The quantification and characterization of circulating immune cells provide key indicators of human health and disease. To identify the relative effects of environmental and genetic factors on variation in the parameters of innate and adaptive immune cells in homeostatic conditions, we combined standardized flow cytometry of blood leukocytes and genome-wide DNA genotyping of 1,000 healthy, unrelated people of Western European ancestry. We found that smoking, together with age, sex and latent infection with cytomegalovirus, were the main non-genetic factors that affected variation in parameters of human immune cells. Genome-wide association studies of 166 immunophenotypes identified 15 loci that showed enrichment for disease-associated variants. Finally, we demonstrated that the parameters of innate cells were more strongly controlled by genetic variation than were those of adaptive cells, which were driven by mainly environmental exposure. Our data establish a resource that will generate new hypotheses in immunology and highlight the role of innate immunity in susceptibility to common autoimmune diseases.

ObjectivesAntitumour necrosis factor (TNF) therapy has revolutionised treatment of several chronic inflammatory diseases, including spondyloarthritis (SpA). However, TNF inhibitors (TNFi) are not effective in all patients and the biological basis for treatment failure remains unknown. We have analysed induced immune responses to define the mechanism of action of TNF blockers in SpA and to identify immunological correlates of responsiveness to TNFi.MethodsImmune responses to microbial and pathway-specific stimuli were analysed in peripheral blood samples from 80 patients with axial SpA before and after TNFi treatment, using highly standardised whole-blood stimulation assays. Cytokines and chemokines were measured in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, and gene expression was monitored using nCounter assays.ResultsAnti-TNF therapy induced profound changes in patients’ innate immune responses. TNFi action was selective, and had only minor effects on Th1/Th17 immunity. Modular transcriptional repertoire analysis identified prostaglandin E2 synthesis and signalling, leucocyte recirculation, macrophage polarisation, dectin and interleukin (IL)-1 signalling, as well as the nuclear factor kappa B (NF-kB) transcription factor family as key pathways targeted by TNF blockers in vivo. Analysis of induced immune responses before treatment initiation revealed that expression of molecules associated with leucocyte adhesion and invasion, chemotaxis and IL-1 signalling are correlated with therapeutic responses to anti-TNF.ConclusionsWe show that TNFi target multiple immune cell pathways that cooperate to resolve inflammation. We propose that immune response profiling provides new insight into the biology of TNF-blocker action in patients and can identify signalling pathways associated with therapeutic responses to biological therapies.

Aspartame and Stevia are widely substituted for sugar. Little is known about cerebral activation in response to low-caloric sweeteners in comparison with high-caloric sugar, whereas these molecules lead to different metabolic effects. We aimed to compare gustatory evoked potentials (GEPs) obtained in response to sucrose solution in young, healthy subjects, with GEPs obtained in response to aspartame and Stevia. Twenty healthy volunteers were randomly stimulated with three solutions of similar intensities of sweetness: Sucrose 10 g/100 mL of water, aspartame 0.05 g/100 mL, and Stevia 0.03 g/100 mL. GEPs were recorded with EEG (Electroencephalogram) electrodes. Hedonic values of each solution were evaluated using the visual analog scale (VAS). The main result was that P1 latencies of GEPs were significantly shorter when subjects were stimulated by the sucrose solution than when they were stimulated by either the aspartame or the Stevia one. P1 latencies were also significantly shorter when subjects were stimulated by the aspartame solution than the Stevia one. No significant correlation was noted between GEP parameters and hedonic values marked by VAS. Although sucrose, aspartame, and Stevia lead to the same taste perception, cerebral activation by these three sweet solutions are different according to GEPs recording. Besides differences of taste receptors and cerebral areas activated by these substances, neural plasticity, and change in synaptic connections related to sweet innate preference and sweet conditioning, could be the best hypothesis to explain the differences in cerebral gustatory processing after sucrose and sweeteners activation.

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