Immune System In Type Research Articles

Reduced expression of central innate defense molecules in pancreatic biopsies from subjects with Type 1 diabetes

Aims/HypothesisDefensins play a crucial role in the innate immune system's first defense against microbial threats. However, little is known about the defensin system in the pancreas, especially in relation to Type 1 diabetes. We explore the expression of defensins in different disease stages of Type 1 diabetes and correlated obtained findings to the degree of inflammation, providing new insights into the disease and the innate immune system.Material and methodsPancreases from non-diabetic human organ donors of different age groups and donors with Type 1 diabetes with different disease duration were examined. Sections from head, body and tail of the pancreas were stained for eight different defensins and for immune cells; CD3+, CD45+, CD68+ and NES+ (granulocytes).ResultsIn non-diabetic adult controls the level of expression for defensins Beta-1,Alpha-1, Cathelicidin and REG3A correlated with the level of inflammation. In contrast, individuals with Type 1 diabetes exhibit a reduction or absence of several central defensins regardless of the level of inflammation in their pancreas. The expression of Cathelicidin is present in neutrophils and macrophages but not in T-cells in subjects with Type 1 diabetes.ConclusionsObtained findings suggest a pancreatic dysfunction in the innate immune system and the bridging to the adaptive system in Type 1 diabetes. Further studies on the role of the local innate immune system in Type 1 diabetes is needed.

Mutual modulation of gut microbiota and the immune system in type 1 diabetes models

The transgenic 116C-NOD mouse strain exhibits a prevalent Th17 phenotype, and reduced type 1 diabetes (T1D) compared to non-obese diabetic (NOD) mice. A cohousing experiment between both models revealed lower T1D incidence in NOD mice cohoused with 116C-NOD, associated with gut microbiota changes, reduced intestinal permeability, shifts in T and B cell subsets, and a transition from Th1 to Th17 responses. Distinct gut bacterial signatures were linked to T1D in each group. Using a RAG-2−/− genetic background, we found that T cell alterations promoted segmented filamentous bacteria proliferation in young NOD and 116C-NOD, as well as in immunodeficient NOD.RAG-2−/− and 116C-NOD.RAG-2−/− mice across all ages. Bifidobacterium colonization depended on lymphocytes and thrived in a non-diabetogenic environment. Additionally, 116C-NOD B cells in 116C-NOD.RAG-2−/− mice enriched the gut microbiota in Adlercreutzia and reduced intestinal permeability. Collectively, these results indicate reciprocal modulation between gut microbiota and the immune system in rodent T1D models.

Investigating the Role of Immune System in Type 1 Diabetes

Type 1 diabetes (T1D) refers to the immune system's eradication of the cells that produce insulin in the patients’ islets. Dendritic cells (DCs), macrophages, and lymphocytes are some of the immune cells attended in the relevant immune responses and have been connected to the pathogenesis of T1D. In addition, it is also highlighted that cytokines also activate regulatory processes, like tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and interleukin 7 (IL-7). It is possible to develop clinical trials for T1D that combine selective cytokine blocking as a component of preventive or interventional immunotherapy. In this project, the current knowledge on the relationship between inflammation and T1D is summarized. Non-specific immune system and specific immune system are highly involved in the complex mechanism and have specific responsibilities respectively. In addition, the roles of different types of cytokines in T1D and cytokine-related potential treatment options are also be discussed in this article.

Expression of CD47 in the pancreatic β-cells of people with recent-onset type 1 diabetes varies according to disease endotype.

We are studying the dialogue between β-cells and the immune system in type 1 diabetes and have identified a cell surface receptor, signal regulatory protein-alpha (SIRPα) as an important component in the regulation of β-cell survival. SIRPα interacts with another protein, CD47, to mediate signalling. In the present work, we have studied the expression and role of CD47 in human islet cells in type 1 diabetes. Clonal EndoC-βH1 cells were employed for functional studies. Cells were exposed to pro-inflammatory cytokines and their viability monitored by flow cytometry after staining with propidium iodide. Targeted knockdown of CD47 or SIRPα was achieved with small interference RNA molecules and the expression of relevant proteins studied by Western blotting or immunocytochemistry. Human pancreas sections were selected from the Exeter Archival Diabetes Biobank and used to examine the expression of CD47 by immunofluorescence labelling. Image analysis was employed to quantify expression. CD47 is abundantly expressed in both α and β cells in human pancreas. In type 1 diabetes, the levels of CD47 are increased in α cells across all age groups, whereas the expression in β-cells varies according to disease endotype. Knockdown of either CD47 or SIRPα in EndoC-βH1 cells resulted in a loss of viability. We conclude that the CD47 plays a previously unrecognised role in the regulation of β-cell viability. This system is dysregulated in type 1 diabetes suggesting that it may be targeted therapeutically to slow disease progression.

Genetic predisposition in the 2\u2032-5\u2032A pathway in the development of type 1 diabetes: potential contribution to dysregulation of innate antiviral immunity

Aims/hypothesisThe incidence of type 1 diabetes is increasing more rapidly than can be explained by genetic drift. Viruses may play an important role in the disease, as they seem to activate the 2′-5′-linked oligoadenylate (2′-5′A) pathway of the innate antiviral immune system. Our aim was to investigate this possibility.MethodsInnate antiviral immune pathways were searched for type 1 diabetes-associated polymorphisms using genome-wide association study data. SNPs within ±250kb flanking regions of the transcription start site of 64 genes were examined. These pathways were also investigated for type 1 diabetes-associated RNA expression profiles using laser-dissected islets from two to five tissue sections per donor from the Diabetes Virus Detection (DiViD) study and the network of Pancreatic Organ Donors (nPOD).ResultsWe found 27 novel SNPs in genes nominally associated with type 1 diabetes. Three of those SNPs were located upstream of the 2′-5′A pathway, namely SNP rs4767000 (p = 1.03 × 10−9, OR 1.123), rs1034687 (p = 2.16 × 10−7, OR 0.869) and rs739744 (p = 1.03 × 10−9, OR 1.123). We also identified a large group of dysregulated islet genes in relation to type 1 diabetes, of which two were novel. The most aberrant genes were a group of IFN-stimulated genes. Of those, the following distinct pathways were targeted by the dysregulation (compared with the non-diabetic control group): OAS1 increased by 111% (p < 1.00 × 10−4, 95% CI −0.43, −0.15); MX1 increased by 142% (p < 1.00 × 10−4, 95% CI −0.52, −0.22); and ISG15 increased by 197% (p = 2.00 × 10−4, 95% CI −0.68, −0.18).Conclusions/interpretationWe identified a genetic predisposition in the 2′-5′A pathway that potentially contributes to dysregulation of the innate antiviral immune system in type 1 diabetes. This study describes a potential role for the 2′-5′A pathway and other components of the innate antiviral immune system in beta cell autoimmunity.Graphical abstract

Extracellular Vesicles Derived Human-miRNAs Modulate the Immune System in Type 1 Diabetes.

Extracellular vesicles with their molecular cargo can modulate target cell response and may affect the pathogenesis of diseases. The extracellular vesicles containing micro-RNAs (miRNAs), which are often studied as disease biomarkers, but rarely as mediators of the disease development. The role of extracellular vesicles derived miRNAs in type 1 diabetes is currently not well established. We observed a fraction of blood plasma extracellular vesicles positive for membrane proteins potentially associated with insulin-producing beta-cells and identified differentially expressed extracellular vesicles derived miRNAs in individuals with type 1 diabetes. These differentially expressed extracellular vesicles derived human miRNAs in participants with type 1 diabetes and participants with Langerhans islets beta-cells destruction showed the ability to activate TLR7/8 signaling cascade and increase activation as well as cytotoxicity of the effector blood immune cells with cytokine and chemokine release. Our results illustrate extracellular vesicles derived human miRNAs as modulators of the immune system in type 1 diabetes autoimmunity, providing potentially new insight into the pathogenesis of the disease, and novel molecular targets for intervention and type 1 diabetes prevention.

Carbamazepine, a beta-cell protecting drug, reduces type 1 diabetes incidence in NOD mice

Pancreatic beta-cells are selectively destroyed by the host immune system in type 1 diabetes. Thus, drugs that preserve beta-cell mass and/or function have the potential to prevent or slow the progression of this disease. We recently reported that the use-dependent sodium channel blocker, carbamazepine, protects beta-cells from inflammatory cytokines in vitro. Here, we tested the effects of carbamazepine treatment in female non-obese diabetic (NOD) mice by supplementing LabDiet 5053 with 0.5% w/w carbamazepine to achieve serum carbamazepine levels of 14.98 ± 3.19 µM. Remarkably, diabetes incidence over 25 weeks, as determined by fasting blood glucose, was ~50% lower in carbamazepine treated animals. Partial protection from diabetes in carbamazepine-fed NOD mice was also associated with improved glucose tolerance at 6 weeks of age, prior to the onset of diabetes in our colony. Less insulitis was detected in carbamazepine treated NOD mice at 6 weeks of age, but we did not observe differences in CD4+ and CD8+ T cell composition in the pancreatic lymph node, as well as circulating markers of inflammation. Taken together, our results demonstrate that carbamazepine reduces the development of type 1 diabetes in NOD mice by maintaining functional beta-cell mass.

Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes.

Unresolved inflammation is key in linking metabolic dysregulation and the immune system in type 2 diabetes. Successful regulation of acute inflammation requires biosynthesis of specialized proresolving lipid mediators, such as E-series resolvin (RvE) 1, and activation of cognate G protein-coupled receptors. RvE1 binds to leukotriene B4 (BLT-1) on neutrophils and to ERV-1/ChemR23 on monocyte/macrophages. We show novel actions of RvE1 and expression patterns of neutrophil receptors in type 2 diabetes. Neutrophils from healthy subjects express functional BLT-1, low levels of minimally functional ERV-1, and inversed coexpression when compared to neutrophils from type 2 diabetes subjects. Stimulation with TNF-α or LPS increased the expression of ERV-1 by healthy and diabetic neutrophils. RvE1 counteracted LPS and TNF-α induction of ERV-1 overexpression and endogenous diabetic overexpression, activating phagocytosis and resolution signals. Functional ERV-1 was determined by phosphorylation of the signaling protein ribosomal S6. Receptor-antagonism experiments revealed that the increase in phosphorylation of ribosomal S6 was mediated by BLT-1 in healthy subject neutrophils and by ERV-1 in diabetes. Metabololipidomics reveal a proinflammatory profile in diabetic serum. Cell phagocytosis is impaired in type 2 diabetes and requires RvE1 for activation. The dose of RvE1 required to activate resolution signals in type 2 diabetic neutrophils was significantly higher than in healthy controls. RvE1 rescues the dysregulation seen on neutrophil receptor profile and, following a therapeutic dosage, activates phagocytosis and resolution signals in type 2 diabetes. These findings reveal the importance of resolution receptors in health, disease, and dysregulation of inflammation in type 2 diabetes.

Immunoregulatory effects of vitamin D3 in experimentally induced type 1 diabetes

The mechanism underlying the impairment of the function of the cellular component of the immune response and its regulation by vitamin D3 in diabetes mellitus remains incompletely characterized. The present study addresses the specific features of the functioning of the T-cell link of immune response and the humoral response to injecyion of an artificial antigen in a diabetes model and after prolonged administration of vitamin D3. Chronic hyperglycemia occurring in diabetes induced a 2.3-fold decrease of the content of the marker substance 25OHD3, the major precursor of hormonally active forms of vitamin D3, in the serum. The development of vitamin D3 deficiency is accompanied by an impairment of the proliferative activity of T cells and a change in relative numbers of regulatory (CD4+) and cytotoxic (CD8+) lymphocytes. An increase of the content of the phosphorylated p65 subunit of the nuclear factor κB and more intensive translocation of this protein to the nucleus were detected in total lysates of T lymphocytes from the spleen. Moreover, enhancement of the humoral IgG response to intraperitoneal administration of a recombinant B subunit of diphtheria toxin was demonstrated. Impairment of the cellular component of the immune response was accompanied by increased apoptotic death of splenocytes, as is evident from the increased binding of the Annexin V-GFP tag to phosphatidyl serine residues exposed on the external side of the plasmalemma during apoptosis. Prolonged administration of vitamin D3 (during 2 months; dose 20 IU) promoted the normalization of proliferative activity and the relative size of T-cell subpopulations, led to a decrease of the content of the phosphorylated p65 subunit of NF-κB, and improved the balance of the secretion of IgG targeting the artificial antigen in diabetic animals. These changes were accompanied by a decrease in the number of apoptotic events in the entire splenocyte population. The results of the present study demonstrate the important role of vitamin D3 in the regulation of the functions of the immune system in type 1 diabetes.

Effects of type 1 diabetes-associated IFIH1 polymorphisms on MDA5 function and expression.

Recent evidence has highlighted the role of the innate immune system in type 1 diabetes (T1D) pathogenesis. Specifically, aberrant activation of the interferon response prior to seroconversion of T1D-associated autoantibodies supports a role for the interferon response as a precipitating event toward activation of autoimmunity. Melanoma differentiation-associated protein 5 (MDA5), encoded by IFIH1, mediates the innate immune system's interferon response to certain viral species that form double-stranded RNA (dsRNA), the MDA5 ligand, during their life cycle. Extensive research has associated single nucleotide polymorphisms (SNPs) within the coding region of IFIH1 with T1D. This review discusses the different risk and protective IFIH1 alleles in the context of recent structural and functional analysis that relate to MDA5 regulation of interferon responses. These studies have provided a functional hypothesis for IFIH1 T1D-associated SNPs' effects on MDA5-mediated interferon responses as well as supporting the genome-wide association (GWA) studies that first associated IFIH1 with T1D.

Role of immune system in type 1 diabetes mellitus pathogenesis.

The immune system is the body's natural defense system against invading pathogens. It protects the body from infection and works to communicate an individual's well-being through a complex network of interconnected cells and cytokines. This system is an associated host defense. An uncontrolled immune system has the potential to trigger negative complications in the host. Type 1 diabetes results from the destruction of pancreatic β-cells by a β-cell-specific autoimmune process. Examples of β-cell autoantigens are insulin, glutamic acid decarboxylase, tyrosine phosphatase, and insulinoma antigen. There are many autoimmune diseases, but type 1 diabetes mellitus is one of the well-characterized autoimmune diseases. The mechanisms involved in the β-cell destruction are still not clear; it is generally believed that β-cell autoantigens, macrophages, dendritic cells, B lymphocytes, and T lymphocytes are involved in the β-cell-specific autoimmune process. It is necessary to determine what exact factors are causing the immune system to become unregulated in such a manner as to promote an autoimmune response.

Targeting inflammation in the treatment of type 2 diabetes

Islets of patients with type 2 diabetes display the typical features of an inflammatory process characterized by the presence of cytokines, chemokines, immune cell infiltration, impaired function and tissue destruction with fibrotic areas. Functional studies have shown that targeting inflammation may improve insulin secretion and sensitivity. In particular clinical proof of concept studies using modulators of the interleukin-1β (IL-1β)-nuclear factor--κB (NF-κB) pathway demonstrated the role of the innate immune system in type 2 diabetes. This programme has now entered the phase 3 of clinical development. Other targets such as tumour necrosis factor α (TNFα) may be equally important but have been neglected based on poorly designed studies. In this article we discuss the mechanisms of islet inflammation in type 2 diabetes and review the opportunity of clinical translation.

FUT2 Nonfunctional Variant: A “Missing Link” Between Genes and Environment in Type 1 Diabetes?

Recent worldwide epidemiological studies demonstrate that the incidence for type 1 diabetes in most regions has been increasing by 2–5% and that type 1 diabetes prevalence in the U.S. is approximately 1 in 300 by the age of 18 (1). In other regions, the rate of increase has been even higher. For example, just 35 years ago type 1 diabetes was a very rare disorder in China, but recent rapid economic development along with changes in lifestyle and, presumably, the living environment have rendered this country with an annual increase of 7.4% for type 1 diabetes prevalence (2). Indeed, the incidence of type 1 diabetes among different geographic/ethnic regions varies up to 500-fold (3). The dramatic increase of type 1 diabetes incidence worldwide in genetically stable populations, the significant international discrepancies for disease incidence, and reports of increased incidence when individuals migrate from low-incidence to high-incidence areas (4,5) cannot be accounted for by the genetic factors alone—thus demonstrating the implication of the complex interactions between susceptibility genes, the environmental/stochastic factors, and the immune system in type 1 diabetes etiology. The famous “hygiene hypothesis” has been frequently used to explain the rapid increase and discrepancy of type 1 diabetes incidence (6). It is believed that our increasingly hygienic environment, resulting from improvements in health care delivery and sanitation, has decreased the frequency of childhood infections, perhaps resulting in concomitant alterations in the gut microbiome, leading to a modulation of the developing immune system in genetically predisposed individuals and favoring the development of autoimmunity. Indeed, recent …

State of the union between metabolism and the immune system in type 2 diabetes

Lymphocytes and myeloid cells (monocyte/macrophages) have important roles in multiple types of diseases characterized by unresolved inflammation. The relatively recent appreciation of obesity, insulin resistance and type 2 diabetes (T2D) as chronic inflammatory diseases has stimulated interest in understanding the role of immune cells in metabolic imbalance. Myeloid cells regulate inflammation through cytokine production and the adipose tissue remodeling that accompanies hyper-nutrition, thus are critical players in metabolic homeostasis. More recently, multiple studies have indicated a role for T cells in obesity-associated inflammation and insulin resistance in model organisms, with parallel work indicating that pro-inflammatory changes in T cells also associate with human T2D. Furthermore, the expansion of T cells with similar antigen-binding sites in obesity and T2D indicates these diseases share characteristics previously attributed to inflammatory autoimmune disorders. Parallel pro-inflammatory changes in the B-cell compartment of T2D patients have also been identified. Taken together, these studies indicate that in addition to accepted pro-inflammatory roles of myeloid cells in T2D, pro-inflammatory skewing of both major lymphocyte subsets has an important role in T2D disease pathogenesis. Basic immunological principles suggest that alterations in lymphocyte function in obesity and T2D patients are an integral part of a feed-forward pro-inflammatory loop involving additional cell types. Importantly, the pro-inflammatory loop almost inevitably includes adipocytes, known to respond to pro-inflammatory, pro-diabetogenic cytokines originating from the myeloid and lymphoid compartments. We propose a model for inflammation in T2D that functionally links lymphocyte, myeloid and adipocyte contributions, and importantly proposes that tools for B-cell ablation or regulation of T-cell subset balance may have a place in the endocrinologist's limited arsenal.

Stem cell approaches for diabetes: towards beta cell replacement

Stem cells hold great promise for pancreatic beta cell replacement therapy for diabetes. In type 1 diabetes, beta cells are mostly destroyed, and in type 2 diabetes beta cell numbers are reduced by 40% to 60%. The proof-of-principle that cellular transplants of pancreatic islets, which contain insulin-secreting beta cells, can reverse the hyperglycemia of type 1 diabetes has been established, and there is now a need to find an adequate source of islet cells. Human embryonic stem cells can be directed to become fully developed beta cells and there is expectation that induced pluripotent stem (iPS) cells can be similarly directed. iPS cells can also be generated from patients with diabetes to allow studies of the genomics and pathogenesis of the disease. Some alternative approaches for replacing beta cells include finding ways to enhance the replication of existing beta cells, stimulating neogenesis (the formation of new islets in postnatal life), and reprogramming of pancreatic exocrine cells to insulin-producing cells. Stem-cell-based approaches could also be used for modulation of the immune system in type 1 diabetes, or to address the problems of obesity and insulin resistance in type 2 diabetes. Herein, we review recent advances in our understanding of diabetes and beta cell biology at the genomic level, and we discuss how stem-cell-based approaches might be used for replacing beta cells and for treating diabetes.

The Effects of Weight Loss and Gastric Banding on the Innate and Adaptive Immune System in Type 2 Diabetes and Prediabetes

The Effects of Weight Loss and Gastric Banding on the Innate and Adaptive Immune System in Type 2 Diabetes and Prediabetes

The Effects of Weight Loss and Gastric Banding on the Innate and Adaptive Immune System in Type 2 Diabetes and Prediabetes

Obesity-related chronic inflammation is implicated in the pathogenesis of type 2 diabetes (T2D). The objective of the study was to determine the effects of weight loss on immune cells in T2D and prediabetes. Thirteen obese subjects with T2D or prediabetes underwent 24 wk dietary energy restriction with gastric banding surgery at 12 wk. Measures included weight, waist, and insulin resistance; surface activation marker expression on circulating immune cells; T-helper cell polarization: type 1 (Th1), type 2 (Th2); adipose tissue macrophage number and activation in sc and visceral adipose tissue. Mean total weight loss was 13.5%. There were significant decreases in expression of proinflammatory activation markers: granulocyte CD11b, monocyte CD66b, and T cell CD69 and CD25. Proinflammatory Th1 cell numbers fell by greater than 80%, as did the Th1 to Th2 ratio. The fall in Th1 to Th2 ratio related to weight (P < 0.05) and waist loss (P < 0.05). Reduction in immune cell activation was more pronounced in subjects with prediabetes. Weight and abdominal fat loss were predicted by lower activation of adipose tissue macrophage in sc and visceral adipose tissue (P < 0.05). Energy restriction before and after gastric banding attenuates activation of circulating immune cells of the innate and adaptive immune system in T2D and prediabetes. The role of immune cells in the chronic inflammation of obesity and T2D requires further investigation.

Immunomodulation with heat shock protein DiaPep277 to preserve beta cell function in type 1 diabetes – an update

Importance of the field: Type 1 diabetes is a chronic autoimmune disease in which pancreatic beta cells are selectively destroyed. Ultimately hyperglycemia develops and insulin substitution becomes necessary. Immunomodulation aims at arresting this autoimmune attack. DiaPep277, the major T-cell epitope of heat shock protein 60 (hsp60), has been shown to be effective as a modulator of the immune system in type 1 diabetes and is the focus of this review.Areas covered in this review: A literature search of Pubmed listed publications covering 1990 – 2009 and a website search of the licensing company were performed.What the reader will gain: DiaPep277 has been successfully employed in animal models and has been investigated in Phase I – III studies in humans. A combined analysis of the Phase II trials showed a significant preservation of beta cell function in adults without adverse effects, but HbA1c was not changed. A Phase III clinical trial is ongoing, and a second Phase III trial will start in early 2010. Addressing the underlying autoimmune process is the call of the future in type 1 diabetes.Take home message: Use of Diapep277 is a promising therapeutic strategy currently being tested in Phase III trials.

Correlations of sleep disturbance with the immune system in type 2 diabetes mellitus

Aims The circadian rhythm and immune system are thought to be associated with the pathological state of diabetes. The aim of this study was to examine the correlation of circadian rhythm disturbance including sleep disturbance with the immune state in patients with type 2 diabetes compared to healthy controls. Methods Nineteen patients with type 2 diabetes (11 males and 8 females; aged 46–85 years) and 19 healthy controls (7 males and 12 males; aged 45–85 years) were recruited, and the presence of circadian rhythm disturbance including sleep disturbance was examined using an actigraph. Immunological parameters were also measured. Results Sleep and circadian rhythm disturbances were more frequently noted in diabetic patients than in healthy controls. Higher fasting plasma glucose and hemoglobin A1c levels were correlated with stronger sleep and circadian rhythm disturbances. The levels of B lymphocytes, helper T lymphocytes, natural killer cells, natural killer activity, and several cytokines were increased in diabetic patients compared to healthy controls. Correlations were shown among sleep disturbance (circadian rhythm disturbance), immunological measures, and diabetic indices. Conclusion The exacerbation of diabetes was related to the level of sleep disturbance, circadian rhythm disturbance, and activation of the immune system.

Genomics in cardiac metabolism

Cell biology is in transition from reductionism to a more integrated science. Large-scale quantitative analysis of genome structure, gene expression, and metabolites were becoming mature technologies available for studies on cardiac metabolism, including diseases known to modify cardiac function. Still, these technologies have several limitations which are progressively going to be reduced. (1) The genome wide association studies are a real revolution in molecular genetics and had already identified several new variants associated to cardiac metabolism in common CV diseases, including variants in the immune system in type 2 diabetes, markers of the cell cycle in atheroma.