Type 1 diabetes

Type 1 diabetes is a chronic disease caused by autoimmune destruction of pancreatic β cells. Individuals with type 1 diabetes are reliant on insulin for survival. Despite enhanced knowledge related to the pathophysiology of the disease, including interactions between genetic, immune, and environmental contributions, and major strides in treatment and management, disease burden remains high. Studies aimed at blocking the immune attack on β cells in people at risk or individuals with very early onset type 1 diabetes show promise in preserving endogenous insulin production. This Seminar will review the field of type 1 diabetes, highlighting recent progress within the past 5 years, challenges to clinical care, and future directions in research, including strategies to prevent, manage, and cure the disease

100 years post-insulin: immunotherapy as the next frontier in type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterised by T cell-mediated destruction of the insulin-producing β cells in the pancreas. Similar to other autoimmune diseases, the incidence of T1D is increasing globally. The discovery of insulin 100 years ago dramatically changed the outlook for people with T1D, preventing this from being a fatal condition. As we celebrate the centenary of this milestone, therapeutic options for T1D are once more at a turning point. Years of effort directed at developing immunotherapies are finally starting to pay off, with signs of progress in new onset and even preventative settings. Here, we review a selection of immunotherapies that have shown promise in preserving β cell function and highlight future considerations for immunotherapy in the T1D setting

100 years post-insulin: immunotherapy as the next frontier in type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterised by T cell-mediated destruction of the insulin-producing β cells in the pancreas. Similar to other autoimmune diseases, the incidence of T1D is increasing globally. The discovery of insulin 100 years ago dramatically changed the outlook for people with T1D, preventing this from being a fatal condition. As we celebrate the centenary of this milestone, therapeutic options for T1D are once more at a turning point. Years of effort directed at developing immunotherapies are finally starting to pay off, with signs of progress in new onset and even preventative settings. Here, we review a selection of immunotherapies that have shown promise in preserving β cell function and highlight future considerations for immunotherapy in the T1D setting

Stratification of PD-1 blockade response in melanoma using pre- and post-treatment immunophenotyping of peripheral blood

Efficacy of checkpoint inhibitor therapies in cancer varies greatly, with some patients showing complete responses while others do not respond and experience progressive disease. We aimed to identify correlates of response and progression following PD-1-directed therapy by immunophenotyping peripheral blood samples from 20 patients with advanced malignant melanoma before and after treatment with the PD-1 blocking antibody pembrolizumab. Our data reveal that individuals responding to PD-1 blockade were characterised by increased CD8 T cell proliferation following treatment, while progression was associated with an increase in CTLA-4-expressing Treg. Remarkably, unsupervised clustering analysis of pre-treatment T cell subsets revealed differences in individuals that went on to respond to PD-1 blockade compared to individuals that did not. These differences mapped to expression of the proliferation marker Ki67 and the costimulatory receptor CD28 as well as the inhibitory molecules 2B4 and KLRG1. While these results require validation in larger patient cohorts, they suggest that flow cytometric analysis of a relatively small number of T cell markers in peripheral blood could potentially allow stratification of PD-1 blockade treatment response prior to therapy initiation

IL-21 shapes germinal center polarization via light zone B cell selection and cyclin D3 upregulation

Germinal center (GC) dysregulation has been widely reported in the context of autoimmunity. Here, we show that interleukin 21 (IL-21), the archetypal follicular helper T cell (Tfh) cytokine, shapes the scale and polarization of spontaneous chronic autoimmune as well as transient immunization-induced GC. We find that IL-21 receptor deficiency results in smaller GC that are profoundly skewed toward a light zone GC B cell phenotype and that IL-21 plays a key role in selection of light zone GC B cells for entry to the dark zone. Light zone skewing has been previously reported in mice lacking the cell cycle regulator cyclin D3. We demonstrate that IL-21 triggers cyclin D3 upregulation in GC B cells, thereby tuning dark zone inertial cell cycling. Lastly, we identify Foxo1 regulation as a link between IL-21 signaling and GC dark zone formation. These findings reveal new biological roles for IL-21 within GC and have implications for autoimmune settings where IL-21 is overproduced

Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation

CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation and inhibition of T cell responses, respectively. Although both receptors share the same ligands, CD80 and CD86, the specific requirement for two distinct ligands remains obscure. In the present study, we demonstrate that, although CTLA-4 targets both CD80 and CD86 for destruction via transendocytosis, this process results in separate fates for CTLA-4 itself. In the presence of CD80, CTLA-4 remained ligand bound, and was ubiquitylated and trafficked via late endosomes and lysosomes. In contrast, in the presence of CD86, CTLA-4 detached in a pH-dependent manner and recycled back to the cell surface to permit further transendocytosis. Furthermore, we identified clinically relevant mutations that cause autoimmune disease, which selectively disrupted CD86 transendocytosis, by affecting either CTLA-4 recycling or CD86 binding. These observations provide a rationale for two distinct ligands and show that defects in CTLA-4-mediated transendocytosis of CD86 are associated with autoimmunity

B cell depletion in autoimmune diabetes:insights from murine models

INTRODUCTION: The incidence of type 1 diabetes (T1D) is rising for reasons that largely elude us. New strategies aimed at halting the disease process are needed. One type of immune cell thought to contribute to T1D is the B lymphocyte. The first Phase II trial of B cell depletion in new onset T1D patients indicated that this slowed the destruction of insulin-producing pancreatic beta cells. The mechanistic basis of the beneficial effects remains unclear. AREAS COVERED: Studies of B cell depletion and deficiency in animal models of T1D. How B cells can influence T cell-dependent autoimmune diabetes in animal models. The heterogeneity of B cell populations and current evidence for the potential contribution of specific B cell subsets to diabetes, with emphasis on marginal zone B cells and B1 B cells. EXPERT OPINION: B cells can influence the T cell response to islet antigens and B cell depletion or genetic deficiency is associated with decreased insulitis in animal models. New evidence suggests that B1 cells may contribute to diabetes pathogenesis. A better understanding of the roles of individual B cell subsets in disease will permit fine-tuning of therapeutic strategies to modify these populations

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Treatment of congenital thrombocytopenia and decreased collagen reactivity in G6b-B-deficient mice

Mice lacking the immunoreceptor tyrosine-based inhibition motif-containing co-inhibitory receptor G6b-B (Mpig6b, G6b knockout, KO) are born with a complex megakaryocyte (MK)/platelet phenotype characterized by severe macrothrombocytopenia, expansion of the MK population and focal myelofibrosis in the bone marrow and spleen. Platelets are almost completely devoid of the GPVI-FcRγ-chain collagen receptor complex, have reduced collagen integrin α2β1, elevated Syk tyrosine kinase activity, and a subset have increased surface immunoglobulins. A strikingly similar phenotype was recently reported in patients with null and loss-of-function mutations in MPIG6B. To better understand the cause and treatment of this pathology, we used pharmacological- and genetic-based approaches to rescue platelet counts and function in G6b KO mice. Intravenous-immunoglobulin resulted in a transient partial recovery of platelet counts, whereas immune deficiency had no bearing on platelet count or receptor expression in G6b KO mice. Syk loss-of-function (R41A) rescued macrothrombocytopenia, GPVI and α2β1 expression in G6b KO mice, whereas treatement with the Syk kinase inhibitor BI1002494 partially rescued platelet counts, but had no effect on GPVI and α2β1 expression, or bleeding. Src family kinase inhibitor dasatinib had no benefit in G6b KO mice. In contrast, treatment with the thrombopoietin mimetic romiplostim rescued thrombocytopenia, GPVI expression, and platelet reactivity to collagen, suggesting this may be a promising therapeutic for patients lacking functional G6b-B. Intriguingly, GPVI and α2β1 expression are significantly downregulated in romiplostim-treated wild-type mice, whereas GPVI was upregulated in romiplostim-treated G6b KO mice, suggesting a cell intrinsic feedback mechanism that auto-regulates platelet reactivity, depending physiological needs