes has been prevailed worldwide. Though the pathogenesis of molecular mechanisms remains still unclear, there are solid evidence that disturbed immune homeostasis leads to pancreatic ß cell failure. Currently, autoimmunity and uncontrolled inflammatory signaling pathways have been considered the major factors in the pathogenesis of diabetes. Many components of immune system have been reported to implicate pancreatic ß cell failure, including helper T cells, cytotoxic T cells, regulatory T cells and gut microbiota. Immune modulation of those components using small molecules and antibodies, and fecal microbiota transplantation are undergoing in many clinical trials for the treatment of type I and type II diabetes. In this review we will discuss the basis of molecular pathogenesis focusing on the disturbed immune homeostasis in type I and type II diabetes, leading to pancreatic ß cell destruction. Finally, we will introduce current therapeutic strategies and clinical trials by modulation of immune system for the treatment of type I and type II diabetes patients.

Natural Killer Cells as Key Mediators in Type I Diabetes Immunopathology.

The immunopathology of type I diabetes (T1D) presents a complicated case in part because of the multifactorial origin of this disease. Typically, T1D is thought to occur as a result of autoimmunity toward islets of Langerhans, resulting in the destruction of insulin-producing cells (ß cells) and thus lifelong reliance on exogenous insulin. However, that explanation obscures much of the underlying mechanism, and the actual precipitating events along with the associated actors (latent viral infection, diverse immune cell types and their roles) are not completely understood. Notably, there is a malfunctioning in the regulation of cytotoxic CD8+ T cells that target endocrine cells through antigen-mediated attack. Further examination has revealed the likelihood of an imbalance in distinct subpopulations of tolerogenic and cytotoxic natural killer (NK) cells that may be the catalyst of adaptive immune system malfunction. The contributions of components outside the immune system, including environmental factors such as chronic viral infection also need more consideration, and much of the recent literature investigating the origins of this disease have focused on these factors. In this review, the details of the immunopathology of T1D regarding NK cell disfunction is discussed, along with how those mechanisms stand within the context of general autoimmune disorders. Finally, the rarer cases of latent autoimmune, COVID-19 (viral), and immune checkpoint inhibitor (ICI) induced diabetes are discussed as their exceptional pathology offers insight into the evolution of the disease as a whole.