COVID-19, caused by SARS-CoV-2 infection, is mild to moderate in the majority of previously healthy individuals, but can cause life-threatening disease or persistent debilitating symptoms in some ...cases. The most important determinant of disease severity is age, with individuals over 65 years having the greatest risk of requiring intensive care, and men are more susceptible than women. In contrast to other respiratory viral infections, young children seem to be less severely affected. It is now clear that mild to severe acute infection is not the only outcome of COVID-19, and long-lasting symptoms are also possible. In contrast to severe acute COVID-19, such 'long COVID' is seemingly more likely in women than in men. Also, postinfectious hyperinflammatory disease has been described as an additional outcome after SARS-CoV-2 infection. Here I discuss our current understanding of the immunological determinants of COVID-19 disease presentation and severity and relate this to known immune-system differences between young and old people and between men and women, and other factors associated with different disease presentations and severity.
SARS-CoV-2 infections mostly lead to mild or even asymptomatic infections in children, but the reasons for this are not fully understood. More efficient local tissue responses, better thymic ...function, and cross-reactive immunity have all been proposed to explain this. In rare cases of children and young people, but very rarely in adults, post-infectious hyperinflammatory syndromes can develop and be serious. Here, I will discuss our current understanding of SARS-CoV-2 infections in children and hypothesize that a life history and energy allocation perspective might offer an additional explanation to mild infections, viral dynamics, and the higher incidence of rare multisystem inflammatory syndromes in children and young people.
Brodin summarizes the current understanding of immune responses to SARS-CoV-2 infections in children and the possible explanations for the overall milder COVID-19 disease in young versus older individuals. To explain the combined observations to date, Brodin proposes an energy allocation perspective to explain mild disease, viral dynamics, and MIS-C in children and young people.
The human immune system consists of multiple, layered mechanisms of sensing and responding to cellular stress, infection and tissue damage to ensure defense from pathogens, maintenance of tissue ...homeostasis, and the integrity of the holobiont. Every single cell in the body has a role to play, but a few dozen, specialized white blood cells are particularly important in this respect. Understanding the overall state of this multifaceted system in a single individual is challenging, and we are only beginning to do this across populations of individuals, to understand the vast range of inter-individual variation, and the influences of genes and environmental factors that collectively shape the immune system in a given individual. We are also only beginning to understand the changes occurring within this system over time, and how this relates to health and disease susceptibility. Several technological breakthroughs in recent years have enabled these developments and the emergence of a new, complementary approach to studying human immune systems, namely systems immunology. In this paradigm, the focus is shifted from the understanding of individual immune system components and their mechanisms of action, towards analyses of cell–cell interactions, and mechanisms of coordination and regulation within the human immune system.
From the early days of natural killer (NK) cell research, it was clear that MHC genes controlled the specificity of mouse NK cell-dependent responses, such as the ability to reject transplanted ...allogeneic bone marrow and to kill tumour cells. Although several mechanisms that are involved in this 'education' process have been clarified, most of the mechanisms have still to be identified. Here, we review the current understanding of the processes that are involved in NK cell education, including how the host MHC class I molecules regulate responsiveness and receptor repertoire formation in NK cells and the signalling pathways that are involved.
The immune system of an individual human is determined by heritable traits and a continuous process of adaptation to a broad variety of extrinsic, non-heritable factors such as viruses, bacteria, ...dietary components and more. Cytomegalovirus (CMV) successfully infects the majority of the human population and establishes latency, thereby exerting a life-long influence on the immune system of its host. CMV has been shown to influence the majority of immune parameters in healthy individuals. Here we focus on adaptive changes induced by CMV in subsets of Natural Killer (NK) cells, changes that question our very definition of adaptive and innate immunity by suggesting that adaptations of immune cells to environmental influences occur across the entire human immune system and not restricted to the classical adaptive branch of the immune system.
Mass cytometry enables an unprecedented number of parameters to be measured in individual cells at a high throughput, but the large dimensionality of the resulting data severely limits approaches ...relying on manual “gating.” Clustering cells based on phenotypic similarity comes at a loss of single-cell resolution and often the number of subpopulations is unknown a priori. Here we describe ACCENSE, a tool that combines nonlinear dimensionality reduction with density-based partitioning, and displays multivariate cellular phenotypes on a 2D plot. We apply ACCENSE to 35-parameter mass cytometry data from CD8 ⁺ T cells derived from specific pathogen-free and germ-free mice, and stratify cells into phenotypic subpopulations. Our results show significant heterogeneity within the known CD8 ⁺ T-cell subpopulations, and of particular note is that we find a large novel subpopulation in both specific pathogen-free and germ-free mice that has not been described previously. This subpopulation possesses a phenotypic signature that is distinct from conventional naive and memory subpopulations when analyzed by ACCENSE, but is not distinguishable on a biaxial plot of standard markers. We are able to automatically identify cellular subpopulations based on all proteins analyzed, thus aiding the full utilization of powerful new single-cell technologies such as mass cytometry.
Blood is the predominant source for molecular analyses in humans, both in clinical and research settings. It is the target for many therapeutic strategies, emphasizing the need for comprehensive ...molecular maps of the cells constituting human blood. In this study, we performed a genome-wide transcriptomic analysis of protein-coding genes in sorted blood immune cell populations to characterize the expression levels of each individual gene across the blood cell types. All data are presented in an interactive, open-access Blood Atlas as part of the Human Protein Atlas and are integrated with expression profiles across all major tissues to provide spatial classification of all protein-coding genes. This allows for a genome-wide exploration of the expression profiles across human immune cell populations and all major human tissues and organs.
Immune-microbe interactions early in life influence the risk of allergies, asthma, and other inflammatory diseases. Breastfeeding guides healthier immune-microbe relationships by providing nutrients ...to specialized microbes that in turn benefit the host’s immune system. Such bacteria have co-evolved with humans but are now increasingly rare in modern societies. Here we show that a lack of bifidobacteria, and in particular depletion of genes required for human milk oligosaccharide (HMO) utilization from the metagenome, is associated with systemic inflammation and immune dysregulation early in life. In breastfed infants given Bifidobacterium infantis EVC001, which expresses all HMO-utilization genes, intestinal T helper 2 (Th2) and Th17 cytokines were silenced and interferon β (IFNβ) was induced. Fecal water from EVC001-supplemented infants contains abundant indolelactate and B. infantis-derived indole-3-lactic acid (ILA) upregulated immunoregulatory galectin-1 in Th2 and Th17 cells during polarization, providing a functional link between beneficial microbes and immunoregulation during the first months of life.
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•An ordered sequence of immune changes after birth driven by microbial interactions•Lack of gut bifidobacteria and HMO-utilization genes correlates with systemic inflammation•Feeding B. infantis EVC001 upregulates IFNβ and silences intestinal Th2 and Th17•EVC001-associated indole-3-lactic acid upregulates inhibitory galectin-1 in T cells
A lack of bifidobacteria and/or their genes required for the utilization of human milk oligosaccharides from breast milk is associated with systemic inflammation and immune imbalance early in life. Infant supplementation of Bifidobacterium infantis EVC001 shows promise in mitigating this by reducing Th2 and Th17 cytokines in the intestine through upregulation of the immunoregulatory factor galectin-1.
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