Tissue-resident memory (T
) CD8
T cells are largely derived from recently activated effector T cells, but the mechanisms that control the extent of T
differentiation within tissue microenvironments ...remain unresolved. Here, using an IFNγ-YFP reporter system to identify CD8
T cells executing antigen-dependent effector functions, we define the transcriptional consequences and functional mechanisms controlled by TCR-signaling strength that occur within the skin during viral infection to promote T
differentiation. TCR-signaling both enhances CXCR6-mediated migration and suppresses migration toward sphingosine-1-phosphate, indicating the programming of a 'chemotactic switch' following secondary antigen encounter within non-lymphoid tissues. Blimp1 was identified as the critical target of TCR re-stimulation that is necessary to establish this chemotactic switch and for T
differentiation to efficiently occur. Collectively, our findings show that access to antigen presentation and strength of TCR-signaling required for Blimp1 expression establishes the chemotactic properties of effector CD8
T cells to promote residency within non-lymphoid tissues.
De novo mutations affect risk for many diseases and disorders, especially those with early-onset. An example is autism spectrum disorders (ASD). Four recent whole-exome sequencing (WES) studies of ...ASD families revealed a handful of novel risk genes, based on independent de novo loss-of-function (LoF) mutations falling in the same gene, and found that de novo LoF mutations occurred at a twofold higher rate than expected by chance. However successful these studies were, they used only a small fraction of the data, excluding other types of de novo mutations and inherited rare variants. Moreover, such analyses cannot readily incorporate data from case-control studies. An important research challenge in gene discovery, therefore, is to develop statistical methods that accommodate a broader class of rare variation. We develop methods that can incorporate WES data regarding de novo mutations, inherited variants present, and variants identified within cases and controls. TADA, for Transmission And De novo Association, integrates these data by a gene-based likelihood model involving parameters for allele frequencies and gene-specific penetrances. Inference is based on a Hierarchical Bayes strategy that borrows information across all genes to infer parameters that would be difficult to estimate for individual genes. In addition to theoretical development we validated TADA using realistic simulations mimicking rare, large-effect mutations affecting risk for ASD and show it has dramatically better power than other common methods of analysis. Thus TADA's integration of various kinds of WES data can be a highly effective means of identifying novel risk genes. Indeed, application of TADA to WES data from subjects with ASD and their families, as well as from a study of ASD subjects and controls, revealed several novel and promising ASD candidate genes with strong statistical support.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Broadly neutralizing antibodies (Abs) that bind the influenza virus hemagglutinin (HA) stem may enable universal influenza vaccination. Here, we show that anti-stem Abs sterically inhibit viral ...neuraminidase (NA) activity against large substrates, with activity inversely proportional to the length of the fibrous NA stalk that supports the enzymatic domain. By modulating NA stalk length in recombinant IAVs, we show that anti-stem Abs inhibit virus release from infected cells by blocking NA, accounting for their in vitro neutralization activity. NA inhibition contributes to anti-stem Ab protection in influenza-infected mice, likely due at least in part to NA-mediated inhibition of FcγR-dependent activation of innate immune cells by Ab bound to virions. Food and Drug Administration-approved NA inhibitors enhance anti-stem-based Fc-dependent immune cell activation, raising the possibility of therapeutic synergy between NA inhibitors and anti-stem mAb treatment in humans.
We present a new multiproxy (TEX86, δ18O and Mg/Ca), marine temperature history for Canterbury Basin, eastern New Zealand, that extends from middle Paleocene to middle Eocene, including the ...Paleocene–Eocene thermal maximum (PETM) and early Eocene climatic optimum (EECO). In light of concerns that proxy-based sea surface temperature (SST) estimates are untenably warm for the southwest Pacific during the Eocene, we review the assumptions that underlie the proxies and develop a preliminary paleo-calibration for TEX86 that is based on four multiproxy Eocene records that represent an SST range of 15–34°C. For the southwest Pacific Paleogene, we show that TEX86L exhibits the best fit with the Eocene paleo-calibration. SSTs derived from related proxies (TEX86H, 1/TEX86) exhibit a systematic warm bias that increases as TEX86 values decrease (a warm bias of 4–7°C where TEX86<0.7). The TEX86L proxy indicates that southwest Pacific SST increased by ∼10°C from middle Paleocene to early Eocene, with SST maxima of 26–28°C (tropical) during the PETM and EECO and an SST minimum of 13–16°C (cool–warm temperate) at the middle/late Paleocene transition (58.7Ma). The base of the EECO is poorly defined in these records but the top is well-defined in Canterbury Basin by a 2–5°C decrease in SST and bottom water temperature (BWT) in the latest early Eocene (49.3Ma); BWT falls from a maximum of 18–20°C in the EECO to 12–14°C in the middle Eocene. Overall, cooler temperatures are recorded in the mid-Waipara section, which may reflect a deeper (∼500m water depth) and less neritic depositional setting compared with Hampden and ODP 1172 (∼200m water depth). The high SSTs and BWTs inferred for the PETM and EECO can be reconciled with Eocene coupled climate model results if the proxies are biased towards seasonal maxima and the likely effect of a proto-East Australian Current is taken into account.
► A revised multiproxy marine temperature record from middle Paleocene to middle Eocene, Southwest Pacific Ocean. ► Paleo-calibration of GDGT-based SST proxies supports use of TEX86L for southern high-latitude Paleogene records. ► Peak sea surface temperatures (SSTs) during the PETM and EECO of 25–28°C. ► Minimum SSTs during the late Paleocene of 13–15°C.
Aortic dissection is a life-threatening condition caused by a tear in the intimal layer of the aorta or bleeding within the aortic wall, resulting in the separation (dissection) of the layers of the ...aortic wall. Aortic dissection is most common in those 65-75 years of age, with an incidence of 35 cases per 100,000 people per year in this population. Other risk factors include hypertension, dyslipidaemia and genetic disorders that involve the connective tissue, such as Marfan syndrome. Swift diagnostic confirmation and adequate treatment are crucial in managing affected patients. Contemporary management is multidisciplinary and includes serial non-invasive imaging, biomarker testing and genetic risk profiling for aortopathy. The choice of approach for repairing or replacing the damaged region of the aorta depends on the severity and the location of the dissection and the risks of complication from surgery. Open surgical repair is most commonly used for dissections involving the ascending aorta and the aortic arch, whereas minimally invasive endovascular intervention is appropriate for descending aorta dissections that are complicated by rupture, malperfusion, ongoing pain, hypotension or imaging features of high risk. Recent advances in the understanding of the underlying pathophysiology of aortic dissection have led to more patients being considered at substantial risk of complications and, therefore, in need of endovascular intervention rather than only medical or surgical intervention.
Immunodominance (ID) defines the hierarchical immune response to competing antigens in complex immunogens. Little is known regarding B cell and antibody ID despite its importance in immunity to ...viruses and other pathogens. We show that B cells and serum antibodies from inbred mice demonstrate a reproducible ID hierarchy to the five major antigenic sites in the influenza A virus hemagglutinin globular domain. The hierarchy changed as the immune response progressed, and it was dependent on antigen formulation and delivery. Passive antibody transfer and sequential infection experiments demonstrated 'original antigenic suppression', a phenomenon in which antibodies suppress memory responses to the priming antigenic site. Our study provides a template for attaining deeper understanding of antibody ID to viruses and other complex immunogens.
Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related ...acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.
Spontaneously arising (de novo) mutations have an important role in medical genetics. For diseases with extensive locus heterogeneity, such as autism spectrum disorders (ASDs), the signal from de ...novo mutations is distributed across many genes, making it difficult to distinguish disease-relevant mutations from background variation. Here we provide a statistical framework for the analysis of excesses in de novo mutation per gene and gene set by calibrating a model of de novo mutation. We applied this framework to de novo mutations collected from 1,078 ASD family trios, and, whereas we affirmed a significant role for loss-of-function mutations, we found no excess of de novo loss-of-function mutations in cases with IQ above 100, suggesting that the role of de novo mutations in ASDs might reside in fundamental neurodevelopmental processes. We also used our model to identify ∼1,000 genes that are significantly lacking in functional coding variation in non-ASD samples and are enriched for de novo loss-of-function mutations identified in ASD cases.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
ABSTRACT Antibody responses to influenza vaccines tend to be focused on epitopes encountered during prior influenza exposures, with little production of de novo responses to novel epitopes. To ...examine the contribution of circulating antibodies to this phenomenon, we passively transferred a hemagglutinin (HA)-specific monoclonal antibody (mAb) into mice before immunizing with whole inactivated virions. The HA mAb inhibited de novo HA-specific antibodies, plasmablasts, germinal center B cells, and memory B cells, while responses to a second antigen in the vaccine, neuraminidase (NA), were uninhibited. The HA mAb potently inhibited de novo antibody responses against epitopes near the HA mAb binding site. The HA mAb also promoted IgG1 class switching, an effect that, unlike the inhibition of HA responses, relied on signaling through Fc-gamma receptors. These studies suggest that circulating antibodies inhibit de novo B cell responses in an antigen-specific manner, which likely contributes to differences in antibody specificities elicited during primary and secondary influenza virus exposures. IMPORTANCE Most humans are exposed to influenza viruses in childhood and then subsequently exposed to antigenically drifted influenza variants later in life. It is unclear if antibodies elicited by earlier influenza virus exposures impact immunity against new influenza virus strains. Here, we used a mouse model to investigate how an anti-hemagglutinin (HA) monoclonal antibody (mAb) affects de novo B cell and antibody responses to the protein targeted by the monoclonal antibody (HA) and a second protein not targeted by the monoclonal antibody neuraminidase (NA). Collectively, our studies suggest that circulating anti-influenza virus antibodies can potently modulate the magnitude and specificity of antibody responses elicited by secondary influenza virus exposures.
Most humans are exposed to influenza viruses in childhood and then subsequently exposed to antigenically drifted influenza variants later in life. It is unclear if antibodies elicited by earlier influenza virus exposures impact immunity against new influenza virus strains. Here, we used a mouse model to investigate how an anti-hemagglutinin (HA) monoclonal antibody (mAb) affects de novo B cell and antibody responses to the protein targeted by the monoclonal antibody (HA) and a second protein not targeted by the monoclonal antibody neuraminidase (NA). Collectively, our studies suggest that circulating anti-influenza virus antibodies can potently modulate the magnitude and specificity of antibody responses elicited by secondary influenza virus exposures.
Human antibody-based immunity to influenza A virus is limited by antigenic drift resulting from amino acid substitutions in the hemagglutinin (HA) head domain. Glycan addition can cause large ...antigenic changes but is limited by fitness costs to viral replication. Here, we report that glycans are added to H1 and H3 HAs at discrete 5-to-7-year intervals, until they reach a functional glycan limit, after which glycans are swapped at approximately 2-fold-longer intervals. Consistent with this pattern, 2009 pandemic H1N1 added a glycan at residue N162 over the 2015-2016 season, an addition that required two epistatic HA head mutations for complete glycosylation. These strains rapidly replaced H1N1 strains globally, by 2017 dominating H3N2 and influenza B virus strains for the season. The pattern of glycan modulation that we outline should aid efforts for tracing the epidemic potential of evolving human IAV strains.
Frequent mutation of its major antibody target, the glycoprotein hemagglutinin, ensures that the influenza virus is perennially both a rapidly emerging virus and a major threat to public health. One type of mutation escapes immunity by adding a glycan onto an area of hemagglutinin that many antibodies recognize. This study revealed that these glycan changes follow a simple temporal pattern. Every 5 to 7 years, hemagglutinin adds a new glycan, up to a limit. After this limit is reached, no net additions of glycans occur. Instead, glycans are swapped or lost at longer intervals. Eventually, a pandemic replaces the terminally glycosylated hemagglutinin with a minimally glycosylated one from the animal reservoir, restarting the cycle. This pattern suggests the following: (i) some hemagglutinins are evolved for this decades-long process, which is both defined by and limited by successive glycan addition; and (ii) hemagglutinin's antibody dominance and its capacity for mutations are highly adapted features that allow influenza to outpace our antibody-based immunity.
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