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Diabetes and other autoimmune endocrine diseases
Oral
Zuzana Parackova, Student
Motol University Hospital and 2nd Faculty of Medicine Prague, Czech Republic
Anna Sediva, MD,PhD
Motol University Hospital and 2nd Medical Faculty Prague, Czech Republic
Irena Zentsova
Motol University Hospital and 2nd Faculty of Medicine Prague, Czech Republic
Adam Klocperk
Motol University Hospital and 2nd Faculty of Medicine Prague, Czech Republic
Zdenek Sumnik
Motol University Hospital and 2nd Faculty of Medicine Prague, Czech Republic
Stepanka Pruhova
Motol University Hospital and 2nd Faculty of Medicine Prague, Czech Republic
Lenka Petrutzelkova
Motol University Hospital and 2nd Faculty of Medicine Prague, Czech Republic
Neutrophil extracellular traps (NETs) have been shown to be powerful initiators of inflammation, which lead to exploration of their role in the pathogenesis of numerous autoimmune diseases, including type 1 diabetes (T1D). Netting neutrophils infiltrate the pancreas prior to T1D onset; however, the precise nature of their contribution to disease pathology remains poorly defined. To examine how NETs may contribute to the development of T1D, we investigated NET composition and their effect on dendritic cells (DCs), monocytes and T lymphocytes in T1D children. We showed that patient NET composition differs substantially from that of healthy controls, in particular by containing more mitochondrial DNA, more histone-associated DNA and fewer antimicrobial proteins. Additionally, the presence of NETs in a mixed PBMC culture caused a strong shift towards IFNγ-producing T lymphocytes in T1D patients, but not in healthy controls. The NET-induced activation of innate immune cells in a PBMC demonstrated by the upregulation of costimulatory molecules on myeloid and plasmacytoid DCs as well as on monocytes was observed in both healthy and T1D. NETs induced cytokine production was detectable solely on monocytes in healthy controles, whereas T1D patients displayed strong cytokine production by both monocytes and dendritic cells. Importantly, in a targeted model of monocyte-derived DCs culture, NETs induced cytokine production, phenotype change, glycolysis activation and T cell polarization towards IFNγ-producing T cells in T1D patients, but not in healthy controls. In summary, NETs composition differ and promote a distinct proinflammatory response in T1D subjects and healthy controls.