Date

2016

Author

Gül, Ersin

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Type-I interferonopathies are a heterogeneous group of diseases arising from deregulation in nucleic acid sensing pathways, leading to constitutive type-I interferon release and pathology. DNA damage, if not repaired can also potentially activate such pathways. To test the hypothesis that 2 different DNA damage repair and immune deficiencies, Ataxia telangiectasia (AT) and Artemis deficiency could suffer from clinical manifestations associated with elevated type I IFN response, we compared the immune status of AT and Artemis deficient patients to healthy controls and to two patients with confirmed type I interferonopathies (one SAVI (STING-associated vasculopathy with onset in infancy) and one TREX-1 deficient patient diagnosed with Aicardi-Goutières Syndrome (AGS)). Our results demonstrated that type-I and III interferon signatures were elevated in plasma and peripheral blood cells of AT and Artemis deficient patients. Specifically, compared to healthy controls, circulating IP-10 (9- and 14-fold), IFN (5- and 7-fold) and IFN1 (4- and 5-fold) concentrations were significantly higher in AT and Artemis deficient patients, respectively. Moreover, AT and Artemis deficient peripheral blood mononuclear cells (PBMC) secreted ~4- and ~5 fold more IFN-α than healthy controls in the absence of any stimulation. This exaggerated response was still maintained when cells were stimulated with the STING ligand 2’3’-cGAMP (6- and 31-fold more IFN secretion from AT and Artemis deficient cells). Measurement of phosphorylated STAT1 concentrations within PBMCs revealed elevated levels in AT and Artemis deficient patients with respect to healthy controls. These results suggest that AT and Artemis deficient patients have immune features consistent with elevated type I IFN signature. Next, we hypothesized that aberrant IFN production could activate neutrophils and contribute to tissue damage. Herein, we show for the first time that neutrophils of AT, Artemis deficient and SAVI patients spontaneously produced neutrophil extracellular traps (NETs). Consistent with neutrophil activation, plasma elastase was significantly higher in all tested patient groups suggesting that neutrophils might be contributing to tissue damage in classical and proposed type-I interferonopathies.

Subject Keywords

Interferon., Immunology., Immunotherapy., Immune system.

URI

http://etd.lib.metu.edu.tr/upload/12620254/index.pdf
https://hdl.handle.net/11511/25865

Collections

Graduate School of Natural and Applied Sciences, Thesis