Innate immune stimulation of whole blood reveals IFN-1 hyper-responsiveness in type 1 diabetes

Rodrigues, Kameron B.; Dufort, Matthew J.; Llibre, Alba; Speake, Cate; Rahman, M. Jubayer; Bondet, Vincent; Quiel, Juan; Linsley, Peter S.; Duffy, Darragh; Tarbell, Kristin V.

doi:10.1007/s00125-020-05179-4

Cited by 28 publications

(29 citation statements)

References 57 publications

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“…Free LIGHT assays were performed by Myriad RBM in their central laboratory in Austin, TX, using Quanterix’s fully automated HD-1 Analyzer and single molecule array (Simoa) technology as described elsewhere(17, 18). All incubations were performed at room temperature inside the Simoa HD-1 analyzer.…”

Section: Methodsmentioning

confidence: 99%

“…IL-6 levels were determined as described elsewhere(18, 19) using MyriadRBM at their central laboratory in Austin, TX using their proprietary InflammationMAP™ Panel, a set of multiplexed assays which is microsphere-based and consists of using antigen-specific antibodies optimized in a capture-sandwich format. All incubations were performed at room temperature.…”

Section: Methodsmentioning

confidence: 99%

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Levels of the TNF related cytokine, LIGHT increase in hospitalized COVID-19 patients with Cytokine Release Syndrome and ARDS

Perlin

Zafir-Lavie

Roadcap

et al. 2020

Preprint

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Many COVID-19 patients demonstrate lethal respiratory complications caused by cytokine release syndrome (CRS). Multiple cytokines have been implicated in CRS, but TNFSF14 (LIGHT) has not been previously measured in this setting. In this study, we observed significantly elevated serum LIGHT levels in hospitalized COVID-19 patients as compared to healthy age and gender matched control patients. The assay detected bioavailable LIGHT unbound to the inhibitor Decoy receptor-3 (DcR3). Bioavailable LIGHT levels were elevated in patients both on and off ventilatory support, with a trend toward higher levels in patients requiring mechanical ventilation. In hospitalized patients over the age of 60, who exhibited a mortality rate of 82%, LIGHT levels were significantly higher (p=0.0209) in those who died compared to survivors. As previously reported, interleukin 6 (IL-6) levels were also elevated in these patients with significantly (p=0.0076) higher levels observed in patients who died vs. survivors, paralleling the LIGHT levels. Although attempts to block IL-6 binding to its receptor have shown limited effect in COVID-19 CRS, neutralization of LIGHT may prove to be more effective owing to its more central role in regulating antiviral immune responses.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Levels of the TNF related cytokine, LIGHT increase in hospitalized COVID-19 patients with Cytokine Release Syndrome and ARDS

Perlin

Zafir-Lavie

Roadcap

et al. 2020

Preprint

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“…In individuals with type 1 diabetes, the expression of IFN-α is increased in the islets of Langerhans and peripheral blood. Inflammation mediated by IFN signalling can potentially drive programmed cell death in beta cells and initiate autoreactivity against beta cell antigens [ 5 ]. Type 1 IFNs display differential tissue expression and binding affinity to their receptor complexes, which give rise to various outcomes including inflammation and antiviral, antiproliferative and immunomodulatory activity.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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Aims/hypothesis The 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. Methods Innate 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). Results We 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/interpretation We 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

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“…TruCulture is implemented at our hospital, enabling real‐time monitoring of patients' immune function based on the concentrations of cytokine responses to different standardized immune stimulants. It has previously been used to characterize the immune responses in healthy individuals 15 and in type 1 diabetes, 16 schizophrenia 17 and after pancreaticoduodenectomy, 18 but not in patients undergoing HCT.…”

Section: Introductionmentioning

confidence: 99%

Functional immune reconstitution early after allogeneic haematopoietic cell transplantation: A comparison of pre‐ and post‐transplantation cytokine responses in stimulated whole blood

et al. 2021

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We aimed to use a novel standardized whole‐blood stimulation system to evaluate differences in the functional immune reconstitution in patients early after allogeneic haematopoietic cell transplantation (HCT). Between April and September 2018, 30 patients undergoing HCT had whole blood samples collected around day −21 (day 0 being the day of haematopoietic cell infusion) and day +28. Whole blood was transferred to TruCulture assays comprising prefilled incubation tubes with cell culture medium and a standardized stimulus. We used a panel of four stimuli (lipopolysaccharide, resiquimod, heat‐killed Candida albicans and polyinosinic:polycytidylic acid) and a blank, designed to evaluate the function of critical extra‐ and intracellular immunological signalling pathways. For each stimulus, the cytokine response was assessed by the concentration of interferon‐γ, interleukin (IL)‐12p40, IL‐10, IL‐1β, IL‐6, IL‐8, IL‐10, IL‐12p40, IL‐17A and tumour necrosis factor‐α using a multiplex Luminex assay. Pre‐HCT cytokine responses were globally decreased across several different stimuli. Despite patients receiving immunosuppressive prophylaxis at the time, post‐HCT cytokine responses were higher and less intercorrelated than pre‐HCT responses, also after adjusting for differences in the leukocyte differential counts. For the resiquimod and heat‐killed Candida albicans stimuli, we identified a cluster of patients in whom post‐HCT responses were lower than average across several cytokines, indicating a possible functional immune deficiency. Our findings suggest that the standardized whole blood stimulation system can be used to reveal heterogeneity in the in vitro cytokine responses to various stimuli after HCT. Larger studies are needed to address if the functional immune reconstitution after HCT can predict the risk of infections.

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Innate immune stimulation of whole blood reveals IFN-1 hyper-responsiveness in type 1 diabetes

Cited by 28 publications

References 57 publications

Levels of the TNF related cytokine, LIGHT increase in hospitalized COVID-19 patients with Cytokine Release Syndrome and ARDS

Levels of the TNF related cytokine, LIGHT increase in hospitalized COVID-19 patients with Cytokine Release Syndrome and ARDS

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

Functional immune reconstitution early after allogeneic haematopoietic cell transplantation: A comparison of pre‐ and post‐transplantation cytokine responses in stimulated whole blood

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