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- PublicationAlpha-1 antitrypsin augmentation therapy decreases miR-199a-5p, miR-598 and miR-320a expression in monocytes via inhibition of NFκBAlpha-1 antitrypsin (AAT) augmentation therapy involves infusion of plasma-purified AAT to AAT deficient individuals. Whether treatment affects microRNA expression has not been investigated. This study's objectives were to evaluate the effect of AAT augmentation therapy on altered miRNA expression in monocytes and investigate the mechanism. Monocytes were isolated from non-AAT deficient (MM) and AAT deficient (ZZ) individuals, and ZZs receiving AAT. mRNA (qRT-PCR, microarray), miRNA (miRNA profiling, qRT-PCR), and protein (western blotting) analyses were performed. Twenty one miRNAs were differentially expressed 3-fold between ZZs and MMs. miRNA validation studies demonstrated that in ZZ monocytes receiving AAT levels of miR-199a-5p, miR-598 and miR-320a, which are predicted to be regulated by NFκB, were restored to levels similar to MMs. Validated targets co-regulated by these miRNAs were reciprocally increased in ZZs receiving AAT in vivo and in vitro. Expression of these miRNAs could be increased in ZZ monocytes treated ex vivo with an NFκB agonist and decreased by NFκB inhibition. p50 and p65 mRNA and protein were significantly lower in ZZs receiving AAT than untreated ZZs. AAT augmentation therapy inhibits NFκB and decreases miR-199a-5p, miR-598 and miR-320a in ZZ monocytes. These NFκB-inhibitory properties may contribute to the anti-inflammatory effects of AAT augmentation therapy.
261Scopus© Citations 5
- PublicationCytomegalovirus Infection in Ireland: Seroprevalence, HLA Class I Alleles, and ImplicationsCytomegalovirus (CMV) infections occur worldwide and primary infection usually occurs in early childhood and is often asymptomatic whereas primary infection in adults may result in symptomatic illness. CMV establishes a chronic latent infection with intermittent periods of reactivation. Primary infection or reactivation associate with increased mortality and morbidity in those who are immunocompromised. Transplacental transmission may result in significant birth defects or long-term sensorineural hearing loss. We performed a study to determine the CMV seroprevalence and the association between HLA Class I alleles and frequency of CMV infection in Ireland. The presence of CMV IgG, a marker of previous CMV infection, was determined for a cohort of 1849 HLA typed solid organ transplant donors between 1990 and 2013. The presence of CMV IgG was correlated with HLA type. The CMV seroprevalence in solid organ transplant donors was 33.4% (range 22–48% per annum) over the time period 1990 to 2013. Multivariate logistic regression analysis showed that both age and HLA alleles were associated with CMV seropositivity. A significant and positive relationship between age and CMV seropositivity was observed (OR = 1.013, P < 0.001, CI [1.007, 1.019]). Chi-square analysis revealed that the female gender was independently associated with CMV seropositivity (P < 0.01). Seroprevalence in women of reproductive age (20–39 years) was significantly higher than men of the same age (37% vs 26%, P < 0.01). The frequencies of HLA-A1, HLA-A2, and HLA-A3 in our cohort were 40.8%, 48.8%, and 25.9%, respectively. Logistic regression analysis showed that the presence of HLA-A1 but not HLA-A2 or HLA-A3 was independently associated with CMV seronegativity (P < 0.01). Interestingly, individuals who co-expressed HLA-A2 and HLA-A3 alleles were significantly more likely to be CMV seropositive (P < 0.02). The frequencies of HLA-B5, HLA-B7, and HLA-B8 in our cohort were 6.1%, 31.2%, and 30.8%, respectively. The presence of the most common inherited haplotype in the Irish population, HLA-A1, B8 was significantly associated with CMV seronegativity (OR = 1.278, P < 0.001, CI [1.049, 1.556]). CMV seroprevalence is lower in Ireland compared with other countries. The high frequency of HLA-A1 in the Irish population may, in part, have a role in the reduced susceptibility to CMV infection.
362Scopus© Citations 16
- PublicationPlasma EBV microRNAs in paediatric renal transplant recipientsBackground: Epstein-Barr virus (EBV) was the first human virus identified to express microRNA (miRNA). To date, 44mature miRNAs are encoded for within the EBV genome. EBV miRNAs have not been profiled in paediatric renal transplant recipients. In this study, we investigated circulating EBV miRNA profiles as novel biomarkers in paediatric renal transplant patients. Methods: Forty-two microRNAs encoded within 2 EBV open reading frames (BART and BHRF) were examined in renal transplant recipients who resolved EBV infection (REI) or maintained chronic high viral loads (CHL), and in non-transplant patients with acute infectious mononucleosis (IM). Results: Plasma EBV-miR-BART2-5p was present in higher numbers of IM (7/8) and CHL (7/10) compared to REI (7/12)patients. A trend was observed between the numbers of plasma EBV miRNAs expressed and EBV viral load (p < 0.07).Several EBV-miRs including BART7-3p, 15, 9-3p, 11-3p, 1-3p and 3-3p were detected in IM and CHL patients only. Thelytic EBV-miRs, BHRF1-2-3p and 1-1, indicating active viral replication, were detected in IM patients only. One CHL patient developed post-transplant lymphoproliferative disease (PTLD) after several years and analysis of 10 samples over a 30-month period showed an average 24-fold higher change in plasma EBV-miR-BART2-5p compared to the CHL group and 110-fold higher change compared to the REI group.Conclusions Our results suggest that EBV-miR-BART2-5p, which targets the stress-induced immune ligand MICB to escape recognition and elimination by NK cells, may have a role in sustaining high EBV viral loads in CHL paediatric kidney transplant recipients.
Scopus© Citations 13 548