Increased Plasma Soluble Interleukin-2 Receptor Alpha Levels in Patients With Long-Term Type 1 Diabetes With Vascular Complications Associated With IL2RA and PTPN2 Gene Polymorphisms

Magdalena Keindl*, Olena Fedotkina, Elsa du Plessis, Ruchi Jain, Brith Bergum, Troels Mygind Jensen, Cathrine Laustrup Møller, Henrik Falhammar, Thomas Nyström, Sergiu Bogdan Catrina, Gun Jörneskog, Leif Groop, Mats Eliasson, Björn Eliasson, Kerstin Brismar, Peter M. Nilsson, Tore Julsrud Berg, Silke Appel, Valeriya Lyssenko

*Corresponding author for this work

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Abstract

Type 1 diabetes (T1D) is largely considered an autoimmune disease leading to the destruction of insulin-producing pancreatic β cells. Further, patients with T1D have 3–4-fold increased risk of developing micro- and macrovascular complications. However, the contribution of immune-related factors contributing to these diabetes complications are poorly understood. Individuals with long-term T1D who do not progress to vascular complications offer a great potential to evaluate end-organ protection. The aim of the present study was to investigate the association of inflammatory protein levels with vascular complications (retinopathy, nephropathy, cardiovascular disease) in individuals with long-term T1D compared to individuals who rapidly progressed to complications. We studied a panel of inflammatory markers in plasma of patients with long-term T1D with (n = 81 and 26) and without (n = 313 and 25) vascular complications from two cross-sectional Scandinavian cohorts (PROLONG and DIALONG) using Luminex technology. A subset of PROLONG individuals (n = 61) was screened for circulating immune cells using multicolor flow cytometry. We found that elevated plasma levels of soluble interleukin-2 receptor alpha (sIL-2R) were positively associated with the complication phenotype. Risk carriers of polymorphisms in the IL2RA and PTPN2 gene region had elevated plasma levels of sIL-2R. In addition, cell surface marker analysis revealed a shift from naïve to effector T cells in T1D individuals with vascular complications as compared to those without. In contrast, no difference between the groups was observed either in IL-2R cell surface expression or in regulatory T cell population size. In conclusion, our data indicates that IL2RA and PTPN2 gene variants might increase the risk of developing vascular complications in people with T1D, by affecting sIL-2R plasma levels and potentially lowering T cell responsiveness. Thus, elevated sIL-2R plasma levels may serve as a biomarker in monitoring the risk for developing diabetic complications and thereby improve patient care.

Original languageEnglish
Article number575469
JournalFrontiers in Endocrinology
Volume11
ISSN1664-2392
DOIs
Publication statusPublished - 30. Oct 2020

Keywords

  • cardiovascular disease
  • Cluster of Differentiation 25 (CD25)
  • diabetes complications
  • nephropathy
  • regulatory T cells
  • retinopathy
  • sIL-2R

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