Longitudinal monitoring of Type 1 Diabetes progression to disease onset
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE299709 | GEO | 2025/12/21
REPOSITORIES: GEO
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Project description:Monocytes are immune regulators implicated in the pathogenesis of Type 1 diabetes (T1D), an autoimmune disease that targets the insulin-producing pancreatic β-cell. We determined that monocytes of recent onset (RO) T1D patients and their healthy siblings express proinflammatory/cytolytic transcriptomes and hyper-secrete cytokines in response to lipopolysaccharide exposure compared to unrelated healthy controls (uHC). Flow cytometry measured elevated circulating abundances of intermediate monocytes and >2-fold more CD14+CD16+HLADR+KLRD1+PRF1+ NK-like monocytes among ROT1D patients compared to uHC. The intermediate to nonclassical monocyte ratio among ROT1D patients correlated with the decline in functional β-cell mass during the first 24 months post-onset. Among sibling non-progressors, flow cytometry measured temporal decreases in the intermediate to nonclassical monocyte ratio and NK-like monocyte abundances; these changes coincided with increases in peripheral activated regulatory T-cells. In contrast, these monocyte populations exhibited stability among T1D progressors. This study associates heightened monocyte proinflammatory/cytolytic activity with T1D susceptibility and progression and offers insight to the age-dependent decline in T1D susceptibility.
2024-01-01 | GSE232310 | GEO
Project description:Monocytes are immune regulators implicated in the pathogenesis of Type 1 diabetes (T1D), an autoimmune disease that targets the insulin-producing pancreatic β-cell. We determined that monocytes of recent onset (RO) T1D patients and their healthy siblings express proinflammatory/cytolytic transcriptomes and hyper-secrete cytokines in response to lipopolysaccharide exposure compared to unrelated healthy controls (uHC). Flow cytometry measured elevated circulating abundances of intermediate monocytes and >2-fold more CD14+CD16+HLADR+KLRD1+PRF1+ NK-like monocytes among ROT1D patients compared to uHC. The intermediate to nonclassical monocyte ratio among ROT1D patients correlated with the decline in functional β-cell mass during the first 24 months post-onset. Among sibling non-progressors, flow cytometry measured temporal decreases in the intermediate to nonclassical monocyte ratio and NK-like monocyte abundances; these changes coincided with increases in peripheral activated regulatory T-cells. In contrast, these monocyte populations exhibited stability among T1D progressors. This study associates heightened monocyte proinflammatory/cytolytic activity with T1D susceptibility and progression and offers insight to the age-dependent decline in T1D susceptibility.
2024-01-01 | GSE239501 | GEO
Project description:A need exists for biomarkers in T1D that can 1) sensitively and specifically detect disease-related immune activity prior to, and independent of, measurement of auto-antibodies towards islet cell antigens; 2) define immunopathological mechanisms; and 3) monitor changes in the inflammatory state associated with disease progression or response to therapeutic intervention. In an effort to fill this gap, we have applied a novel bioassay to both human and BB rat T1D whereby the complex milieu of inflammatory mediators present in plasma can be indirectly detected through their ability to drive transcription in peripheral blood mononuclear cells drawn from healthy, unrelated donors. The resultant gene expressions are comprehensively measured with a microarray. In our human studies, we find that plasma of recent-onset T1D patients induces expression of a pro-inflammatory signature consisting in part of many interleukin-1 (IL-1) regulated genes related to immunological activation and immunocyte chemotaxis compared to unrelated healthy controls. This signature has been found to resolve in long-standing T1D subjects (>10 years post-onset), thus associating it with active autoimmunity. Importantly, this signature has been detected in pre-onset samples of progressors to T1D years prior to onset and prior to development of auto-antibodies directed towards islet antigens. Fresh PBMCs of a healthy control donor were isolated by density gradient centrifugation. These cells were then stimulated with 20% plasma from a longitudinally monitored sibling of a T1D patient that progressed to T1D (n= 6 timepoints) at 37C in 5% CO2. Gene expression analysis was perfromed in order to evaluate the transcriptional signature associated with T1D pathogenesis.
2013-06-01 | E-GEOD-40496 | biostudies-arrayexpress
Project description:A need exists for biomarkers in T1D that can 1) sensitively and specifically detect disease-related immune activity prior to, and independent of, measurement of auto-antibodies towards islet cell antigens; 2) define immunopathological mechanisms; and 3) monitor changes in the inflammatory state associated with disease progression or response to therapeutic intervention. In an effort to fill this gap, we have applied a novel bioassay to both human and BB rat T1D whereby the complex milieu of inflammatory mediators present in plasma can be indirectly detected through their ability to drive transcription in peripheral blood mononuclear cells drawn from healthy, unrelated donors. The resultant gene expressions are comprehensively measured with a microarray. In our human studies, we find that plasma of recent-onset T1D patients induces expression of a pro-inflammatory signature consisting in part of many interleukin-1 (IL-1) regulated genes related to immunological activation and immunocyte chemotaxis compared to unrelated healthy controls. This signature has been found to resolve in long-standing T1D subjects (>10 years post-onset), thus associating it with active autoimmunity. Importantly, this signature has been detected in pre-onset samples of progressors to T1D years prior to onset and prior to development of auto-antibodies directed towards islet antigens.
2013-06-01 | GSE40496 | GEO
Project description:A need exists for biomarkers in T1D that can 1) sensitively and specifically detect disease-related immune activity prior to, and independent of, measurement of auto-antibodies towards islet cell antigens; 2) define immunopathological mechanisms; and 3) monitor changes in the inflammatory state associated with disease progression or response to therapeutic intervention. In an effort to fill this gap, we have applied a novel bioassay to both human and BB rat T1D whereby the complex milieu of inflammatory mediators present in plasma can be indirectly detected through their ability to drive transcription in peripheral blood mononuclear cells (PBMCs) drawn from healthy, unrelated donors. The resultant gene expressions are comprehensively measured with a microarray. In our human studies, we find that plasma of recent-onset T1D patients induces expression of a pro-inflammatory signature consisting in part of many interleukin-1 (IL-1) regulated genes related to immunological activation and immunocyte chemotaxis compared to unrelated healthy controls. This signature has been found to resolve in long-standing T1D subjects (>10 years post-onset), thus associating it with active autoimmunity. Importantly, this signature has been detected in pre-onset samples of progressors to T1D years prior to onset and prior to development of auto-antibodies directed towards islet antigens. In applying this approach to the BN rat, we observed that samples collected from both sub-strains at 60 days of age induced transcription of genes encoding cytokines, immune receptors, and signaling molecules consistent with a their shared susceptibility and immune activation. The DRlyp/lyp signature was differentiated from that of the DR+/+ by more robust induction of many interleukin (IL)-1M-bM-^@M-^Sregulated genes. Treatment of DRlyp/lyp rats with IL-1 receptor antagonist (IL-1RN) delayed onset and, in part, normalized the signature, suggesting that this approach may prove useful in monitoring the effect of therapeutic interventions in human T1D. Consistent with the presence of TREG cells in DR+/+ rats, we observed induction of a signature possessing negative regulators of transcription and inflammation. Fresh PBMCs of healthy Brown Norway (BN) rats (~180 days old males, to avoid variation introduced by estrous or pubertal status) were isolated by density gradient centrifugation. Transcription was induced by culturing PBMCs for 6 h at 37M-BM-0C in 5% CO2 with 20% allogeneic BN (healthy-unrelated control), DRlyp/lyp, or DR+/+ plasma [PMID 18209091]. DRlyp/lyp and DR+/+ Plasma was pooled at various ages (30, 40, 50, 60 days old) to represent timepoints prior to onset in the DRlyp/lyp strain.
2013-06-01 | E-GEOD-40497 | biostudies-arrayexpress
Project description:Monozygotic (MZ) twin pair discordance for childhood-onset Type 1 Diabetes (T1D) is ~50%, implicating roles for genetic and non-genetic factors in the aetiology of this complex autoimmune disease. Although significant progress has been made in elucidating the genetics of T1D in recent years, the non-genetic component has remained poorly defined. We hypothesized that epigenetic variation could underlie some of the non-genetic component of T1D aetiology and, thus, performed an epigenome-wide association study (EWAS) for this disease. We generated genome-wide DNA methylation profiles of purified CD14+ monocytes (an immune effector cell type relevant to T1D pathogenesis) from 15 T1D-discordant MZ twin pairs. This identified 132 different CpG sites at which the direction of the intra-MZ pair DNA methylation difference significantly correlated with the diabetic state, i.e. T1D-associated methylation variable positions (T1D-MVPs). We confirmed these T1D-MVPs display statistically significant intra-MZ pair DNA methylation differences in the expected direction in an independent set of T1D-discordant MZ pairs (P = 0.035). Then, to establish the temporal origins of the T1D-MVPs, we generated two further genome-wide datasets and established that, when compared with controls, T1D-MVPs are enriched in singletons both before (P = 0.001) and at (P = 0.015) disease diagnosis, and also in singletons positive for diabetes-associated autoantibodies but disease-free even after 12 years follow-up (P = 0.0023). Combined, these results suggest that T1D-MVPs arise very early in the etiological process that leads to overt T1D. Our EWAS of T1D represents an important contribution toward understanding the etiological role of epigenetic variation in type 1 diabetes, and it is also the first systematic analysis of the temporal origins of disease-associated epigenetic variation for any human complex disease. Bisulphite converted DNA from the 100 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2
2014-04-09 | E-GEOD-56606 | biostudies-arrayexpress
Project description:A need exists for biomarkers in T1D that can 1) sensitively and specifically detect disease-related immune activity prior to, and independent of, measurement of auto-antibodies towards islet cell antigens; 2) define immunopathological mechanisms; and 3) monitor changes in the inflammatory state associated with disease progression or response to therapeutic intervention. In an effort to fill this gap, we have applied a novel bioassay to both human and BB rat T1D whereby the complex milieu of inflammatory mediators present in plasma can be indirectly detected through their ability to drive transcription in peripheral blood mononuclear cells (PBMCs) drawn from healthy, unrelated donors. The resultant gene expressions are comprehensively measured with a microarray. In our human studies, we find that plasma of recent-onset T1D patients induces expression of a pro-inflammatory signature consisting in part of many interleukin-1 (IL-1) regulated genes related to immunological activation and immunocyte chemotaxis compared to unrelated healthy controls. This signature has been found to resolve in long-standing T1D subjects (>10 years post-onset), thus associating it with active autoimmunity. Importantly, this signature has been detected in pre-onset samples of progressors to T1D years prior to onset and prior to development of auto-antibodies directed towards islet antigens. In applying this approach to the BN rat, we observed that samples collected from both sub-strains at 60 days of age induced transcription of genes encoding cytokines, immune receptors, and signaling molecules consistent with a their shared susceptibility and immune activation. The DRlyp/lyp signature was differentiated from that of the DR+/+ by more robust induction of many interleukin (IL)-1–regulated genes. Treatment of DRlyp/lyp rats with IL-1 receptor antagonist (IL-1RN) delayed onset and, in part, normalized the signature, suggesting that this approach may prove useful in monitoring the effect of therapeutic interventions in human T1D. Consistent with the presence of TREG cells in DR+/+ rats, we observed induction of a signature possessing negative regulators of transcription and inflammation.
2013-06-01 | GSE40497 | GEO
Project description:Naturally occurring FoxP3+CD4+CD25+high regulatory T cells (Tregs) play an important role in dominant tolerance, suppressing auto-reactive CD4+CD25- T cell activity. Although Tregs from T1D subjects are functionally deficient, there is little knowledge of the molecular mechanisms that orchestrate this loss of Treg function. We observed increased apoptosis (by a novel YOPRO-1/7AAD dual staining protocol) and decreased suppression in polyclonal Tregs in the periphery from high at-risk and T1D subjects. We hypothesize that prior to and during the onset of disease, Tregs lack pro-survival signals and are caught up in a relatively deficient cytokine milieu whose effects may be detectable in the periphery. Microarray analysis was performed on un-stimulated Tregs from 12 subjects with newly diagnosed T1D and 15 healthy controls. Experiment Overall Design: Recent-onset T1D subjects were T1D patients diagnosed within 1 year. At the time of each visit, the following clinical measurements were taken: HbA1c, glucose level, height, weight and BMI. The presence of auto-antibodies was measured from peripheral blood. Peripheral blood mononuclear cells (PBMCs) were collected and Tregs were isolated using FACS isolation. RNA was isolated, amplified and cRNA was fragmented and hybridized to Affymetrix whole genome U133Plus2.0 arrays having 54675 probe-sets. Bayesian Hierarchical analysis (BGX) was used to analyze the data.
2008-04-07 | E-GEOD-10586 | biostudies-arrayexpress
Project description:We evaluated the predictive ability of various gene signatures in baseline peripheral blood mononuclear cell samples to distinguish Mtb-infected individuals who eventually progress to TB disease (progressors) or who remain asymptomatic (non-progressors) during clinical follow-up; we also compare long-term Mtb-infected non-progressors from patients with TB disease
2020-02-25 | GSE112104 | GEO
Project description:Naturally occurring FoxP3+CD4+CD25+high regulatory T cells (Tregs) play an important role in dominant tolerance, suppressing auto-reactive CD4+CD25- T cell activity. Although Tregs from T1D subjects are functionally deficient, there is little knowledge of the molecular mechanisms that orchestrate this loss of Treg function. We observed increased apoptosis (by a novel YOPRO-1/7AAD dual staining protocol) and decreased suppression in polyclonal Tregs in the periphery from high at-risk and T1D subjects. We hypothesize that prior to and during the onset of disease, Tregs lack pro-survival signals and are caught up in a relatively deficient cytokine milieu whose effects may be detectable in the periphery. Microarray analysis was performed on un-stimulated Tregs from 12 subjects with newly diagnosed T1D and 15 healthy controls. Keywords: disease-state analysis
2008-02-22 | GSE10586 | GEO