Explore the vast range of titles available.

The purpose of this randomized controlled trial was to determine the effects of resistance training (RT) on markers of inflammation and immune function in breast cancer survivors. Thirty-nine breast cancer survivors were randomly assigned to a RT ( n  = 20) or control ( n  = 19) group. RT performed supervized exercise three times per week. Natural killer cell (NK) and natural killer T-cell (NKT) function, and markers of inflammation (serum TNF-α, IL-6, IL-10, and CRP) were measured before and after training. Changes in NK and NKT cell function were analyzed using ANCOVA, with the change score the dependent variable, and the baseline value of the same variable the covariate. Effect sizes (ES) were calculated via partial eta-squared. We found a significant reduction, and large associated ESs, in the RT group compared to the control group for change in NK cell expression of TNF-α ( p  = 0.005, ES = 0.21) and NKT cell expression of TNF-α ( p  = 0.04, ES = 0.12). No differences were observed in any serum marker. Significant improvements in all measurements of strength were found in RT compared to control ( p  < 0.001; large ESs ranging from 0.32 to 0.51). These data demonstrate that RT has a beneficial effect on the NK and NKT cell expression of TNF-α indicating that RT may be beneficial in improving the inflammatory profile in breast cancer survivors.

HIV-1 and related viruses require co-receptors, in addition to CD4, to infect target cells. The chemokine receptor CCR-5 (ref. 1) was recently demonstrated to be a co-receptor for macrophage-tropic (M-tropic) HIV-1 strains 2–6 , and the orphan 7 receptor LESTR (also called fusin) allows infection by strains adapted for growth in transformed T-cell lines (T-tropic strains). Here we show that a mutant allele of CCR-5 is present at a high frequency in caucasian populations (allele frequency, 0.092), but is absent in black populations from Western and Central Africa and Japanese populations. A 32-base-pair deletion within the coding region results in a frame shift, and generates a non-functional receptor that does not support membrane fusion or infection by macrophage- and dual-tropic HIV-1 strains. In a cohort of HIV-1-infected caucasian subjects, no individual homozygous for the mutation was found, and the frequency of heterozygotes was 35% lower than in the general population. White blood cells from an individual homozygous for the null allele were found to be highly resistant to infection by M-tropic HIV-1 viruses, confirming that CCR-5 is the major co-receptor for primary HIV-1 strains. The lower frequency of heterozygotes in seropositive patients may indicate partial resistance.

The species-specific phenolic glycolipid 1 (PGL-1) is suspected to play a critical role in the pathogenesis of leprosy, a chronic disease of the skin and peripheral nerves caused by Mycobacterium leprae. Based on studies using the purified compound, PGL-1 was proposed to mediate the tropism of M. leprae for the nervous system and to modulate host immune responses. However, deciphering the biological function of this glycolipid has been hampered by the inability to grow M. leprae in vitro and to genetically engineer this bacterium. Here, we identified the M. leprae genes required for the biosynthesis of the species-specific saccharidic domain of PGL-1 and reprogrammed seven enzymatic steps in M. bovis BCG to make it synthesize and display PGL-1 in the context of an M. leprae-like cell envelope. This recombinant strain provides us with a unique tool to address the key questions of the contribution of PGL-1 in the infection process and to study the underlying molecular mechanisms. We found that PGL-1 production endowed recombinant BCG with an increased capacity to exploit complement receptor 3 (CR3) for efficient invasion of human macrophages and evasion of inflammatory responses. PGL-1 production also promoted bacterial uptake by human dendritic cells and dampened their infection-induced maturation. Our results therefore suggest that M. leprae produces PGL-1 for immune-silent invasion of host phagocytic cells.

Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2 , ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease. We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants ( P < 1 × 10 −4 ) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations ( P < 5 × 10 −8 ) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10 −10 , odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 −10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 −14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

STING (stimulator of interferon genes) is a central molecule that binds to cyclic dinucleotides produced by the cyclic GMP-AMP synthase (cGAS) to activate innate immunity against microbial infection. Here we report that STING harbors classic LC-3 interacting regions (LIRs) and mediates autophagy through its direct interaction with LC3. We observed that poly(dA:dT), cGAMP, and HSV-1 induced STING-dependent autophagy and degradation of STING immediately after TBK1 activation. STING induces non-canonical autophagy that is dependent on ATG5, whereas other autophagy regulators such as Beclin1, Atg9a, ULK1, and p62 are dispensable. LIR mutants of STING abolished its interaction with LC3 and its activation of autophagy. Also, mutants that abolish STING dimerization and cGAMP-binding diminished the STING-LC3 interaction and subsequent autophagy, suggesting that STING activation is indispensable for autophagy induction. Our results thus uncover dual functions of STING in activating the immune response and autophagy, and suggest that STING is involved in ensuring a measured innate immune response.

We treated a 27-year-old patient with Duchenne’s muscular dystrophy (DMD) with recombinant adeno-associated virus (rAAV) serotype 9 containing d Sa Cas9 (i.e., “dead” Staphylococcus aureus Cas9, in which the Cas9 nuclease activity has been inactivated) fused to VP64; this transgene was designed to up-regulate cortical dystrophin as a custom CRISPR–transactivator therapy. The dose of rAAV used was 1×10 14 vector genomes per kilogram of body weight. Mild cardiac dysfunction and pericardial effusion developed, followed by acute respiratory distress syndrome (ARDS) and cardiac arrest 6 days after transgene treatment; the patient died 2 days later. A postmortem examination showed severe diffuse alveolar damage. Expression of transgene in the liver was minimal, and there was no evidence of AAV serotype 9 antibodies or effector T-cell reactivity in the organs. These findings indicate that an innate immune reaction caused ARDS in a patient with advanced DMD treated with high-dose rAAV gene therapy. (Funded by Cure Rare Disease.) A 27-year-old man with Duchenne’s muscular dystrophy who was treated with a CRISPR-Cas9 transgene died from an innate immune response to the high dose of recombinant AAV used for delivery of the transgene.

Classical immunological memory, carried out by T and B lymphocytes, ensures that we feel the ill effects of many pathogens only once. Netea et al. review how cells of the innate immune system, which lack the antigen specificity, clonality, and longevity of T cell and B cells, have some capacity to remember, too. Termed “trained immunity,” the property allows macrophages, monocytes, and natural killer cells to show enhanced responsiveness when they reencounter pathogens. Epigenetic changes largely drive trained immunity, which is shorter lived and less specific than classical memory but probably still gives us a leg up during many infections. Science , this issue p. 10.1126/science.aaf1098 The general view that only adaptive immunity can build immunological memory has recently been challenged. In organisms lacking adaptive immunity, as well as in mammals, the innate immune system can mount resistance to reinfection, a phenomenon termed “trained immunity” or “innate immune memory.” Trained immunity is orchestrated by epigenetic reprogramming, broadly defined as sustained changes in gene expression and cell physiology that do not involve permanent genetic changes such as mutations and recombination, which are essential for adaptive immunity. The discovery of trained immunity may open the door for novel vaccine approaches, new therapeutic strategies for the treatment of immune deficiency states, and modulation of exaggerated inflammation in autoinflammatory diseases.

Complete and accurate DNA replication requires the progression of replication forks through DNA damage, actively transcribed regions, structured DNA and compact chromatin. Recent studies have revealed a remarkable plasticity of the replication process in dealing with these obstacles, which includes modulation of replication origin firing, of the architecture of replication forks, and of the functional organization of the replication machinery in response to replication stress. However, these specialized mechanisms also expose cells to potentially dangerous transactions while replicating DNA. In this Review, we discuss how replication forks are actively stalled, remodelled, processed, protected and restarted in response to specific types of stress. We also discuss adaptations of the replication machinery and the role of chromatin modifications during these transactions. Finally, we discuss interesting recent data on the relevance of replication fork plasticity to human health, covering its role in tumorigenesis, its crosstalk with innate immunity responses and its potential as an effective cancer therapy target.Different obstacles can stall the progression of replication forks. Recent studies have revealed that stalled forks are remarkably diverse in their composition and architecture. This plasticity enables fork remodelling, processing and restart in response to specific types of replication stress, thereby influencing tumorigenesis and innate immunity.

Circadian rhythms are a ubiquitous feature of virtually all living organisms, regulating a wide diversity of physiological systems. It has long been established that the circadian clockwork plays a key role in innate immune responses, and recent studies reveal that several aspects of adaptive immunity are also under circadian control. We discuss the latest insights into the genetic and biochemical mechanisms linking immunity to the core circadian clock of the cell and hypothesize as to why the immune system is so tightly controlled by circadian oscillations. Finally, we consider implications for human health, including vaccination strategies and the emerging field of chrono-immunotherapy.

Most rheumatic and musculoskeletal diseases (RMDs) can be placed along a spectrum of disorders, with autoinflammatory diseases (including monogenic systemic autoinflammatory diseases) and autoimmune diseases (such as systemic lupus erythematosus and antiphospholipid syndrome) representing the two ends of this spectrum. However, although most autoinflammatory diseases are characterized by the activation of innate immunity and inflammasomes and classical autoimmunity typically involves adaptive immune responses, there is some overlap in the features of autoimmunity and autoinflammation in RMDs. Indeed, some ‘mixed-pattern’ diseases such as spondyloarthritis and some forms of rheumatoid arthritis can also be delineated. A better understanding of the pathogenic pathways of autoinflammation and autoimmunity in RMDs, as well as the preferential cytokine patterns observed in these diseases, could help us to design targeted treatment strategies.Most rheumatic and musculoskeletal diseases (RMDs) fall along a spectrum of disorders from autoinflammatory diseases to autoimmune diseases, with ‘mixed-pattern’ RMDs having features of autoinflammation and autoimmunity. A better understanding of the pathogenic pathways of autoinflammation and autoimmunity in RMDs should enhance targeted treatment strategies.