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Vitamin D attenuates COVID-19 complications via modulation of proinflammatory cytokines, antiviral proteins, and autophagy.
Gilani, SJ, Bin-Jumah, MN, Nadeem, MS, Kazmi, I
Expert review of anti-infective therapy. 2022;(2):231-241
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INTRODUCTION Global emergence of coronavirus disease-19 (COVID-19) has clearly shown variable severity, mortality, and frequency between and within populations worldwide. These striking differences have made many biological variables attractive for future investigations. One of these variables, vitamin D, has been implicated in COVID-19 with rapidly growing scientific evidence. AREAS COVERED The review intended to systematically explore the sources, and immunomodulatory role of vitamin D in COVID-19. Search engines and data sources including Google Scholar, PubMed, NCBI, Scopus, and Web of Science were used for data collection. The search terms used were Vitamin D, COVID-19, immune system, and antiviral mechanism. Overall, 232 sources of information were collected and 188 were included in this review. EXPERT OPINION Interaction of vitamin D and vitamin D receptor (VDR) triggers the cellular events to modulate the immune system by regulation of many genes. Vitamin D operates as a double-edged sword against COVID-19. First, in macrophages, it promotes the production of antimicrobial and antiviral proteins like β-defensin 2 and cathelicidin, and these proteins inhibit the replication of viral particles and promote the clearance of virus from the cells by autophagy. Second, it suppresses cytokine storm and inflammatory processes in COVID-19.
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A Review of Alpha-1 Antitrypsin Binding Partners for Immune Regulation and Potential Therapeutic Application.
O'Brien, ME, Murray, G, Gogoi, D, Yusuf, A, McCarthy, C, Wormald, MR, Casey, M, Gabillard-Lefort, C, McElvaney, NG, Reeves, EP
International journal of molecular sciences. 2022;(5)
Abstract
Alpha-1 antitrypsin (AAT) is the canonical serine protease inhibitor of neutrophil-derived proteases and can modulate innate immune mechanisms through its anti-inflammatory activities mediated by a broad spectrum of protein, cytokine, and cell surface interactions. AAT contains a reactive methionine residue that is critical for its protease-specific binding capacity, whereby AAT entraps the protease on cleavage of its reactive centre loop, neutralises its activity by key changes in its tertiary structure, and permits removal of the AAT-protease complex from the circulation. Recently, however, the immunomodulatory role of AAT has come increasingly to the fore with several prominent studies focused on lipid or protein-protein interactions that are predominantly mediated through electrostatic, glycan, or hydrophobic potential binding sites. The aim of this review was to investigate the spectrum of AAT molecular interactions, with newer studies supporting a potential therapeutic paradigm for AAT augmentation therapy in disorders in which a chronic immune response is strongly linked.
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Predicting neurological recovery after traumatic spinal cord injury by time-resolved analysis of monocyte subsets.
Heller, RA, Seelig, J, Crowell, HL, Pilz, M, Haubruck, P, Sun, Q, Schomburg, L, Daniel, V, Moghaddam, A, Biglari, B
Brain : a journal of neurology. 2021;(10):3159-3174
Abstract
Monocytes and lymphocytes elicit crucial activities for the regenerative processes after various types of injury. The survival of neurons exposed to mechanical and oxidative stress after traumatic spinal cord injury depends on a multitude of factors. In this study, we sought to evaluate a correlation between remission after traumatic spinal cord injury and the dynamics of monocyte subsets in respect to the lymphocytes' responsive potential, cytokine expression, patterns of trace element concentration and clinical covariates. We examined prospectively 18 (three female, 15 male) patients after traumatic spinal cord injury. Blood samples were drawn at admission and 4 h, 9 h, 12 h, 1 and 3 days as well as 1 and 2 weeks and 1, 2 and 3 months after the trauma. Analysis of cytokines (CCL2, IL-10, enolase 2, CXCL12, TGF-β1, TGF-β2) was performed using a multiplex cytokine panel. Plasma trace element concentrations of selenium, copper and zinc were determined by total reflection X-ray fluorescence analysis; neopterin, selenoprotein P (SELENOP) and ceruloplasmin (CP) by enzyme-linked immunosorbent assay; and selenium binding protein 1 (SELENBP1) by luminometric immunoassay. The responsive potential of lymphocytes was assessed using transformation tests. The monocyte subsets (classical, intermediate, and non-classical) and expression of CD14, CD16, CXCR4 and intracellular IL-10 were identified using a multi-colour flow cytometry analysis. The dynamics of the cluster of intermediate CD14-/CD16+/IL10+/CXCR4int monocytes differed significantly between patients with an absence of neurological remission (G0) from those with an improvement (G1) by 1 or 2 American Spinal Injury Association Impairment Scale (AIS) steps (Kruskal-Wallis Test, P = 0.010, G0 < G1, AIS+: 1 < G1, AIS+: 2) in the first 24 h. These dynamics were associated inversely with an increase in enolase and SELENBP1 14 days after the injury. In the elastic net regularized model, we identified an association between the increase of a subpopulation of intermediate CD14-/CD16+/IL10+/CXCR4int monocytes and exacerbated immune response within 24 h after the injury. These findings were reflected in the consistently elevated response to mitogen stimulation of the lymphocytes of patients with significant neurological remission. Early elevated concentrations of CD14-/CD16+/IL10+/CXCR4int monocytes were related to higher odds of CNS regeneration and enhanced neurological remission. The cluster dynamics of CD14-/CD16+/IL10+/CXCR4int monocytes in the early-acute phase after the injury revealed a maximum of prognostic information regarding neurological remission (mean parameter estimate: 0.207; selection count: 818/1000 repetitions). We conclude that early dynamics in monocyte subsets allow a good prediction of recovery from traumatic spinal cord injury.
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Acute FPIES reactions are associated with an IL-17 inflammatory signature.
Berin, MC, Lozano-Ojalvo, D, Agashe, C, Baker, MG, Bird, JA, Nowak-Wegrzyn, A
The Journal of allergy and clinical immunology. 2021;(3):895-901.e6
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BACKGROUND Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by profuse vomiting within hours of ingestion of the causative food. We have previously reported that FPIES is associated with systemic innate immune activation in the absence of a detectable antigen-specific antibody or T-cell response. The mechanism of specific food recognition by the immune system remains unclear. OBJECTIVE Our aim was to identify immune mechanisms underlying FPIES reactions by proteomic and flow cytometric analysis of peripheral blood. METHODS Children with a history of FPIES underwent supervised oral food challenge. Blood samples were taken at baseline, at symptom onset, and 4 hours after symptom onset. We analyzed samples from 23 children (11 reactors and 12 outgrown). A total of 184 protein markers were analyzed by proximity ligation assay and verified by multiplex immunoassay. Analysis of cell subset activation was performed by mass cytometry and spectral cytometry. RESULTS Symptomatic FPIES challenge results were associated with significant elevation of levels of cytokines and chemokines, including IL-17 family markers (IL-17A, IL-22, IL-17C, and CCL20) and T-cell activation (IL-2), and innate inflammatory markers (IL-8, oncostatin M, leukemia inhibitory factor, TNF-α, IL-10, and IL-6). The level of the mucosal damage marker regenerating family member 1 alpha (REG1A) was also significantly increased. These biomarkers were not increased in asymptomatic challenges or IgE-mediated allergy. The level of phospho-STAT3 was significantly elevated in myeloid and T cells after challenge in individuals with symptoms. Mass cytometry indicated preferential activation of nonconventional T-cell populations, including γδ T cells and CD3+CD4-CD8-CD161+ cells; however, the potential sources of IL-17 in PBMCs were primarily CD4+ TH17 cells. CONCLUSIONS These results demonstrate a unique IL-17 signature and activation of innate lymphocytes in FPIES.
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Effects of vitamin D supplementation on circulating concentrations of growth factors and immune-mediators in healthy women during pregnancy.
Khatiwada, A, Wolf, BJ, Mulligan, JK, Shary, JR, Hewison, M, Baatz, JE, Newton, DA, Hawrylowicz, C, Hollis, BW, Wagner, CL
Pediatric research. 2021;(3):554-562
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BACKGROUND For the second aim of the Kellogg Foundation grant, this double-blind RCT investigated the impact of plasma vitamin D metabolite 25-hydroxyvitamin D (25(OH)D) on plasma immune-mediators during pregnancy. We hypothesized that higher 25(OH)D concentrations would associate with reduced pro-inflammatory and increased tolerogenic immune-mediator concentrations. METHODS Pregnant women enrolled at 10-14 weeks gestation were randomized to 400 or 4400 IU vitamin D3/day. Data on health, safety, circulating 25(OH)D, and 9 immune-mediators were collected at each trimester. Associations between immune-mediators and 25(OH)D at baseline and at second and third trimesters were examined. RESULTS Baseline TGF-β and second and third trimesters IFN-γ and IL-2 were associated with baseline 25(OH)D. Baseline immune-mediators were associated with immune-mediators at second and third trimesters for all immune-mediators except IL-5 and IL-10. Race was associated with baseline TGF-β, VEGF and IL-10 and with IL-10 at second and third trimesters. CONCLUSIONS Both treatment groups had increased 25(OH)D at second and third trimesters, greatest in the 4400 IU group. Though associations between baseline 25(OH)D and baseline TGF-β and second and third trimester IFN-γ and IL-2 were noted, vitamin D supplementation throughout pregnancy did not impact immune-mediators at later trimesters. Supplementing with vitamin D before conception conceivably influences immune-mediator responses during pregnancy. IMPACT In this vitamin D supplementation clinical trial, baseline (first trimester) but not increasing plasma 25(OH)D concentration impacted select plasma immune-mediator profiles in pregnant women. Baseline 25(OH)D was associated with baseline TGF-β and with IFN-γ and IL-2 at second and third trimesters. Baseline IFN-γ, CRP, TGF-β, TNF-α, VEGF, IL-2, and IL-4 were associated with concentrations at second and third trimesters for respective immune-mediators; however, 25(OH)D concentration at second and third trimesters were not. Some racial differences existed in immune-mediator concentrations at baseline and at second and third trimesters. This study assesses the impact of vitamin D supplementation on multiple immune-mediators in pregnant women of different racial/ethnic groups using longitudinal data from a relatively large randomized controlled trial. This study found that race was associated with baseline TGF-β, VEGF, and IL-10 and with IL-10 at second and third trimesters, a novel finding that sheds light where relationships were less well defined. The results of this study suggest that vitamin D supplementation before conception or early in pregnancy, rather than during pregnancy, may be necessary to significantly impact immune-mediator response. This study sets premise for future clinical trials to evaluate the effect of vitamin D supplementation before conception or prior to pregnancy.
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Effects of 14-weeks betaine supplementation on pro-inflammatory cytokines and hematology status in professional youth soccer players during a competition season: a double blind, randomized, placebo-controlled trial.
Nobari, H, Cholewa, JM, Pérez-Gómez, J, Castillo-Rodríguez, A
Journal of the International Society of Sports Nutrition. 2021;(1):42
Abstract
OBJECTIVE Systemic elevations in pro-inflammatory cytokines are a marker of non-functional over reaching, and betaine has been shown to reduce the secretion of pro-inflammatory cytokines in vitro. The aim of this study was to investigate the effects of betaine supplementation on tumor necrosis factor alpha (TNF-α), interleukins-1 beta (IL-1β), - 6 (IL-6) and the complete blood cell (CBC) count in professional youth soccer players during a competitive season. METHODS Twenty-nine soccer players (age, 15.5 ± 0.3 years) were randomly divided into two groups based on playing position: betaine group (BG, n = 14, 2 g/day) or placebo group (PG, n = 15). During the 14-week period, training load was matched and well-being indicators were monitored daily. The aforementioned cytokines and CBC were assessed at pre- (P1), mid- (P2), and post- (P3) season. RESULTS Significant (p < 0.05) group x time interactions were found for TNF-α, IL-1β, and IL-6. These variables were lower in the BG at P2 and P3 compared to P1, while IL-1β was greater in the PG at P3 compared to P1 (p = 0.033). The CBC count analysis showed there was significant group by time interactions for white blood cells (WBC), red blood cells (RBC), hemoglobin (Hb), and mean corpuscular hemoglobin concentration (MCHC). WBC demonstrated increases at P3 compared to P2 in PG (p = 0.034); RBC was less at P3 compared to P1 in BG (p = 0.020); Hb was greater at P2 compared to P1, whilst it was less at P3 compared to P3 for both groups. MCHC was greater at P3 and P2 compared to P1 in BG, whereas MCHC was significantly lower at P3 compared to P2 in the PG (p = 0.003). CONCLUSION The results confirmed that 14 weeks of betaine supplementation prevented an increase in pro-inflammatory cytokines and WBC counts. It seems that betaine supplementation may be a useful nutritional strategy to regulate the immune response during a fatiguing soccer season.
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Use of Cytokine Mix-, Imiquimod-, and Serum-Induced Monoculture and Lipopolysaccharide- and Interferon Gamma-Treated Co-Culture to Establish In Vitro Psoriasis-like Inflammation Models.
Bocheńska, K, Moskot, M, Gabig-Cimińska, M
Cells. 2021;(11)
Abstract
Psoriasis (Ps), commonly perceived as a skin and joint disorder, has a complex basis and results from disturbances in the sophisticated network between skin and the immune system. This makes it difficult to properly depict the complete pathomechanism on an in vitro scale. Deciphering the complicated or even subtle modulation of intra- and intercellular factors, assisted by the implementation of in vitro human skin models, may provide the opportunity to dissect the disease background step by step. In addition to reconstructed artificial skin substitutes, which mimic the native physiological context, in vitro models are conducive to the broad "3 Rs" philosophy (reduce, refine, and replace) and represent important tools for basic and applied skin research. To meet the need for a more comprehensive in vitro Ps model, a set of various experimental conditions was applied in this study. The selection of in vitro treatment that mimicked the Ps phenotype was illustrated by analyses of discriminating biomarker genes involved in the pathogenesis of the disease, i.e., keratinocyte differentiation markers, antimicrobial peptides, chemokines, and proliferation markers. This resulted in a reproducible protocol for the use of the primary skin keratinocyte (pKC) monoculture treated with a cytokine cocktail (5MIX, i.e., interleukin (IL) 1 alpha (IL-1α), IL-17A, IL-22, oncostatin M (OSM), and tumour necrosis factor alpha (TNF-α)) at a calcium (Ca2+) concentration (i.e., 2 mM) in an applied medium, which best mirrored the in vitro Ps-like inflammatory model. In addition, based on waste skin material, the method has the potential for extensive experimentation, both in detailed molecular studies and preclinical tests.
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Prognostic tools for hypertrophic scar formation based on fundamental differences in systemic immunity.
de Bakker, E, van der Putten, MAM, Heymans, MW, Spiekstra, SW, Waaijman, T, Butzelaar, L, Negenborn, VL, Beekman, VK, Akpinar, EO, Rustemeyer, T, et al
Experimental dermatology. 2021;(1):169-178
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Unpredictable hypertrophic scarring (HS) occurs after approximately 35% of all surgical procedures and causes significant physical and psychological complaints. Parallel to the need to understanding the mechanisms underlying HS formation, a prognostic tool is needed. The objective was to determine whether (systemic) immunological differences exist between patients who develop HS and those who develop normotrophic scars (NS) and to assess whether those differences can be used to identify patients prone to developing HS. A prospective cohort study with NS and HS groups in which (a) cytokine release by peripheral blood mononuclear cells (PBMC) and (b) the irritation threshold (IT) after an irritant (sodium lauryl sulphate) patch test was evaluated. Univariate regression analysis of PBMC cytokine secretion showed that low MCP-1, IL-8, IL-18 and IL-23 levels have a strong correlation with HS (P < .010-0.004; AUC = 0.790-0.883). Notably, combinations of two or three cytokines (TNF-a, MCP-1 and IL-23; AUC: 0.942, Nagelkerke R2 : 0.727) showed an improved AUC indicating a better correlation with HS than single cytokine analysis. These combination models produce good prognostic results over a broad probability range (sensitivity: 93.8%, specificity 86.7%, accuracy 90,25% between probability 0.3 and 0.7). Furthermore, the HS group had a lower IT than the NS group and an accuracy of 68%. In conclusion, very fundamental immunological differences exist between individuals who develop HS and those who do not, whereas the cytokine assay forms the basis of a predictive prognostic test for HS formation, the less invasive, easily performed irritant skin patch test is more accessible for daily practice.
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Prognostic Value of a Combination of Circulating Biomarkers in Critically Ill Patients with Traumatic Brain Injury: Results from the European CREACTIVE Study.
Gradisek, P, Carrara, G, Antiga, L, Bottazzi, B, Chieregato, A, Csomos, A, Fainardi, E, Filekovic, S, Fleming, J, Hadjisavvas, A, et al
Journal of neurotrauma. 2021;(19):2667-2676
Abstract
Individualized patient care is essential to reduce the global burden of traumatic brain injury (TBI). This pilot study focused on TBI patients admitted to intensive care units (ICUs) and aimed at identifying patterns of circulating biomarkers associated with the disability level at 6 months from injury, measured by the extended Glasgow Outcome Scale (GOS-E). The concentration of 107 biomarkers, including proteins related to inflammation, innate immunity, TBI, and central nervous system, were quantified in blood samples collected on ICU admission from 80 patients. Patients were randomly selected among those prospectively enrolled in the Collaborative Research on Acute Traumatic Brain Injury in Intensive Care Medicine in Europe (CREACTIVE) observational study. Six biomarkers were selected to be associated with indicators of primary or secondary brain injury: three glial proteins (glial cell-derived neurotrophic factor, glial fibrillary acidic protein, and S100 calcium-binding protein B) and three cytokines (stem cell factor, fibroblast growth factor [FGF] 23 and FGF19). The subjects were grouped into three clusters according to the expression of these proteins. The distribution of the 6-month GOS-E was significantly different across clusters (p < 0.001). In two clusters, the number of 6-month deaths or vegetative states was significantly lower than expected, as calculated according to a customization of the corticosteroid randomization after significant head injury (CRASH) scores (observed/expected [O/E] events = 0.00, 95% confidence interval [CI]: 0.00-0.90 and 0.00, 95% CI: 0.00-0.94). In one cluster, less-than-expected unfavorable outcomes (O/E = 0.50, 95% CI: 0.05-0.95) and more-than-expected good recoveries (O/E = 1.55, 95% CI: 1.05-2.06) were observed. The improved prognostic accuracy of the pattern of these six circulating biomarkers at ICU admission upon established clinical parameters and computed tomography results needs validation in larger, independent cohorts. Nonetheless, the results of this pilot study are promising and will prompt further research in personalized medicine for TBI patients.
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Cytokine-specific autoantibodies shape the gut microbiome in autoimmune polyendocrine syndrome type 1.
Petersen, AØ, Jokinen, M, Plichta, DR, Liebisch, G, Gronwald, W, Dettmer, K, Oefner, PJ, Vlamakis, H, Chung, DC, Ranki, A, et al
The Journal of allergy and clinical immunology. 2021;(3):876-888
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BACKGROUND Gastrointestinal dysfunction is a frequent and disabling manifestation of autoimmune polyendocrine syndrome type 1 (APS-1), a rare monogenic multiorgan autoimmune disease caused by the loss of central AIRE-controlled immune tolerance. OBJECTIVES This study aimed to understand the role of the gut microbiome in APS-1 symptoms and potentially alleviate common gastrointestinal symptoms by probiotic intervention. METHODS This study characterized the fecal microbiomes of 28 patients with APS-1 and searched for associations with gastrointestinal symptoms, circulating anti-cytokine autoantibodies, and tryptophan-related metabolites. Additionally, daily doses of the probiotic Lactobacillus rhamnosus GG were administered for 3 months. RESULTS Of 581 metagenomic operational taxonomic units (mOTUs) characterized in total, 14 were significantly associated with patients with APS-1 compared with healthy controls, with 6 mOTUs depleted and 8 enriched in patients with APS-1. Four overabundant mOTUs were significantly associated with severity of constipation. Phylogenetically conserved microbial associations with autoantibodies against cytokines were observed. After the 3-month intervention with the probiotic L rhamnosus GG, a subset of gastrointestinal symptoms were alleviated. L rhamnosus GG abundance was increased postintervention and corresponded with decreased abundances of Alistipes onderdonkii and Collinsella aerofaciens, 2 species positively associated with severity of diarrhea in patients with APS-1. CONCLUSIONS The APS-1 microbiome correlates with several APS-1 symptoms, some of which are alleviated after a 3-month L rhamnosus GG intervention. Autoantibodies against cytokines appear to shape the gut microbiome by positively correlating with a taxonomically consistent group of bacteria.