Temporal response characterization across individual multiomics profiles of prediabetic and diabetic subjects

Longitudinal deep multi-omics profiling, which combines biomolecular, physiological, environmental and clinical measures data, shows great promise for precision health. However, integrating and understanding the complexity of such data remains a big challenge. Here we propose a bottom-up framework starting from assessing single individuals' multi-omics time series, and using individual responses to assess multi-individual grouping based directly on similarity of their longitudinal deep multi-omics profiles. We applied our method to individual profiles from a study profiling longitudinal responses in type 2 diabetes mellitus. After generating periodograms for individual subject omics signals, we constructed within-person omics networks and analyzed personal-level immune changes. The results showed that our method identified both individual-level responses to immune perturbation, and the clusters of individuals that have similar behaviors in immune response and which was associated to measures of their diabetic status.

Analysis of transcriptional changes associated with pubertal development

Puberty is an important developmental period marked by hormonal, metabolic and immune changes, which have been implicated in predisposition to immune diseases later in life. Yet, little is known about the gene expression changes in immune cells that occur during pubertal development. In a longitudinal cohort of 251 children we assessed pubertal development and leukocyte gene expression. We identified largely overlapping gene expression changes in boys and girls for thousands of genes over a short time period. For 108 genes we detected gene expression changes associated with pubertal development. Substantial transcriptional changes were detected between pre- and post-menarcheal girls, which suggested a shift from predominantly innate to adaptive immunity as girls sexually matured. We identified genetic effects on gene expression that dynamically change during pubertal development for IGKV1-27 and PGAP1 in males, DSC1 and TRBV30 in females. We discovered that menarche is associated with a change in sign of a genetic effect on the expression of the asthma-associated gene FLOT2. Using a Transcriptome-Wide Association Study approach, we discovered that in girls, gene expression changes during puberty are associated with age at menarche. For example, expression of the endometrial cancer risk gene EEFSEC increases as girls become older, suggesting a link between age at menarche, transcriptional changes happening during puberty and poor health outcomes. These findings shed light on immune gene expression processes accompanying puberty and can advance the understanding of the molecular mechanisms through which pubertal development relates to immune diseases later in life.

Early-Life Adversity Leaves Its Imprint on the Oral Microbiome for More Than 20 Years and Is Associated with Long-Term Immune Changes

The early-life microbiome (ELM) interacts with the psychosocial environment, in particular during early-life adversity (ELA), defining life-long health trajectories. The ELM also plays a significant role in the maturation of the immune system. We hypothesised that, in this context, the resilience of the oral microbiomes, despite being composed of diverse and distinct communities, allows them to retain an imprint of the early environment. Using 16S amplicon sequencing on the EpiPath cohort, we demonstrate that ELA leaves an imprint on both the salivary and buccal oral microbiome 24 years after exposure to adversity. Furthermore, the changes in both communities were associated with increased activation, maturation, and senescence of both innate and adaptive immune cells, although the interaction was partly dependent on prior herpesviridae exposure and current smoking. Our data suggest the presence of multiple links between ELA, Immunosenescence, and cytotoxicity that occur through long-term changes in the microbiome.

Analysis of Common Pathways and Markers From Non-Alcoholic Fatty Liver Disease to Immune-Mediated Diseases

Metabolic associated fatty liver disease (MAFLD) is the most prevalent form of liver disease worldwide, accounting for a high liver-related mortality and morbidity with extensive multi-organ involvement. This entity has displaced viral hepatitis as the main cause of severe forms of hepatic diseases, although the onset and transition of MAFLD stages still remains unclear. Nevertheless, innate and adaptive immune responses seem to play an essential role in the establishment and further progression of this disease. The immune system is responsible of safeguard and preserves organs and systems function, and might be altered under different stimuli. Thus, the liver suffers from metabolic and immune changes leading to different injuries and loss of function. It has been stablished that cell-cell crosstalk is a key process in the hepatic homeostasis maintenance. There is mounting evidence suggesting that MAFLD pathogenesis is determined by a complex interaction of environmental, genetic and host factors that leads to a full plethora of outcomes. Therefore, herein we will revisit and discuss the interplay between immune mechanisms and MAFLD, highlighting the potential role of immunological markers in an attempt to clarify its relationship.

Role of sleep deprivation in immune-related disease risk and outcomes

Modern societies are experiencing an increasing trend of reduced sleep duration, with nocturnal sleeping time below the recommended ranges for health. Epidemiological and laboratory studies have demonstrated detrimental effects of sleep deprivation on health. Sleep exerts an immune-supportive function, promoting host defense against infection and inflammatory insults. Sleep deprivation has been associated with alterations of innate and adaptive immune parameters, leading to a chronic inflammatory state and an increased risk for infectious/inflammatory pathologies, including cardiometabolic, neoplastic, autoimmune and neurodegenerative diseases. Here, we review recent advancements on the immune responses to sleep deprivation as evidenced by experimental and epidemiological studies, the pathophysiology, and the role for the sleep deprivation-induced immune changes in increasing the risk for chronic diseases. Gaps in knowledge and methodological pitfalls still remain. Further understanding of the causal relationship between sleep deprivation and immune deregulation would help to identify individuals at risk for disease and to prevent adverse health outcomes.

Fatty Liver Degeneration in Cardiovascular Diseases

Research relevance: fatty liver disease is one of the common worldwide disorders and is a public health problem, with obesity and other metabolic disorders. Research methods and materials: article is based on the publications review concerning fatty liver degeneration in cardiovascular diseases. Research objectives: to identify the course, etiology, and clinical picture of metabolic and immune changes in fatty liver degeneration. Research results: pathogenic factors associated with fatty liver disease are multifactorial and include inflammation, adipokines, intestinal dysbiosis, oxidative stress, which are established signs of cardiovascular disease. Conclusions: The accumulation of fat in the liver may be associated with ectopic adipose tissue, including myocardial fat and adipose tissue surrounding the heart, which is a central aspect.

Perturbed NK Cell Homeostasis Associated with Disease Severity in Chronic Neutropenia

Neutrophils have been suggested to play a critical role in terminal differentiation of NK cells. Whether this is a direct effect or a consequence of global immune changes with effects on NK cell homeostasis remains unknown. Here, we used high-resolution flow- and mass cytometry to examine NK cell repertoires in 64 patients with neutropenia and 27 healthy age- and gender-matched donors. A subgroup of patients with chronic neutropenia showed severely disrupted NK cell homeostasis manifested as increased frequencies of CD56bright NK cells and a lack of mature CD56dim NK cells. These immature NK cell repertoires were characterized by expression of proliferation/exhaustion markers Ki-67, Tim-3 and TIGIT and displayed blunted tumor target cell responses. Systems-level immune mapping revealed that the changes in immunophenotypes were confined to NK cells, leaving T cell differentiation intact. RNA sequencing of NK cells from these patients showed upregulation of a network of genes, including TNFSF9, CENPF, MKI67 and TOP2A, associated with apoptosis and the cell cycle, different from conventional CD56bright signatures. Profiling of 249 plasma proteins showed a coordinated enrichment of pathways related to apoptosis and cell turnover, which correlated with immature NK cell repertoires. Notably, most of these patients exhibited severe-grade neutropenia, suggesting that the profoundly altered NK cell homeostasis was connected to the severity of their underlying etiology. Hence, although our data suggests that neutrophils are dispensable for NK cell development and differentiation, some patients displayed a specific gap in the NK repertoire, associated with poor cytotoxic function and more severe disease manifestations.

Sustained peripheral immune hyper-reactivity (SPIHR): an enduring biomarker of altered inflammatory responses in adult rats after perinatal brain injury

Background Chorioamnionitis (CHORIO) is a principal risk factor for preterm birth and is the most common pathological abnormality found in the placentae of preterm infants. CHORIO has a multitude of effects on the maternal–placental–fetal axis including profound inflammation. Cumulatively, these changes trigger injury in the developing immune and central nervous systems, thereby increasing susceptibility to chronic sequelae later in life. Despite this and reports of neural–immune changes in children with cerebral palsy, the extent and chronicity of the peripheral immune and neuroinflammatory changes secondary to CHORIO has not been fully characterized. Methods We examined the persistence and time course of peripheral immune hyper-reactivity in an established and translational model of perinatal brain injury (PBI) secondary to CHORIO. Pregnant Sprague–Dawley rats underwent laparotomy on embryonic day 18 (E18, preterm equivalent). Uterine arteries were occluded for 60 min, followed by intra-amniotic injection of lipopolysaccharide (LPS). Serum and peripheral blood mononuclear cells (PBMCs) were collected at young adult (postnatal day P60) and middle-aged equivalents (P120). Serum and PBMCs secretome chemokines and cytokines were assayed using multiplex electrochemiluminescent immunoassay. Multiparameter flow cytometry was performed to interrogate immune cell populations. Results Serum levels of interleukin-1β (IL-1β), IL-5, IL-6, C–X–C Motif Chemokine Ligand 1 (CXCL1), tumor necrosis factor-α (TNF-α), and C–C motif chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) were significantly higher in CHORIO animals compared to sham controls at P60. Notably, CHORIO PBMCs were primed. Specifically, they were hyper-reactive and secreted more inflammatory mediators both at baseline and when stimulated in vitro. While serum levels of cytokines normalized by P120, PBMCs remained primed, and hyper-reactive with a robust pro-inflammatory secretome concomitant with a persistent change in multiple T cell populations in CHORIO animals. Conclusions The data indicate that an in utero inflammatory insult leads to neural–immune changes that persist through adulthood, thereby conferring vulnerability to brain and immune system injury throughout the lifespan. This unique molecular and cellular immune signature including sustained peripheral immune hyper-reactivity (SPIHR) and immune cell priming may be a viable biomarker of altered inflammatory responses following in utero insults and advances our understanding of the neuroinflammatory cascade that leads to perinatal brain injury and later neurodevelopmental disorders, including cerebral palsy.