Blood-based signatures in type 1 diabetes

Cabrera, Susanne M.; Chen, Yi Guang; Hagopian, William; Hessner, Martin J.

doi:10.1007/s00125-015-3843-x

Cited by 52 publications

(37 citation statements)

References 114 publications

(162 reference statements)

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“…In parallel with this impaired IFNAR response, endogenous ligands for innate receptors, such as TLRs, RIG-I-like helicases (immunoreceptors for viral RNA), and nucleotide-binding oligomerization domainlike receptors (NLRs), can enhance inflammatory responses and pathogenesis in T1D (10)(11)(12). Elevated inflammatory responses have been demonstrated by the transcriptome analysis of whole blood and immune cells as well as through increased circulating proinflammatory cytokines, such as TNF-α, IL-6, IL-1β, in NOD mice and patients at onset of T1D (13)(14)(15)(16). IL-1 is an important cytokine that enhances adaptive immune responses by inducing Th1 and Th17 differentiation and proliferation, and the IL-1 gene has been implicated in risk for T1D development (17).…”

Section: Introductionmentioning

confidence: 99%

Restoration of the type I IFN–IL-1 balance through targeted blockade of PTGER4 inhibits autoimmunity in NOD mice

et al. 2018

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Type I IFN (IFN-I) dysregulation contributes to type 1 diabetes (T1D) development, and although increased IFN-I signals are pathogenic at the initiation of autoimmune diabetes, IFN-I dysregulation at later pathogenic stages more relevant for therapeutic intervention is not well understood. We discovered that 5 key antigen-presenting cell subsets from adult prediabetic NOD mice have reduced responsiveness to IFN-I that is dominated by a decrease in the tonic-sensitive subset of IFN-I response genes. Blockade of IFNAR1 in prediabetic NOD mice accelerated diabetes and increased Th1 responses. Therefore, IFN-I responses shift from pathogenic to protective as autoimmunity progresses, consistent with chronic IFN-I exposure. In contrast, IL-1-associated inflammatory pathways were elevated in prediabetic mice. These changes correlated with human T1D onset-associated gene expression. Prostaglandin E2 (PGE2) and prostaglandin receptor 4 (PTGER4), a receptor for PGE2 that mediates both inflammatory and regulatory eicosanoid signaling, were higher in NOD mice and drive innate immune dysregulation. Treating prediabetic NOD mice with a PTGER4 antagonist restored IFNAR signaling, decreased IL-1 signaling, and decreased infiltration of leukocytes into the islets. Therefore, innate cytokine alterations contribute to both T1D-associated inflammation and autoimmune pathogenesis. Modulating innate immune balance via signals such as PTGER4 may contribute to treatments for autoimmunity.

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Section: Introductionmentioning

confidence: 99%

Restoration of the type I IFN–IL-1 balance through targeted blockade of PTGER4 inhibits autoimmunity in NOD mice

et al. 2018

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“…Gene expression was induced by culturing commercially cryopreserved PBMCs from a single healthy donor (UPN727; Cellular Technology Ltd, Shaker Heights, OH) for 9 h at 37°C in 5% CO 2 with media supplemented with sera of cancer patients from each of the 2 groups (local or metastatic), as previously described by Hessner et al [ 4 , 5 ]. The composition of the UPN727 cell by a standard flow panel was described in a previous publication and was found to be in the “normal range” [ 6 ].…”

Section: Methodsmentioning

confidence: 99%

“…PBMCs contain a breadth of surface receptors due to their varied cell populations of T and B lymphocytes, monocytes, NK cells, and dendritic cells. This assay was previously shown to be sensitive and accurate for detecting inflammatory biomarkers that predict type 1 diabetes as well as characterizing inflammation associated with inflammatory bowel disease and disorders characterized by airway infection and inflammation [ 4 , 5 ]. Using sera from patients with squamous cell carcinoma (SCC) of the cervix, we identified a gene expression signature for metastatic cervical cancer.…”

Section: Introductionmentioning

confidence: 99%

Identification of a serum-induced transcriptional signature associated with metastatic cervical cancer

Palatnik

Kendziorski

et al. 2017

PLoS ONE

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ObjectiveTumor cells that escape local tissue control can convert inflammatory cells from tumor suppressors to tumor promoters. Moreover, soluble immune-modulating factors secreted from the tumor environment can be difficult to identify in patient serum due to their low abundance. We used an alternative strategy to infer a metastatic signature induced by sera of cervical cancer patients.MethodsSera from patients with local and metastatic cervical cancer were used to induce a disease-specific transcriptional signature in cultured, healthy peripheral blood mononuclear cells (PBMCs). An empirical Bayesian method, EBarrays, was used to identify differentially expressed (DE) genes with a target false discovery rate of <5%. Ingenuity Pathway Analysis (IPA) software was used to detect the top molecular and cellular functions associated with the DE genes. IPA and in silco analysis was used to pinpoint candidate upstream regulators, including cancer-related microRNAs (miRNAs).ResultsWe identified enriched pathways in the metastatic cervical group related to immune surveillance functions, such as downregulation of engulfment, accumulation, and phagocytosis of hematopoietic cells. The predicted top upstream genes were IL-10 and immunoglobulins. In silco analysis identified miRNAs predicted to drive the transcriptional signature. Two of the 4 miRNAs (miR-23a-3p and miR-944) were validated in a cohort of women with local and metastatic cervical cancer.ConclusionsThis study supports the use of a cell-based assay that uses PBMC “reporters” to predict biologically relevant factors in patient serum. Further, disease-specific transcriptional signatures induced by patient sera have the potential to differentiate patients with local versus metastatic disease.

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“…Biomarkers have been correlated with rate of progression ( Fig. 1 ), and used in research studies [26,[29][30][31] , but most have not been validated in longitudinal studies and none have reached a stage where they have become standard of care for informing treatment.…”

Section: Stages Of T1dmentioning

confidence: 99%

“…Several approaches beyond genetics are being investigated to predict early in life risk of developing T1D including: metabolomics and lipidomics [41,42] , type 1 interferon or inflammatory signature patterns with use of transcriptional profiling [30,[43][44][45][46][47] , proteomics [48] , and intestinal microbiome metagenomics and metabolites [49][50][51][52][53] . Epidemiological data can also be applied as illustrated by the risk of excessive weight gain in the first year of life, which is associated with increased risk of progression to stage 1 T1D [54,55] .…”

Section: Progression From Pre-stage 1 T1dmentioning

confidence: 99%

Type 1 Diabetes: Disease Stratification

Insel¹,

Dutta²,

Hedrick³

2017

Biomed Hub

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Type 1 diabetes, a disorder characterized by immune-mediated loss of functional pancreatic beta cells, is a disease continuum with specific presymptomatic stages with defined risk of progression to symptomatic disease. Prognostic biomarkers have been developed for disease staging and for stratification of subjects that address the heterogeneity in rate of disease progression. Using biomarkers for stratification of subjects at different stages of type 1 diabetes will enable smaller and shorter intervention clinical trials with greater effect size. Addressing the heterogeneity of the disease will allow precision medicine-based approaches to prevention and interception of presymptomatic stages of disease and treatment and cure of symptomatic disease.

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Blood-based signatures in type 1 diabetes

Cited by 52 publications

References 114 publications

Restoration of the type I IFN–IL-1 balance through targeted blockade of PTGER4 inhibits autoimmunity in NOD mice

Restoration of the type I IFN–IL-1 balance through targeted blockade of PTGER4 inhibits autoimmunity in NOD mice

Identification of a serum-induced transcriptional signature associated with metastatic cervical cancer

Type 1 Diabetes: Disease Stratification

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