scholarly journals The intermediate proteasome is constitutively expressed in pancreatic beta cells and upregulated by stimulatory, non-toxic concentrations of interleukin 1 β

2019 ◽  
Author(s):  
Muhammad Saad Khilji ◽  
Danielle Verstappen ◽  
Tina Dahlby ◽  
Michala Cecilie Burstein Prause ◽  
Celina Pihl ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Mhc Class I ◽  
Pancreatic Beta Cells ◽  
Interleukin 1 ◽  
Class I ◽  
Β Cells ◽  
Autoimmune Attack ◽  
Active Intermediate ◽  
Toxic Concentrations

AbstractA central and still open question regarding the pathogenesis of autoimmune diseases, such as type 1 diabetes, concerns the processes that underlie the generation of MHC-presented autoantigenic epitopes that become targets of autoimmune attack. Proteasomal degradation is a key step in processing of proteins for MHC class I presentation. Different types of proteasomes can be expressed in cells dictating the repertoire of peptides presented by the MHC class I complex. Of particular interest for type 1 diabetes is the proteasomal configuration of pancreatic β cells, as this might facilitate autoantigen presentation by β cells and thereby their T-cell mediated destruction. Here we investigated whether so-called inducible subunits of the proteasome are constitutively expressed in β cells, regulated by inflammatory signals and participate in the formation of active intermediate or immuno-proteasomes.We show that inducible proteasomal subunits are constitutively expressed in human and rodent islets and an insulin-secreting cell-line. Moreover, the β5i subunit is incorporated into active intermediate proteasomes that are bound to 19S or 11S regulatory particles. Finally, inducible subunit expression along with increase in total proteasome activities are further upregulated by non-toxic concentrations of IL-1β stimulating proinsulin biosynthesis. These findings suggest that the β cell proteasomal repertoire is more diverse than assumed previously and may be highly responsive to a local inflammatory islet environment.

scholarly journals Similarities Between Bacterial GAD and Human GAD65: Implications in Gut Mediated Autoimmune Type 1 Diabetes

2021 ◽  
Author(s):  
Monica Westley ◽  
Tiffany Richardson ◽  
Suhana Bedi ◽  
Baofeng Jia ◽  
Fiona S.L. Brinkman ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Gut Microbiome ◽  
Pancreatic Beta Cells ◽  
Acid Decarboxylase ◽  
Host Immune System ◽  
Gamma Aminobutyric Acid ◽  
Human Gut ◽  
Autoimmune Attack

Abstract    A variety of islet autoantibodies (AAbs) can predict and possibly dictate eventual type 1 diabetes (T1D) diagnosis. Upwards of 75% of those with T1D are positive for AAbs against glutamic acid decarboxylase (GAD65), a producer of gamma-aminobutyric acid (GABA) in human pancreatic beta cells. Interestingly, bacterial populations within the human gut also express GAD65 and produce GABA. Evidence suggests that dysbiosis of the microbiome may correlate with T1D pathogenesis and physiology. Therefore, autoimmune linkages between the gut microbiome and islets susceptible to autoimmune attack need to be further elucidated. Utilizing silico analyses, we show here that 25 GAD sequences from different human gut bacterial sources show sequence and motif similarities to human beta cell GAD65. Our motif analyses determined that a majority of gut GAD sequences contain the pyroxical dependent decarboxylase domain of human GAD65 which is important for its enzymatic activity. Additionally, we showed overlap with known human GAD65 T-cell receptor epitopes which may implicate the immune destruction of beta cells. Thus, we propose a physiological hypothesis in which changes in the gut microbiome in those with T1D result in a release of bacterial GAD, thus causing miseducation of the host immune system. Due to the notable similarities, we found between humans and bacterial GAD, these deputized immune cells may then go on to target human beta cells leading to the development of T1D.

Harnessing immune cells to enhance β-cell mass in type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Ercument Dirice ◽  
Rohit N Kulkarni
Keyword(s):  
Type 1 Diabetes ◽  
Mononuclear Cells ◽  
Islet Cells ◽  
Cell Mass ◽  
Cell Loss ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Autoimmune Attack

Type 1 diabetes is characterized by early β-cell loss leading to insulin dependence in virtually all patients with the disease in order to maintain glucose homeostasis. Most studies over the past few decades have focused on limiting the autoimmune attack on the β cells. However, emerging data from patients with long-standing diabetes who continue to harbor functional insulin-producing cells in their diseased pancreas have prompted scientists to examine whether proliferation of existing β cells can be enhanced to promote better glycemic control. In support of this concept, several studies indicate that mononuclear cells that infiltrate the islets have the capacity to trigger proliferation of islet cells including β cells. These observations indicate the exciting possibility of identifying those mononuclear cell types and their soluble factors and harnessing their ability to promote β-cell growth concomitant with autoimmune therapy to prevent the onset and/or halt the progression of the disease.

scholarly journals The acquisition of an insulin-secreting phenotype by HGF-treated rat pancreatic ductal cells (ARIP) is associated with the development of susceptibility to cytokine-induced apoptosis

2005 ◽  
Vol 34 (2) ◽  
pp. 367-376 ◽  
Author(s):  
E Anastasi ◽  
C Santangelo ◽  
A Bulotta ◽  
F Dotta ◽  
B Argenti ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Pancreatic Beta Cells ◽  
Interleukin 1 ◽  
Pancreatic Beta Cell ◽  
Necrosis Factor Alpha ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells ◽  
Induced Apoptosis

The elucidation of mechanisms regulating the regeneration and survival of pancreatic beta cells has fundamental implications in the cell therapy of type 1 diabetes. The present study had the following three aims: 1. to investigate whether pancreatic ductal epithelial cells can be induced to differentiate into insulin-producing cells by exposing them to hepatocyte growth factor (HGF); 2. to characterize some of the molecular events leading to their differentiation toward a beta-cell-like phenotype; 3. to evaluate the susceptibility of newly differentiated insulin-secreting cells to cytokine-induced apoptosis, a mechanism of beta-cell destruction occurring in type 1 diabetes. We demonstrated that HGF-treated rat pancreatic ductal cell line (ARIP) cells acquired the capability to transcribe the insulin gene and translate its counterpart protein. HGF-treated cells also exhibited a glucose-dependent capability to secrete insulin into the cultured medium. Expression analysis of some of the genes regulating pancreatic beta-cell differentiation revealed a time-dependent transcription of neurogenin-3 and Neuro-D in response to HGF. Finally, we determined the susceptibility to proinflammatory cytokine (PTh1)-induced apoptosis by incubating HGF-treated and untreated ARIP cells with a cocktail of interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). Such treatment induced apoptotic death, as determined by the TUNEL technique, in about 40% of HGF-treated, insulin-secreting ARIP cells, while untreated ARIP cells were resistant to PTh1-induced apoptosis. In conclusion, we showed that HGF promotes the differentiation of ARIP cells into pancreatic beta-cell-like cells, and that the differentiation toward an insulin-secreting phenotype is associated with the appearance of susceptibility to cytokine-induced apoptosis.

Association between the transmembrane region polymorphism of MHC class I chain related Gene-A and type 1 diabetes mellitus in Sweden

2003 ◽  
Vol 64 (5) ◽  
pp. 553-561 ◽  
Author(s):  
Manu Gupta ◽  
Liene Nikitina-Zake ◽  
Marjan Zarghami ◽  
Mona Landin-Olsson ◽  
Ingrid Kockum ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Mhc Class I ◽  
Class I ◽  
Related Gene ◽  
Transmembrane Region

Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library

10.1038/12465 ◽  
1999 ◽  
Vol 5 (9) ◽  
pp. 1026-1031 ◽  
Author(s):  
F. Susan Wong ◽  
Jaana Karttunen ◽  
Caroline Dumont ◽  
Li Wen ◽  
Irene Visintin ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cdna Library ◽  
Mhc Class I ◽  
Class I ◽  
Organ Specific

scholarly journals Potential Mimicry of Viral and Pancreatic β Cell Antigens Through Non-Spliced and cis-Spliced Zwitter Epitope Candidates in Type 1 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Michele Mishto ◽  
Artem Mansurkhodzhaev ◽  
Teresa Rodriguez-Calvo ◽  
Juliane Liepe
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Viral Infections ◽  
Hla Class I ◽  
Class I ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

Increasing evidence suggests that post-translational peptide splicing can play a role in the immune response under pathological conditions. This seems to be particularly relevant in Type 1 Diabetes (T1D) since post-translationally spliced epitopes derived from T1D-associated antigens have been identified among those peptides bound to Human Leucocyte Antigen (HLA) class I and II complexes. Their immunogenicity has been confirmed through CD4+ and CD8+ T cell-mediated responses in T1D patients. Spliced peptides theoretically have a large sequence variability. This might increase the frequency of viral-human zwitter peptides, i.e. peptides that share a complete sequence homology irrespective of whether they originate from human or viral antigens, thereby impinging upon the discrimination between self and non-self antigens by T cells. This might increase the risk of autoimmune responses triggered by viral infections. Since enteroviruses and other viral infections have historically been associated with T1D, we investigated whether cis-spliced peptides derived from selected viruses might be able to trigger CD8+ T cell-mediated autoimmunity. We computed in silico viral-human non-spliced and cis-spliced zwitter epitope candidates, and prioritized peptide candidates based on: (i) their binding affinity to HLA class I complexes, (ii) human pancreatic β cell and medullary thymic epithelial cell (mTEC) antigens’ mRNA expression, (iii) antigen association with T1D, and (iv) potential hotspot regions in those antigens. Neglecting potential T cell receptor (TCR) degeneracy, no viral-human zwitter non-spliced peptide was found to be an optimal candidate to trigger a virus-induced CD8+ T cell response against human pancreatic β cells. Conversely, we identified some zwitter peptide candidates, which may be produced by proteasome-catalyzed peptide splicing, and might increase the likelihood of pancreatic β cells recognition by virus-specific CD8+ T cell clones, therefore promoting β cell destruction in the context of viral infections.

MHC Class I Chain-Related Gene Alleles 5 and 5.1 Are Transmitted More Frequently to Type 1 Diabetes Offspring in HBDI Families

2006 ◽  
Vol 958 (1) ◽  
pp. 309-311 ◽  
Author(s):  
L. NIKITINA ZAKE ◽  
M. GHADERI ◽  
Y. S. PARK ◽  
S. BABU ◽  
G. EISENBARTH ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Mhc Class I ◽  
Class I ◽  
Related Gene ◽  
Diabetes Offspring

MHC Class I Chain-Related Gene-A Is Associated with IA2 and IAA but Not GAD in Swedish Type 1 Diabetes Mellitus

2006 ◽  
Vol 1079 (1) ◽  
pp. 229-239 ◽  
Author(s):  
M. GUPTA ◽  
J. GRAHAM ◽  
B. MCNEENY ◽  
M. ZARGHAMI ◽  
M. LANDIN-OLSSON ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Mhc Class I ◽  
Class I ◽  
Related Gene

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Robert C. Sharp ◽  
Matthew E. Brown ◽  
Melanie R. Shapiro ◽  
Amanda L. Posgai ◽  
Todd M. Brusko
Keyword(s):  
Type 1 Diabetes ◽  
Regulatory Protein ◽  
Human Leukocyte ◽  
Significant Heterogeneity ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Risk Variants ◽  
Intronic Polymorphism ◽  
Autoimmune Attack

BackgroundThe 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 β-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 ReviewIn 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 β-cells could potentially promote T1D development.Major ConclusionsWe 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 β-cell destruction. Thus, we present several novel therapeutic strategies for modulation of SIRPs and CD47 to intervene in T1D.

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