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Low-dose IL-2 reduces IL-21+ T cell frequency and induces anti-inflammatory gene expression in type 1 diabetes.
Despite early clinical successes, the mechanisms of action of low-dose interleukin-2 (LD-IL-2) immunotherapy remain only partly understood. Here we examine the effects of interval administration of low-dose recombinant IL-2 (iLD-IL-2) in type 1 diabetes using high-resolution single-cell multiomics and flow cytometry on longitudinally-collected peripheral blood samples. Our results confirm that iLD-IL-2 selectively expands thymic-derived FOXP3+HELIOS+ regulatory T cells and CD56bright NK cells, and show that the treatment reduces the frequency of IL-21-producing CD4+ T cells and of two innate-like mucosal-associated invariant T and Vγ9Vδ2 CD8+ T cell subsets. The cellular changes induced by iLD-IL-2 associate with an anti-inflammatory gene expression signature, which remains detectable in all T and NK cell subsets analysed one month after treatment. These findings warrant investigations into the potential longer-term clinical benefits of iLD-IL-2 in immunotherapy.
Embryonic keratin19+ progenitors generate multiple functionally distinct progeny to maintain epithelial diversity in the adult thymus medulla
AbstractThe thymus medulla is a key site for immunoregulation and tolerance, and its functional specialisation is achieved through the complexity of medullary thymic epithelial cells (mTEC). While the importance of the medulla for thymus function is clear, the production and maintenance of mTEC diversity remains poorly understood. Here, using ontogenetic and inducible fate-mapping approaches, we identify mTEC-restricted progenitors as a cytokeratin19+ (K19+) TEC subset that emerges in the embryonic thymus. Importantly, labelling of a single cohort of K19+ TEC during embryogenesis sustains the production of multiple mTEC subsets into adulthood, including CCL21+ mTEClo, Aire+ mTEChi and thymic tuft cells. We show K19+ progenitors arise prior to the acquisition of multiple mTEC-defining features including RANK and CCL21 and are generated independently of the key mTEC regulator, Relb. In conclusion, we identify and define a multipotent mTEC progenitor that emerges during embryogenesis to support mTEC diversity into adult life.
Evolving regulatory perspectives on digital health technologies for medicinal product development.
Digital health technology tools (DHTTs) present real opportunities for accelerating innovation, improving patient care, reducing clinical trial duration and minimising risk in medicines development. This review is comprised of four case studies of DHTTs used throughout the lifecycle of medicinal products, starting from their development. These cases illustrate how the regulatory requirements of DHTTs used in medicines development are based on two European regulatory frameworks (medical device and the medicinal product regulations) and highlight the need for increased collaboration between various stakeholders, including regulators (medicines regulators and device bodies), pharmaceutical sponsors, manufacturers of devices and software, and academia. As illustrated in the examples, the complexity of the interactions is further increased by unique challenges related to DHTTs. These case studies are the main examples of DHTTs with a regulatory assessment thus far, providing an insight into the applicable current regulatory approach; they were selected by a group of authors, including regulatory specialists from pharmaceutical sponsors, technology experts, academic researchers and employees of the European Medicines Agency. For each case study, the challenges faced by sponsors and proposed potential solutions are discussed, and the benefit of a structured interaction among the different stakeholders is also highlighted.
Economic burden and health-related quality-of-life among infants with respiratory syncytial virus infection: A multi-country prospective cohort study in Europe.
BACKGROUND: Respiratory syncytial virus (RSV) causes a considerable disease burden in young children globally, but reliable estimates of RSV-related costs and health-related quality-of-life (HRQoL) are scarce. This study aimed to evaluate the RSV-associated costs and HRQoL effects in infants and their caregivers in four European countries. METHODS: Healthy term-born infants were recruited at birth and actively followed up in four European countries. Symptomatic infants were systematically tested for RSV. Caregivers recorded the daily HRQoL of their child and themselves, measured by a modified EQ-5D with Visual Analogue Scale, for 14 consecutive days or until symptoms resolved. At the end of each RSV episode, caregivers reported healthcare resource use and work absenteeism. Direct medical costs per RSV episode were estimated from a healthcare payer's perspective and indirect costs were estimated from a societal perspective. Means and 95% confidence intervals (CI) of direct medical costs, total costs (direct costs + productivity loss) and quality-adjusted life-day (QALD) loss per RSV episode were estimated per RSV episode, as well as per subgroup (medical attendance, country). RESULTS: Our cohort of 1041 infants experienced 265 RSV episodes with a mean symptom duration of 12.5 days. The mean (95% CI) cost per RSV episode was €399.5 (242.3, 584.2) and €494.3 (317.7, 696.1) from the healthcare payer's and societal perspective, respectively. The mean QALD loss per RSV episode of 1.9 (1.7, 2.1) was independent of medical attendance (in contrast to costs, which also differed by country). Caregiver and infant HRQoL evolved similarly. CONCLUSION: This study fills essential gaps for future economic evaluations by prospectively estimating direct and indirect costs and HRQoL effects on healthy term infants and caregivers separately, for both medically attended (MA) and non-MA laboratory-confirmed RSV episodes. We generally observed greater HRQoL losses than in previous studies which used non-community and/or non-prospective designs.
Rapid escape of new SARS-CoV-2 Omicron variants from BA.2-directed antibody responses.
In November 2021, Omicron BA.1, containing a raft of new spike mutations, emerged and quickly spread globally. Intense selection pressure to escape the antibody response produced by vaccines or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection then led to a rapid succession of Omicron sub-lineages with waves of BA.2 and then BA.4/5 infection. Recently, many variants have emerged such as BQ.1 and XBB, which carry up to 8 additional receptor-binding domain (RBD) amino acid substitutions compared with BA.2. We describe a panel of 25 potent monoclonal antibodies (mAbs) generated from vaccinees suffering BA.2 breakthrough infections. Epitope mapping shows potent mAb binding shifting to 3 clusters, 2 corresponding to early-pandemic binding hotspots. The RBD mutations in recent variants map close to these binding sites and knock out or severely knock down neutralization activity of all but 1 potent mAb. This recent mAb escape corresponds with large falls in neutralization titer of vaccine or BA.1, BA.2, or BA.4/5 immune serum.
The female protective effect against autism spectrum disorder
Autism spectrum disorder (ASD) is diagnosed three to four times more frequently in males than in females. Genetic studies of rare variants support a female protective effect (FPE) against ASD. However, sex differences in common inherited genetic risk for ASD are less studied, particularly within families. Leveraging the Danish iPSYCH resource, we found siblings of female ASD cases (n = 1,707) had higher rates of ASD than siblings of male ASD cases (n = 6,270; p < 1.0 × 10−10). In the Simons Simplex and SPARK collections, mothers of ASD cases (n = 7,436) carried more polygenic risk for ASD than fathers of ASD cases (n = 5,926; 0.08 polygenic risk score [PRS] SD; p = 7.0 × 10−7). Further, male unaffected siblings under-inherited polygenic risk (n = 1,519; p = 0.03). Using both epidemiologic and genetic approaches, our findings strongly support an FPE against ASD's common inherited influences.
High-throughput characterization of the role of non-B DNA motifs on promoter function
Alternative DNA conformations, termed non-B DNA structures, can affect transcription, but the underlying mechanisms and their functional impact have not been systematically characterized. Here, we used computational genomic analyses coupled with massively parallel reporter assays (MPRAs) to show that certain non-B DNA structures have a substantial effect on gene expression. Genomic analyses found that non-B DNA structures at promoters harbor an excess of germline variants. Analysis of multiple MPRAs, including a promoter library specifically designed to perturb non-B DNA structures, functionally validated that Z-DNA can significantly affect promoter activity. We also observed that biophysical properties of non-B DNA motifs, such as the length of Z-DNA motifs and the orientation of G-quadruplex structures relative to transcriptional direction, have a significant effect on promoter activity. Combined, their higher mutation rate and functional effect on transcription implicate a subset of non-B DNA motifs as major drivers of human gene-expression-associated phenotypes.
The Polygenic and Monogenic Basis of Blood Traits and Diseases.
Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.
The Polygenic and Monogenic Basis of Blood Traits and Diseases
SummaryBlood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.
Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders.
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
Analysis of genetic dominance in the UK Biobank
Classical statistical genetics theory defines dominance as any deviation from a purely additive, or dosage, effect of a genotype on a trait, which is known as the dominance deviation. Dominance is well documented in plant and animal breeding. Outside of rare monogenic traits, however, evidence in humans is limited. We systematically examined common genetic variation across 1060 traits in a large population cohort (UK Biobank, N = 361,194 samples analyzed) for evidence of dominance effects. We then developed a computationally efficient method to rapidly assess the aggregate contribution of dominance deviations to heritability. Lastly, observing that dominance associations are inherently less correlated between sites at a genomic locus than their additive counterparts, we explored whether they may be leveraged to identify causal variants more confidently.
Paternal-age-related de novo mutations and risk for five disorders
AbstractThere are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the male germline is unknown. Quantifying this risk would clarify the clinical significance of delayed paternity. Using parent-child trio whole-exome-sequencing data, we estimate the relationship between paternal-age-related dnSNVs and risk for five disorders: autism spectrum disorder (ASD), congenital heart disease, neurodevelopmental disorders with epilepsy, intellectual disability and schizophrenia (SCZ). Using Danish registry data, we investigate whether epidemiologic associations between each disorder and older fatherhood are consistent with the estimated role of dnSNVs. We find that paternal-age-related dnSNVs confer a small amount of risk for these disorders. For ASD and SCZ, epidemiologic associations with delayed paternity reflect factors that may not increase with age.
Practical considerations for a TB controlled human infection model (TB-CHIM); the case for TB-CHIM in Africa, a systematic review of the literature and report of 2 workshop discussions in UK and Malawi.
Background: Tuberculosis (TB) remains a major challenge in many domains including diagnosis, pathogenesis, prevention, treatment, drug resistance and long-term protection of the public health by vaccination. A controlled human infection model (CHIM) could potentially facilitate breakthroughs in each of these domains but has so far been considered impossible owing to technical and safety concerns. Methods: A systematic review of mycobacterial human challenge studies was carried out to evaluate progress to date, best possible ways forward and challenges to be overcome. We searched MEDLINE (1946 to current) and CINAHL (1984 to current) databases; and Google Scholar to search citations in selected manuscripts. The final search was conducted 3 rd February 2022. Inclusion criteria: adults ≥18 years old; administration of live mycobacteria; and interventional trials or cohort studies with immune and/or microbiological endpoints. Exclusion criteria: animal studies; studies with no primary data; no administration of live mycobacteria; retrospective cohort studies; case-series; and case-reports. Relevant tools (Cochrane Collaboration for RCTs and Newcastle-Ottawa Scale for non-randomised studies) were used to assess risk of bias and present a narrative synthesis of our findings. Results: The search identified 1,388 titles for review; of these 90 were reviewed for inclusion; and 27 were included. Of these, 15 were randomised controlled trials and 12 were prospective cohort studies. We focussed on administration route, challenge agent and dose administered for data extraction. Overall, BCG studies including fluorescent BCG show the most immediate utility, and genetically modified Mycobacteria tuberculosis is the most tantalising prospect of discovery breakthrough. Conclusions: The TB-CHIM development group met in 2019 and 2022 to consider the results of the systematic review, to hear presentations from many of the senior authors whose work had been reviewed and to consider best ways forward. This paper reports both the systematic review and the deliberations. Registration: PROSPERO ( CRD42022302785; 21 January 2022).
Transcriptomic response and immunological responses to chimpanzee adenovirus- and MVA viral-vectored vaccines for RSV in healthy adults.
Cohorts of healthy younger adults (18-50yrs) and healthy older adults (60-75yrs) were immunized intramuscularly or intranasally with an adenovirus-vectored RSV vaccine (PanAd3-RSV) as a prime dose and boosted with PanAd3-RSV or a poxvirus-vectored vaccine (MVA-RSV) encoding the same insert. Whole blood gene expression was measured at baseline, three- and seven-days post vaccination. Intramuscular prime vaccination with PanAd3-RSV induced differential expression of 643 genes (DEGs, FDR < 0.05). Intranasal prime vaccination with PanAd3-RSV did not induce any differentially expressed genes (DEGs) in blood samples at three days post vaccination. Intranasally primed participants showed greater numbers of DEGS on boosting than intramuscularly primed participants. The most highly enriched biological processes related to DEGs after both prime and boost vaccination were type-1 interferon related pathways, lymphocytic and humoral immune responses.