Fat-to-blood recirculation of partially dysfunctional PD-1+CD4 Tconv cells is associated with dysglycemia in human obesity.

Obesity is characterized by the accumulation of T cells in insulin-sensitive tissues, including the visceral adipose tissue (VAT), that can interfere with the insulin signaling pathway eventually leading to insulin resistance (IR) and type 2 diabetes. Here, we found that PD-1+CD4 conventional T (Tconv) cells, endowed with a transcriptomic and functional profile of partially dysfunctional cells, are diminished in VAT of obese patients with dysglycemia (OB-Dys), without a concomitant increase in apoptosis. These cells showed enhanced capacity to recirculate into the bloodstream and had a non-restricted TCRß repertoire divergent from that of normoglycemic obese and lean individuals. PD-1+CD4 Tconv were reduced in the circulation of OB-Dys, exhibited an altered migration potential, and were detected in the liver of patients with non-alcoholic steatohepatitis. The findings suggest a potential role for partially dysfunctional PD-1+CD4 Tconv cells as inter-organ mediators of IR in obese patients with dysglycemic.

HOMA-IR and the Matsuda Index as predictors of progression to type 1 diabetes in autoantibody-positive relatives.

AIM/HYPOTHESIS: We assessed whether HOMA-IR and the Matsuda Index are associated with transitions through stages of type 1 diabetes. METHODS: Autoantibody (AAb)-positive relatives of individuals with type 1 diabetes (n=6256) from the TrialNet Pathway to Prevention were studied. Associations of indicators of insulin resistance (HOMA-IR) and insulin sensitivity (Matsuda Index) with BMI percentile (BMIp) and age were assessed with adjustments for measures of insulin secretion, Index60 and insulinogenic index (IGI). Cox regression was used to determine if tertiles of HOMA-IR and Matsuda Index predicted transitions from Not Staged (<2 AAbs) to Stage 1 (≥2 AAbs and normoglycaemia), from Stage 1 to Stage 2 (≥2 AAbs with dysglycaemia), and progression to Stage 3 (diabetes as defined by WHO/ADA criteria). RESULTS: There were strong associations of HOMA-IR (positive) and Matsuda Index (inverse) with baseline age and BMIp (p<0.0001). After adjustments for Index60, transitioning from Stage 1 to Stage 2 was associated with higher HOMA-IR and lower Matsuda Index (HOMA-IR: HR=1.71, p<0.0001; Matsuda Index, HR=0.40, p<0.0001), as with progressing from Stages 1 or 2 to Stage 3 (HOMA-IR: HR=1.98, p<0.0001; Matsuda Index: HR=0.46, p<0.0001). Without adjustments, associations of progression to Stage 3 were inverse for HOMA-IR and positive for Matsuda Index, opposite in directionality with adjustments. When IGI was used in place of Index60, the findings were similar. CONCLUSIONS/INTERPRETATION: Progression to Stages 2 and 3 of type 1 diabetes increases with HOMA-IR and decreases with the Matsuda Index after adjustments for insulin secretion. Indicators of insulin secretion appear helpful for interpreting associations of progression to type 1 diabetes with HOMA-IR or the Matsuda Index in AAb-positive relatives.

Mechanisms and risk factors of metabolic syndrome in children and adolescents.

Metabolic syndrome (MetS) is a complex disorder characterized by abdominal obesity, elevated blood pressure, hyperlipidemia, and elevated fasting blood glucose levels. The diagnostic criteria for MetS in adults are well-established, but there is currently no consensus on the definition in children and adolescents. The etiology of MetS is believed to involve a complex interplay between genetic predisposition and environmental factors. While genetic predisposition explains only a small part of MetS pathogenesis, modifiable environmental risk factors play a significant role. Factors such as maternal weight during pregnancy, children's lifestyle, sedentariness, high-fat diet, fructose and branched-chain amino acid consumption, vitamin D deficiency, and sleep disturbances contribute to the development of MetS. Early identification and treatment of MetS in children and adolescents is crucial to prevent the development of chronic diseases later in life. In this review we discuss the latest research on factors contributing to the pathogenesis of MetS in children, focusing on non-modifiable and modifiable risk factors, including genetics, dysbiosis and chronic low-grade inflammation.

Genetic determinants of type 1 diabetes in individuals with weak evidence of islet autoimmunity at disease onset.

AIMS/HYPOTHESIS: Islet autoantibodies (AAbs) are detected in >90% of individuals with clinically suspected type 1 diabetes at disease onset. A single AAb, sometimes at low titre, is often detected in some individuals, making their diagnosis uncertain. Type 1 diabetes genetic risk scores (GRS) are a useful tool for discriminating polygenic autoimmune type 1 diabetes from other types of diabetes, particularly the monogenic forms, but testing is not routinely performed in the clinic. Here, we used a type 1 diabetes GRS to screen for monogenic diabetes in individuals with weak evidence of autoimmunity, i.e. with a single AAb at disease onset. METHODS: In a pilot study, we genetically screened 142 individuals with suspected type 1 diabetes, 42 of whom were AAb-negative, 27 of whom had a single AAb (single AAb-positive) and 73 of whom had multiple AAbs (multiple AAb-positive) at disease onset. Next-generation sequencing (NGS) was performed in 41 AAb-negative participants, 26 single AAb-positive participants and 60 multiple AAb-positive participants using an analysis pipeline of more than 200 diabetes-associated genes. RESULTS: The type 1 diabetes GRS was significantly lower in AAb-negative individuals than in those with a single and multiple AAbs. Pathogenetic class 4/5 variants in MODY or monogenic diabetes genes were identified in 15/41 (36.6%) AAb-negative individuals, while class 3 variants of unknown significance were identified in 17/41 (41.5%). Residual C-peptide levels at diagnosis were higher in individuals with mutations compared to those without pathogenetic variants. Class 3 variants of unknown significance were found in 11/26 (42.3%) single AAb-positive individuals, and pathogenetic class 4/5 variants were present in 2/26 (7.7%) single AAb-positive individuals. No pathogenetic class 4/5 variants were identified in multiple AAb-positive individuals, but class 3 variants of unknown significance were identified in 19/60 (31.7%) patients. Several patients across the three groups had more than one class 3 variant. CONCLUSIONS/INTERPRETATION: These findings provide insights into the genetic makeup of patients who show weak evidence of autoimmunity at disease onset. Absence of islet AAbs or the presence of a single AAb together with a low type 1 diabetes GRS may be indicative of a monogenic form of diabetes, and use of NGS may improve the accuracy of diagnosis.

Compartmentalization and persistence of dominant (regulatory) T cell clones indicates antigen skewing in juvenile idiopathic arthritis.

Autoimmune inflammation is characterized by tissue infiltration and expansion of antigen-specific T cells. Although this inflammation is often limited to specific target tissues, it remains yet to be explored whether distinct affected sites are infiltrated with the same, persistent T cell clones. Here, we performed CyTOF analysis and T cell receptor (TCR) sequencing to study immune cell composition and (hyper-)expansion of circulating and joint-derived Tregs and non-Tregs in juvenile idiopathic arthritis (JIA). We studied different joints affected at the same time, as well as over the course of relapsing-remitting disease. We found that the composition and functional characteristics of immune infiltrates are strikingly similar between joints within one patient, and observed a strong overlap between dominant T cell clones, especially Treg, of which some could also be detected in circulation and persisted over the course of relapsing-remitting disease. Moreover, these T cell clones were characterized by a high degree of sequence similarity, indicating the presence of TCR clusters responding to the same antigens. These data suggest that in localized autoimmune disease, there is autoantigen-driven expansion of both Teffector and Treg clones that are highly persistent and are (re)circulating. These dominant clones might represent interesting therapeutic targets.

Combined unsupervised and semi-automated supervised analysis of flow cytometry data reveals cellular fingerprint associated with newly diagnosed pediatric type 1 diabetes.

An unbiased and replicable profiling of type 1 diabetes (T1D)-specific circulating immunome at disease onset has yet to be identified due to experimental and patient selection limitations. Multicolor flow cytometry was performed on whole blood from a pediatric cohort of 107 patients with new-onset T1D, 85 relatives of T1D patients with 0-1 islet autoantibodies (pre-T1D_LR), 58 patients with celiac disease or autoimmune thyroiditis (CD_THY) and 76 healthy controls (HC). Unsupervised clustering of flow cytometry data, validated by a semi-automated gating strategy, confirmed previous findings showing selective increase of naïve CD4 T cells and plasmacytoid DCs, and revealed a decrease in CD56brightNK cells in T1D. Furthermore, a non-selective decrease of CD3+CD56+ regulatory T cells was observed in T1D. The frequency of naïve CD4 T cells at disease onset was associated with partial remission, while it was found unaltered in the pre-symptomatic stages of the disease. Thanks to a broad cohort of pediatric individuals and the implementation of unbiased approaches for the analysis of flow cytometry data, here we determined the circulating immune fingerprint of newly diagnosed pediatric T1D and provide a reference dataset to be exploited for validation or discovery purposes to unravel the pathogenesis of T1D.

The Contribution of Neutrophils and NETs to the Development of Type 1 Diabetes.

Type 1 diabetes (T1D) is an autoimmune disease resulting from the destruction of insulin-producing beta cells in pancreatic islets. T lymphocytes are the claimed pathogenic effectors but abnormalities of other immune cell types, including neutrophils, also characterize T1D development. During human T1D natural history, neutrophils are reduced in the circulation, while accumulate in the pancreas where release of neutrophil extracellular traps (NETs), or NETosis, is manifest. Recent-onset T1D patients also demonstrate activated circulating neutrophils, associated with a unique neutrophil gene signature. Neutrophils can bind to platelets, leading to the formation of platelet-neutrophil aggregates (PNAs). PNAs increase in the circulation during the development of human T1D and provide a mechanism for neutrophil activation and mobilization/recruitment to the pancreas. In non-obese diabetic or NOD mice, T1D autoimmunity is accompanied by dynamic changes in neutrophil numbers, activation state, PNAs and/or NETosis/NET proteins in the circulation, pancreas and/or islets. Such properties differ between stages of T1D disease and underpin potentially indirect and direct impacts of the innate immune system in T1D pathogenesis. Supporting the potential for a pathogenic role in T1D, NETs and extracellular histones can directly damage isolated islets in vitro, a toxicity that can be prevented by small polyanions. In human T1D, NET-related damage can target the whole pancreas, including both the endocrine and exocrine components, and contribute to beta cell destruction, providing evidence for a neutrophil-associated T1D endotype. Future intervention in T1D could therefore benefit from combined strategies targeting T cells and accessory destructive elements of activated neutrophils.

Circulating platelet-neutrophil aggregates characterize the development of type 1 diabetes in humans and NOD mice.

Platelet-neutrophil aggregates (PNAs) facilitate neutrophil activation and migration and could underpin the recruitment of neutrophils to the pancreas during type 1 diabetes (T1D) pathogenesis. PNAs, measured by flow cytometry, were significantly elevated in the circulation of autoantibody-positive (Aab+) children and new-onset T1D children, as well as in pre-T1D (at 4 weeks and 10-12 weeks) and T1D-onset NOD mice, compared with relevant controls, and PNAs were characterized by activated P-selectin+ platelets. PNAs were similarly increased in pre-T1D and T1D-onset NOD isolated islets/insulitis, and immunofluorescence staining revealed increased islet-associated neutrophil extracellular trap (NET) products (myeloperoxidase [MPO] and citrullinated histones [CitH3]) in NOD pancreata. In vitro, cell-free histones and NETs induced islet cell damage, which was prevented by the small polyanionic drug methyl cellobiose sulfate (mCBS) that binds to histones and neutralizes their pathological effects. Elevated circulating PNAs could, therefore, act as an innate immune and pathogenic biomarker of T1D autoimmunity. Platelet hyperreactivity within PNAs appears to represent a previously unrecognized hematological abnormality that precedes T1D onset. In summary, PNAs could contribute to the pathogenesis of T1D and potentially function as a pre-T1D diagnostic.

Neutrophils and their role in the aetiopathogenesis of type 1 and type 2 diabetes.

Multiple and complex aetiological processes underlie diabetes mellitus, which invariably result in the development of hyperglycaemia. Although there are two prevalent distinct forms of the disease, that is, type 1 and type 2 diabetes, accumulating evidence indicates that these syndromes share more aetiopathological mechanisms than originally thought. This compels a rethinking of the approaches to prevent and treat the different manifestations of what eventually becomes a hyperglycaemic state. This review aims to address the involvement of neutrophils, the most abundant type of granulocytes involved in the initiation of the acute phase of inflammation, in the aetiopathogenesis of diabetes mellitus, with a focus on type 1 and type 2 diabetes. We review the evidence that neutrophils are the first leucocytes to react to and accumulate inside target tissues of diabetes, such as the pancreas and insulin-sensitive tissues. We then review available data on the role of neutrophils and their functional alteration, with a focus on NETosis, in the progression towards clinical disease. Finally, we review potential approaches as secondary and adjunctive treatments to limit neutrophil-mediated damage in the prevention of the progression of subclinical disease to clinical hyperglycaemia.

Exocrine pancreas function is impaired in adult relatives of patients with type 1 diabetes.

AIMS: Alterations of the exocrine pancreas have been reported in type 1 diabetes, but their contribution to the pathogenesis of the disease is poorly understood. Here, we investigated markers of exocrine pancreas dysfunction in individuals at-risk of developing type 1 diabetes. METHODS: Serum P-amylase and lipase levels were assessed in samples obtained from healthy controls, patients with new onset type 1 diabetes, relatives participating to the TrialNet Pathway to Prevention who were, at blood collection, autoantibody negative or positive for a single autoantibody (low-risk individuals), and positive for multiple autoantibodies (high-risk individuals). Linear mixed models were adopted to estimate variation of pancreatic enzymes among the groups and to evaluate the influence of high-risk HLA genotypes and residual beta cell function on exocrine pancreas function. RESULTS: In adults, but not children, reduced levels of P-amylase and lipase were shown in at-risk individuals, including (for P-amylase levels only) those at low-risk, and in T1Dnew. Furthermore, while high-risk HLA genotypes negatively affected P-amylase levels in autoantibody negative adult individuals, fasting C-peptide levels did not correlate with pancreatic enzyme levels. CONCLUSIONS: Exocrine pancreas dysfunction precedes the onset of type 1 diabetes in adult at-risk individuals and may be unrelated to fasting C-peptide levels.

Autoimmune Inflammation and Insulin Resistance: Hallmarks So Far and Yet So Close to Explain Diabetes Endotypes.

PURPOSE OF REVIEW: Diabetes mellitus can be categorized into two major variants, type 1 and type 2. A number of traits such as clinical phenotype, age at disease onset, genetic background, and underlying pathogenesis distinguish the two forms. RECENT FINDINGS: Recent evidence indicates that type 1 diabetes can be accompanied by insulin resistance and type 2 diabetes exhibits self-reactivity. These two previously unknown conditions can influence the progression and outcome of the disease. Unlike most conventional considerations, diabetes appears to consist of a spectrum of intermediate phenotypes that includes monogenic and polygenic loci linked to inflammatory processes including autoimmunity, beta cell impairment, and insulin resistance. Here we discuss why a shift of the classical bi-modal view of diabetes (autoimmune vs. non-autoimmune) is necessary in favor of a model of an immunological continuum of endotypes lying between the two extreme "insulin-resistant" and "autoimmune beta cell targeting," shaped by environmental and genetic factors which contribute to determine specific immune-conditioned outcomes.

Conserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation.

Treg cells are critical regulators of immune homeostasis, and environment-driven Treg cell differentiation into effector (e)Treg cells is crucial for optimal functioning. However, human Treg cell programming in inflammation is unclear. Here, we combine transcriptional and epigenetic profiling to identify a human eTreg cell signature. Inflammation-derived functional Treg cells have a transcriptional profile characterized by upregulation of both a core Treg cell (FOXP3, CTLA4, TIGIT) and effector program (GITR, BLIMP-1, BATF). We identify a specific human eTreg cell signature that includes the vitamin D receptor (VDR) as a predicted regulator in eTreg cell differentiation. H3K27ac/H3K4me1 occupancy indicates an altered (super-)enhancer landscape, including enrichment of the VDR and BATF binding motifs. The Treg cell profile has striking overlap with tumor-infiltrating Treg cells. Our data demonstrate that human inflammation-derived Treg cells acquire a conserved and specific eTreg cell profile guided by epigenetic changes, and fine-tuned by environment-specific adaptations.

Modulation of Leukocytes of the Innate Arm of the Immune System as a Potential Approach to Prevent the Onset and Progression of Type 1 Diabetes.

Type 1 diabetes (T1D) is characterized by insulin deficiency resulting from the selective destruction of pancreatic ß-cells by self-reactive T cells. Recent evidence demonstrates that innate immune responses substantially contribute to the pathogenesis of T1D, as they represent a first line of response to danger/damage signals. Here we discuss evidence on how, in a relapsing-remitting pattern, pancreas remodeling, diet, microbiota, gut permeability, and viral/bacterial infections induce the accumulation of leukocytes of the innate arm of the immune system throughout the pancreas. The subsequent acquisition and presentation of endocrine and exocrine antigens to the adaptive arm of the immune system results in a chronic progression of pancreatic damage. This process provides for the generation of self-reactive T-cell responses; however, the relative weight that genetic and environmental factors have on the etiopathogenesis of T1D is endotype imprinted and patient specific. With this Perspectives in Diabetes, our goal is to encourage the scientific community to rethink mechanisms underlying T1D pathogenesis and to consider therapeutic approaches that focus on these processes in intervention trials within new-onset disease as well as in efforts seeking the disorder's prevention in individuals at high risk.

Plasma circulating miR-23~27~24 clusters correlate with the immunometabolic derangement and predict C-peptide loss in children with type 1 diabetes.

AIMS/HYPOTHESIS: We aimed to analyse the association between plasma circulating microRNAs (miRNAs) and the immunometabolic profile in children with type 1 diabetes and to identify a composite signature of miRNAs/immunometabolic factors able to predict type 1 diabetes progression. METHODS: Plasma samples were obtained from children at diagnosis of type 1 diabetes (n = 88) and at 12 (n = 32) and 24 (n = 30) months after disease onset and from healthy control children with similar sex and age distribution (n = 47). We quantified 60 robustly expressed plasma circulating miRNAs by quantitative RT-PCR and nine plasma immunometabolic factors with a recognised role at the interface of metabolic and immune alterations in type 1 diabetes. Based on fasting C-peptide loss over time, children with type 1 diabetes were stratified into the following groups: those who had lost >90% of C-peptide compared with diagnosis level; those who had lost <10% of C-peptide; those showing an intermediate C-peptide loss. To evaluate the modulation of plasma circulating miRNAs during the course of type 1 diabetes, logistic regression models were implemented and the correlation between miRNAs and immunometabolic factors was also assessed. Results were then validated in an independent cohort of children with recent-onset type 1 diabetes (n = 18). The prognostic value of the identified plasma signature was tested by a neural network-based model. RESULTS: Plasma circulating miR-23~27~24 clusters (miR-23a-3p, miR-23b-3p, miR-24-3p, miR-27a-3p and miR-27b-3p) were upmodulated upon type 1 diabetes progression, showed positive correlation with osteoprotegerin (OPG) and were negatively correlated with soluble CD40 ligand, resistin, myeloperoxidase and soluble TNF receptor in children with type 1 diabetes but not in healthy children. The combination of plasma circulating miR-23a-3p, miR-23b-3p, miR-24-3p, miR-27b-3p and OPG, quantified at disease onset, showed a significant capability to predict the decline in insulin secretion 12 months after disease diagnosis in two independent cohorts of children with type 1 diabetes. CONCLUSIONS/INTERPRETATIONS: We have pinpointed a novel miR-23a-3p/miR-23b-3p/miR-24-3p/miR-27b-3p/OPG plasma signature that may be developed into a novel blood-based method to better stratify patients with type 1 diabetes and predict C-peptide loss.

Enrichment of Tc1 cells and T cell resistance to suppression are associated with dysglycemia in the visceral fat in human obesity.

OBJECTIVE: Insulin resistance, defined as tissue inflammation leading to type 2 diabetes, is a feature of obesity. The immune system has been implicated in its pathogenesis, but the role of adaptive immunity in humans remains uncertain. Here, we aim to determine whether specific phenotypic and functional properties of visceral adipose tissue (VAT)-derived CD4 conventional T cells (Tconv) and CD8 T cells are associated with dysglycemia in human obesity. RESEARCH DESIGN AND METHODS: Peripheral blood and the stromal vascular fraction of obese patients without dysglycemia (n=23), with impaired fasting glucose or type 2 diabetes (n=17), and non-diabetic lean controls (n=11) were studied. Characterization of memory, activation profile, cytokine production, proliferative capacity, cytotoxic potential and transforming growth factor-ß-mediated suppression of CD4 Tconv and CD8 T cells was performed. Correlation between anthropometric/metabolic parameters and VAT-derived T cell subsets was determined. RESULTS: In the VAT of the overall obese population, reduced frequency of interferon-γ-producing or tumor necrosis factor-α-producing CD4 (ie, T helper 1, Th1) and CD8 (ie, cytotoxic type 1, Tc1) T cells, as well as interleukin-17-producing CD8 T cells (ie, Tc17), was evident when compared with lean controls. However, enrichment of Tc1 cells, together with the impaired ability of CD4 and CD8 T cells to be suppressed, distinguished the visceral fat of obese patients with dysglycemia from the one of non-diabetic obese patients. Moreover, accumulation of Th1 and Tc1 cells in the VAT correlated with anthropometric and metabolic parameters. CONCLUSIONS: Here, we define the VAT-specific characteristics of T cells in human obesity, showing that accumulation of Tc1 cells and T cell resistance to suppression can be harmful to the development of obesity-induced diabetes. These findings open new directions to investigate immunological targets in the obesity setting.

Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes.

The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.

New Evidence of Exocrine Pancreatopathy in Pre-symptomatic and Symptomatic Type 1 Diabetes.

PURPOSE OF REVIEW: Type 1 diabetes (T1D) is one of the most frequent chronic autoimmune diseases in humans, characterized by the lack of insulin production resulting in high blood glucose levels and lifelong requirement of exogenous insulin administration for survival. It is now recognized that the autoimmune process begins years before the clinical onset, in a stage called pre-symptomatic T1D, in which the presence of ß-cell-specific autoantibodies is detectable. Our aim is to review evidence for T1D as a "whole-pancreas disease," featured by both endocrine and exocrine pancreas alterations already at early disease stages. RECENT FINDINGS: In this review, we discuss a series of recent observations indicating that in genetically predisposed individuals, structural and functional abnormalities as well as immune cell infiltration of the exocrine pancreas are already present in the pre-symptomatic stages of the disease. Despite T1D being considered a ß-cell-specific disease, numerous reports point to the presence of exocrine pancreas subclinical abnormalities occurring during disease development. These observations challenge the long-standing idea that T1D exocrine damage exists as a mere consequence of disease progression and provide further explanation of mechanisms underlying T1D pathogenesis.

Neutrophils and type 1 diabetes: current knowledge and suggested future directions.

PURPOSE OF REVIEW: Purpose of this review is to describe the most recent human studies on neutrophils in type 1 diabetes (T1D) and to focus on the key questions that still need to be addressed. RECENT FINDINGS: Recent evidences demonstrate that neutrophils have marked abnormalities in phenotype and function and play a central role in initiation and perpetuation of aberrant immune responses and organ damage in various systemic autoimmune diseases such as lupus erythematosus and rheumatoid arthritis. In T1D, we have recently demonstrated that reduced circulating neutrophil numbers precede and accompany the disease and that neutrophils infiltrate the pancreas and extrude neutrophil extracellular traps already before the onset of clinical symptoms. However, few other evidences of alterations in neutrophil phenotype and function have been reported in humans, especially in the T1D presymptomatic phases. SUMMARY: Dissecting the pathogenic role of these cells in human T1D is crucial for a better understanding of the disease and to open new therapeutic opportunities.

PD-1+CD8+ T cells are clonally expanding effectors in human chronic inflammation.

Chronic inflammatory diseases are characterized by recurrent inflammatory attacks in the tissues mediated by autoreactive T cells. Identity and functional programming of CD8+ T cells at the target site of inflammation still remain elusive. One key question is whether, in these antigen-rich environments, chronic stimulation leads to CD8+ T cell exhaustion comparable to what is observed in infectious disease contexts. In the synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients, a model of chronic inflammation, an overrepresentation of PD-1+CD8+ T cells was found. Gene expression profiling, gene set enrichment analysis, functional studies, and extracellular flux analysis identified PD-1+CD8+ T cells as metabolically active effectors, with no sign of exhaustion. Furthermore, PD-1+CD8+ T cells were enriched for a tissue-resident memory (Trm) cell transcriptional profile and demonstrated increased clonal expansion compared with the PD-1- counterpart, suggesting antigen-driven expansion of locally adapted cells. Interestingly, this subset was also found increased in target tissues in other human chronic inflammatory diseases. These data indicate that local chronic inflammation drives the induction and expansion of CD8+ T cells endowed with potential detrimental properties. Together, these findings lay the basis for investigation of PD-1-expressing CD8+ T cell targeting strategies in human chronic inflammatory diseases.

Women in Translational Medicine: Tools to Break the Glass Ceiling.

Despite the recent movements for female equality and empowerment, few women occupy top positions in scientific decision-making. The challenges women face during their career may arise from societal biases and the current scientific culture. We discuss the effect of such biases at three different levels of the career and provide suggestions to tackle them. At the societal level, gender roles can create a negative feedback loop in which women are discouraged from attaining top positions and men are discouraged from choosing a home-centred lifestyle. This loop can be broken early in life by providing children with female role models that have a work-centred life and opening up the discussion about gender roles at a young age. At the level of hiring, unconscious biases can lead to a preference for male candidates. The introduction of (unbiased) artificial intelligence algorithms and gender champions in the hiring process may restore the balance and give men and women an equal chance. At the level of coaching and evaluation, barriers that women face should be addressed on a personal level through the introduction of coaching and mentoring programmes. In addition, women may play a pivotal role in shifting the perception of scientific success away from bibliometric outcomes only towards a more diverse assessment of quality and societal relevance. Taken together, these suggestions may break the glass ceiling in the scientific world for women; create more gender diversity at the top and improve translational science in medicine.