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From complexity to consensus: A roadmap for neutrophil classification.
Neutrophils, previously considered a homogeneous immune cell population, exhibit substantial heterogeneity. Their diverse phenotypic and functional states are shaped by tissue microenvironments and disease-specific signals. However, the lack of robust fate-mapping methods and standardized classification criteria has led to overlapping and ambiguous descriptions of neutrophil heterogeneity. The growing number of neutrophil subpopulations reported in recent years highlights the need for a standardized framework to report how they might relate to each other. Here, we propose a framework that integrates maturation, tissue localization, and functional adaptations. This standardized system aims to harmonize research efforts, foster clearer cross-disciplinary communication, and accelerate both fundamental discoveries in neutrophil biology and the development of targeted therapies.
Matrix-producing neutrophils populate and shield the skin.
Defence from environmental threats is provided by physical barriers that confer mechanical protection and prevent the entry of microorganisms1. If microorganisms overcome those barriers, however, innate immune cells use toxic chemicals to kill the invading cells2,3. Here we examine immune diversity across tissues and identify a population of neutrophils in the skin that expresses a broad repertoire of proteins and enzymes needed to build the extracellular matrix. In the naive skin, these matrix-producing neutrophils contribute to the composition and structure of the extracellular matrix, reinforce its mechanical properties and promote barrier function. After injury, these neutrophils build 'rings' of matrix around wounds, which shield against foreign molecules and bacteria. This structural program relies on TGFβ signalling; disabling the TGFβ receptor in neutrophils impaired ring formation around wounds and facilitated bacterial invasion. We infer that the innate immune system has evolved diverse strategies for defence, including one that physically shields the host from the outside world.
Defining the genetic determinants of CD8+ T cell receptor repertoire in the context of immune checkpoint blockade.
The relationship between genetic variation and CD8+ T cell receptor (TCR) repertoire usage in patients receiving immune checkpoint blockade (ICB) therapy for cancer is unexplored. We have conducted a genome-wide and human leukocyte antigen (HLA)-focused analysis of CD8+ TCR repertoire to identify genetic determinants of variable gene (V-gene) and CDR3 K-nucleotide oligomer usage from samples taken before and after ICB (n = 250). We identify 11 cis and 10 trans V-gene associations, primarily to the MHC, that meet genome-wide significance. TCR clones containing HLA associated V-genes were less stable across treatment, while, at the single-cell level, genetically associated clones demonstrate subset enrichment and increased tumor reactivity expression profiles. Notably, patients with HLA-matched TCR clones demonstrate improved overall survival. Our work indicates a complex relationship between genotype and TCR repertoire in the context of ICB treatment, with implications for understanding factors relating to therapeutic response and patient outcomes.
Development and Validation of a Type 1 Diabetes Multi-Ancestry Polygenic Score.
OBJECTIVE: Polygenic scores strongly predict type 1 diabetes risk, but most scores were developed in European-ancestry populations. In this study, we developed a multi-ancestry polygenic score to accurately predict type 1 diabetes risk across diverse populations. RESEARCH DESIGN AND METHODS: We used recent multi-ancestry genome-wide association studies to create a type 1 diabetes multi-ancestry polygenic score (T1D MAPS). We trained the score in the Mass General Brigham (MGB) Biobank (372 individuals with type 1 diabetes) and tested the score in the All of Us program (86 individuals with type 1 diabetes). We evaluated the area under the receiver operating characteristic curve (AUC), and we compared the AUC to two published single-ancestry scores: T1D GRS2EUR and T1D GRSAFR. We also developed an updated score (T1D MAPS2) that combines T1D GRS2EUR and T1D MAPS. RESULTS: Among individuals with non-European ancestry, the AUC of T1D MAPS was 0.90, significantly higher than T1D GRS2EUR (0.82, P = 0.04) and T1D GRSAFR (0.82, P = 0.007). Among individuals with European ancestry, the AUC of T1D MAPS was slightly lower than T1D GRS2EUR (0.89 vs. 0.91, P = 0.02). However, T1D MAPS2 performed equivalently to T1D GRS2EUR in European ancestry (0.91 vs. 0.91, P = 0.45) while still performing better in non-European ancestry (0.90 vs. 0.82, P = 0.04). CONCLUSIONS: A novel polygenic score improves type 1 diabetes risk prediction in non-European ancestry while maintaining high predictive power in European ancestry. These findings advance the accuracy of type 1 diabetes genetic risk prediction across diverse populations.
Paired analysis of host and pathogen genomes identifies determinants of human tuberculosis.
Infectious disease is the result of interactions between host and pathogen and can depend on genetic variations in both. We conduct a genome-to-genome study of paired human and Mycobacterium tuberculosis genomes from a cohort of 1556 tuberculosis patients in Lima, Peru. We identify an association between a human intronic variant (rs3130660, OR = 10.06, 95%CI: 4.87 - 20.77, P = 7.92 × 10-8) in the FLOT1 gene and a subclavaluee of Mtb Lineage 2. In a human macrophage infection model, we observe hosts with the rs3130660-A allele exhibited stronger interferon gene signatures. The interacting strains have altered redox states due to a thioredoxin reductase mutation. We investigate this association in a 2020 cohort of 699 patients recruited during the COVID-19 pandemic. While the prevalence of the interacting strain almost doubled between 2010 and 2020, its infection is not associated with rs3130660 in this recent cohort. These findings suggest a complex interplay among host, pathogen, and environmental factors in tuberculosis dynamics.
Genomic and Serological Rheumatoid Arthritis Biomarkers, MUC5B Promoter Variant, and Interstitial Lung Abnormalities.
RATIONALE: Rheumatoid arthritis (RA) has been implicated in interstitial lung disease (ILD) as majority of studies have been comprised of patients with known RA. However, it remains unclear whether an underlying risk for RA in combination with genetic risk for pulmonary fibrosis is associated with radiological markers of early lung injury and fibrosis in broader population samples. OBJECTIVE: Determine whether genetic and serological biomarkers of RA risk in combination with the MUC5B (rs35705950) risk allele (T) are associated with interstitial lung abnormalities (ILA) on computed tomography (CT) scans. METHODS: Associations of RA-risk HLA-DRB1 alleles (*04:01, *04:08, *04:05, *04:04, *10:01) and serum RA autoantibodies with ILA in the Multi-Ethnic Study of Atherosclerosis (MESA, n=4,018) and COPDGene (n=5,963) cohorts were modeled using logistic regression and adjusted for age, sex, self-reported race and ethnicity, smoking history, body mass index, and principal components of genetic ancestry. RESULTS: The prevalence of an RA risk HLA-DRB1 allele was 16.5% and 21.9% in MESA and COPDGene, respectively. ILA was present in 3.9% and 11% in MESA and COPDGene, respectively. An RA risk HLA-DRB1 allele was not significantly associated with ILA in MESA and COPDGene. In MESA, higher serum levels of IgA rheumatoid factor (RF) and anti-cyclic citrullinated peptide were associated with an odds ratio (OR) for ILA of 1.20 (95% CI 1.07-1.35) and 1.19 (95% CI 1.04-1.37), respectively. Among smokers without baseline ILA, per doubling of IgM RF was associated with an OR for ILA 10 years later of 1.25 (95% CI 1.08-1.43). Associations were not significantly different by MUC5B risk allele status. CONCLUSIONS: RA-related HLA-DRB1 alleles were not associated with ILA, whereas higher serum levels of IgM RF among smokers without baseline ILA were associated with subsequent ILA.
History of tuberculosis disease is associated with genetic regulatory variation in Peruvians.
A quarter of humanity is estimated to have been exposed to Mycobacterium tuberculosis (Mtb) with a 5-10% risk of developing tuberculosis (TB) disease. Variability in responses to Mtb infection could be due to host or pathogen heterogeneity. Here, we focused on host genetic variation in a Peruvian population and its associations with gene regulation in monocyte-derived macrophages and dendritic cells (DCs). We recruited former household contacts of TB patients who previously progressed to TB (cases, n = 63) or did not progress to TB (controls, n = 63). Transcriptomic profiling of monocyte-derived DCs and macrophages measured the impact of genetic variants on gene expression by identifying expression quantitative trait loci (eQTL). We identified 330 and 257 eQTL genes in DCs and macrophages (False Discovery Rate (FDR) < 0.05), respectively. Four genes in DCs showed interaction between eQTL variants and TB progression status. The top eQTL interaction for a protein-coding gene was with FAH, the gene encoding fumarylacetoacetate hydrolase, which mediates the last step in mammalian tyrosine catabolism. FAH expression was associated with genetic regulatory variation in cases but not controls. Using public transcriptomic and epigenomic data of Mtb-infected monocyte-derived dendritic cells, we found that Mtb infection results in FAH downregulation and DNA methylation changes in the locus. Overall, this study demonstrates effects of genetic variation on gene expression levels that are dependent on history of infectious disease and highlights a candidate pathogenic mechanism through pathogen-response genes. Furthermore, our results point to tyrosine metabolism and related candidate TB progression pathways for further investigation.
Human leukocyte antigen-DQA1*04:01 and rs2040406 variants are associated with elevated risk of childhood Burkitt lymphoma.
Burkitt lymphoma (BL) is responsible for many childhood cancers in sub-Saharan Africa, where it is linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which regulate immune response, are associated with BL has not been well investigated, which limits our understanding of BL etiology. Here we investigate this association among 4,645 children aged 0-15 years, 800 with BL, enrolled in Uganda, Tanzania, Kenya, and Malawi. HLA alleles are imputed with accuracy >90% for HLA class I and 85-89% for class II alleles. BL risk is elevated with HLA-DQA1*04:01 (adjusted odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71 × 10-6), with rs2040406(G) in HLA-DQA1 region (OR = 1.43, 95% CI = 1.26-1.63, P = 4.62 × 10-8), and with amino acid Gln at position 53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10-6). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68, P = 0.019) persist in mutually adjusted models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1 expression in eQTLs in EBV transformed lymphocytes. Our results support the role of HLA variation in the etiology of BL and suggest that a promising area of research might be understanding the link between HLA variation and EBV control.
Viridans Streptococcal Biofilm Evades Immune Detection and Contributes to Inflammation and Rupture of Atherosclerotic Plaques.
BACKGROUND: Bacterial DNA from the oral cavity, respiratory tract, gut, and skin has been detected in atherosclerotic plaques, suggesting a role in chronic inflammation linked to atherosclerosis. Chronic bacterial infections often form biofilms resistant to antibiotics and immune detection, giving rise to a new generation of virulent bacteria in suitable conditions. This study explores the role of the immune system in bacterial-induced inflammation of atherosclerotic plaques. METHODS: Coronary plaques from 121 sudden death victims and endarterectomy samples from 96 surgical patients were analyzed using bacterial real-time quantitative polymerase chain reaction, immunohistochemistry, and genome-wide expression analysis. TLR (toll-like receptor) signaling was examined in bacterial-activated TLR cell lines. RESULTS: Of the bacteria detected, oral viridans group streptococcal DNA was the most common, being found in 42.1% of coronary plaques and 42.9% of endarterectomies. Immunopositivity for viridans streptococci correlated with severe atherosclerosis (P<0.0001) in both series and death from coronary heart disease (P=0.021) or myocardial infarction (P=0.042). Viridans streptococci colonized the core of the atheroma as a biofilm unrecognized by macrophages of the innate immune system. In contrast, immunopositive streptococci that appeared to have originated from the biofilm infiltrated the ruptured fibrous cap of the atheroma in endarterectomy samples and coronary plaques and were detected by pattern-recognizing receptors and coexpressed with the adaptive immune response. Among the viridans streptococcal strains, TLR2 was the most activated bacterial-signaling pathway. Genome-wide expression analysis of endarterectomy samples showed upregulation of bacterial recognition pathways. CONCLUSIONS: Latent chronic bacterial inflammation evades immune detection and may contribute to the pathogenesis of complicated atherosclerotic plaques and fatal myocardial infarction.
OrthoticS for TReatment of symptomatic flat feet In CHildren (OSTRICH): a randomised controlled trial.
BACKGROUND: Children and young people with symptomatic pes planus (flat feet) often seek treatment from healthcare professionals. There are various treatment options, but there is a lack of high-quality evidence about which is most effective. OBJECTIVES: To assess the clinical and cost-effectiveness of prefabricated orthoses, plus exercise and advice, compared with exercise and advice alone on physical function, measured using the physical domain of the Oxford Ankle Foot Questionnaire for Children, among children with symptomatic pes planus. DESIGN AND METHODS: A pragmatic, multicentre, two-armed individually randomised controlled trial with an internal pilot, economic evaluation and qualitative study. SETTING AND PARTICIPANTS: Children and young people aged 6-14 years with symptomatic flat feet were recruited from hospital or community healthcare facilities in England and Wales. Participants were randomised 1 : 1 using a secure web-based randomisation system and followed up for up to 12 months. INTERVENTIONS: We planned to provide all participants with advice and exercises, with the intervention group also receiving a prefabricated orthosis. Due to the nature of the study treatments, blinding of participants or the research team was not possible. MAIN OUTCOME MEASURES: The primary outcome was the physical domain subscale of the Oxford Ankle Foot Questionnaire for Children over the 12-month follow-up. Secondary outcomes included the physical domain subscale at 3, 6 and 12 months, and the 'School and Play' and 'Emotional' domains of the Oxford Ankle Foot Questionnaire, pain scores, healthcare resource use, EQ-5D-Y and Child Health Utility 9D at all time points. The qualitative study drew on health literacy and health belief perspectives and examined fidelity and explored the experiences of being in the trial for those receiving and delivering the study treatments. RESULTS: COVID-19 severely delayed trial set-up and recruitment and the study closed before meeting its recruitment target. Of 549 participants assessed for eligibility, 134 were randomised (intervention n = 70, control n = 64). The mean age of participants was 10.6 years (range 6.3-14.8) and 55.2% were male. No adverse events were reported. The planned statistical and health economic analyses could not be fully conducted due to the limited data. The qualitative study identified pain, posture and gait as the most common concerns by participants with pain relief as the primary motivator for seeking health care. Participants generally reported little understanding of their condition with barriers including misattribution (e.g. growing pains). Misinformation was common emphasising a need for accessible accurate education materials and structured follow-up care. There was a common belief that orthoses were superior to exercises leading to high levels of adherence, satisfaction and outcomes with orthoses compared with poor adherence, and low perceived efficacy with exercises linked to challenges incorporating these into daily routines. LIMITATIONS: We could not deliver the study objectives as planned. Due to the limited data available, we were unable to undertake the planned analysis. CONCLUSIONS: The COVID-19 pandemic significantly impacted trial set-up and recruitment. Extending the study was not feasible due to cost and time constraints. FUTURE WORK: The evidence for the clinical and cost-effectiveness of orthotics for the treatment of symptomatic flat feet in children remains inconclusive and an area for further research. FUNDING: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR127510.