The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity ...in major depression, a relationship of HPA axis activity to cognitive performance and a potential role of HPA axis genetic variation in cognition. The present study investigated the simultaneous roles HPA axis activity, clinical symptomatology and HPA genetic variation play in cognitive performance. Patients with major depression with psychotic major depression (PMD) and with nonpsychotic major depression (NPMD) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, overnight hourly blood sampling for cortisol and genetic assessment. Cognitive performance differed as a function of depression subtype. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher cortisol than did NPMDs and HCs. Cortisol, clinical symptoms and variation in genes, NR3C1 (glucocorticoid receptor; GR) and NR3C2 (mineralocorticoid receptor; MR) that encode for GRs and MRs, predicted cognitive performance. Beyond the effects of cortisol, demographics and clinical symptoms, NR3C1 variation predicted attention and working memory, whereas NR3C2 polymorphisms predicted memory performance. These findings parallel the distribution of GR and MR in primate brain and their putative roles in specific cognitive tasks. HPA axis genetic variation and activity were important predictors of cognition across the entire sample of depressed subjects and HR. GR and MR genetic variation predicted unique cognitive functions, beyond the influence of cortisol and clinical symptoms. GR genetic variation was implicated in attention and working memory, whereas MR was implicated in verbal memory.
Dendritic cells in cancer immunology Murphy, Theresa L; Murphy, Kenneth M
Cellular & Molecular Immunology/Cellular & molecular immunology,
01/2022, Volume:
19, Issue:
1
Journal Article
Peer reviewed
Open access
The clinical success of immune checkpoint therapy (ICT) has produced explosive growth in tumor immunology research because ICT was discovered through basic studies of immune regulation. Much of the ...current translational efforts are aimed at enhancing ICT by identifying therapeutic targets that synergize with CTLA4 or PD1/PD-L1 blockade and are solidly developed on the basis of currently accepted principles. Expanding these principles through continuous basic research may help broaden translational efforts. With this mindset, we focused this review on three threads of basic research directly relating to mechanisms underlying ICT. Specifically, this review covers three aspects of dendritic cell (DC) biology connected with antitumor immune responses but are not specifically oriented toward therapeutic use. First, we review recent advances in the development of the cDC1 subset of DCs, identifying important features distinguishing these cells from other types of DCs. Second, we review the antigen-processing pathway called cross-presentation, which was discovered in the mid-1970s and remains an enigma. This pathway serves an essential in vivo function unique to cDC1s and may be both a physiologic bottleneck and therapeutic target. Finally, we review the longstanding field of helper cells and the related area of DC licensing, in which CD4 T cells influence the strength or quality of CD8 T cell responses. Each topic is connected with ICT in some manner but is also a fundamental aspect of cell-mediated immunity directed toward intracellular pathogens.
Abstract In the literature there are conflicting reports on the optimal scaffold mean pore size required for successful bone tissue engineering. This study set out to investigate the effect of mean ...pore size, in a series of collagen–glycosaminoglycan (CG) scaffolds with mean pore sizes ranging from 85 μm to 325 μm, on osteoblast adhesion and early stage proliferation up to 7 days post-seeding. The results show that cell number was highest in scaffolds with the largest pore size of 325 μm. However, an early additional peak in cell number was also seen in scaffolds with a mean pore size of 120 μm at time points up to 48 h post-seeding. This is consistent with previous studies from our laboratory which suggest that scaffold specific surface area plays an important role on initial cell adhesion. This early peak disappears following cell proliferation indicating that while specific surface area may be important for initial cell adhesion, improved cell migration provided by scaffolds with pores above 300 μm overcomes this effect. An added advantage of the larger pores is a reduction in cell aggregations that develop along the edges of the scaffolds. Ultimately scaffolds with a mean pore size of 325 μm were deemed optimal for bone tissue engineering.
Dendritic cells (DCs) play critical roles in activating innate immune cells and initiating adaptive immune responses. The functions of DCs were originally obscured by their overlap with other ...mononuclear phagocytes, but new mouse models have allowed for the selective ablation of subsets of DCs and have helped to identify their non-redundant roles in the immune system. These tools have elucidated the functions of DCs in host defense against pathogens, autoimmunity, and cancer. This review will describe the mouse models generated to interrogate the role of DCs and will discuss how their use has progressively clarified our understanding of the unique functions of DC subsets.
Durai and Murphy (2016) review the progress made in developing new mouse models for the analysis of the functions of dendritic cell subsets and what these models have revealed about the roles of these cells in immune responses.
Autism spectrum disorder (ASD) is a neurodevelopmental condition with multiple causes, comorbid conditions, and a wide range in the type and severity of symptoms expressed by different individuals. ...This makes the neuroanatomy of autism inherently difficult to describe. Here, we demonstrate how a multiparameter classification approach can be used to characterize the complex and subtle structural pattern of gray matter anatomy implicated in adults with ASD, and to reveal spatially distributed patterns of discriminating regions for a variety of parameters describing brain anatomy. A set of five morphological parameters including volumetric and geometric features at each spatial location on the cortical surface was used to discriminate between people with ASD and controls using a support vector machine (SVM) analytic approach, and to find a spatially distributed pattern of regions with maximal classification weights. On the basis of these patterns, SVM was able to identify individuals with ASD at a sensitivity and specificity of up to 90% and 80%, respectively. However, the ability of individual cortical features to discriminate between groups was highly variable, and the discriminating patterns of regions varied across parameters. The classification was specific to ASD rather than neurodevelopmental conditions in general (e.g., attention deficit hyperactivity disorder). Our results confirm the hypothesis that the neuroanatomy of autism is truly multidimensional, and affects multiple and most likely independent cortical features. The spatial patterns detected using SVM may help further exploration of the specific genetic and neuropathological underpinnings of ASD, and provide new insights into the most likely multifactorial etiology of the condition.
The two major lineages of classical dendritic cells (cDCs) express and require either IRF8 or IRF4 transcription factors for their development and function. IRF8-dependent cDCs promote anti-viral and ...T-helper 1 (Th1) cell responses, whereas IRF4-expressing cDCs have been implicated in controlling both Th2 and Th17 cell responses. Here, we have provided evidence that Kruppel-like factor 4 (Klf4) is required in IRF4-expressing cDCs to promote Th2, but not Th17, cell responses in vivo. Conditional Klf4 deletion within cDCs impaired Th2 cell responses during Schistosoma mansoni infection, Schistosoma egg antigen (SEA) immunization, and house dust mite (HDM) challenge without affecting cytotoxic T lymphocyte (CTL), Th1 cell, or Th17 cell responses to herpes simplex virus, Toxoplasma gondii, and Citrobacter rodentium infections. Further, Klf4 deletion reduced IRF4 expression in pre-cDCs and resulted in selective loss of IRF4-expressing cDCs subsets in several tissues. These results indicate that Klf4 guides a transcriptional program promoting IRF4-expressing cDCs heterogeneity.
Display omitted
•Klf4 is required for the development of a subset of IRF4-expressing cDCs•Klf4 deletion results in reduced pre-cDCs•A specific Klf4-dependent subset can be identified in several tissues•Klf4fl/flItgax-cre mice have selectively impaired Th2 cell immunity
The IRF4-expressing cDCs subset is highly heterogeneous and has been implicated in priming Th17, as well as Th2 cell immunity. Murphy and colleagues dissect this heterogeneity showing a developmental requirement for Klf4 on specific subsets across several tissues. Moreover, Klf4 guides a transcriptional program necessary for Th2 cell immunity.
Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORγt working with multiple other ...essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively bound BATF and IRF4 contribute to initial chromatin accessibility and, with STAT3, initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci. Integration of multiple data sets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease.
Display omitted
► Integrated function of multiple transcription factors in Th17 cell differentiation ► Binding of BATF-IRF4 complexes to DNA mediates chromatin accessibility ► Network-predicted AP-1 factor Fosl2 restricts plasticity of Th17 cells ► Integration of multiple data sets in network most accurately predicts Th17 regulators
Integrating genome-wide regulatory information for key transcription factors involved in the development of proinflammatory Th17 cells produces a highly accurate and predictive network model for lineage specification and function.
Summary Over the past decade, in-vivo MRI studies have provided many invaluable insights into the neural substrates underlying autism spectrum disorder (ASD), which is now known to be associated with ...neurodevelopmental variations in brain anatomy, functioning, and connectivity. These systems-level features of ASD pathology seem to develop differentially across the human lifespan so that the cortical abnormalities that occur in children with ASD differ from those noted at other stages of life. Thus, investigation of the brain in ASD poses particular methodological challenges, which must be addressed to enable the comparison of results across studies. Novel analytical approaches are also being developed to facilitate the translation of findings from the research to the clinical setting. In the future, the insights provided by human neuroimaging studies could contribute to biomarker development for ASD and other neurodevelopmental disorders, and to new approaches to diagnosis and treatment.
PDF
