1.
Upregulated microRNAs in membranous glomerulonephropathy are associated with significant downregulation of IL6 and MYC mRNAs.
Barbagallo, C, Passanisi, R, Mirabella, F, Cirnigliaro, M, Costanzo, A, Lauretta, G, Barbagallo, D, Bianchi, C, Pagni, F, Castorina, S, et al
Journal of cellular physiology. 2019;(8):12625-12636
Abstract
Membranous glomerulonephropathy (MGN) is a glomerulopathy characterized by subepithelial deposits of immune complexes on the extracapillary side of the glomerular basement membrane. Insertion of C5b-9 (complement membrane-attack complex) into the membrane leads to functional impairment of the glomerular capillary wall. Knowledge of the molecular pathogenesis of MGN is actually scanty. MicroRNA (miRNA) profiling in MGN and unaffected tissues was performed by TaqMan Low-Density Arrays. Expression of miRNAs and miRNA targets was evaluated in Real-Time polymerase chain reaction (PCR). In vitro transient silencing of miRNAs was achieved through transfection with miRNA inhibitors. Ten miRNAs (let-7a-5p, let-7b-5p, let-7c-5p, let-7d-5p, miR-107, miR-129-3p, miR-423-5p, miR-516-3p, miR-532-3p, and miR-1275) were differentially expressed (DE) in MGN biopsies compared to unaffected controls. Interleukin 6 (IL6) and MYC messenger RNAs (mRNAs; targets of DE miRNAs) were significantly downregulated in biopsies from MGN patients, and upregulated in A498 cells following let-7a-5p or let-7c-5p transient silencing. Gene ontology analysis showed that DE miRNAs regulate pathways associated with MGN pathogenesis, including cell cycle, proliferation, and apoptosis. A significant correlation between DE miRNAs and mRNAs and clinical parameters (i.e., antiphospholipid antibodies, serum creatinine, estimated glomerular filtration, proteinuria, and serum cholesterol) has been detected. Based on our data, we propose that DE miRNAs and their downstream network may be involved in MGN pathogenesis and could be considered as potential diagnostic biomarkers of MGN.
2.
Synchronizing transcriptional control of T cell metabolism and function.
Man, K, Kallies, A
Nature reviews. Immunology. 2015;(9):574-84
Abstract
During an immune response, cytokines and transcription factors regulate the differentiation and function of effector and memory T cells. At the same time, T cell metabolism undergoes dynamic and differentiation-stage-specific changes that are required for initial T cell activation, rapid proliferation and the acquisition of effector functions. Similarly, during the resolution of an immune response, metabolic regulation is crucial for restraining inflammatory responses and promoting peripheral tolerance, and it is required for the long-term maintenance of memory T cells. T cell receptor (TCR)-induced transcription factors, in particular MYC and interferon-regulatory factor 4 (IRF4), cooperate with canonical nutrient-sensing pathways to integrate antigen-specific and metabolic signals to appropriately modulate adaptive immune responses. In this Review, we focus on the emerging evidence that T cell differentiation and metabolism are closely linked and synchronized by immune cell-specific cytokines and transcription factors that are induced by TCR signalling.
3.
Serum indoleamine 2,3-dioxygenase activity is associated with reduced immunogenicity following vaccination with MVA85A.
Tanner, R, Kakalacheva, K, Miller, E, Pathan, AA, Chalk, R, Sander, CR, Scriba, T, Tameris, M, Hawkridge, T, Mahomed, H, et al
BMC infectious diseases. 2014;:660
Abstract
BACKGROUND There is an urgent need for improved vaccines to protect against tuberculosis. The currently available vaccine Bacille Calmette-Guerin (BCG) has varying immunogenicity and efficacy across different populations for reasons not clearly understood. MVA85A is a modified vaccinia virus expressing antigen 85A from Mycobacterium tuberculosis which has been in clinical development since 2002 as a candidate vaccine to boost BCG-induced protection. A recent efficacy trial in South African infants failed to demonstrate enhancement of protection over BCG alone. The immunogenicity was lower than that seen in UK trials. The enzyme Indoleamine 2,3-dioxygenase (IDO) catalyses the first and rate-limiting step in the breakdown of the essential amino acid tryptophan. T cells are dependent on tryptophan and IDO activity suppresses T-cell proliferation and function. METHODS Using samples collected during phase I trials with MVA85A across the UK and South Africa we have investigated the relationship between vaccine immunogenicity and IDO using IFN-γ ELISPOT, qPCR and liquid chromatography mass spectrometry. RESULTS We demonstrate an IFN-γ dependent increase in IDO mRNA expression in peripheral blood mononuclear cells (PBMC) following MVA85A vaccination in UK subjects. IDO mRNA correlates positively with the IFN-γ ELISPOT response indicating that vaccine specific induction of IDO in PBMC is unlikely to limit the development of vaccine specific immunity. IDO activity in the serum of volunteers from the UK and South Africa was also assessed. There was no change in serum IDO activity following MVA85A vaccination. However, we observed higher baseline IDO activity in South African volunteers when compared to UK volunteers. In both UK and South African serum samples, baseline IDO activity negatively correlated with vaccine-specific IFN-γ responses, suggesting that IDO activity may impair the generation of a CD4+ T cell memory response. CONCLUSIONS Baseline IDO activity was higher in South African volunteers when compared to UK volunteers, which may represent a potential mechanism for the observed variation in vaccine immunogenicity in South African and UK populations and may have important implications for future vaccination strategies. TRIAL REGISTRATION Trials are registered at ClinicalTrials.gov; UK cohort NCT00427830, UK LTBI cohort NCT00456183, South African cohort NCT00460590, South African LTBI cohort NCT00480558.
4.
Inadequate protein intake affects skeletal muscle transcript profiles in older humans.
Thalacker-Mercer, AE, Fleet, JC, Craig, BA, Carnell, NS, Campbell, WW
The American journal of clinical nutrition. 2007;(5):1344-52
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Abstract
BACKGROUND Inadequate dietary protein intake causes adverse changes in the morphology and function of skeletal muscle. These changes may be reflected in early alterations in muscle messenger RNA levels. OBJECTIVE This study assessed whether inadequate protein intake differentially affects skeletal muscle transcript concentrations and expression profiles in older adults. DESIGN Twenty-one older men and women (aged 55-80 y) consumed controlled diets that provided 1.2 g protein x kg(-1) x d(-1) (adequate protein) for 1 wk and then were randomly assigned to consume either 0.5 g protein x kg(-1) x d(-1) [inadequate protein (IP) group; n=11] or 1.2 g protein x kg(-1) x d(-1) (control group; n=10) for a second week. RNA was isolated from fasting-state vastus lateralis biopsy samples obtained at the end of each period, and transcript levels in the IP group were measured by using microarray analysis. Changes in selected transcript levels were confirmed by real-time polymerase chain reaction in both groups. RESULTS Analysis of variance showed 529 differentially expressed transcripts (P<0.05) after inadequate protein intake. Using the false discovery rate (FDR) correction to adjust for multiple comparisons, we observed that 85 transcripts were differentially expressed: 54 were up-regulated and 31 were down-regulated. The differentially expressed transcripts were in functional classes for immune, inflammatory, and stress responses (predominantly up-regulated); contraction, movement, and development (up-regulated); extracellular connective tissue (up-regulated); energy metabolism (down-regulated); protein synthesis (down-regulated); and proliferation (down-regulated). Diet-related differences in the expression of 9 transcripts were cross-validated by using real-time polymerase chain reaction. CONCLUSION The results document changes in skeletal muscle transcript levels induced by short-term inadequate protein intakes in older humans that might precede adverse metabolic, functional, and structural events, including muscle wasting.