Dysregulated Inflammatory Response Research Articles

Activation of cytokine responses by Candida africana

Candida africana is a fungal pathogen that rarely causes invasive infections, but is mainly isolated from patients with vaginal infections. Vulvovaginal candidiasis is associated with dysregulated inflammatory responses of the host, however, the innate immune responses against C. africana are currently unknown. In this study, we explored the cytokine production of human peripheral blood mononuclear cells (PBMCs) in response to different C. africana isolates (intra-species diversity), and compared it with that induced by other yeasts belonging to the C. albicans species complex such as C. dubliniensis and C. albicans. Candida africana isolates induced both pro- and anti-inflammatory cytokines broadly similar to other Candida species. Candida africana-stimulated PBMCs tended to produce lower Interleukin (IL)-17 and IL-22 levels in comparison with C. albicans, whereas the induction of trained immunity was similar between C. africana and other Candida species. Overall, our results demonstrate that C. africana induces similar innate immune responses as the other Candida species. Therefore, its propensity to cause vulvovaginal infections is not due to an increased capacity to induce cytokine-related immune pathology. Nor is the infrequent occurrence of invasive infection by C. africana explained by a quantitatively different cytokine induction.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS SECONDARY TO DISSEMINATED HISTOPLASMOSIS PRESENTING AS DIFFUSE ALVEOLAR HEMORRHAGE IN A 32-YEAR-OLD WOMAN

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS SECONDARY TO DISSEMINATED HISTOPLASMOSIS PRESENTING AS DIFFUSE ALVEOLAR HEMORRHAGE IN A 32-YEAR-OLD WOMAN

A CASE OF COMMON VARIABLE IMMUNODEFICIENCY (CVID) COMPLICATED BY GRANULOMATOUS LYMPHOCYTIC INTERSTITIAL LUNG DISEASE (GLILD) TRIGGERED BY RECENT COVID-19 INFECTION

A CASE OF COMMON VARIABLE IMMUNODEFICIENCY (CVID) COMPLICATED BY GRANULOMATOUS LYMPHOCYTIC INTERSTITIAL LUNG DISEASE (GLILD) TRIGGERED BY RECENT COVID-19 INFECTION

S3313 Acute Sickle Intrahepatic Cholestasis From Sickle Cell SC Disease Causing Acute on Chronic Liver Failure

Introduction: Acute on Chronic Liver Failure (ACLF) is a disorder that results in grave systemic consequences. The dysregulated inflammatory response caused by an acute liver injury often results in multi-organ dysfunction. And while alcoholic/viral hepatitis or infections are common causes of ACLF, hematologic disorders are unusual. We present a case of ACLF due to sickle cell intrahepatic cholestasis from SC disease. Case Description/Methods: A 61-year-old man with history of HTN, sickle-cell trait, alcoholic cirrhosis presented for altered mental status. Initial labs showed TBili 30.7, DBili >20.0, AST/ALT 308/123, ALP 532 and INR 1.6. Phosphatidylethanol level negative. No new history of medication/herbal use, new sexual contacts, or drug use. Workup negative for hepatitis A/B/C/E. ANA negative, ASMA 26.7, IgG 2742. MRI Abdomen showed no liver mass with patent hepatic vasculature/biliary tree. LDH 531, Haptoglobin < 10, reticulocyte count 11.2, and Coombs test was positive. Hb electrophoresis showed 44.4% Hb C and 49.5% Hb S, consistent with SC disease. Hb was 8.5 (baseline), with no known crises since youth. Liver biopsy findings were consistent with sickle cell hepatopathy (sinusoidal dilation and congestion of sickled cells, ballooning degeneration of hepatocytes, and marked intracanalicular cholestasis). Patient had exchange blood transfusion (EBT) with improvement in Hb to 11.8 and decrease in retic count, LDH. Patient however continued to deteriorate, with increasing aminotransferases into thousands, worsening mental status, AKI, and coagulopathy. Patient made hospice care and eventually expired. Discussion: Hemoglobin SC (HbSC) disease is a less common form of sickle cell disease (SCD). Patients with HbSC disease have milder symptoms than SCD but more severe than sickle cell trait. Acute sickle hepatic crisis occurs in 10% of patients with SCD. Acute sickle intrahepatic cholestasis is the most severe form of sickle hepatopathy, associated with increased mortality. It is usually seen in SCD, but rarely in HbSC. Clinical presentation is more severe, with significant hyperbilirubinemia >15 mg/dL and aminotransferase elevations >1000 IU/L, reflecting ischemic injury. ALF/ACLF can evolve rapidly with multi-organ failure. EBT is considered in these situations. Non-responders have poor prognosis. Clinicians should be aware of the liver complications that can arise in patients with sickle cell-related disorders, including HbSC, particularly in patients with chronic liver disease.

KETONE ESTER THERAPY REDUCES CARDIAC INFLAMMATION AND CARDIAC DYSFUNCTION IN SEPSIS

Sepsis is the body's reaction to an infection that often causes lasting cardiac damage and multi-organ injury due to a dysregulated inflammatory response. Currently, there are no effective treatments to reduce inflammation during sepsis and assist in preventing the lasting cardiovascular damage. Not only are sepsis outcomes worse for cardiovascular disease patients, but the permanent organ damage to sepsis survivors also makes them more susceptible to diseases such as heart failure. Thus, therapeutic strategies to reduce the inflammatory response in sepsis are needed to mitigate the development of cardiovascular disease and improve the outcomes and quality of life for cardiovascular patients who survive sepsis.

Elevated IL-18 predicts poor prognosis in critically ill COVID-19 patients at a Brazilian hospital in 2020-21.

Background: A dysregulated inflammatory response contributes to decline in patients with COVID-19. This cross-sectional study evaluated biomarkers of unvaccinated patients admitted to the intensive care unit of a hospital in Fortaleza, Brazil. Methods: Twenty cytokines were quantified upon hospital admission; clinical and laboratory data were analyzed, as well as sociodemographic data, to search for an association with clinical outcomes, including fatal (n = 40) or recovered cases (n = 38). Results: Fatal cases exhibited significantly higher levels of IL-18 (p = 0.009); deceased patients were older (p = 0.0001), had a lower number of platelets (p = 0.0063) and higher neutrophil–lymphocyte ratio (p = 0.0230) than those who recovered. Conclusion: These findings indicate that IL-18 is a possible marker to predict poor prognosis in critically ill patients with COVID-19.

Identification of Novel Loci Involved in Adalimumab Response in Crohn's Disease Patients Using Integration of Genome Profiling and Isoform-Level Immune-Cell Deconvoluted Transcriptome Profiling of Colon Tissue.

Crohn’s disease is a consequence of dysregulated inflammatory response to the host’s microbiota. Although anti-TNF treatment improves the quality of the patient’s life, a large proportion of patients lose response to the treatment. The past decade of research has led to a continuum of studies showcasing the heterogeneity of anti-TNF response; thus, the aim of the present study was to dissect transcriptome-wide findings to transcript isoform specific levels and combine the analyses with refined information of immune cell landscapes in colon tissue, and subsequently select promising candidates using gene ontology and genomic integration. We enrolled Slovenian Crohn’s disease patients who were naïve with respect to adalimumab treatment. We performed colon tissue RNA sequencing and peripheral blood mononuclear cell DNA genotyping with a subsequent contemporary integrative approach to combine immune cell deconvoluted isoform transcript specific transcriptome analysis, gene ontology layering and genomic data. We identified nine genes (MACF1, CTSE, HDLBP, HSPA9, HLA-DMB, TAP2, LGMN, ANAPC11, ACP5) with 15 transcripts and 16 variants involved in the adalimumab response. Our study identified loci, some of which were previously shown to contribute to inflammatory bowel disease susceptibility, as novel loci involved in adalimumab response in Crohn’s disease patients.

Ambulatory Arterial Stiffness, Salivary Inflammation, And Physical Activity In Young Adults With And Without Covid-19

COVID-19 illness may cause a dysregulated systemic inflammatory response, leading to cardiovascular damage and an increased risk for cardiovascular disease (CVD). Physical activity (PA) is inversely associated with systemic inflammation and CVD risk and may be a cardioprotective lifestyle factor for individuals recovering from COVID-19. PURPOSE: 1) To compare CVD risk, assessed as arterial stiffness and systemic inflammatory levels, between young adults recovering from COVID-19 and uninfected controls, and 2) to explore PA as a mediator for the relationship of COVID-19 infection history with arterial stiffness and systemic inflammation. METHODS: Analyses were performed on 23 COVID-19 (15 females, 25.0 ± 8.9 years, 24.1 ± 3.5 kg/m2) and 32 control participants (18 females, 24.4 ± 6.5 years, 25.1 ± 3.5 kg/m2). Arterial stiffness was estimated as pulse wave velocity (PWV) during 24-hour ambulatory blood pressure monitoring with an oscillometric blood pressure device. Systemic inflammation was assessed as salivary C-reactive protein (CRP) levels using the passive drool method. PA was objectively measured via accelerometry and assessed as moderate-to-vigorous PA (MVPA). An independent samples t-test was used to compare measures of arterial stiffness and systemic inflammation between the COVID-19 and control groups. Mediation analysis was used to determine whether there was a significant indirect effect of COVID-19 infection history through MVPA on arterial stiffness and CRP levels. RESULTS: There were no significant differences (p > 0.05) between the SARS-CoV-2 and control groups in PWV (5.0 ± 0.5 m/s vs. 5.1 ± 0.5 m/s) or CRP levels (765.4 ± 672.9 pg/mL vs. 526.3 ± 674.8 pg/mL). Mediation analysis did not reveal a significant indirect effect of COVID-19 infection history through MVPA on arterial stiffness (estimate = 0.02, 95% CI = -0.05 - 0.24) or CRP levels (estimate = 0.03, 95% CI = -0.07 - 0.16). CONCLUSION: These results suggest there are no differences in arterial stiffness and systemic inflammation between young adults recovering from COVID-19 and uninfected controls, and that MVPA may not significantly mediate the relationship for COVID-19 infection history with arterial stiffness and systemic inflammation. Young adults recovering from COVID-19 may not have a heightened CVD risk compared to controls.

Inflammation Controls Susceptibility of Immune-Experienced Mice to Sepsis.

Sepsis, an amplified immune response to systemic infection that leads to life-threatening organ dysfunction, affects >125,000 people/day worldwide with 20% mortality. Modest therapeutic progress for sepsis has been made, in part because of the lack of therapeutic translatability between mouse-based experimental models and humans. One potential reason for this difference stems from the extensive use of immunologically naive specific pathogen-free mice in preclinical research. To address this issue, we used sequential infections with well-defined BSL-2 pathogens to establish a novel immune-experienced mouse model (specific pathogen experienced [SPexp]) to determine the extent to which immunological experience and/or inflammation influences the host capacity to respond to subsequent infections, including sepsis. Consistent with their immunological experience, SPexp inbred or outbred mice had significant changes in the composition and activation status of multiple leukocyte populations known to influence the severity of cecal ligation and puncture-induced sepsis. Importantly, by varying the timing of sepsis induction, we found the level of basal inflammation controls sepsis-induced morbidity and mortality in SPexp mice. In addition, although a beneficial role of NK cells in sepsis was recently demonstrated in specific pathogen-free mice, NK cell depletion before cecal ligation and puncture induction in SPexp mice lead to diminished mortality, suggesting NK cells may have beneficial or detrimental roles in the response to septic insult dependent on host immune status. Thus, data highlight the importance of utilizing immune-experienced models for preclinical studies to interrogate the cellular/molecular mechanism(s) that could be therapeutically exploited during severe and dysregulated infection-induced inflammatory responses, such as sepsis.

Nicotinamide Mononucleotide Administration Triggers Macrophages Reprogramming and Alleviates Inflammation During Sepsis Induced by Experimental Peritonitis.

Peritonitis and subsequent sepsis lead to high morbidity and mortality in response to uncontrolled systemic inflammation primarily mediated by macrophages. Nicotinamide adenine dinucleotide (NAD+) is an important regulator of oxidative stress and immunoinflammatory responses. However, the effects of NAD+ replenishment during inflammatory activation are still poorly defined. Hence, we investigated whether the administration of β-nicotinamide mononucleotide (β-NMN), a natural biosynthetic precursor of NAD+, could modulate the macrophage phenotype and thereby ameliorate the dysregulated inflammatory response during sepsis. For this purpose, C57BL6 mice were subjected to the cecal ligation and puncture (CLP) model to provoke sepsis or were injected with thioglycolate to induce sterile peritonitis with recruitment and differentiation of macrophages into the inflamed peritoneal cavity. β-NMN was administered for 4 days after CLP and for 3 days post thioglycolate treatment where peritoneal macrophages were subsequently analyzed. In the CLP model, administration of β-NMN decreased bacterial load in blood and reduced clinical signs of distress and mortality during sepsis. These results were supported by transcriptomic analysis of hearts and lungs 24 h post CLP-induction, which revealed that β-NMN downregulated genes controlling the immuno-inflammatory response and upregulated genes involved in bioenergetic metabolism, mitochondria, and autophagy. In the thioglycolate model, a significant increase in the proportion of CD206 macrophages, marker of anti-inflammatory M2 phenotype, was detected on peritoneal exudate macrophages from β-NMN-administered mice. Transcriptomic signature of these macrophages after bacterial stimulation confirmed that β-NMN administration limited the pro-inflammatory M1 phenotype and induced the expression of specific markers of M2 type macrophages. Furthermore, our data show that β-NMN treatment significantly impacts NAD + metabolism. This shift in the macrophage phenotype and metabolism was accompanied by a reduction in phagolysosome acidification and secretion of inflammatory mediators in macrophages from β-NMN-treated mice suggesting a reduced pro-inflammatory activation. In conclusion, administration of β-NMN prevented clinical deterioration and improved survival during sepsis. These effects relied on shifts in the metabolism of organs that face up an increased energy requirement caused by bacterial infection and in innate immunity response, including reprogramming of macrophages from a highly inflammatory phenotype to an anti-inflammatory/pro-resolving profile.

Comprehensive phenotyping of circulating immune cell subsets in people living with HIV

Systemic chronic inflammation and immune dysfunction are recognized as drivers of the development of non-AIDS related comorbidities (NARCs) in people living with HIV (PLHIV). In order to lower the risk of NARCs, it is critical to elucidate what is the contribution of alterations in the composition and function of circulating immune cells to NARCs-related pathogenesis. Findings from previous immunophenotyping studies in PLHIV are highly heterogeneous and it is not fully understood to what extent phenotypic changes on immune cells play a role in the dysregulated inflammatory response observed.In this study, three flow cytometry panels were designed and standardized to phenotypically and functionally identify the main circulating immune cell subsets in PLHIV. To reduce variability, up to 10 markers out of the approximately 20 markers in each panel were used in a custom dry format DURA Innovations (LUCID product line). Intra-assay precision tests performed for the selected cell subsets showed that the three panels had a %CV below 18% for percent of positive cells and the MFI (mean fluorescent intensity) of lineage markers. Our reported pipeline for immunophenotypic analysis facilitated the discrimination of 1153 cell populations, providing an integrated overview of circulating innate and adaptative immune cells as well as the cells’ functional status in terms of activation, exhaustion, and maturation. When combined with unsupervised computational techniques, this standardized immunophenotyping approach may support the discovery of novel phenotypes with clinical relevance in NARCs and demonstrate future utility in other immune-mediated diseases.

The role of synbiotics in improving inflammatory status in nasopharyngeal carcinoma patients.

Nasopharyngeal carcinoma (NPC) is a malignant tumor that grows from the epithelial cells of nasopharynx. NPC has the ability to modify its metabolism and leads thepatient to suffer from malnutrition and cachexia, therefore aggravates the occurrence of impaired inflammatory response. Currently, available treatments for NPC are chemotherapy, radiotherapy, or chemoradiotherapy. Despite of its efficacy, these regimens have been known to elicit various inflammation-related side effects including infection, diarrhea, and mucositis. It has long been established that increased activity of inflammatory response is associated to low survival rate in both early and advanced stage of cancer. Furthermore, uncontrolled and dysregulated inflammatory response are significantly correlated with malignant progression of cancer. Considering how pivotal inflammation to malignancy progression, there is a need for effective strategies to modulate inflammatory response. Various strategies have been proposed to improve immune response in NPC patients including dietary supplementation of synbiotics. Synbiotics refers to the manipulation of both probiotics and prebiotics to provide a synergistic benefit to the host by promoting the growth of beneficial bacteria while inhibiting the growth of pathogenic bacteria. There is a growing number of evidences related to the potential of synbiotics in modulating the pro-inflammatory response and improve immune systems in a variety of conditions, including cancer. In this study, we will discuss the immunomodulatory effects of synbiotics in the nasopharyngeal carcinoma occurrences.

Impact of IL-21-associated peripheral and brain crosstalk on the Alzheimer’s disease neuropathology

Alzheimer’s disease (AD) is associated with dysregulated immune and inflammatory responses. Emerging evidence indicates that peripheral immune activation is linked to neuroinflammation and AD pathogenesis. The present study focuses on determining the role of IL-21 in the pathogenesis of AD using human samples and the 5xFAD mice model. We find that the levels of IL-21 are increased in the periphery of both humans and mice in AD. In addition, the proportions of IL-21 target cells, Tfh and B plasma cells as well as activation of monocytes is increased in PBMCs from AD and mild cognitively impaired (MCI) subjects as compared to age-matched controls, indicating immune activation. In contrast, the percentage of B1 cells that control inflammation is decreased. These changes are due to IL-21 as the expression of IL-21 receptor (IL-21R) is higher on all these cells in AD. Furthermore, treatment with recombinant IL-21 in AD mice also leads to similar alterations in Tfh, B, B1, and macrophages. The effect of IL-21 is not confined to the periphery since increased expression of IL-21R is also observed in both humans and mice hippocampus derived from the AD brains. In addition, mice injected with IL-21 display increased deposition of amyloid beta (Aβ) plaques in the brain which is reduced following anti-IL-21R antibody that blocks the IL-21 signaling. Moreover, activation of microglia was enhanced in IL-21-injected mice. In keeping with enhanced microglial activation, we also observed increased production of pro-inflammatory cytokines, IL-18 and IL-6 in IL-21-injected mice. The microglial activation and cytokines were both inhibited following IL-21R blockage. Altogether, IL-21 escalates AD pathology by enhancing peripheral and brain immune and inflammatory responses leading to increased Aβ plaque deposition.Graphical abstractIL-21 impacts AD neuropathology by enhancing peripheral and neuronal immuneactivation, inflammation, and Aβ plaque deposition. Increased levels of IL-21 in the circulationof AD and MCI subjects enhances the proportions of Tfh and B plasma cells indicative ofperipheral immune activation. On the other hand, the proportions of B1 cells that help reduceinflammation and clear Aβ are reduced. In addition to the periphery, IL-21 also acts on the brainvia IL-21 receptor, IL-21R that displays increased expression in the hippocampi of AD and MCIsubjects. IL-21 enhances the activation of microglia, induces the secretion of pro-inflammatorycytokines and deposition of Aβ plaques in the brain in AD.

IMMUNOLOGICAL RESPONSE TO SARS-COV 2 AND IMMUNOPATHOLOGY OF COVID-19 INFECTION

SARS-CoV-2 is a new beta coronavirus, similar to SARS-CoV-1, that emerged at the end of 2019 in the Hubei province of China. It is responsible for coronavirus disease 2019 (COVID-19), which was declared a pandemic by the World Health Organization on March 11, 2020. The ability to gain quick control of the pandemic has been hampered by a lack of detailed knowledge about SARS-CoV-2-host interactions, mainly in relation to viral biology and host immune response. The rapid clinical course seen in COVID-19 indicates that infection control in asymptomatic patients or patients with mild disease is probably due to the innate immune response, as, considering that SARS -CoV-2 is new to humans, an effective adaptive response would not be expected to occur until approximately 2---3 weeks after contact with the virus. Antiviral innate immunity has humoral components (complement and coagulation -fibrinolysis systems, soluble proteins that recognize glycans on cell surface, interferons, chemokines, and naturally occurring antibodies) and cellular components (natural killer cells and other innate lymphocytes). Failure of this system would pave the way for uncontrolled viral replication in the airways and the mounting of an adaptive immune response, potentially amplified by an inflammatory cascade. Severe COVID-19 appears to be due not only to viral infection but also to a dysregulated immune and inflammatory response. In this paper, the authors review the most recent publications on the immunobiology of SARS-CoV-2, virus interactions with target cells, and host immune responses, and highlight possible associations between deficient innate and acquired immune responses and disease progression and mortality. Immunotherapeutic strategies targeting both the virus and dysfunctional immune responses are also addressed.

Non-Coding RNA Networks as Potential Novel Biomarker and Therapeutic Target for Sepsis and Sepsis-Related Multi-Organ Failure.

According to “Sepsis-3” consensus, sepsis is a life-threatening clinical syndrome caused by a dysregulated inflammatory host response to infection. A rapid identification of sepsis is mandatory, as the extent of the organ damage triggered by both the pathogen itself and the host’s immune response could abruptly evolve to multiple organ failure and ultimately lead to the death of the patient. The most commonly used therapeutic strategy is to provide hemodynamic and global support to the patient and to rapidly initiate broad-spectrum empiric antibiotic therapy. To date, there is no gold standard diagnostic test that can ascertain the diagnosis of sepsis. Therefore, once sepsis is suspected, the presence of organ dysfunction can be assessed using the Sepsis-related Organ Failure Assessment (SOFA) score, although the diagnosis continues to depend primarily on clinical judgment. Clinicians can now rely on several serum biomarkers for the diagnosis of sepsis (e.g., procalcitonin), and promising new biomarkers have been evaluated, e.g., presepsin and adrenomedullin, although their clinical relevance in the hospital setting is still under discussion. Non-codingRNA, including long non-codingRNAs (lncRNAs), circularRNAs (circRNAs) and microRNAs (miRNAs), take part in a complex chain of events playing a pivotal role in several important regulatory processes in humans. In this narrative review we summarize and then analyze the function of circRNAs-miRNA-mRNA networks as putative novel biomarkers and therapeutic targets for sepsis, focusing only on data collected in clinical settings in humans.

Construction of an HLA Classifier for Early Diagnosis, Prognosis, and Recognition of Immunosuppression in Sepsis by Multiple Transcriptome Datasets

Background: Sepsis is a clinical syndrome, due to a dysregulated inflammatory response to infection. Accumulating evidence shows that human leukocyte antigen (HLA) genes play a key role in the immune responses to sepsis. Nevertheless, the effects of HLA genes in sepsis have still not been comprehensively understood. Methods: A systematical search was performed in the Gene Expression Omnibus (GEO) and ArrayExpress databases from inception to 10 September 2021. Random forest (RF) and modified Lasso penalized regression were conducted to identify hub genes in multi-transcriptome data, thus we constructed a prediction model, namely the HLA classifier. ArrayExpress databases, as external validation, were utilized to evaluate its diagnostic, prognostic, and predictive performance. Immune cell infiltration score was calculated via CIBERSORTx tools and single-sample gene set enrichment analysis (ssGSEA). Gene set variation analysis (GSVA) and ssGSEA were conducted to determine the pathways that are significantly enriched in different subgroups. Next, we systematically correlated the HLA classifier with immunological characteristics from multiple perspectives, such as immune-related cell infiltration, pivotal molecular pathways, and cytokine expression. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to validate the expression level of HLA genes in clinical samples. Results: A total of nine datasets comprising 1,251 patients were included. Based on RF and modified Lasso penalized regression in multi-transcriptome datasets, five HLA genes (B2M, HLA-DQA1, HLA-DPA1, TAP1, and TAP2) were identified as hub genes, which were used to construct an HLA classifier. In the discovery cohort, the HLA classifier exhibited superior diagnostic value (AUC = 0.997) and performed better in predicting mortality (AUC = 0.716) than clinical characteristics or endotypes. Encouragingly, similar results were observed in the ArrayExpress databases. In the E-MTAB-7581 dataset, the use of hydrocortisone in the HLA high-risk subgroup (OR: 2.84, 95% CI 1.07–7.57, p = 0.037) was associated with increased risk of mortality, but not in the HLA low-risk subgroup. Additionally, immune infiltration analysis by CIBERSORTx and ssGSEA revealed that B cells, activated dendritic cells, NK cells, T helper cells, and infiltrating lymphocytes (ILs) were significantly richer in HLA low-risk phenotypes, while Tregs and myeloid-derived suppressor cells (MDSCs) were more abundant in HLA high-risk phenotypes. The HLA classifier was significantly negatively correlated with B cells, activated dendritic cells, NK cells, T helper cells, and ILs, yet was significantly positively correlated with Tregs and MDSCs. Subsequently, molecular pathways analysis uncovered that cytokine-cytokine receptor (CCR) interaction, human leukocyte antigen (HLA), and antigen-presenting cell (APC) co-stimulation were significantly enriched in HLA low-risk endotypes, which was significantly negatively correlated with the HLA classifier in multi-transcriptome data. Finally, the expression levels of several cytokines (IL-10, IFNG, TNF) were significantly different between the HLA subgroups, and the ratio of IL-10/TNF was significantly positively correlated with HLA score in multi-transcriptome data. Results of qRT-PCR validated the higher expression level of B2M as well as lower expression level of HLA-DQA1, HLA-DPA1, TAP1, and TAP2 in sepsis samples compared to control sample. Conclusion: Based on five HLA genes, a diagnostic and prognostic model, namely the HLA classifier, was established, which is closely correlated with responses to hydrocortisone and immunosuppression status and might facilitate personalized counseling for specific therapy.

Biomarker combinations in predicting sepsis in hospitalized children with fever

Sepsis is among the leading causes of critical illness worldwide. It includes physiologic, pathologic, and biochemical abnormalities, induced by infection. Novel methods for recognizing a dysregulated inflammatory response and predicting associated mortality must be developed. Our aim was to investigate biomarkers that characterize a pro-inflammatory and anti-inflammatory response in patients with fever by comparing predictive validity for sepsis. 165 patients with fever were enrolled in this study, 55 of them had sepsis according to pSOFA criteria. All patients had blood samples drawn at the time of inclusion and after 24 h. CRP, PCT and also IL-6, IL-8 and sFAS levels were significantly higher in patients with sepsis. The AUC of CRP to predict sepsis was 0.799, all the other biomarkers had AUC’s lower than that. Cytokines, when used as a single marker, did not show a significant diagnostic performance We analyzed various models of biomarker combinations. CRP combined with sFAS showed increase in sensitivity in predicting sepsis (88% vs. 83%). The highest AUC was achieved, when CRP, IL-6, sFAS and sVCAM-1 markers were combined 0.830 (95% CI 0.762–0.884) with a sensitivity of 70% and specificity of 84%. vs. 0.799 for CRP alone.

Rediscovering the Therapeutic Potential of Agarwood in the Management of Chronic Inflammatory Diseases.

The inflammatory response is a central aspect of the human immune system that acts as a defense mechanism to protect the body against infections and injuries. A dysregulated inflammatory response is a major health concern, as it can disrupt homeostasis and lead to a plethora of chronic inflammatory conditions. These chronic inflammatory diseases are one of the major causes of morbidity and mortality worldwide and the need for them to be managed in the long term has become a crucial task to alleviate symptoms and improve patients’ overall quality of life. Although various synthetic anti-inflammatory agents have been developed to date, these medications are associated with several adverse effects that have led to poor therapeutic outcomes. The hunt for novel alternatives to modulate underlying chronic inflammatory processes has unveiled nature to be a plentiful source. One such example is agarwood, which is a valuable resinous wood from the trees of Aquilaria spp. Agarwood has been widely utilized for medicinal purposes since ancient times due to its ability to relieve pain, asthmatic symptoms, and arrest vomiting. In terms of inflammation, the major constituent of agarwood, agarwood oil, has been shown to possess multiple bioactive compounds that can regulate molecular mechanisms of chronic inflammation, thereby producing a multitude of pharmacological functions for treating various inflammatory disorders. As such, agarwood oil presents great potential to be developed as a novel anti-inflammatory therapeutic to overcome the drawbacks of existing therapies and improve treatment outcomes. In this review, we have summarized the current literature on agarwood and its bioactive components and have highlighted the potential roles of agarwood oil in treating various chronic inflammatory diseases.

Vitamin D-induced LL-37 modulates innate immune responses of human primary macrophages during DENV-2 infection.

Epidemics of dengue, an acute and potentially severe disease caused by mosquito-borne dengue virus (DENV), pose a major challenge to clinicians and health care services across the sub(tropics). Severe disease onset is associated with a dysregulated inflammatory response to the virus, and there are currently no drugs to alleviate disease symptoms. LL-37 is a potent antimicrobial peptide with a wide range of immunoregulatory properties. In this study, we assessed the effect of LL-37 on DENV-2-induced responses in human monocyte-derived macrophages (MDMs). We show that simultaneous exposure of exogenous LL-37 and DENV-2 resulted in reduced replication of the virus in MDMs, while the addition of LL-37 postexposure to DENV-2 did not. Interestingly, the latter condition reduced the production of IL-6 and increased the expression of genes involved in virus sensing and antiviral response. Finally, we demonstrate that low endogenous levels and limited production of LL-37 in MDMs in response to DENV-2 infection can be increased by differentiating MDMs in the presence of Vitamin D (VitD3). Taken together, this study demonstrates that in addition to its antimicrobial properties, LL-37 has immunomodulatory properties in the curse of DENV infection and its production can be increased by VitD3.

Ketone Therapy Reduces Systemic and Organ Inflammation in Sepsis

IntroductionSepsis is the body's reaction to an infection that often causes lasting multi‐organ injury due to a dysregulated inflammatory response. Currently, there are no effective treatments to reduce inflammation during sepsis and assist in preventing the lasting inflammation‐mediated damage and thus, sepsis accounts for approximately 20% of all global causes of death. In addition, many patients who recover from sepsis have permanent damage to many organ systems which makes them more susceptible to future injury that likely affects them more severely. Thus, therapeutic strategies to reduce the inflammatory response in sepsis are needed to save lives and improve the outcomes and quality of life of those who survive sepsis. Herein, we tested the efficacy of a ketone therapy that increases circulating ketones via ketone ester supplementation. Ketones are small molecules that are normally produced by the liver and are elevated during carbohydrate‐deprived states, such as fasting or exercise. While ketones are classically known to be a metabolic source of energy, they also have non‐metabolic effects, such as inhibiting inflammation, which can be of therapeutic importance. We hypothesized that ketones have potent anti‐inflammatory effects in a mouse model of lipopolysaccharide (LPS)‐induced sepsis and that ketones can be used to mitigate the inflammation‐mediated organ damage.ObjectiveTo determine if ketone supplementation can effectively reduce inflammation and organ dysfunction/damage in a model of LPS‐induced sepsis.Methods8‐week‐old mice orally received either vehicle or a clinically tested ketone ester (KE) for 3 days. On day 3, mice were injected with saline or LPS to induce systemic inflammation and organ damage. 24 hours post‐injection, cardiac function was assessed and then mice were euthanized to assess systemic and organ inflammation from the 3 groups (control, LPS, LPS+KE).ResultsLPS‐treated mice had higher blood ketones compared to controls, suggesting that ketones may be important as an innate defense mechanism, and this response was further augmented in KE‐treated septic mice. While LPS‐treated mice had an induction of systemic pro‐inflammatory cytokines (e.g., IL‐1β, IL‐6, interferon‐γ) these cytokines were significantly lower in KE‐treated septic mice. Similarly, LPS induced numerous inflammatory markers in the heart, kidney, and liver, a large majority of which were reduced in the KE‐treated septic mice. LPS‐induced cardiac dysfunction and renal fibrosis was also significantly lower in KE‐treated septic mice. Finally, there was either no change or a reduction of ketolytic enzymes in various organs, suggesting that these protective and anti‐inflammatory effects do not depend on ketone metabolism for energy production.ConclusionTogether, these data are the first to show that ketone therapy may be a novel approach to reducing systemic and organ inflammation and dysfunction, and subsequent organ damage in a model of LPS‐induced sepsis.