Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma.

Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies

The Caenorhabditis elegans Gene mfap-1 Encodes a Nuclear Protein That Affects Alternative Splicing

RNA splicing is a major regulatory mechanism for controlling eukaryotic gene expression. By generating various splice isoforms from a single pre–mRNA, alternative splicing plays a key role in promoting the evolving complexity of metazoans. Numerous splicing factors have been identified. However, the in vivo functions of many splicing factors remain to be understood. In vivo studies are essential for understanding the molecular mechanisms of RNA splicing and the biology of numerous RNA splicing-related diseases. We previously isolated a Caenorhabditis elegans mutant defective in an essential gene from a genetic screen for suppressors of the rubberband Unc phenotype of unc-93(e1500) animals. This mutant contains missense mutations in two adjacent codons of the C. elegans microfibrillar-associated protein 1 gene mfap-1. mfap-1(n4564 n5214) suppresses the Unc phenotypes of different rubberband Unc mutants in a pattern similar to that of mutations in the splicing factor genes uaf-1 (the C. elegans U2AF large subunit gene) and sfa-1 (the C. elegans SF1/BBP gene). We used the endogenous gene tos-1 as a reporter for splicing and detected increased intron 1 retention and exon 3 skipping of tos-1 transcripts in mfap-1(n4564 n5214) animals. Using a yeast two-hybrid screen, we isolated splicing factors as potential MFAP-1 interactors. Our studies indicate that C. elegans mfap-1 encodes a splicing factor that can affect alternative splicing.National Natural Science Foundation (China) (Grant 30971639)United States. National Institutes of Health (Grant GM24663

Jet quenching

We present a comprehensive review of the physics of hadron and jet production at large transverse momentum in high-energy nucleus-nucleus collisions. Emphasis is put on experimental and theoretical "jet quenching" observables that provide direct information on the (thermo)dynamical properties of hot and dense QCD matter.Comment: Springer Verlag. Landolt-Boernstein Vol. 1-23A. 49 pages. 36 figures. Minor corrections & references adde

Proteomic analysis of extracellular vesicles reveals an immunogenic cargo in rheumatoid arthritis synovial fluid

Objectives: Extracellular vesicles (EVs) from rheumatoid arthritis (RA) synovial fluid (SF) have been reported to stimulate the release of pro-inflammatory mediators from recipient cells. We recently developed a size exclusion chromatography (SEC)-based method for EV isolation capable of high-quality enrichments from human SF. Here, we employed this method to accurately characterise the SF EV proteome and investigate potential contributions to inflammatory pathways in RA. Methods: Using our SEC-based approach, SF EVs were purified from the joints of RA patients classified as having high-level (n = 7) or low-level inflammation (n = 5), and from osteoarthritis (OA) patients (n = 5). Protein profiles were characterised by mass spectrometry. Potential contributions of EV proteins to pathological pathways and differences in protein expression between disease groups were investigated. Results: Synovial fluid EVs were present at higher concentrations in RA joints with high-level inflammation (P-value = 0.004) but were smaller in diameter (P-value = 0.03) than in low-level inflammation. In total, 1058 SF EV proteins were identified by mass spectrometry analysis. Neutrophil and fibroblast markers were overrepresented in all disease groups. Numerous proteins with potential to modulate inflammatory and immunological processes were detected, including nine citrullinated peptides. Forty-five and 135 EV-associated proteins were significantly elevated in RA joints with high-level inflammation than in RA joints with low-level inflammation and OA joints, respectively. Gene ontology analysis revealed significant enrichment for proteins associated with 'neutrophil degranulation' within SF EVs from RA joints with high-level inflammation. Conclusion: Our results provide new information about SF EVs and insight into how EVs might contribute to the perpetuation of RA

GM-CSF primes cardiac inflammation in a mouse model of Kawasaki disease

Kawasaki disease (KD) is the leading cause of pediatric heart disease in developed countries. KD patients develop cardiac inflammation, characterized by an early infiltrate of neutrophils and monocytes that precipitates coronary arteritis. Although the early inflammatory processes are linked to cardiac pathology, the factors that regulate cardiac inflammation and immune cell recruitment to the heart remain obscure. In this study, using a mouse model of KD (induced by a cell wall Candida albicans water-soluble fraction [CAWS]), we identify an essential role for granulocyte/macrophage colony-stimulating factor (GM-CSF) in orchestrating these events. GM-CSF is rapidly produced by cardiac fibroblasts after CAWS challenge, precipitating cardiac inflammation. Mechanistically, GM-CSF acts upon the local macrophage compartment, driving the expression of inflammatory cytokines and chemokines, whereas therapeutically, GM-CSF blockade markedly reduces cardiac disease. Our findings describe a novel role for GM-CSF as an essential initiating cytokine in cardiac inflammation and implicate GM-CSF as a potential target for therapeutic intervention in KD

Screening for atherosclerosis in patients with rheumatoid arthritis

C1 - Journal Articles Referee

SIDT2 RNA Transporter Promotes Lung and Gastrointestinal Tumor Development

RNautophagy is a newly described type of selective autophagy whereby cellular RNAs are transported into lysosomes for degradation. This process involves the transmembrane protein SIDT2, which transports double-stranded RNA (dsRNA) across the endolysosomal membrane. We previously demonstrated that SIDT2 is a transcriptional target of p53, but its role in tumorigenesis, if any, is unclear. Unexpectedly, we show here that Sidt2-/- mice with concurrent oncogenic KrasG12D activation develop significantly fewer tumors than littermate controls in a mouse model of lung adenocarcinoma. Consistent with this observation, loss of SIDT2 also leads to enhanced survival and delayed tumor development in an Apcmin/+ mouse model of intestinal cancer. Within the intestine, Apcmin/+;Sidt2-/- mice display accumulation of dsRNA in association with increased phosphorylation of eIF2α and JNK as well as elevated rates of apoptosis. Taken together, our data demonstrate a role for SIDT2, and by extension RNautophagy, in promoting tumor development

Increased 30-day and 1-year mortality rates and lower coronary revascularisation rates following acute myocardial infarction in patients with autoimmune rheumatic disease

INTRODUCTION: It is now well-recognised that patients with autoimmune rheumatic disease (AIRD) have a predisposition to cardiovascular disease that results in increased morbidity and mortality. Following myocardial infarction (MI), patients with rheumatoid arthritis have been shown to have an increased case fatality rate; however, this has not been demonstrated in other forms of AIRD. The aim of this study was to compare case fatality rates following a first MI in patients with AIRD versus the general population. The secondary aim was to compare revascularisation treatment following MI in patients with AIRD versus the general population. METHODS: A retrospective cohort study using two population-based linked databases was undertaken. Cases of first MI from July 2001 to June 2007 were identified based on International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification, codes. Thirty-day and one-year mortality rates were calculated (all-cause and cardiovascular causes of death). Logistic regression models were fitted to calculate the odds of mortality by AIRD status with adjustment for relevant characteristics. RESULTS: There were 79,390 individuals with a first MI, of whom 1,409 (1.8%) had AIRD. After adjusting for relevant covariates, the odds ratio (OR) for 30-day cardiovascular mortality in patients with AIRD was 1.44 (95% confidence interval (CI): 1.25 to 1.66), and the OR for 12-month cardiovascular mortality was 1.71 (95% CI: 1.51 to 1.94). The 90-day adjusted odds of percutaneous transluminal coronary angioplasty and coronary artery bypass graft were significantly lower in the AIRD group compared with controls (OR: 0.81, 95% CI: 0.70 to 0.94, and OR: 0.52, 95% CI: 0.39 to 0.69, respectively). CONCLUSIONS: We identified a higher risk-adjusted mortality rate for the majority of patients with AIRD at 30 days and 12 months after first MI. We also identified lower post-MI revascularisation rates in the AIRD group, suggesting there may be current gaps in cardiovascular treatment for patients with AIRD

Post-infectious group A streptococcal autoimmune syndromes and the heart.

There is a pressing need to reduce the high global disease burden of rheumatic heart disease (RHD) and its harbinger, acute rheumatic fever (ARF). ARF is a classical example of an autoimmune syndrome and is of particular immunological interest because it follows a known antecedent infection with group A streptococcus (GAS). However, the poorly understood immunopathology of these post-infectious diseases means that, compared to much progress in other immune-mediated diseases, we still lack useful biomarkers, new therapies or an effective vaccine in ARF and RHD. Here, we summarise recent literature on the complex interaction between GAS and the human host that culminates in ARF and the subsequent development of RHD. We contrast ARF with other post-infectious streptococcal immune syndromes - post-streptococcal glomerulonephritis (PSGN) and the still controversial paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), in order to highlight the potential significance of variations in the host immune response to GAS. We discuss a model for the pathogenesis of ARF and RHD in terms of current immunological concepts and the potential for application of in depth "omics" technologies to these ancient scourges.info:eu-repo/semantics/publishe