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- Espes, Daniel, 1985-, et al.
(författare)
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Increased Interleukin-35 Levels in Patients With Type 1 Diabetes With Remaining C-Peptide
- 2017
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 40:8, s. 1090-1095
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Tidskriftsartikel (refereegranskat)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.
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| 3. |
- Luo, Zhengkang, et al.
(författare)
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Interleukin-35 Prevents Development of Autoimmune Diabetes Possibly by Maintaining the Phenotype of Regulatory B Cells
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:23
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Tidskriftsartikel (refereegranskat)abstract
- The anti-inflammatory role of regulatory B cells (Breg cells) has been associated with IL-35 based on studies of experimental autoimmune uveitis and encephalitis. The role of Breg cells and IL-35(+) Breg cells for type 1 diabetes (T1D) remains to be investigated. We studied PBMCs from T1D subjects and healthy controls (HC) and found lowered proportions of Breg cells and IL-35(+) Breg cells in T1D. To elucidate the role of Breg cells, the lymphoid organs of two mouse models of T1D were examined. Lower proportions of Breg cells and IL-35(+) Breg cells were found in the animal models of T1D compared with control mice. In addition, the systemic administration of recombinant mouse IL-35 prevented hyperglycemia after multiple low dose streptozotocin (MLDSTZ) injections and increased the proportions of Breg cells and IL-35(+) Breg cells. A higher proportion of IFN-gamma(+) cells among Breg cells were found in the PBMCs of the T1D subjects. In the MLDSTZ mice, IL-35 administration decreased the proportions of IFN-gamma(+) cells among the Breg cells. Our data illustrate that Breg cells may play an important role in the development of T1D and that IL-35 treatment prevents the development of hyperglycemia by maintaining the phenotype of the Breg cells under an experimental T1D condition.
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| 4. |
- Martinell, Mats, 1971-, et al.
(författare)
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Characterization of Cellular Immunology in LADA Patients
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objective: Patients with latent autoimmune diabetes mellitus in adults (LADA) have antibodies against the insulin-producing b-cells but at disease onset they are not insulin-dependent. This study presents cellular immunological differences between LADA, type 1, type 2 diabetes and healthy controls.Research Design and Methods: All patients and matched (by age, gender and body mass index) healthy controls were recruited from the County of Uppsala, Sweden. Peripheral blood mononuclear cells were isolated from freshly collected blood to determine proportions of innate, adaptive and regulatory immune cells by using flow cytometry. Results: Included were 14 patients with LADA, 16 with type 1 diabetes, 16 with type 2 diabetes and 13 healthy controls. The proportion of CD11c+CD123- antigen presenting cells (APCs) was lower, whilst proportions of CD11c+CD123+ APCs and Interleukin (IL)-35+ tolerogenic APCs were higher in LADA patients compared to patients with type 1 diabetes. The proportion of CD3-CD56highCD16+ Natural Killer (NK) cells was higher in LADA patients than in both healthy controls and type 2 diabetes patients. IL-35+ Treg cell numbers were similar to those observed in both type 1 diabetes and type 2 diabetes patients, but a lower frequency of IL-35+ regulatory T (Treg) cells was observed in LADA patients than in healthy controls. The proportion of regulatory B (Breg) cells in LADA patients was higher than in healthy controls, type 1 and type 2 diabetes patients and IL-35+ Breg cell numbers were higher than in type 1 diabetes patients. Conclusions: LADA patients present a mixed cellular immunological pattern compared to type 1 and type 2 diabetes patients. Numbers of APCs, IL-35+ tolerogenic APCs and IL-35+ Breg cells in LADA patients are similar to those observed in type 2 diabetes patients, whereas the changes in NK cells are similar to those observed in type 1 diabetes patients.
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| 5. |
- Singh, Kailash, et al.
(författare)
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Cellular immunological changes in patients with LADA are a mixture of those seen in patients with type 1 and type 2 diabetes
- 2019
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 197:1, s. 64-73
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Tidskriftsartikel (refereegranskat)abstract
- There is currently scarce knowledge of the immunological profile of patients with latent autoimmune diabetes mellitus in the adult (LADA) when compared with healthy controls (HC) and patients with classical type 1 diabetes (T1D) and type 2 diabetes (T2D). The objective of this study was to investigate the cellular immunological profile of LADA patients and compare to HC and patients with T1D and T2D. All patients and age-matched HC were recruited from Uppsala County. Peripheral blood mononuclear cells were isolated from freshly collected blood to determine the proportions of immune cells by flow cytometry. Plasma concentrations of the cytokine interleukin (IL)-35 were measured by enzyme-linked immunosorbent assay (ELISA). The proportion of CD11c(+)CD123(-) antigen-presenting cells (APCs) was lower, while the proportions of CD11c(+)CD123(+) APCs and IL-35(+) tolerogenic APCs were higher in LADA patients than in T1D patients. The proportion of CD3(-)CD56(high)CD16(+) natural killer (NK) cells was higher in LADA patients than in both HC and T2D patients. The frequency of IL-35(+) regulatory T cells and plasma IL-35 concentrations in LADA patients were similar to those in T1D and T2D patients, but lower than in HC. The proportion of regulatory B cells in LADA patients was higher than in healthy controls, T1D and T2D patients, and the frequency of IL-35(+) regulatory B cells was higher than in T1D patients. LADA presents a mixed cellular immunological pattern with features overlapping with both T1D and T2D.
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| 6. |
- Singh, Kailash, et al.
(författare)
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The Increased Circulating Plasma Levels of Vascular Endothelial Growth Factor in Patients with Type 1 Diabetes Do Not Correlate to Metabolic Control
- 2017
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Ingår i: Journal of Diabetes Research. - : Hindawi Limited. - 2314-6745 .- 2314-6753.
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Tidskriftsartikel (refereegranskat)abstract
- Aim. To characterize the plasma levels of vascular endothelial growth factor ( VEGF) in type 1 diabetes mellitus (T1D) and its relation to both present and historical metabolic control and microvascular complications.Methods. Plasma levels of VEGF and routine clinical parameters were analyzed in 115 patients with long-standing T1D and 45 healthy controls (HC). All patients were under clinical routine diabetes treatment at Uppsala University Hospital.Results. The plasma levels of VEGF were increased by 37% in patients with T1D when compared to HC (18.2 +/- 0.8 versus 13.2 +/- 1.0 pg/ml, p < 0.001). The levels of VEGF correlated to insulin needs and BMI but not to present or historical metabolic control. The levels of VEGF were similar in patients with T1D and microvascular complications (microalbuminuria and retinopathy) when compared with patients without microvascular complications. Historical HbA1c levels were found to be the best predictor for present metabolic control.Conclusion. Circulating plasma levels of VEGF do not correlate to present or historical metabolic control in long-standing T1D and the levels are not affected by the presence of microvascular complications.
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