Many paths lead to immunology.

While some people pore over the textbook and train through the classics of the field, many scientists come to immunology when they discover it intersecting with their "first love" interests. Five of these "accidental immunologists" tell us how they found their way to a fascination with the immune system.

A Tale of Three Systems: Toward a Neuroimmunoendocrine Model of Obesity.

The prevalence of obesity is on the rise. What was once considered a simple disease of energy imbalance is now recognized as a complex condition perpetuated by neuro- and immunopathologies. In this review, we summarize the current knowledge of the neuroimmunoendocrine mechanisms underlying obesity. We examine the pleiotropic effects of leptin action in addition to its established role in the modulation of appetite, and we discuss the neural circuitry mediating leptin action and how this is altered with obesity, both centrally (leptin resistance) and in adipose tissues (sympathetic neuropathy). Finally, we dissect the numerous causal and consequential roles of adipose tissue macrophages in obesity and highlight recent key studies demonstrating their direct role in organismal energy homeostasis.

Immunomodulatory leptin receptor+ sympathetic perineurial barrier cells protect against obesity by facilitating brown adipose tissue thermogenesis.

Adipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor-positive (LepR+) sympathetic perineurial barrier cells (SPCs) present in mice and humans, which uniquely co-express Lepr and interleukin-33 (Il33) and ensheath AT sympathetic axon bundles. Brown ATs (BATs) of mice lacking IL-33 in SPCs (SPCΔIl33) had fewer regulatory T (Treg) cells and eosinophils, resulting in increased BAT inflammation. SPCΔIl33 mice were more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCΔIl33 mice had impaired adaptive thermogenesis and were unresponsive to leptin-induced rescue of metabolic adaptation. We therefore identify LepR+ SPCs as a source of IL-33, which orchestrate an anti-inflammatory BAT environment, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+IL-33+ SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research.

Old and "hangry" monocytes turn from friend to foe under assault.

Fasting is known to impact monocyte dynamics and phenotype, but the mechanics and functional significance of this response remain unclear. In this issue of Immunity, Janssen and colleagues demonstrate that fasting and re-feeding causes monocytes to re-enter the bone marrow and alter the host response to infection.

An IL-23R/IL-22 Circuit Regulates Epithelial Serum Amyloid A to Promote Local Effector Th17 Responses.

RORγt(+) Th17 cells are important for mucosal defenses but also contribute to autoimmune disease. They accumulate in the intestine in response to microbiota and produce IL-17 cytokines. Segmented filamentous bacteria (SFB) are Th17-inducing commensals that potentiate autoimmunity in mice. RORγt(+) T cells were induced in mesenteric lymph nodes early after SFB colonization and distributed across different segments of the gastrointestinal tract. However, robust IL-17A production was restricted to the ileum, where SFB makes direct contact with the epithelium and induces serum amyloid A proteins 1 and 2 (SAA1/2), which promote local IL-17A expression in RORγt(+) T cells. We identified an SFB-dependent role of type 3 innate lymphoid cells (ILC3), which secreted IL-22 that induced epithelial SAA production in a Stat3-dependent manner. This highlights the critical role of tissue microenvironment in activating effector functions of committed Th17 cells, which may have important implications for how these cells contribute to inflammatory disease.

Sympathetic neuro-adipose connections mediate leptin-driven lipolysis.

Leptin is a hormone produced by the adipose tissue that acts in the brain, stimulating white fat breakdown. We find that the lipolytic effect of leptin is mediated through the action of sympathetic nerve fibers that innervate the adipose tissue. Using intravital two-photon microscopy, we observe that sympathetic nerve fibers establish neuro-adipose junctions, directly "enveloping" adipocytes. Local optogenetic stimulation of sympathetic inputs induces a local lipolytic response and depletion of white adipose mass. Conversely, genetic ablation of sympathetic inputs onto fat pads blocks leptin-stimulated phosphorylation of hormone-sensitive lipase and consequent lipolysis, as do knockouts of dopamine ß-hydroxylase, an enzyme required for catecholamine synthesis. Thus, neuro-adipose junctions are necessary and sufficient for the induction of lipolysis in white adipose tissue and are an efferent effector of leptin action. Direct activation of sympathetic inputs to adipose tissues may represent an alternative approach to induce fat loss, circumventing central leptin resistance. PAPERCLIP.

Illuminating Neuroimmunity: A Humoral Brain.

The hypothalamic-pituitary-adrenal axis modulates immunity in response to stress. In a recent report in the May 14, 2020 issue of Nature, Zhang et al. use optogenetic tools to investigate whether the splenic immune response is directly controlled by descending neuronal circuits activated in response to stress.

Neuro-mesenchymal units control ILC2 and obesity via a brain-adipose circuit.

Signals from sympathetic neurons and immune cells regulate adipocytes and thereby contribute to fat tissue biology. Interactions between the nervous and immune systems have recently emerged as important regulators of host defence and inflammation1-4. Nevertheless, it is unclear whether neuronal and immune cells co-operate in brain-body axes to orchestrate metabolism and obesity. Here we describe a neuro-mesenchymal unit that controls group 2 innate lymphoid cells (ILC2s), adipose tissue physiology, metabolism and obesity via a brain-adipose circuit. We found that sympathetic nerve terminals act on neighbouring adipose mesenchymal cells via the ß2-adrenergic receptor to control the expression of glial-derived neurotrophic factor (GDNF) and the activity of ILC2s in gonadal fat. Accordingly, ILC2-autonomous manipulation of the GDNF receptor machinery led to alterations in ILC2 function, energy expenditure, insulin resistance and propensity to obesity. Retrograde tracing and chemical, surgical and chemogenetic manipulations identified a sympathetic aorticorenal circuit that modulates ILC2s in gonadal fat and connects to higher-order brain areas, including the paraventricular nucleus of the hypothalamus. Our results identify a neuro-mesenchymal unit that translates cues from long-range neuronal circuitry into adipose-resident ILC2 function, thereby shaping host metabolism and obesity.

Antibody isotype epitope mapping of SARS-CoV-2 Spike RBD protein: Targets for COVID-19 symptomatology and disease control.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still poses a challenge for biomedicine and public health. To advance the development of effective diagnostic, prognostic, and preventive interventions, our study focused on high-throughput antibody binding epitope mapping of the SARS-CoV-2 spike RBD protein by IgA, IgM and IgG antibodies in saliva and sera of different cohorts from healthy uninfected individuals to SARS-CoV-2-infected unvaccinated and vaccinated asymptomatic, recovered, nonsevere, and severe patients. Identified candidate diagnostic (455-LFRKSNLKPFERD-467), prognostic (395-VYADSFVIRGDEV-407-C-KLH, 332-ITNLCPFGEV-342-C-KLH, 352-AWNRKRI-358-C-KLH, 524-VCGPKKSTNLVKN-536-KLH), and protective (MKLLE-487-NCYFPLQSYGFQPTNGVG-504-GGGGS-446-GGNYNYLYRLFRKSNLKPFERD-467) epitopes were validated with sera from prevaccine and postvaccine cohorts. The results identified neutralizing epitopes and support that antibody recognition of linear B-cell epitopes in RBD protein is associated with antibody isotype and disease symptomatology. The findings in asymptomatic individuals suggest a role for anti-RBD antibodies in the protective response against SARS-CoV-2. The possibility of translating results into diagnostic interventions for the early diagnosis of asymptomatic individuals and prognosis of disease severity provides new tools for COVID-19 surveillance and evaluation of risks in hospitalized patients. These results, together with other approaches, may contribute to the development of new vaccines for the control of COVID-19 and other coronavirus-related diseases using a quantum vaccinomics approach through the combination of protective epitopes.

Peritoneal Protein Loss With Time in Peritoneal Dialysis.

Longitudinal evolution of peritoneal protein loss (PPL), a reflection of hydrostatic pressure-driven leak of plasma proteins through the large-pore pathway, is not clear. Time on PD causes loss of mesothelial cells, vasculopathy, and increased thickness of the submesothelial fibrous layer. Are these structural changes associated with progressive increase of PPL, in a parallel with the rise in the D/P creatinine? The aim of the present study was to identify longitudinal changes of PPL over time. This single-center, longitudinal study included 52 peritoneal dialysis (PD) patients with a median follow-up of 26.5 months, evaluated at two different time points with a minimum interval of 6 months. Repeated measures analysis was performed using paired sample t-test or the nonparametric Wilcoxon signed-rank test, depending on the distribution. After a median interval of 15.5 months, lower levels of residual renal function and urine volume, lower Kt/V, and creatinine clearance were found. D/P creatinine and PPL were stable, but a decrease in ultrafiltration was present. Systemic inflammation, nutrition, and volume overload showed no significant change with time on PD. Analysis of a subpopulation with over 48 months between initial and subsequential assessment (n = 11) showed again no difference in inflammation, nutritional and hydration parameters from baseline, but importantly PPL decreased after more than 4 years on PD (mean difference 1.2 g/24, p = 0.033). D/P creatinine and dip of sodium remained unchanged. The absence of deleterious effects of time on PD is reassuring, pointing to the benefit of updated PD prescription, including the standard use of more biocompatible solutions towards membrane preservation and adjusted prescription avoiding overhydration and inflammation while maintaining nutritional status. After controlling for confounders, PPL may act as a biomarker of acquired venous vasculopathy, even if small pore fluid transport rates and free water transport are preserved.

Retraction Note: DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions.

Change History: This Article has been retracted; see accompanying Retraction. Corrected online 20 January: In this Article, author Frank Rigo was incorrectly listed with a middle initial; this has been corrected in the online versions of the paper.

Applicability of machine learning techniques in food intake assessment: A systematic review.

The evaluation of food intake is important in scientific research and clinical practice to understand the relationship between diet and health conditions of an individual or a population. Large volumes of data are generated daily in the health sector. In this sense, Artificial Intelligence (AI) tools have been increasingly used, for example, the application of Machine Learning (ML) algorithms to extract useful information, find patterns, and predict diseases. This systematic review aimed to identify studies that used ML algorithms to assess food intake in different populations. A literature search was conducted using five electronic databases, and 36 studies met all criteria and were included. According to the results, there has been a growing interest in the use of ML algorithms in the area of nutrition in recent years. Also, supervised learning algorithms were the most used, and the most widely used method of nutritional assessment was the food frequency questionnaire. We observed a trend in using the data analysis programs, such as R and WEKA. The use of ML in nutrition is recent and challenging. Therefore, it is encouraged that more studies are carried out relating these themes for the development of food reeducation programs and public policies.

Protein Loss in Peritoneal Effluent: Different Meaning for 24-h versus PET Samples.

INTRODUCTION: Quantification of peritoneal protein loss (PPL) may be expressed according to a timely collection (24-h measurement or 4-h PET assessment) and as a concentration. The aim of this study was to compare the quantification methods of 24-h and 4-h collections. METHODS: This study included 81 prevalent peritoneal dialysis patients. Demographics and clinical and bioelectrical impedance features were registered. PPL was measured (4-h PET and 24-h results) and peritoneal protein clearance was calculated. A linear regression model was performed. RESULTS: Age and continuous ambulatory peritoneal dialysis (compared to cycler) were positively associated with greater PPL on 24-h collections. Neither cardiovascular disease, hypertension, diabetes nor the comorbidity Charlson Index was significantly associated with PPL. There was a consistent univariable relationship with D/P creatinine, whichever sampling method was used. Only 24-h measurements of PPL correlated with body composition variables. In multiple linear regression analysis, D/P creatinine association with PPL stands out. On the other hand, 24-h determinations (in grams or clearance) were associated with overhydration. PET protein quantification was associated with peritoneal creatinine clearance. DISCUSSION/CONCLUSION: Different methods sign different pathophysiological pathways. PET protein loss quantification should be regarded as a marker of peritoneal membrane intrinsic permeability. Measurements of a 24-h sample might be closer to patients' clinical status and prognosis, signalizing opportunities for therapy intervention.

Relationship between food consumption and improvements in circulating melatonin in humans: an integrative review.

Melatonin is an important hormone in the regulation of circadian rhythms and has great antioxidant power. Recent studies have demonstrated the benefits of its supplementation in the metabolic profile. Food sources have also been studied for complementary therapies. However, information on the bioavailability of food sources of melatonin is still scarce. Thus, the objective of this review is to gather in the literature studies that evaluate the relationship between food consumption and improvements in circulating melatonin in humans. In total, 178 studies were found, of which 11 were included in this review. The results show increases in the excretion of the melatonin metabolite (6­sulfatoxymelatonin) or circulating melatonin for foods such as cherries, grapes, bananas, pineapples, dark green vegetables, Japanese vegetables and beer. Significant increases in melatonin were observed even after ingesting cultivars with low concentrations of this hormone. It was possible to assume that other nutrients that precede their synthesis (serotonin and tryptophan) could also have led to this increase. Although consumption of the foods found is beneficial in increasing circulating melatonin, further confirmatory studies are needed.

Ultra-processed food consumption and dietary, lifestyle and social determinants: a path analysis in Brazilian graduates (CUME project).

OBJECTIVE: To explore the relationship between ultra-processed foods (UPF) consumption and dietary, lifestyle and social determinants using pathway analysis in the baseline of the Cohort of Universities of Minas Gerais (CUME project). DESIGN: Cross-sectional study, in which path analysis was used to estimate direct and indirect effects of dietary practices, sleep, time on the computer and professional status on UPF consumption. SETTING: Data were collected in 2016, through an online questionnaire composed of sociodemographic, anthropometric, lifestyle and dietary practices questions, and a FFQ. PARTICIPANTS: Baseline participants from the CUME Project (n 2826), adults who graduated from Universidade Federal de Viçosa or Universidade Federal de Minas Gerais, Brazil. RESULTS: Being employed (P = 0·024), the time spent on the computer (P = 0·031) and the frequency of fried food intake (P < 0·001) were positively and directly associated with UPF consumption, whereas the sleep duration (P = 0·007) and the number of meals per d (P < 0·001) were negatively and directly associated with UPF consumption. Indirect effects were observed between being employed, mediated by the sleep duration (P = 0·032) and fried food intake (P = 0·005), whereas being a student is mediated by the time on the computer (P = 0·048). CONCLUSION: The time spent on the computer, sleep duration and fried food consumption showed direct effects on UPF consumption. They also acted as mediators on the relationship between professional status and UPF consumption. Besides, the number of meals eaten each day also was directly associated with UPF consumption.

DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions.

T helper 17 (TH17) lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by RORγt, a ligand-regulated nuclear receptor. Here we identify the RNA helicase DEAD-box protein 5 (DDX5) as a RORγt partner that coordinates transcription of selective TH17 genes, and is required for TH17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with RORγt and coactivate its targets depends on intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA), Rmrp, which is mutated in patients with cartilage-hair hypoplasia. A targeted Rmrp gene mutation in mice, corresponding to a gene mutation in cartilage-hair hypoplasia patients, altered lncRNA chromatin occupancy, and reduced the DDX5-RORγt interaction and RORγt target gene transcription. Elucidation of the link between Rmrp and the DDX5-RORγt complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation, and provides new opportunities for therapeutic intervention in TH17-dependent diseases.

Melatonin intake and potential chronobiological effects on human health.

Melatonin is an indolamine with a recognized chronobiotic role. In turn, the supplementation of melatonin through capsules has been shown to be efficient in the modulation of inflammatory markers, oxidative stress, as well as in the control of hypertension and metabolic syndrome. However, the science of nutrition is interested in the study of the food sources of this hormone and its possible therapeutic effects. Thus, this review aimed to identify and present scientific papers that quantified melatonin in foods and evaluated its application in intervention studies. In total, 278 studies were found, of which 17 were included in this review. The results show that meats, fish, eggs, cereals, tubers, oilseeds, mushrooms, fruits, vegetables, alcoholic and non-alcoholic beverages and dairy products had some items analyzed for their melatonin concentrations. The concentrations reported presented considerable amplitude among different foods and even within the same species, possibly due to differences in cultivation and different hormonal dosing techniques. Also, different concentrations of melatonin can be presented for the same food when submitted to processes such as cooking, roasting or fermentation. The intervention studies presented positive results regarding the consumption of foods rich in melatonin and clinical-metabolic indicators. However, in order to guide nutritional behavior, it is necessary to consult a composition table that makes melatonin concentrations available and considers the processes involved in the preparation of the food. With this table, it will be possible to analyze the real effect of habitual consumption of melatonin from food on health.

Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons.

Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing. Phasic firing of the neurons, which is well known to encode reward signals, is upregulated by repeated social-defeat stress, a highly validated mouse model of depression. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals. However, direct evidence--in real time--linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, whereas inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.