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Background Severe trauma induces a widespread response of the immune system. This 'genomic storm' can lead to poor outcomes, including Multiple Organ Dysfunction Syndrome (MODS). MODS carries a high mortality and morbidity rate and adversely affects long-term health outcomes. Contemporary management of MODS is entirely supportive, and no specific therapeutics have been shown to be effective in reducing incidence or severity. The pathogenesis of MODS remains unclear, and several models are proposed, such as excessive inflammation, a second-hit insult, or an imbalance between pro- and anti-inflammatory pathways. We postulated that the hyperacute window after trauma may hold the key to understanding how the genomic storm is initiated and may lead to a new understanding of the pathogenesis of MODS. Methods and findings We performed whole blood transcriptome and flow cytometry analyses on a total of 70 critically injured patients (Injury Severity Score [ISS] [greater than or equal to] 25) at The Royal London Hospital in the hyperacute time period within 2 hours of injury. We compared transcriptome findings in 36 critically injured patients with those of 6 patients with minor injuries (ISS [less than or equal to] 4). We then performed flow cytometry analyses in 34 critically injured patients and compared findings with those of 9 healthy volunteers. Immediately after injury, only 1,239 gene transcripts (4%) were differentially expressed in critically injured patients. By 24 hours after injury, 6,294 transcripts (21%) were differentially expressed compared to the hyperacute window. Only 202 (16%) genes differentially expressed in the hyperacute window were still expressed in the same direction at 24 hours postinjury. Pathway analysis showed principally up-regulation of pattern recognition and innate inflammatory pathways, with down-regulation of adaptive responses. Immune deconvolution, flow cytometry, and modular analysis suggested a central role for neutrophils and Natural Killer (NK) cells, with underexpression of T- and B cell responses. In the transcriptome cohort, 20 critically injured patients later developed MODS. Compared with the 16 patients who did not develop MODS (NoMODS), maximal differential expression was seen within the hyperacute window. In MODS versus NoMODS, 363 genes were differentially expressed on admission, compared to only 33 at 24 hours postinjury. MODS transcripts differentially expressed in the hyperacute window showed enrichment among diseases and biological functions associated with cell survival and organismal death rather than inflammatory pathways. There was differential up-regulation of NK cell signalling pathways and markers in patients who would later develop MODS, with down-regulation of neutrophil deconvolution markers. This study is limited by its sample size, precluding more detailed analyses of drivers of the hyperacute response and different MODS phenotypes, and requires validation in other critically injured cohorts. Conclusions In this study, we showed how the hyperacute postinjury time window contained a focused, specific signature of the response to critical injury that led to widespread genomic activation. A transcriptomic signature for later development of MODS was present in this hyperacute window; it showed a strong signal for cell death and survival pathways and implicated NK cells and neutrophil populations in this differential response., Author(s): Claudia P. Cabrera 1, Joanna Manson 2, Joanna M. Shepherd 2,*, Hew D. Torrance 3, David Watson 1, M. Paula Longhi 4, Mimoza Hoti 5, Minal B. Patel 1, [...]

Summary: Healthy white adipose tissue (WAT) participates in regulating systemic metabolism, whereas dysfunctional WAT plays a prominent role in the development of obesity‐associated co‐morbidities. Tissue‐resident immune cells are important for maintaining WAT homeostasis, including conventional dendritic cells (cDCs) which are critical in the initiation and regulation of adaptive immune responses. Due to phenotypic overlap with other myeloid cells, the distinct contribution of WAT cDCs has been poorly understood. This review will discuss the contribution of cDCs in the maintenance of WAT homeostasis. In particular, the review will focus on the metabolic cross‐talk between cDCs and adipocytes that regulates local immune responses during physiological conditions. Tissue resident immune cells are important for maintaining white adipose tissue (WAT) homeostasis, including conventional dendritic cells (cDCs) which are critical in the initiation and regulation of adaptive immune responses. We discuss the contribution of cDCs in the maintenance of WAT homeostasis and focus on the metabolic cross‐talk between cDCs and adipocytes that regulates local immune responses during physiological conditions. [ABSTRACT FROM AUTHOR]

Protein-based vaccines offer safety and cost advantages but require adjuvants to induce immunity. Here we examined the adjuvant capacity of glucopyranosyl lipid A (GLA), a new synthetic non-toxic analogue of lipopolysaccharide. In mice, in comparison with non-formulated LPS and monophosphoryl lipid A, formulated GLA induced higher antibody titers and generated Type 1 T-cell responses to HIV gag-p24 protein in spleen and lymph nodes, which was dependent on TLR4 expression. Immunization was greatly improved by targeting HIV gag p24 to DCs with an antibody to DEC-205, a DC receptor for antigen uptake and processing. Subcutaneous immunization induced antigen-specific T-cell responses in the intestinal lamina propria. Immunity did not develop in mice transiently depleted of DCs. To understand how GLA works, we studied DCs directly from vaccinated mice. Within 4 h, GLA caused DCs to upregulate CD86 and CD40 and produce cytokines including IL-12p70 in vivo. Importantly, DCs removed from mice 4 h after vaccination became immunogenic, capable of inducing T-cell immunity upon injection into naïve mice. These data indicate that a synthetic and clinically feasible TLR4 agonist rapidly stimulates full maturation of DCs in vivo, allowing for adaptive immunity to develop many weeks to months later. [ABSTRACT FROM AUTHOR]

Summary: Dendritic cells (DCs), critical antigen-presenting cells for immune control, normally derive from bone marrow precursors distinct from monocytes. It is not yet established if the large reservoir of monocytes can develop into cells with critical features of DCs in vivo. We now show that fully differentiated monocyte-derived DCs (Mo-DCs) develop in mice and DC-SIGN/CD209a marks the cells. Mo-DCs are recruited from blood monocytes into lymph nodes by lipopolysaccharide and live or dead gram-negative bacteria. Mobilization requires TLR4 and its CD14 coreceptor and Trif. When tested for antigen-presenting function, Mo-DCs are as active as classical DCs, including cross-presentation of proteins and live gram-negative bacteria on MHC I in vivo. Fully differentiated Mo-DCs acquire DC morphology and localize to T cell areas via L-selectin and CCR7. Thus the blood monocyte reservoir becomes the dominant presenting cell in response to select microbes, yielding DC-SIGN+ cells with critical functions of DCs. [Copyright &y& Elsevier]

The aetiology of atrial fibrillation (AF) remains poorly understood, despite its growing prevalence and associated morbidity, mortality, and healthcare costs. Obesity is implicated in myriad different disease processes and is now recognized a major risk factor in the pathogenesis of AF. Moreover, the role of distinct adipose tissue depots is a matter of intense scientific interest with the depot directly surrounding the heart-epicardial adipose tissue (EAT) appearing to have the greatest correlation with AF presence and severity. Similarly, inflammation is implicated in the pathophysiology of AF with EAT thought to act as a local depot of inflammatory mediators. These can easily diffuse into atrial tissue with the potential to alter its structural and electrical properties. Various meta-analyses have indicated that EAT size is an independent risk factor for AF with adipose tissue expansion being inevitably associated with a local inflammatory process. Here, we first briefly review adipose tissue anatomy and physiology then move on to the epidemiological data correlating EAT, inflammation, and AF. We focus particularly on discussing the mechanistic basis of how EAT inflammation may precipitate and maintain AF. Finally, we review how EAT can be utilized to help in the clinical management of AF patients and discuss future avenues for research., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)