Differentiation and adaptation of natural killer cells for anti-malarial immunity

Natural killer cells employ a diverse arsenal of effector mechanisms to target intracellular pathogens. Differentiation of natural killer (NK) cell activation pathways occurs along a continuum from reliance on innate pro-inflammatory cytokines and stress-induced host ligands through to interaction with signals derived from acquired immune responses. Importantly, the degree of functional differentiation of the NK cell lineage influences the magnitude and specificity of interactions with host cells infected with viruses, bacteria, fungi, and parasites. Individual humans possess a vast diversity of distinct NK cell clones, each with the capacity to vary along this functional differentiation pathway, which - when combined - results in unique individual responses to different infections. Here we summarize these NK cell differentiation events, review evidence for direct interaction of malaria-infected host cells with NK cells and assess how innate inflammatory signals induced by malaria parasite-associated molecular patterns influence the indirect activation and function of NK cells. Finally, we discuss evidence that anti-malarial immunity develops in parallel with advancing NK differentiation, coincident with a loss of reliance on inflammatory signals, and a refined capacity of NK cells to target malaria parasites more precisely, particularly through antibody-dependent mechanisms

Functional Significance of CD57 Expression on Human NK Cells and Relevance to Disease.

Historically, human NK cells have been identified as CD3(-)CD56(+)CD16(±) lymphocytes. More recently it has been established that CD57 expression defines functionally discrete sub-populations of NK cells. On T cells, CD57 expression has been regarded as a marker of terminal differentiation and (perhaps wrongly) of anergy and senescence. Similarly, CD57 expression seems to identify the final stages of peripheral NK cell maturation; its expression increases with age and is associated with chronic infections, particularly human cytomegalovirus infection. However, CD57(+) NK cells are highly cytotoxic and their presence seems to be beneficial in a number of non-communicable diseases. The purpose of this article is to review our current understanding of CD57 expression as a marker of NK cell function and disease prognosis, as well as to outline areas for further research

MicroRNAs in Aldosterone Production and Action

The secretion of aldosterone by the adrenal cortex is a tightly regulated process. Loss of this control can result in severe hypertension and end-organ damage, so detailed understanding of the various mechanisms by which the body regulates aldosterone biosynthesis is key. The emergence of microRNAs (miRNAs) as negative regulators of numerous physiological processes has naturally led to their study in the context of aldosterone production. We summarise several studies that have demonstrated a significant role for microRNAs in aldosterone biosynthesis and action, thereby presenting a possible therapeutic role in the treatment of common forms of hypertension such as primary aldosteronism. Furthermore, the presence of microRNAs in the circulation offers the prospect of accessible and informative biomarkers that may simplify the currently protracted and technically difficult diagnosis of such conditions

Hosts of avian brood parasites have evolved egg signatures with elevated information content.

Hosts of brood-parasitic birds must distinguish their own eggs from parasitic mimics, or pay the cost of mistakenly raising a foreign chick. Egg discrimination is easier when different host females of the same species each lay visually distinctive eggs (egg 'signatures'), which helps to foil mimicry by parasites. Here, we ask whether brood parasitism is associated with lower levels of correlation between different egg traits in hosts, making individual host signatures more distinctive and informative. We used entropy as an index of the potential information content encoded by nine aspects of colour, pattern and luminance of eggs of different species in two African bird families (Cisticolidae parasitized by cuckoo finches Anomalospiza imberbis, and Ploceidae by diederik cuckoos Chrysococcyx caprius). Parasitized species showed consistently higher entropy in egg traits than did related, unparasitized species. Decomposing entropy into two variation components revealed that this was mainly driven by parasitized species having lower levels of correlation between different egg traits, rather than higher overall levels of variation in each individual egg trait. This suggests that irrespective of the constraints that might operate on individual egg traits, hosts can further improve their defensive 'signatures' by arranging suites of egg traits into unpredictable combinations.EMC was supported by the Pomona College-Downing College Student Exchange Scholarship, MS by a BBSRC David Phillips Research Fellowship (BB/G022887/1), and CNS by a Royal Society Dorothy Hodgkin Fellowship, a BBSRC David Phillips Research Fellowship (BB/J014109/1), and the DST-NRF Centre of Excellence at the Percy FitzPatrick Institute.This is the final version of the article. It first appeared from Royal Society Publishing via http://dx.doi.org/10.1098/rspb.2015.059

Improving the effectiveness and efficiency of outpatient services: a scoping review of interventions at the primary-secondary care interface.

Objectives Variation in patterns of referral from primary care can lead to inappropriate overuse or underuse of specialist resources. Our aim was to review the literature on strategies involving primary care that are designed to improve the effectiveness and efficiency of outpatient services. Methods A scoping review to update a review published in 2006. We conducted a systematic literature search and qualitative evidence synthesis of studies across five intervention domains: transfer of services from hospital to primary care; relocation of hospital services to primary care; joint working between primary care practitioners and specialists; interventions to change the referral behaviour of primary care practitioners and interventions to change patient behaviour. Results The 183 studies published since 2005, taken with the findings of the previous review, suggest that transfer of services from secondary to primary care and strategies aimed at changing referral behaviour of primary care clinicians can be effective in reducing outpatient referrals and in increasing the appropriateness of referrals. Availability of specialist advice to primary care practitioners by email or phone and use of store-and-forward telemedicine also show potential for reducing outpatient referrals and hence reducing costs. There was little evidence of a beneficial effect of relocation of specialists to primary care, or joint primary/secondary care management of patients on outpatient referrals. Across all intervention categories there was little evidence available on cost-effectiveness. Conclusions There are a number of promising interventions which may improve the effectiveness and efficiency of outpatient services, including making it easier for primary care clinicians and specialists to discuss patients by email or phone. There remain substantial gaps in the evidence, particularly on cost-effectiveness, and new interventions should continue to be evaluated as they are implemented more widely. A move for specialists to work in the community is unlikely to be cost-effective without enhancing primary care clinicians' skills through education or joint consultations with complex patients.This project was funded by the National Institute for Health Research Health Services and Delivery Research programme (project number 12/135/02).This is the final version of the article. It first appeared from SAGE via http://dx.doi.org/10.1177/1355819616648982

Differential activation of CD57-defined natural killer cell subsets during recall responses to vaccine antigens

Natural killer (NK) cells contribute to the effector phase of vaccine-induced adaptive immune responses, secreting cytokines and releasing cytotoxic granules. The proportion of responding NK cells varies between individuals and by vaccine, suggesting that functionally discrete subsets of NK cells with different activation requirements may be involved. Here, we have used responses to individual components of the DTP vaccine [tetanus toxoid (TT), diphtheria toxoid (DT), whole cell inactivated pertussis] to characterize the NK cell subsets involved in interleukin-2-dependent recall responses. Culture with TT, DT or pertussis induced NK cell CD25 expression and interferon-γ production in previously vaccinated individuals. Responses were the most robust against whole cell pertussis, with responses to TT being particularly low. Functional analysis of discrete NK cell subsets revealed that transition from CD56bright to CD56dim correlated with increased responsiveness to CD16 cross-linking, whereas increasing CD57 expression correlated with a loss of responsiveness to cytokines. A higher frequency of CD56dim CD57− NK cells expressed CD25 and interferon-γ following stimulation with vaccine antigen compared with CD56dim CD57+ NK cells and made the largest overall contribution to this response. CD56dim CD57int NK cells represent an intermediate functional phenotype in response to vaccine-induced and receptor-mediated stimuli. These findings have implications for the ability of NK cells to contribute to the effector response after vaccination and for vaccine-induced immunity in older individuals

Diet quality and depressive symptoms in adolescence: no cross-sectional or prospective associations following adjustment for covariates.

OBJECTIVE: Adolescence is a critical period for development of depression and understanding of behavioural risk factors is needed to support appropriate preventive strategies. We examined associations between adolescent diet quality and depressive symptoms, cross-sectionally and prospectively, in a large community cohort, adjusting for behavioural and psychosocial covariates. DESIGN: Prospective community-based cohort study (ROOTS). SETTING: Secondary schools in Cambridgeshire and Suffolk, UK. SUBJECTS: Study participants (n 603) who completed 4 d diet diaries at age 14 years and reported depressive symptoms (Moods and Feelings Questionnaire (MFQ)) at 14 and 17 years of age. RESULTS: Diet data were processed to derive a Mediterranean diet score (MDS) and daily servings of fruit and vegetables, and fish. At age 14 years, a negative association between fruit and vegetable intake and MFQ score was seen in the unadjusted cross-sectional regression model (β=-0·40; 95 % CI -0·71,-0·10), but adjustment for behavioural covariates, including smoking and alcohol consumption, attenuated this association. Fish intake and MDS were not cross-sectionally associated with MFQ score. No prospective associations were found between MDS, fruit and vegetable intake or fish intake and later MFQ score. CONCLUSIONS: Diet quality was not associated with depressive symptoms in mid-adolescence. Previously reported associations in this age range may be due to confounding. Further longitudinal studies are needed that investigate associations between adolescent diet and depression across different time frames and populations, ensuring appropriate adjustment for covariates