Myeloid-derived suppressor cells (MDSC) represent a heterogeneous group of immature myeloid cells with immunoregulatory function in cancer and autoimmune diseases. In humans, two subsets of MDSC were ...determined based on the characteristic surface markers, monocytic MDSC (M-MDSC) and granulocytic MDSC (G-MDSC). Expansion of MDSC has been reported in some murine models and patients with autoimmune diseases and their immune-suppressive properties were characterized. However, the exact role of MDSC in the pathogenesis of autoimmune diseases is more complex and/or controversial. In type 1 diabetes mellitus (T1D), the increased frequency of MDSC was found in the blood of T1D patients but their suppressor capacity was diminished. In our study, we assessed the role of M-MDSC in the pathogenesis of T1D and showed for the first time the increased frequency of M-MDSC not only in the blood of T1D patients but also in their at-risk relatives compared to healthy donors. T1D patients with inadequate long term metabolic control showed an elevation of M-MDSC compared to patients with better disease control. Furthermore, we described the positive correlation between the percentage of M-MDSC and Th17 cells and IFN-γ producing T cells in T1D patients and their at-risk relatives. Finally, we found that the ability of M-MDSC to suppress autologous T cells is efficient only at the high MDSC: T cells ratio and dependent on cell-cell-contact and TGF-β production. Our data show that the engagement of MDSC in the pathogenesis of T1D is evident, yet not entirely explored and more experiments are required to clarify whether MDSC are beneficial or harmful in T1D.
Sarcopenia and osteoporosis are among the late complications of type 1 diabetes (T1D) in adults. Whether and to what extent musculoskeletal impairment is present in childhood and adolescence has yet ...to be determined. The aim of this study was to assess volumetric bone mineral density (BMD) and dynamic muscle function in adolescents with T1D and to assess the clinical and biochemical predictors of their musculoskeletal system.
Ninety-five children and adolescents (59 boys and 36 girls, mean age 16.2±1.2years) with T1D were included in this cross-sectional study. Study participants were divided into two groups according to the duration of the disease (<6years and >9years, respectively). Volumetric BMD of the non-dominant tibia was assessed using peripheral quantitative computed tomography (pQCT). Dynamic muscle function was evaluated using jumping mechanography. Gender- and height-specific Z-scores were calculated using published reference data. HbA1c was evaluated retrospectively as an average over the past 5years.
Relative muscle power (Pmax/mass) and force (Fmax/body weight) were significantly decreased in T1D subjects (mean Z-scores −0.4±1.0; p<0.001, and −0.3±1.1; p<0.01, respectively). The duration of T1D negatively affected Pmax/mass (p<0.01) but not Fmax/body weight (p=0.54). Patients with T1D had also decreased trabecular BMD, the Strength-Strain Index and cortical thickness (mean Z-scores −0.8±1.3; −0.5±0.8 and −1.1±0.8, respectively, p<0.001 for all) whereas cortical BMD was increased when compared to controls (Z-score 1.2±0.90, p<0.001). No association was observed between the HbA1c and 25-hydroxyvitamin D levels and bone or muscle parameters.
T1D influences the musculoskeletal system in adolescence. Decreased muscle function could contribute to the osteoporosis reported in adult diabetic patients.
•Adolescents with T1D have alterations of the musculoskeletal system.•T1D duration negatively affects muscle functions in these individuals.•Musculoskeletal impairment in T1D is independent from 25-OHD serum levels.
Neutrophils releasing neutrophil extracellular traps (NETs) infiltrate the pancreas prior to type 1 diabetes (T1D) onset; however, the precise nature of their contribution to disease remains poorly ...defined. To examine how NETs affect immune functions in T1D, we investigated NET composition and their effect on dendritic cells (DCs) and T lymphocytes in T1D children. We showed that T1D patient NET composition differs substantially from that of healthy donors and that the presence of T1D-NETs in a mixed peripheral blood mononuclear cell culture caused a strong shift toward IFNγ-producing T lymphocytes, mediated through activation of innate immunity cells in T1D samples. Importantly, in a monocyte-derived DC (moDC) culture, NETs induced cytokine production, phenotypic change and IFNγ-producing T cells only in samples from T1D patients but not in those from healthy donors. RNA-seq analysis revealed that T1D-NETs presence causes TGFβ downregulation and IFNα upregulation and creates pro-T1D signature in healthy moDCs.
Type 1 diabetes (T1D) is an autoimmune disorder with unambiguous involvement of both innate and adaptive immune mechanisms in the destruction of pancreatic beta cells. Recent evidence demonstrated ...that neutrophils infiltrate the pancreas prior to disease onset and therein extrude neutrophil extracellular traps (NETs), web-like structures of DNA and nuclear proteins with a strong pro-inflammatory biologic activity. Our previous work showed that T1D NETs activate dendritic cells, which consequently induce IFNγ-producing Th1 lymphocytes. The aim of this study was to assess direct
biomarkers of NETosis in the serum of recent onset and long-term pediatric T1D patients, their first-degree relatives and healthy controls. To this end we evaluated serum levels of myeloperoxidase (MPO), neutrophil elastase (NE), proteinase 3 (PR3), protein arginine deiminase 4 (PAD4), LL37 and cell-free DNA-histone complexes in sex- and age-matched cohorts of T1D first-degree relatives, recent-onset T1D patients, and in patients 12 months after clinical manifestation of the disease. Our data shows that disease onset is accompanied by peripheral neutrophilia and significant elevation of MPO, NE, PR3, PAD4 and cell-free DNA-histone complexes. Most biomarkers subsequently decrease but do not always normalize in long-term patients. First-degree relatives displayed an intermediate phenotype, except for remarkably high levels of LL37. Together, this report provides evidence for the presence of ongoing NETosis in pediatric patients with T1D at time of clinical manifestation of the disease, which partly subsides in subsequent years.
The growth hormone deficiency (GHD) diagnosis is controversial especially due to low specificity of growth hormone (GH) stimulation tests. It is therefore believed that children diagnosed with GHD ...form a heterogeneous group with growth disorder frequently independent on GH function. No study evaluating the complex etiology of growth failure in children with diagnosed GHD has been performed thus far.
To discover genetic etiology of short stature in children with diagnosed GHD from families with short stature.
Fifty-two children diagnosed with primary GHD and vertically transmitted short stature (height SDS in the child and his/her shorter parent <-2 SD) were included to our study. The GHD diagnosis was based on growth data suggestive of GHD, absence of substantial disproportionality (sitting height to total height ratio <-2 SD or >+2 SD), IGF-1 levels <0 for age and sex specific SD and peak GH concentration <10 ug/L in two stimulation tests. All children were examined using next-generation sequencing methods, and the genetic variants were subsequently evaluated by American College of Medical Genetics standards and guidelines.
The age of children at enrollment into the study was 11 years (median, IQR 9-14 years), their height prior to GH treatment was -3.0 SD (-3.6 to -2.8 SD), IGF-1 concentration -1.4 SD (-2.0 to -1.1 SD), and maximal stimulated GH 6.3 ug/L (4.8-7.6 ug/L). No child had multiple pituitary hormone deficiency or a midbrain region pathology. Causative variant in a gene that affects growth was discovered in 15/52 (29%) children. Of them, only 2 (13%) had a genetic variant affecting GH secretion or function (
and
). Interestingly, in 10 (67%) children we discovered a primary growth plate disorder (
,
,
,
,
,
,
,
,
2x), in one (7%) a genetic variant impairing IGF-1 action (
) and in two (12%) a variant in miscellaneous genes (
,
).
In children with vertically transmitted short stature, genetic results frequently did not correspond with the clinical diagnosis of GH deficiency. These results underline the doubtful reliability of methods standardly used to diagnose GH deficiency.
The proportion of children with type 1 diabetes (T1D) who have experience with low-carbohydrate diet (LCD) is unknown. Our goal was to map the frequency of LCD among children with T1D and to describe ...their clinical and laboratory data.
Caregivers of 1040 children with T1D from three centers were addressed with a structured questionnaire regarding the children's carbohydrate intake and experience with LCD (daily energy intake from carbohydrates below 26% of age-recommended values). The subjects currently on LCD were compared to a group of non-LCD respondents matched to age, T1D duration, sex, type and center of treatment.
A total of 624/1040 (60%) of the subjects completed the survey. A total of 242/624 (39%) subjects reported experience with voluntary carbohydrate restriction with 36/624 (5.8%) subjects currently following the LCD. The LCD group had similar HbA1c (45 vs. 49.5,
= 0.11), lower average glycemia (7.0 vs. 7.9,
= 0.02), higher time in range (74 vs. 67%,
= 0.02), lower time in hyperglycemia >10 mmol/L (17 vs. 20%,
= 0.04), tendency to more time in hypoglycemia <3.9 mmol/L(8 vs. 5%,
= 0.05) and lower systolic blood pressure percentile (43 vs. 74,
= 0.03). The groups did not differ in their lipid profile nor in current body height, weight or BMI. The LCD was mostly initiated by the parents or the subjects themselves and only 39% of the families consulted their decision with the diabetologist.
Low carbohydrate diet is not scarce in children with T1D and is associated with modestly better disease control. At the same time, caution should be applied as it showed a tendency toward more frequent hypoglycemia.
Aims
The development of the immune phenotype in patients with type 1 diabetes (T1D) during the first year following disease onset remains poorly described, and studies analysing the longitudinal ...development of a complex set of immunological and metabolic parameters are missing. Thus, we aim to provide such complex view in a cohort of 38 children with new onset T1D who were prospectively followed for 1 year.
Methods
All subjects were tested for a set of immunological parameters (complete blood count; serum immunoglobulins; and T, B and dendritic cells), HbA1c and daily insulin dose at baseline and at 6 and 12 months after T1D diagnosis. A mixed meal tolerance test was administered to each of the subjects 12 months after diagnosis, and the C-peptide area under the curve (AUC) was noted and was then tested for association with all immunological parameters.
Results
A gradual decrease in leukocytes (adjusted
p
= 0.0012) was reflected in a significant decrease in neutrophils (adjusted
p
= 0.0061) over the post-onset period, whereas Tregs (adjusted
p
= 0.0205) and originally low pDCs (adjusted
p
< 0.0001) increased. The expression of the receptor for BAFF (BAFFR) on B lymphocytes (adjusted
p
= 0.0127) markedly increased after onset. No immunological parameters were associated with C-peptide AUC; however, we observed a linear increase in C-peptide AUC with the age of the patients (
p
< 0.0001).
Conclusions
Our study documents substantial changes in the innate and adaptive immune system over the first year after disease diagnosis but shows no association between immunological parameters and residual beta-cell activity. The age of patients remains the best predictor of C-peptide AUC, whereas the role of the immune system remains unresolved.
Introduction: The aim of the study was to assess the differences in key parameters of type 1 diabetes (T1D) control associated with treatment and monitoring modalities including newly introduced ...hybrid closed-loop (HCL) algorithm in children and adolescents with T1D (CwD) using the data from the population-wide pediatric diabetes registry ČENDA. Methods: CwD younger than 19 years with T1D duration >1 year were included and divided according to the treatment modality and type of CGM used: multiple daily injection (MDI), insulin pump without (CSII) and with HCL function, intermittently scanned continuous glucose monitoring (isCGM), real-time CGM (rtCGM), and intermittent or no CGM (noCGM). HbA1c, times in glycemic ranges, and glucose risk index (GRI) were compared between the groups. Results: Data of a total of 3,251 children (mean age 13.4 ± 3.8 years) were analyzed. 2,187 (67.3%) were treated with MDI, 1,064 (32.7%) with insulin pump, 585/1,064 (55%) with HCL. The HCL users achieved the highest median TIR 75.4% (IQR 6.3) and lowest GRI 29.1 (7.8), both p < 0.001 compared to other groups, followed by MDI rtCGM and CSII groups with TIR 68.8% (IQR 9.0) and 69.0% (7.5), GRI 38.8 (12.5) and 40.1 (8.5), respectively (nonsignificant to each other). These three groups did not significantly differ in their HbA1c medians (51.8 IQR 4.5, 50.7 4.5, and 52.7 5.7 mmol/mol, respectively). NoCGM groups had the highest HbA1c and GRI and lowest TIR regardless of the treatment modality. Conclusion: This population-based study shows that the HCL technology is superior to other treatment modalities in CGM-derived parameters and should be considered as a treatment of choice in all CwD fulfilling the indication criteria.
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