Helminth-induced Th2 cell dysfunction is distinct from exhaustion and is maintained in the absence of antigen

T cell-intrinsic regulation, such as anergy, adaptive tolerance and exhaustion, is central to immune regulation. In contrast to Type 1 and Type 17 settings, knowledge of the intrinsic fate and function of Th2 cells in chronic Type 2 immune responses is lacking. We previously showed that Th2 cells develop a PD-1/PD-L2-dependent intrinsically hypo-responsive phenotype during infection with the filarial nematode Litomosoides sigmodontis, denoted by impaired functionality and parasite killing. This study aimed to elucidate the transcriptional changes underlying Th2 cell-intrinsic hypo-responsiveness, and whether it represents a unique and stable state of Th2 cell differentiation. We demonstrated that intrinsically hypo-responsive Th2 cells isolated from L. sigmodontis infected mice stably retained their dysfunctional Th2 phenotype upon transfer to naïve recipients, and had a divergent transcriptional profile to classical Th2 cells isolated prior to hypo-responsiveness and from mice exposed to acute Type 2 stimuli. Hypo-responsive Th2 cells displayed a distinct transcriptional profile to exhausted CD4+ T cells, but upregulated Blimp-1 and the anergy/regulatory-associated transcription factors Egr2 and c-Maf, and shared characteristics with tolerised T cells. Hypo-responsive Th2 cells increased mRNA expression of the soluble regulatory factors Fgl2, Cd38, Spp1, Areg, Metrnl, Lgals3, and Csf1, and a subset developed a T-bet+IFN-γ+ Th2/Th1 hybrid phenotype, indicating that they were not functionally inert. Contrasting with their lost ability to produce Th2 cytokines, hypo-responsive Th2 cells gained IL-21 production and IL-21R blockade enhanced resistance to L. sigmodontis. IL-21R blockade also increased the proportion of CD19+PNA+ germinal centre B cells and serum levels of parasite specific IgG1. This indicates a novel regulatory role for IL-21 during filarial infection, both in controlling protection and B cell responses. Thus, Th2 cell-intrinsic hypo-responsiveness is a distinct and stable state of Th2 cell differentiation associated with a switch from a classically active IL-4+IL-5+ Th2 phenotype, to a non-classical dysfunctional and potentially regulatory IL-21+Egr2+c-Maf+Blimp-1+IL-4loIL-5loT-bet+IFN-γ+ Th2 phenotype. This divergence towards alternate Th2 phenotypes during chronicity has broad implications for the outcomes and treatment of chronic Type 2-related infections and diseases

Regulatory T cell-derived extracellular vesicles modify dendritic cell function

Regulatory T cells (Treg) are a subpopulation of T cells that maintain tolerance to self and limit other immune responses. They achieve this through different mechanisms including the release of extracellular vesicles (EVs) such as exosomes as shown by us, and others. One of the ways that Treg derived EVs inhibit target cells such as effector T cells is via the transfer of miRNA. Another key target for the immunoregulatory function of Tregs is the dendritic cells (DCs). In this study we demonstrate directly, and for the first time, that miRNAs are transferred from Tregs to DCs via Treg derived EVs. In particular two miRNAs, namely miR-150-5p and miR-142-3p, were increased in DCs following their interaction with Tregs and Treg derived exosomes. One of the consequences for DCs following the acquisition of miRNAs contained in Treg derived EVs was the induction of a tolerogenic phenotype in these cells, with increased IL-10 and decreased IL-6 production being observed following LPS stimulation. Altogether our findings provide data to support the idea that intercellular transfer of miRNAs via EVs may be a novel mechanism by which Tregs regulate DC function and could represent a mechanism to inhibit immune reactions in tissues

Circulating Plasma microRNAs can differentiate Human Sepsis and Systemic Inflammatory Response Syndrome (SIRS)

Systemic inflammation in humans may be triggered by infection, termed sepsis, or non-infective processes, termed non-infective systemic inflammatory response syndrome (SIRS). MicroRNAs regulate cellular processes including inflammation and may be detected in blood. We aimed to establish definitive proof-of-principle that circulating microRNAs are differentially affected during sepsis and non-infective SIRS. Critically ill patients with severe (n = 21) or non-severe (n = 8) intra-abdominal sepsis; severe (n = 23) or non-severe (n = 21) non-infective SIRS; or no SIRS (n = 16) were studied. Next-generation sequencing and qRT-PCR were used to measure plasma microRNAs. Detectable blood miRNAs (n = 116) were generally up-regulated in SIRS compared to no-SIRS patients. Levels of these 'circulating inflammation-related microRNAs' (CIR-miRNAs) were 2.64 (IQR: 2.10-3.29) and 1.52 (IQR: 1.15-1.92) fold higher for non-infective SIRS and sepsis respectively (p < 0.0001), hence CIR-miRNAs appeared less abundant in sepsis than in SIRS. Six CIR-miRNAs (miR-30d-5p, miR-30a-5p, miR-192-5p, miR-26a-5p, miR-23a-5p, miR-191-5p) provided good-to-excellent discrimination of severe sepsis from severe SIRS (0.742-0.917 AUC of ROC curves). CIR-miRNA levels inversely correlated with pro-inflammatory cytokines (IL-1, IL-6 and others). Thus, among critically ill patients, sepsis and non-infective SIRS are associated with substantial, differential changes in CIR-miRNAs. CIR-miRNAs may be regulators of inflammation and warrant thorough evaluation as diagnostic and therapeutic targets

Maternal and child health interventions in Nigeria: a systematic review of published studies from 1990 to 2014

BACKGROUND: Poor maternal and child health indicators have been reported in Nigeria since the 1990s. Many interventions have been instituted to reverse the trend and ensure that Nigeria is on track to achieve the Millennium Development Goals. This systematic review aims at describing and indirectly measuring the effect of the Maternal, Newborn, and Child Health (MNCH) interventions implemented in Nigeria from 1990 to 2014. METHODS: PubMed and ISI Web of Knowledge were searched from 1990 to April 2014 whereas POPLINE® was searched until 16 February 2015 to identify reports of interventions targeting Maternal, Newborn, and Child Health in Nigeria. Narrative and graphical synthesis was done by integrating the results of extracted studies with trends of maternal mortality ratio (MMR) and under five mortality (U5MR) derived from a joint point regression analysis using Nigeria Demographic and Health Survey data (1990-2013). This was supplemented by document analysis of policies, guidelines and strategies of the Federal Ministry of Health developed for Nigeria during the same period. RESULTS: We identified 66 eligible studies from 2,662 studies. Three interventions were deployed nationwide and the remainder at the regional level. Multiple study designs were employed in the enrolled studies: pre- and post-intervention or quasi-experimental (n = 40; 61%); clinical trials (n = 6;9%); cohort study or longitudinal evaluation (n = 3;5%); process/output/outcome evaluation (n = 17;26%). The national MMR shows a consistent reduction (Annual Percentage Change (APC) = -3.10%, 95% CI: -5.20 to -1.00 %) with marked decrease in the slope observed in the period with a cluster of published studies (2004-2014). Fifteen intervention studies specifically targeting under-five children were published during the 24 years of observation. A statistically insignificant downward trend in the U5MR was observed (APC = -1.25%, 95% CI: -4.70 to 2.40%) coinciding with publication of most of the studies and development of MNCH policies. CONCLUSIONS: The development of MNCH policies, implementation and publication of interventions corresponds with the downward trend of maternal and child mortality in Nigeria. This systematic review has also shown that more MNCH intervention research and publications of findings is required to generate local and relevant evidence

Heavy metals content of grains commonly sold in markets in south-east, Nigeria

Heavy metals levels in legume and cereal grains were determined using atomic absorption spectrophotometry. The ranges of concentrations (mg/kg) in legume grains were: Ni (1.23 – 5.91); Cd (0.03-0.11); Cu (3.03 – 7.94); Zn (38.46 – 57.72); Fe (59.00 – 102.40); Mn (12.86 – 27.65); and Co (0.43 – 0.66); while Pb was below detectable level in all the samples. In the cereal grains, the ranges were; Cd (0.007 – 0.023); Cu (0.351 – 0.764); Zn (0.05 – 0.119); Fe (6.393 – 12.643) and Pb (0.007 – 0.032), in mg/kg, dry weight. The much higher concentrations of these metals in the legume grains is attributable to the fact that legume grains have high protein content, thereby easily accumulate these trace metals which have high affinity for active sites of proteins. The presence of lead in all the cereal grain samples could be possibly attributed to one or more of these factors-soil pollution, use and type of fertilizers and pesticides in the farms. All concentrations in this study were below the WHO recommended limits. However, the legume grains were found to be fairly rich sources of some of the essential nutrients, namely; Fe, Zn, Mn, Cu, Cr, and Ni. The low levels of heavy metals are indicative of low levels of contamination of farmlands by these trace metals in spite of increasing use of fertilizers and pesticides in modern agriculture, as well as emissions from other anthropogenic sources. The data show largely the background levels of the trace heavy metals in the farms