Daniel Espes1,2, Kailash Singh3, Stellan Sandler3, Per-Ola Carlsson3,2. 1. Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden daniel.espes@mcb.uu.se. 2. Department of Medical Sciences, Uppsala University, Uppsala, Sweden. 3. Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Abstract
OBJECTIVE: Many patients with long-standing type 1 diabetes have remaining functional β-cells. This study investigated immunological differences between patients with or without measurable remaining endogenous insulin production after ≥10 years duration of disease. RESEARCH DESIGN AND METHODS: Patients (n = 113; ≥18 years of age) with type 1 diabetes and with disease duration of ≥10 years were recruited at Uppsala University Hospital. Residual β-cell function was determined with an ultrasensitive C-peptide ELISA. Circulating cytokines, including interleukin-35 (IL-35), were determined in plasma. Additional blood samples were collected from 14 of the identified C-peptide-positive patients and 12 of the C-peptide-negative patients, as well as from 15 healthy control subjects, and were used for immediate investigation of peripheral blood mononuclear cells. RESULTS: The blood concentration of the cytokine IL-35 was markedly lower in C-peptide-negative patients, and this was associated with a simultaneous decrease in the proportion of IL-35+ regulatory T cells (Tregs), IL-35+ regulatory B cells, and IL-35-producing CD8+Foxp3+ cells. IL-35 has previously been shown to maintain the phenotype of Tregs, block the differentiation of T-helper 17 cells, and thereby dampen immune assaults to β-cells. We found that the proportions of IL-17a+ cells among the Tregs, CD4+ T cells, and CD8+ T cells were lower in the C-peptide-positive patients. CONCLUSIONS: Patients with remaining endogenous β-cell function after >10 years duration of type 1 diabetes differ immunologically from other patients with long-standing type 1 diabetes. In particular, they have a much higher IL-35 production.
OBJECTIVE: Many patients with long-standing type 1 diabetes have remaining functional β-cells. This study investigated immunological differences between patients with or without measurable remaining endogenous insulin production after ≥10 years duration of disease. RESEARCH DESIGN AND METHODS: Patients (n = 113; ≥18 years of age) with type 1 diabetes and with disease duration of ≥10 years were recruited at Uppsala University Hospital. Residual β-cell function was determined with an ultrasensitive C-peptide ELISA. Circulating cytokines, including interleukin-35 (IL-35), were determined in plasma. Additional blood samples were collected from 14 of the identified C-peptide-positive patients and 12 of the C-peptide-negative patients, as well as from 15 healthy control subjects, and were used for immediate investigation of peripheral blood mononuclear cells. RESULTS: The blood concentration of the cytokine IL-35 was markedly lower in C-peptide-negative patients, and this was associated with a simultaneous decrease in the proportion of IL-35+ regulatory T cells (Tregs), IL-35+ regulatory B cells, and IL-35-producing CD8+Foxp3+ cells. IL-35 has previously been shown to maintain the phenotype of Tregs, block the differentiation of T-helper 17 cells, and thereby dampen immune assaults to β-cells. We found that the proportions of IL-17a+ cells among the Tregs, CD4+ T cells, and CD8+ T cells were lower in the C-peptide-positive patients. CONCLUSIONS:Patients with remaining endogenous β-cell function after >10 years duration of type 1 diabetes differ immunologically from other patients with long-standing type 1 diabetes. In particular, they have a much higher IL-35 production.
Authors: Henrik Hill; Andris Elksnis; Per Lundkvist; Kumari Ubhayasekera; Jonas Bergquist; Bryndis Birnir; Per-Ola Carlsson; Daniel Espes Journal: Biomedicines Date: 2021-12-31