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Introduction: Chronic kidney disease (CKD) may affect the human microbiome via increased concentrations of uremic toxins such as urea and creatinine. Methods: We have profiled the oral microbiota in patients with CKD before and one week after kidney transplantation. Living kidney donors were also longitudinally tracked over a similar period, allowing direct comparison between a group undergoing transplant surgery alone (donors) (n=13) and a group additionally undergoing the introduction of immunosuppressive agents and the resolution of CKD (recipients) (n=45). Results: Transplantation was associated with a similar pattern of decreasing alpha diversity in the oral microbiome in recipients and donors via Kruskal-Wallis testing, within one week of transplantation. Amplicon sequence variants (ASVs) associated with Haemophilus parainfluenzae, Aggregatibacteria segnis, Peptostreptococcus and Actinobacillus were significantly decreased in recipients within a week of transplantation. Discussion: A reduction in ASVs in these genera could influence the risk of bacterial endocarditis, a rare but high-mortality kidney transplantation complication. A range of factors may drive the observed changes in oral microbiome including both factors associated with surgery itself and the decreases in salivary urea, administration of macrolide antibiotic immunosuppressants, and disruption to immune function that characterise kidney transplant. [ABSTRACT FROM AUTHOR]

D-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of D-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of D-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3[sup.+] regulatory T cells (T[sub.reg] cells) in mice. In vitro, D-mannose stimulated T[sub.reg] cell differentiation in human and mouse cells by promoting TGF-[beta] activation, which in turn was mediated by upregulation of integrin [alpha][sub.v][beta][sub.8] and reactive oxygen species generated by increased fatty acid oxidation. This previously unrecognized immunoregulatory function of D-mannose may have clinical applications for immunopathology., Author(s): Dunfang Zhang [1, 2]; Cheryl Chia [1]; Xue Jiao [1, 3]; Wenwen Jin [1]; Shimpei Kasagi [1]; Ruiqing Wu [1, 2]; Joanne E Konkel [1]; Hiroko Nakatsukasa [1]; Peter [...]

Tregs not only keep immune responses to autoantigens in check, but also restrain those directed toward pathogens and the commensal microbiota. Control of peripheral immune homeostasis by Tregs relies on [...]

[CD4.sup.+] T-helper cells that selectively produce interleukin (IL)-17 ([T.sub.H]17), are critical for host defence and autoimmunity (1-4). Although crucial for [T.sub.H]17 cells in vivo (5,6), IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-[β.sub.1] have been proposed to be the factors responsible for initiating specification (7-10). Here we show that [T.sub.H]17 differentiation can occur in the absence of TGF-β signalling. Neither IL-6 nor IL-23 alone efficiently generated [T.sub.H]17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naive precursors, independently of TGF-β. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed RORγt (encoded by Rorc) and T-bet. [T-bet.sup.+] RORy[t.sup.+] [T.sub.H]17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred [T.sub.H]17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data indicate an alternative mode for [T.sub.H]17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications., TGF-βl is important for murine [T.sub.H]17 differentiation (7,8) and accordingly, transgenic expression of a mutant TGF-β subunit receptor II (CD4dnTGF-βRII) in T cells interferes with the generation of [T.sub.H]17 cells [...]

Myeloid upheaval in severe COVID-19: Severe COVID-19 disease is associated with immune hyperactivation accompanied by "cytokine storm." Mann et al. used longitudinal analysis of fresh blood samples from hospitalized COVID-19 patients to search for biomarkers that signal impending progression to severe disease. Several phenotypic and functional abnormalities of CD14+ blood monocytes emerged as early-stage biomarkers predictive of increased severity of disease. Monocytes from patients with severe COVID-19 activated in vitro with lipopolysaccharide displayed increased proliferation and decreased expression of the prostaglandin-synthesizing cyclooxygenase-2 (COX-2) enzyme. Premature release of immature myeloid cells from the bone marrow contributes to innate immune dysfunction, causing more extensive lung damage and poorer clinical outcomes. These findings suggest that early treatment of COVID-19 targeting emergency myelopoiesis may help reduce the risk of subsequent clinical deterioration. COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells of hospitalized patients during the peak of the COVID-19 pandemic in the United Kingdom. Here, we report key immune signatures present shortly after hospital admission that were associated with the severity of COVID-19. Immune signatures were related to shifts in neutrophil to T cell ratio, elevated serum IL-6, MCP-1, and IP-10 and modulation of CD14+ monocyte phenotype and function. Modified features of CD14+ monocytes included poor induction of the prostaglandin-producing enzyme, COX-2, and enhanced expression of the cell cycle marker Ki-67. Longitudinal analysis revealed reversion of some immune features back to the healthy median level in patients with a good eventual outcome. These findings identify previously unappreciated alterations in the innate immune compartment of patients with COVID-19 and lend support to the idea that therapeutic strategies targeting release of myeloid cells from bone marrow should be considered in this disease. Moreover, they demonstrate that features of an exaggerated immune response are present early after hospital admission, suggesting that immunomodulating therapies would be most beneficial at early time points. [ABSTRACT FROM AUTHOR]

Background: Stroke is a major cause of disability and mortality. Poorer outcome after stroke is associated with concomitant inflammatory and infectious disease. Periodontitis is a chronic inflammatory disease of the dental supporting structures and is a prominent risk factor for many systemic disorders, including cardiovascular disease and stroke. While epidemiological studies suggest that periodontitis increases the likelihood of stroke, its impact on stroke severity is poorly understood. Here, we sought to determine the contribution of periodontitis to acute stroke pathology. Methods: We characterized a murine ligature model of periodontitis for inflammatory responses that could potentially impact stroke outcome. We applied this model and then subjected mice to either transient or permanent middle cerebral artery occlusion. We also enhanced the periodontitis model with repeated intravenous administration of a periodontal-specific lipopolysaccharide to better mimic the clinical condition. Results: Ligature-induced periodontitis caused bone loss, bacterial growth, and increased local inflammatory cell trafficking. Systemically, periodontitis increased circulating levels of pro-inflammatory cytokines, and primed bone marrow monocytes to produce elevated tumour necrosis factor-alpha (TNFα). Despite these changes, periodontitis alone or in tandem with repeated lipopolysaccharide challenge did not alter infarct volume, blood–brain barrier breakdown, or systemic inflammation after experimental stroke. Conclusions: Our data show that despite elevated systemic inflammation in periodontitis, oral inflammatory disease does not impact acute stroke pathology in terms of severity, determined primarily by infarct volume. This indicates that, at least in this experimental paradigm, periodontitis alone does not alter acute outcome after cerebral ischemia. [ABSTRACT FROM AUTHOR]