The anti-inflammatory IL-1 receptor antagonist (IL-1ra) protects against the development of islet autoimmunity.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE14368 | GEO | 2012/12/01
SECONDARY ACCESSION(S): PRJNA111409
REPOSITORIES: GEO
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Project description:Through gene expression profiling in cultured lymphocytes and PBMCs from a large set of T1D patients and controls, we demonstrate that IL-1ra may protect against the development of islet autoimmunity and T1D through down-regulating a large number of inflammatory genes and pathways. Keywords: autoimmunity; IL-1Ra;Type 1 diabetes (T1D) To elucidate the molecular mechanism underlying the action of IL-1ra, we profiled gene expression in peripheral blood mononuclear cells (PBMC) cultured with sera from low or high IL-1ra subjects. To avoid potential heterogeneity in responder cells from different subjects, PBMCs from one healthy donor were cultured for six hours with 20% of sera from six subjects with low IL-1ra and six subjects with high IL-1ra. Gene expression in the cultured cells was analyzed with the Illumina HumanRef-8 v3.0 beadchips
2012-12-01 | E-GEOD-14368 | biostudies-arrayexpress
Project description:The gastrointestinal ecosystem is a highly complex environment with a profound influence on human health. Inflammation in the gut, linked to an altered gut microbiome has been associated with the development of multiple human conditions including type 1 diabetes (T1D). Viruses infecting the gastrointestinal tract, especially enteroviruses, are also thought to play an important role in T1D pathogenesis possibly via overlapping mechanisms. Here, we apply an integrative approach to combine comprehensive faecal virome, microbiome and metaproteome data sampled before and at the onset of islet autoimmunity in 40 children. We show strong age and antibody related effects across the datasets. Mastadenovirus infection was associated with profound functional changes in the faecal metaproteome. Multiomic factor analysis modelling revealed proteins associated with carbohydrate transport from the genus Faecalibacterium were associated with islet autoimmunity. These findings demonstrate functional remodelling of the gut microbiota accompanies both islet autoimmunity and viral infection.
2022-08-22 | PXD032997 | Pride
Project description:HBV vaccine is composed of surface antigen (HBsAg) that spontaneously assembles into subvirus particles. Factors that impede its humoral immunity in 5-10% of vaccinees remain elusive. Herein we showed that the low-level interleukin-1 receptor antagonist (IL-1Ra) can predict antibody protection both in mice and humans. Mechanistically, murine IL-1Ra inhibited Tfh cell expansion and subsequent GC dependent humoral immunity, resulting in significantly weakened protection against HBV challenge. Compared to soluble antigens, HBsAg particle antigen displayed a unique capture/uptake and innate immune activation, including IL-1Ra expression, preferably of medullary sinus macrophages (MSM). In humans, a unique polymorphism in RelA/p65 binding site of IL-1Ra enhancer associated IL-1Ra levels with ethnicity dependent vaccination outcome. Therefore, the differential IL-1Ra response to particle antigens probably creates a suppressive milieu for Tfh/GC development, and neutralization of IL-1Ra would resurrect antibody response in HBV vaccine non-responders.
2021-05-12 | GSE165250 | GEO
Project description:Human type 1 diabetes (T1D) arises through autoimmunity towards the insulin-producing pancreatic β cells and is modeled by the BioBreeding (BB) rat. Factors associated with islet autoimmunity are dilute and difficult to directly measure in the periphery. Therefore, we previously utilized microarray-based bioassay where human T1D sera were used to induce a disease-specific gene expression signature in unrelated, healthy peripheral blood mononuclear cells (PBMC). Here we report that sera of both spontaneously diabetic BB DRlyp/lyp and diabetes inducible BB DR+/+ rats induce inflammatory signatures in healthy PBMC of non-diabetic Brown Norway (BN) rats, while allogeneic BN sera does not. Consistent with their common T1D susceptibility, transcriptional signatures of both BB sub-strains share identity, including cytokines, immune receptors and signaling molecules. However, like the human T1D signature, the DRlyp/lyp signature, which is associated with progression to diabetes, is differentiated from that of the DR+/+ by induction of many IL-1 regulated genes. Addition of IL-1RA to cultures significantly ablates the DRlyp/lyp signature. Daily treatment of DRlyp/lyp rats with human recombinant IL-1RA significantly delays onset and sera of treated animals do not induce the characteristic IL-1 signature. Consistent with the presence of immune regulation in DR+/+ rats is induction of a signature showing negative regulation of the NFκB pathway. This study supports prior human investigations of serum that reflect disease processes associated with progression to T1D and add to a growing body of evidence implicating the balance of IL-1 and IL-1RA as key factors influencing the severity and outcome of inflammatory responses. Experiment Overall Design: The induction of gene expression was accomplished by culturing the PBMCs of healthy day180 BN donor rats for 6 h at 37°C in 5% CO2 with a) 20% autologous BN plasma(10 replicates), b) allogeneic BN plasma (15 replicates), c) allogeneic DRlyp/lyp plasma (day 60, 4 replicates), or d) DR+/+ plasma (day 60, 4 replicates). Healthy BN PBMCs were also cultured with d60 DRlyp/lyp serum supplemented with IL-1RA (4 replicates) as well as autologous BN serum supplemented with IL-1B (4 replicates), to respectively block or induce IL-1 mediated gene expression. To determine if IL-1RA-treatment of DRlyp/lyp rats would result in modulation of the DRlyp/lyp signature, additional DRlyp/lyp rats were treated with hIL-1RA (n=6) or PBS (n=6). Rats were treated for 10 days, beginning at d30, then serum was collected at d40 and used to induce gene expression in PBMCs isolated from healthy d180 BN rats. Thus, there are a total of 53 chips being the addition of all the sample conditions mentioned above.
2009-12-25 | E-GEOD-19537 | biostudies-arrayexpress
Project description:Type 1 diabetes (T1D) is one of the most prevalent autoimmune diseases among children in Western countries. Earlier metabolomics studies suggest that T1D is preceded by dysregulation of lipid metabolism. Here we used a lipidomics approach to analyze molecular lipids in a prospective series of 428 plasma samples from 40 children who progressed to T1D (PT1D), 40 children who developed at least a single islet autoantibody but did not progress to T1D during the follow-up (P1Ab) and 40 matched controls (CTR). Sphingomyelins were found to be persistently downregulated in PT1D when compared to the P1Ab and CTR groups. Triacylglycerols and phosphatidylcholines were mainly downregulated in PT1D as compared to P1Ab at the age of 3 months. Our study suggests that children who progressed to islet autoimmunity or overt T1D are characterized by distinct lipidomic signatures, which may be helpful in the identification of at-risk children before the initiation of autoimmunity.
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Project description:Longitudinal changes in gene expression during islet autoimmunity (IA) may provide insight into biological processes that explain progression to type 1 diabetes (T1D). We identified individuals from Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, autoantibodies present on two or more visits. Illumina's NovaSeq 6000 was used to quantify gene expression in whole blood. With linear mixed models we tested for changes in expression after IA that differed across individuals who progressed to T1D (progressors) (n = 25), reverted to an autoantibody-negative stage (reverters) (n = 47), or maintained IA positivity but did not develop T1D (maintainers) (n = 66). Weighted gene coexpression network analysis was used to identify coexpression modules. Gene Ontology pathway analysis of the top 150 differentially expressed genes (nominal P < 0.01) identified significantly enriched pathways including leukocyte activation involved in immune response, innate immune response, and regulation of immune response. We identified a module of 14 coexpressed genes with roles in the innate immunity. The hub gene, LTF, is known to have immunomodulatory properties. Another gene within the module, CAMP, is potentially relevant based on its role in promoting β-cell survival in a murine model. Overall, results provide evidence of alterations in expression of innate immune genes prior to onset of T1D.
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Project description:Human type 1 diabetes (T1D) arises through autoimmunity towards the insulin-producing pancreatic β cells and is modeled by the BioBreeding (BB) rat. Factors associated with islet autoimmunity are dilute and difficult to directly measure in the periphery. Therefore, we previously utilized microarray-based bioassay where human T1D sera were used to induce a disease-specific gene expression signature in unrelated, healthy peripheral blood mononuclear cells (PBMC). Here we report that sera of both spontaneously diabetic BB DRlyp/lyp and diabetes inducible BB DR+/+ rats induce inflammatory signatures in healthy PBMC of non-diabetic Brown Norway (BN) rats, while allogeneic BN sera does not. Consistent with their common T1D susceptibility, transcriptional signatures of both BB sub-strains share identity, including cytokines, immune receptors and signaling molecules. However, like the human T1D signature, the DRlyp/lyp signature, which is associated with progression to diabetes, is differentiated from that of the DR+/+ by induction of many IL-1 regulated genes. Addition of IL-1RA to cultures significantly ablates the DRlyp/lyp signature. Daily treatment of DRlyp/lyp rats with human recombinant IL-1RA significantly delays onset and sera of treated animals do not induce the characteristic IL-1 signature. Consistent with the presence of immune regulation in DR+/+ rats is induction of a signature showing negative regulation of the NFκB pathway. This study supports prior human investigations of serum that reflect disease processes associated with progression to T1D and add to a growing body of evidence implicating the balance of IL-1 and IL-1RA as key factors influencing the severity and outcome of inflammatory responses.
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Project description:The endocrine pancreas is one of the most inaccessible organs of the human body. Its autoimmune attack leads to type 1 diabetes (T1D) in a genetically susceptible population and a lifelong need for exogenous insulin replacement. Monitoring disease progression by sampling peripheral blood would provide key insights into T1D immune-mediated mechanisms and potentially change preclinical diagnosis and the evaluation of therapeutic interventions. This effort has been limited to the measurement of circulating anti-islet antibodies, which despite a recognized diagnostic value, remain poorly predictive at the individual level for a fundamentally CD4 T cell-dependent disease. Here, peptide-major histocompatibility complex tetramers were used to profile blood anti-insulin CD4 T cells in mice and human. While percentages of these were not directly informative, the state of activation of anti-insulin T cells measured by RNA and protein profiling was able to distinguish normalcy versus disease progression. Activated anti-insulin CD4 T cell were detected at time of diagnosis but also in patients with established disease and in some at-risk individuals. These results support the concept that antigen specific CD4 T cells might be used to monitor autoimmunity in real time. This advance can inform our approach to T1D diagnosis and therapeutic interventions in the pre-clinical phase of anti-islet autoimmunity.
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