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Fibrosis is a physiological tissue repair mechanism, but excessive fibrosis can disrupt organ function. Alagille syndrome (ALGS), which is caused by mutations in the Notch ligand JAGGED1, results in bile duct paucity, neonatal cholestasis, and a characteristic fibrotic response. Here, we show that Jag1Ndr/Ndr mice, a model for ALGS, recapitulates ALGS-like pericellular fibrosis. Single-cell RNA-seq and multi-color flow cytometry characterization of the liver and spleen revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration in cholestatic Jag1Ndr/Ndr mice, despite an enrichment in extrahepatic (thymic and splenic) regulatory T cells (Tregs). Jag1Ndr/Ndr lymphocyte immune and fibrotic capacity was tested with adoptive immune cell transplantation into Rag1-/- mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1Ndr/Ndr lymphocytes were less inflammatory with fewer activated T cells than Jag1+/+ lymphocytes, in response to DSS. Cholestasis induced by BDL in Rag1-/- mice with Jag1Ndr/Ndr lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1-/- mice with Jag1+/+ lymphocytes. Finally, we show that the Jag1Ndr/Ndr hepatocyte expression profile and Treg overrepresentation are corroborated by transcriptomic data from children with ALGS. In sum, these data lead to a model in which Jag1-driven developmental hepatic and immune defects interact to determine the fibrotic process in ALGS.

Background and Aims: Alagille syndrome (ALGS) is a pediatric genetic disorder, caused by mutations in the Notch ligand JAGGED1, presenting with cholestasis due to intrahepatic bile duct paucity. Despite chronic liver disease, few patients develop severe fibrosis or liver cancer, compared to other chronic liver diseases. In contrast, about 1/3 of ALGS patients suffer from reoccurring infections. Notch signaling regulates both liver and immune system development, but how immune system defects interact with liver pathology in ALGS to influence disease course is not known. Here, we aimed to determine whether a mouse model of ALGS mimics fibrosis and liver cancer, and whether ALGS immune system compromise could positively modulate inflammation or liver disease course. Methods: We used single cell RNA sequencing and 25-color flow cytometry to characterize cell populations in embryonic and postnatal liver in an ALGS mouse model (Jag1Ndr/Ndr mice). We analyzed liver cancer prevalence in Jag1Ndr/Ndr mice, in a cancer-prone genetic background, and thymic and spleen cell composition using flow cytometry. Finally, to test the functionality of the Jag1Ndr/Ndr immune system we performed adaptive immune cell transfer experiments into Rag1-/- mice and assessed inflammatory capacity in an ulcerative colitis model and in a DDC model of hepatocellular damage. Results: Adult Jag1Ndr/Ndr mice do not develop liver tumors (0%) while 45% of control mice do. Interestingly, Jag1Ndr/Ndr mice display ALGS-like chicken-wire hepatocellular fibrosis concomitant with mild inflammation shortly after the onset of liver cholestasis. Comprehensive single cell analysis revealed that liver CD4+ and CD8+ T cells of Jag1Ndr/Ndr mice are dysregulated in favor of CD4+, and Regulatory T-cells (Tregs) manifest reduced activation. Trans-plantation experiments show no difference between Jag1Ndr/Ndr and Jag1+/+ lymphocytes in DDC-induced liver damage. In contrast, Jag1Ndr/Ndr lymphocytes do not mount an inflammatory response to bacterial infection. Conclusion: Here we report immune dysregulation and cancer protection in the hypomorphic Jag1 mouse model of ALGS. Disrupted thymocyte differentiation coincides with limited activation of hepatocytes, blunting the inflammatory response to cholestasis. This may contribute to the pericellular fibrosis and prevent carcinogenesis. These results prompt the question of the relative contribution of Jag1 to liver cell pathology vs immune system in ALGS and high-light the need of future studies focused on dissecting apart how Jag1 modulates susceptibility to infection versus cancer risk. Competing Interest Statement The authors have declared no competing interest.

To evaluate differences in macular and optic disc circulation in patients affected by Wolfram Syndrome (WS) employing optical coherence tomography-angiography (OCTA) imaging. In this retrospective study, 18 eyes from 10 WS patients, 16 eyes of 8 patients affected by type I diabetes and 17 eyes from 17 healthy controls were enrolled. All patients were imaged through OCT and OCTA and vascular parameters, as perfusion density (PD) and vessel length density (VLD) were measured. OCTA showed reduced PD in WS patients at the macular superficial capillary plexus (SCP, 27.8 ± 5.3%), deep vascular complex (DVC, 33.2 ± 1.9%) and optic nerve head (ONH, 21.2 ± 9.1%) compared to both diabetic patients (SCP 33.9 ± 1.9%, P  < 0.0001; DVC 33.2 ± 0.7%, P  = 1.0; ONH 33.9 ± 1.3, P  < 0.0001) and healthy controls (SCP 31.6 ± 2.5, P  = 0.002; DVC 34.0 ± 0.7%, P  = 0.089; ONH 34.6 ± 0.8%, P  < 0.0001). Similarly, VLD was lower in WS patients at the SCP (10.9 ± 2.7%) and ONH levels (7.5 ± 4.1%) compared to diabetic patients (SCP 13.8 ± 1.2%, P  = 0.001; DVC 13.8 ± 0.2%, P  < 0.0001; ONH 13.0 ± 0.7%, P  =  < 0.0001), but higher in DVC (15.7 ± 1.2%, P  < 0.0001). Furthermore, VLD was lower in WS patients in all the vascular parameters compared to controls (SCP 13.8 ± 1.5%, P  < 0.0001; DVC 17.3 ± 0.6%, P  < 0.0001; ONH 15.7 ± 0.5%, P  < 0.0001). A significant microvasculature impairment in the macular SCP and ONH microvasculature was demonstrated in eyes affected by WS. Microvascular impairment may be considered a fundamental component of the neurodegenerative changes in WS.

To describe the trends of type 1 diabetes(T1D) incidence in 0-17-year-olds over the years 2020-2023, and the COVID-19 vaccination uptake in Lombardy region. Data about children and adolescents aged 0-17 years who received a diagnosis of T1D from 2020 to 2023 were extracted from the public computerized registry of the healthcare system of the Lombardy Region (Italy). After calculating the annual T1D incidence, the incidence in 2020, prior to the availability of vaccination, was compared to subsequent years. A separate analysis was conducted for the 12-17 age group, the first to receive vaccination. One thousand two hundred seventy-three T1D onsets were recorded. The distribution of T1D showed no significant annual variation by sex (p-trend = 0.338), mean age (9 years, p = 0.537) and age distribution (p-trend = 0.563). T1D incidence [95% CI/100.000] did not significantly change comparing 2020 [18.94/100.000 (CI 16.88-21.18)] with 2021 [21.82/100.000 (CI 18.90-23.44)], 2022 [20.77/100.000 (CI 18.59-23.13)] and 2023 [19.68/100.000 (CI 16.61-20.94)]. No differences in incidence were observed in the 12-17 age group during 2021-2023 when COVID-19 vaccination was available when compared to 2020 (p-wald > 0.05). The COVID-19 vaccination coverage was lower in children with diabetes onset compared to the same-age general population (38 vs 42%). The incidence of T1D in children remained stable during the COVID-19 pandemic, regardless of the uptake of the vaccination.

Abstract Context In the last decade the Sanger method of DNA sequencing has been replaced by next-generation sequencing (NGS). NGS is valuable in conditions characterized by high genetic heterogeneity such as neonatal diabetes mellitus (NDM). Objective To compare results of genetic analysis of patients with NDM and congenital severe insulin resistance (c.SIR) identified in Italy in 2003-2012 (Sanger) vs 2013-2022 (NGS). Methods We reviewed clinical and genetic records of 104 cases with diabetes onset before 6 months of age (NDM + c.SIR) of the Italian dataset. Results Fifty-five patients (50 NDM + 5 c.SIR) were identified during 2003-2012 and 49 (46 NDM + 3 c.SIR) in 2013-2022. Twenty-year incidence was 1:103 340 (NDM) and 1:1 240 082 (c.SIR) live births. Frequent NDM/c.SIR genetic defects (KCNJ11, INS, ABCC8, 6q24, INSR) were detected in 41 and 34 probands during 2003-2012 and 2013-2022, respectively. We identified a pathogenic variant in rare genes in a single proband (GATA4) (1/42 or 2.4%) during 2003-2012 and in 8 infants (RFX6, PDX1, GATA6, HNF1B, FOXP3, IL2RA, LRBA, BSCL2) during 2013-2022 (8/42 or 19%, P = .034 vs 2003-2012). Notably, among rare genes 5 were recessive. Swift and accurate genetic diagnosis led to appropriate treatment: patients with autoimmune NDM (FOXP3, IL2RA, LRBA) were subjected to bone marrow transplant; patients with pancreas agenesis/hypoplasia (RFX6, PDX1) were supplemented with pancreatic enzymes, and the individual with lipodystrophy caused by BSCL2 was started on metreleptin. Conclusion NGS substantially improved diagnosis and precision therapy of monogenic forms of neonatal diabetes and c.SIR in Italy.

A panel of experts of the Italian Society of Pediatric Endocrinology and Diabetology comprehensively discussed and approved the Italian recommendations regarding self-monitoring of blood glucose, continuous glucose monitoring and other measures of glycemic control in children and adolescents with type 1 diabetes. After an extensive review of the literature, we took these issues into account: self-monitoring blood glucose, continuous glucose monitoring, glycemic variability, glycosuria, ketonuria, ketonemia, glycated hemoglobin, fructosamine and glycated albumin, logbook, data downloading, lancing devices, carbohydrate counting, and glycemic measurements at school. We concluded that clinical guidelines on self-management should be developed in every country with faithful adaptation to local languages and taking into account specific contexts and local peculiarities, without any substantial modifications to the international recommendations. We believe that the National Health Service should provide all necessary resources to ensure self-monitoring of blood glucose and possibly continuous glucose monitoring of all children and adolescents with type 1 diabetes, according to the standards of care provided by these recommendations and internationally.