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The activity of acid sphingomyelinase (ASMase), a key enzyme in sphingolipid metabolism, has been found to be increased in a variety of human diseases. Studies conducted on animal and cellular models showed that sphingolipids and ASMase play a central role in the pathogenesis of type 1 diabetes (T1D) and T1D-related vascular damage. Currently, no studies have investigated the role of ASMase activity in pediatric patients with T1D. Therefore, we conducted a cross-sectional study to evaluate the activity of the secretory form of ASMase (S-ASMase) in the serum of patients with T1D aged 2-16 years in comparison with a control group (healthy subjects matched for age, gender, and pubertal stage). We recruited children and adolescents affected by T1D (including patients with new-onset and established T1D) aged 2-16 years and healthy normal-weight subjects with normal timing of puberty (matched for age, gender, and pubertal stage), who were consecutively admitted-as outpatients-to our institution for screening purposes. Serum lipid profile, glycated hemoglobin (HbA1c), and urine albumin-creatinine ratio (uACR) were assessed in all T1D patients. S-ASMase activity was measured in all study participants through a colorimetric assay. In total, 68 T1D patients and 51 healthy controls were recruited in this study. None of the T1D patients had T1D-related complications. No difference in S-ASMase activity was observed between subjects with T1D and healthy controls. However, when T1D patients were stratified according to the duration of diabetes, we found a significantly higher activity of S-ASMase in patients with new-onset T1D (recruited within 1 week after the disease diagnosis) as compared to that observed in patients with established T1D. In all patients with T1D, S-ASMase activity correlated positively with HbA1c and triglyceride levels, while it correlated negatively with total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels. However, there were no significant differences in S-ASMase activity between T1D patients with new-onset disease who presented with diabetic ketoacidosis (DKA; n = 12) and T1D patients with new-onset disease who did not present with DKA (n = 13). Our study evaluated, for the first time, the in vivo activity of S-ASMase in a pediatric cohort of patients with T1D. In pediatric patients with new-onset T1D, we found a significantly higher S-ASMase activity as compared to that observed in patients with established T1D. In all T1D patients, the positive correlation between S-ASMase activity, HbA1c, and triglyceride levels, as well as the negative correlation between S-ASMase activity and HDL-C levels, suggests a potential role played by sphingolipids in T1D pathophysiology. Further mechanistic studies are needed to better elucidate the role of S-ASMase in patients with T1D at different stages of the disease.

Trillions of microbes survive and thrive inside the human body. These tiny creatures are crucial to the development and maturation of our immune system and to maintain gut immune homeostasis. Microbial dysbiosis is the main driver of local inflammatory and autoimmune diseases such as colitis and inflammatory bowel diseases. Dysbiosis in the gut can also drive systemic autoimmune diseases such as type 1 diabetes, rheumatic arthritis, and multiple sclerosis. Gut microbes directly interact with the immune system by multiple mechanisms including modulation of the host microRNAs affecting gene expression at the post-transcriptional level or production of microbial metabolites that interact with cellular receptors such as TLRs and GPCRs. This interaction modulates crucial immune functions such as differentiation of lymphocytes, production of interleukins, or controlling the leakage of inflammatory molecules from the gut to the systemic circulation. In this review, we compile and analyze data to gain insights into the underpinning mechanisms mediating systemic autoimmune diseases. Understanding how gut microbes can trigger or protect from systemic autoimmune diseases is crucial to (1) tackle these diseases through diet or lifestyle modification, (2) develop new microbiome-based therapeutics such as prebiotics or probiotics, (3) identify diagnostic biomarkers to predict disease risk, and (4) observe and intervene with microbial population change with the flare-up of autoimmune responses. Considering the microbiome signature as a crucial player in systemic autoimmune diseases might hold a promise to turn these untreatable diseases into manageable or preventable ones.

Neutrophil extracellular traps (NETs) and mitochondrial DNA (mtDNA) are inflammatory mediators involved in the development of type 1 diabetes (T1D). Pancreas-infiltrating neutrophils can release NETs, contributing to the inflammatory process. Levels of NETs are increased in serum from patients with T1D and mtDNA is increased in adult T1D patients. Our aim was to investigate extracellular DNA (NETs, mtDNA and nuclear DNA) in children with newly diagnosed T1D and in children at high risk of the disease. We also elucidated if extracellular DNA short after diagnosis could predict loss of endogenous insulin production. Samples were analysed for mtDNA and nuclear DNA using droplet digital PCR and NETs were assessed by a NET-remnants ELISA. In addition, in vitro assays for induction and degradation of NETs, as well as analyses of neutrophil elastase, HLA genotypes, levels of c-peptide, IL-1beta, IFN and autoantibodies (GADA, IA-2A, IAA and ZnT8A) were performed. In serum from children 10 days after T1D onset there was an increase in NETs (p=0.007), mtDNA (p<0.001) and nuclear DNA (p<0.001) compared to healthy children. The elevated levels were found only in younger children. In addition, mtDNA increased in consecutive samples short after onset (p=0.017). However, levels of extracellular DNA short after onset did not reflect future loss of endogenous insulin production. T1D serum induced NETs in vitro and did not deviate in the ability to degrade NETs. HLA genotypes and autoantibodies, except for ZnT8A, were not associated with extracellular DNA in T1D children. Serum from children with high risk of T1D showed fluctuating levels of extracellular DNA, sometimes increased compared to healthy children. Therefore, extracellular DNA in serum from autoantibody positive high-risk children does not seem to be a suitable biomarker candidate for prediction of T1D. In conclusion, we found increased levels of extracellular DNA in children with newly diagnosed T1D, which might be explained by an ongoing systemic inflammation.

Regulatory T (Treg) cells represent a subpopulation of suppressor CD4 T cells critically involved in the establishment of peripheral tolerance through the inhibition of effector T (Teff) cells and the suppression of the immune-mediated tissue destruction toward self-antigens. Treg generation, their suppressive properties and also Treg-Teff cell interactions could be modulated at least in part by programmed cell death-1 (PD-1) expression on their surface and through binding between PD-1 and programmed cell death ligand-1 (PD-L1). Defects involving PD-1 and Tregs can lead to the development of pathological conditions, including autoimmune disorders or promote cancer progression by favoring tumor evasion from the host immune response. At the same time, PD-1 and Tregs could represent attractive targets for treatment, as demonstrated by the therapeutic blockade of PD-L1 applied for the management of different cancer conditions in humans. In the present Review, we focus specifically the role of PD-1/PD-L1 on Treg development and activity.

The preclinical phase of autoimmune disorders is characterized by an initial asymptomatic phase of varying length followed by nonspecific signs and symptoms. A variety of autoimmune and inflammatory manifestations can be present and tend to increase in the last months to years before a clinical diagnosis can be made. The phenotype of an autoimmune disease depends on the involved organs, the underlying genetic susceptibility and pathophysiological processes. There are different as well as shared genetic or environmental risk factors and pathophysiological mechanisms between separate diseases. To shed more light on this, in this narrative review we compare the preclinical disease course of four important autoimmune diseases with distinct phenotypes: rheumatoid arthritis (RA), Systemic Lupus Erythematosus (SLE), multiple sclerosis (MS) and type 1 diabetes (T1D). In general, we observed some notable similarities such as a North-South gradient of decreasing prevalence, a female preponderance (except for T1D), major genetic risk factors at the HLA level, partly overlapping cytokine profiles and lifestyle risk factors such as obesity, smoking and stress. The latter risk factors are known to produce a state of chronic systemic low grade inflammation. A central characteristic of all four diseases is an on average lengthy prodromal phase with no or minor symptoms which can last many years, suggesting a gradually evolving interaction between the genetic profile and the environment. Part of the abnormalities may be present in unaffected family members, and autoimmune diseases can also cluster in families. In conclusion, a promising strategy for prevention of autoimmune diseases might be to address adverse life style factors by public health measures at the population level.

Type 1 diabetes (T1D) is a multifactorial autoimmune disease driven by T-cells against the insulin-producing islet β-cells, resulting in a marked loss of β-cell mass and function. Although a genetic predisposal increases susceptibility, the role of epigenetic and environmental factors seems to be much more significant. A dysbiotic gut microbial profile has been associated with T1D patients. Moreover, new evidence propose that perturbation in gut microbiota may influence the T1D onset and progression. One of the prominent features in clinically silent phase before the onset of T1D is the presence of a microbiota characterized by low numbers of commensals butyrate producers, thus negatively influencing the gut permeability. The loss of gut permeability leads to the translocation of microbes and microbial metabolites and could lead to the activation of immune cells. Moreover, microbiota-based therapies to slow down disease progression or reverse T1D have shown promising results. Starting from this evidence, the correction of dysbiosis in early life of genetically susceptible individuals could help in promoting immune tolerance and thus in reducing the autoantibodies production. This review summarizes the associations between gut microbiota and T1D for future therapeutic perspectives and other exciting areas of research.

[This corrects the article DOI: 10.3389/fimmu.2022.825426.].

Introduction Several different forms of automated insulin delivery systems (AID systems) have recently been developed and are now licensed for type 1 diabetes (T1D). We undertook a systematic review of reported trials and real-world studies for commercial hybrid closed-loop (HCL) systems. Methods Pivotal, phase III and real-world studies using commercial HCL systems that are currently approved for use in type 1 diabetes were reviewed with a devised protocol using the Medline database. Results Fifty-nine studies were included in the systematic review (19 for 670G; 8 for 780G; 11 for Control-IQ; 14 for CamAPS FX; 4 for Diabeloop; and 3 for Omnipod 5). Twenty were real-world studies, and 39 were trials or sub-analyses. Twenty-three studies, including 17 additional studies, related to psychosocial outcomes and were analysed separately. Conclusions These studies highlighted that HCL systems improve time In range (TIR) and arouse minimal concerns around severe hypoglycaemia. HCL systems are an effective and safe option for improving diabetes care. Real-world comparisons between systems and their effects on psychological outcomes require further study.

Aims/hypothesis While the use of insulin pumps in paediatrics has expanded dramatically, there is still considerable variability among countries in the use of pump technology. The present study sought to describe differences in metabolic control and pump use in young people with type 1 diabetes using data collected in three multicentre registries. Methods Data for the years 2011 and 2012 from 54,410 children and adolescents were collected from the Prospective Diabetes Follow-up Registry (DPV; n  = 26,198), T1D Exchange (T1DX; n  = 13,755) and the National Paediatric Diabetes Audit (NPDA; n  = 14,457). The modality of insulin delivery, based on age, sex and ethnic minority status, and the impact of pump use on HbA 1c levels were compared. Results The overall mean HbA 1c level was higher in the NPDA (8.9 ± 1.6% [74 ± 17.5 mmol/mol]) than in the DPV (8.0 ± 1.6% [64 ± 17.0 mmol/mol], p <  0.001) and T1DX (8.3 ± 1.4% [68 ± 15.4 mmol/mol], p <  0.001). Conversely, pump use was much lower in the NPDA (14%) than in the DPV (41%, p <  0.001) and T1DX (47%, p <  0.001). In a pooled analysis, pump use was associated with a lower mean HbA 1c (pump: 8.0 ± 1.2% [64 ± 13.3 mmol/mol] vs injection: 8.5 ± 1.7% [69 ± 18.7 mmol/mol], p <  0.001). In all three registries, those with an ethnic minority status were less likely to be treated with a pump ( p <  0.001) and boys were treated with a pump less often compared with girls ( p <  0.001). Conclusions/interpretation Despite similar clinical characteristics and proportion of minority participants, substantial differences in metabolic control exist across the three large transatlantic registries of paediatric patients with type 1 diabetes, which appears to be due in part to the frequency of insulin pump therapy.