[Importance of nutrition for immune defense. The role of milk and its natural components]. / Importancia de la nutrición en la defensa inmunitaria. Papel de la leche y sus componentes naturales.

INTRODUCTION: The immune system is a complex and integrated system whose main function is to protect the body from external aggression by microorganisms, allergens, or toxic agents. Different studies show that maintaining optimal amounts of different nutrients in the body is essential to ensure the synthesis of different factors related to the immune system. Most interesting nutrients and bioactive compounds include: vitamins A, B6, B12, C, D, E, folic acid (B9) and biotin (B7); minerals such as zinc, iron, selenium, magnesium and copper; proteins (lactoferrin) and bioactive peptides; omega-3 fatty acids; and other nutrients and bioactive compounds such as fiber, polyphenols, carotenoids, probiotics, etc. Following a varied and balanced diet, including the servings recommended by food guides for each food group, is essential to achieve nutrient requirements. Food groups to which special attention should be paid are: fruits and vegetables (because of their high content in micronutrients and antioxidant compounds), fatty fish (because it contains omega-3 fatty acids), and dairy products (because this group contains a large number of nutrients). In particular, milk-especially enriched milk-contains many of the nutrients mentioned above. Moreover, their daily consumption, within a balanced diet, can help significantly cover their nutrient reference values. Finally, it is important to consider kind of milks as a good dietary alternative to increase the intake of some important nutrients for the proper functioning of the immune system, most especially some of them such as vitamin D, since a large percentage of the population have nutritional deficiencies.

INTRODUCCIÓN: El sistema inmunitario es un sistema complejo e integrado cuya función principal es proteger al organismo de agresiones externas provocadas por microorganismos, alergenos o agentes tóxicos. Diferentes estudios ponen de manifiesto que el mantenimiento de las cantidades óptimas de diferentes nutrientes es esencial para garantizar la síntesis de diferentes factores y mediadores de este sistema. Entre los nutrientes y compuestos bioactivos con mayor interés destacan: las vitaminas A, B6, B12, C, D, E, ácido fólico (B9) y biotina (B7); minerales como el zinc, hierro, selenio, magnesio y cobre; proteínas (lactoferrina) y péptidos bioactivos; ácidos grasos omega-3, y otros nutrientes y compuestos bioactivos como fibra, polifenoles, carotenoides, probióticos, etc. El seguimiento de una dieta variada y equilibrada que incluya las raciones recomendadas por las guías alimentarias para cada grupo de alimentos es fundamental para alcanzar los requerimientos de estos nutrientes. Y entre los grupos de alimentos a los que se debe prestar especial atención están: las frutas y verduras (por su alto contenido en micronutrientes y compuestos antioxidantes), los pescados azules (por contener omega-3) y los lácteos (por ser alimentos con gran cantidad de nutrientes). En concreto, la leche, especialmente enriquecida, contiene muchos de los nutrientes anteriormente mencionados y su consumo diario, dentro de una dieta equilibrada, puede contribuir a cubrir cantidades importantes de sus valores de referencia. Por último, es importante considerar las leches enriquecidas como una buena alternativa dietética para aumentar la ingesta de muchos nutrientes importantes para el buen funcionamiento del sistema inmune y, en especial, de algunos de ellos, como la vitamina D, en los que un gran porcentaje de la población presenta deficiencias nutricionales.

Interaction between drugs and the gut microbiome.

The human gut microbiome is a complex ecosystem that can mediate the interaction of the human host with their environment. The interaction between gut microbes and commonly used non-antibiotic drugs is complex and bidirectional: gut microbiome composition can be influenced by drugs, but, vice versa, the gut microbiome can also influence an individual's response to a drug by enzymatically transforming the drug's structure and altering its bioavailability, bioactivity or toxicity (pharmacomicrobiomics). The gut microbiome can also indirectly impact an individual's response to immunotherapy in cancer treatment. In this review we discuss the bidirectional interactions between microbes and drugs, describe the changes in gut microbiota induced by commonly used non-antibiotic drugs, and their potential clinical consequences and summarise how the microbiome impacts drug effectiveness and its role in immunotherapy. Understanding how the microbiome metabolises drugs and reduces treatment efficacy will unlock the possibility of modulating the gut microbiome to improve treatment.

Perinatal Inflammation Reprograms Neuroendocrine, Immune, and Reproductive Functions: Profile of Cytokine Biomarkers.

Viral and bacterial infections causing systemic inflammation are significant risk factors for developing body. Inflammatory processes can alter physiological levels of regulatory factors and interfere with developmental mechanisms. The brain is the main target for the negative impact of inflammatory products during critical ontogenetic periods. Subsequently, the risks of various neuropsychiatric diseases such as Alzheimer's and Parkinson's diseases, schizophrenia, and depression are increased in the offspring. Inflammation-induced physiological disturbances can cause immune and behavioral disorders, reproductive deficiencies, and infertility. The influence of maternal immune stress is mediated by the regulation of pro-inflammatory cytokines such as interleukin (IL)-1ß, IL-6, monocyte chemotactic protein 1, leukemia-inhibiting factor, and tumor necrosis factor-alpha secretion in the maternal-fetal system. The increasing number of patients with neuronal and reproductive disorders substantiates the identification of biomarkers for these disorders targeted at their therapy.

Various Tastes of Sugar: The Potential of Glycosylation in Targeting and Modulating Human Immunity via C-Type Lectin Receptors.

C-type lectin receptors (CLRs) are important in several immune regulatory processes. These receptors recognize glycans expressed by host cells or by pathogens. Whereas pathogens are recognized through their glycans, which leads to protective immunity, aberrant cellular glycans are now increasingly recognized as disease-driving factors in cancer, auto-immunity, and allergy. The vast variety of glycan structures translates into a wide spectrum of effects on the immune system ranging from immune suppression to hyper-inflammatory responses. CLRs have distinct expression patterns on antigen presenting cells (APCs) controlling their role in immunity. CLRs can also be exploited to selectively target specific APCs, modulate immune responses and enhance antigen presentation. Here we will discuss the role of glycans and their receptors in immunity as well as potential strategies for immune modulation. A special focus will be given to different dendritic cell subsets as these APCs are crucial orchestrators of immune responses in infections, cancer, auto-immunity and allergies. Furthermore, we will highlight the potential use of nanoscale lipid bi-layer structures (liposomes) in targeted immunotherapy.

The fate of myofibroblasts during the development of fibrosis in Crohn's disease.

Intestinal fibrosis is a devastating complication in patients with inflammatory bowel disease. Its characteristics include the loss of regular peristalsis and nutrition absorption, excessive deposition of extracellular matrix (ECM) components, thickness of intestinal lumen due to the formation of strictures and of scar tissue. As a major cell type involved in fibrogenesis, the myofibroblasts have already been shown to have a plastic and heterogeneous function in producing abundant collagen, fibronectin and connective tissue growth factor. The primary sources of ECM-producing and vimentin-positive myofibroblasts come from different precursor cells, including bone marrow-derived mesenchymal cells, fibrocytes, pericytes, epithelial to mesenchymal transition and endothelial to mesenchymal transition. Recent immunological research findings suggest that numerous cytokines and chemokines made from macrophages, in addition to T cells and other myeloid cell types, are also important drivers of myofibroblast differentiation and hence of the activation of myofibroblast-mediated transforming growth factor and collagen production. In this review we discuss the origins, roles and cell signaling of myofibroblasts during the development of fibrosis in different organs, particularly in Crohn's disease. Finally, we suggest that the epigenetic and immunological regulation of myofibroblast differentiation may provide a novel antifibrotic strategy in the near future.

Immune System Effects of Insulin-Like Peptide 5 in a Mouse Model.

Introduction: Insulin-like peptide 5 (INSL5) is a peptide hormone with proposed actions in glucose homeostasis and appetite regulation via its cognate receptor, relaxin family peptide receptor 4 (RXFP4). Here, we look for evidence for their involvement in the immune system using a mouse model. Methods: In silico analyses: we queried public databases for evidence of expression of INSL5-RXFP4 in immune system tissues/cells (NCBI's SRA and GeoProfiles) and disorders (EMBO-EBI) and performed phylogenetic footprinting to look for evidence that they are regulated by immune-associated transcription factors (TFs). Experimental analyses: We characterized the expression and correlation of INSL5/RXFP4 and other immune system markers in central and peripheral immune organs from C57/bl6 mice in seven cohorts. We tested whether fluctuations in circulating INSL5 induce an immune response, by injecting mice with 30 µg/kg of INSL5 peptide in the peritoneum, and examining levels of immune markers and metabolic peptides in plasma. Lastly, we quantified the expression of Rxfp4 in T-cells, dendritic cells and cell lines derived from human and mouse and tested the hypothesis that co-incubation of ANA-1 cells in INSL5 and LPS alters cytokine expression. Results: We find Insl5 expression only in thymus (in addition to colon) where its expression was highly correlated with Il-7, a marker of thymocyte development. This result is consistent with our in silico findings that Insl5 is highly expressed in thymic DP, DN thymocytes and cortical TEC's, and with evidence that it is regulated by thymocyte-associated TF's. We find Rxfp4 expression in all immune organs, and moderately high levels in DCs, particularly splenic DCs, and evidence that it is regulated by immune-associated TF's, such as STAT's and GATA. Systemic effects: We observed significantly elevated concentrations of blood GLP-1, GIP, GCG and PYY following intraperitoneal injection of INSL5, and significantly altered expression of cytokines IL-5, IL-7, M-CSF, IL-15, IL-27 and MIP-2. Immune cell effects: Incubation of ANA-1 cells with INSL5 impeded cell growth and led to a transient elevation of IL-15 and sustained reduction in IL-1ß, IL-6 and TNFα. Conclusion: We propose that INSL5-RXFP4 play a novel role in both central and peripheral immune cell signaling.

Emotion Regulation and Immune Functioning During Grief: Testing the Role of Expressive Suppression and Cognitive Reappraisal in Inflammation Among Recently Bereaved Spouses.

OBJECTIVE: Losing a spouse is a distressing life event that can negatively affect both mental and physical health. Stress-induced health consequences often include increased risk of cardiovascular disease and altered immune system functioning marked by increased inflammation. Here, we sought to identify individual difference factors that covary with problematic inflammatory outcomes. METHOD: We measured recently bereaved spouses' (n = 99) propensity to use emotion regulation strategies and peripheral inflammation, as measured by levels of proinflammatory cytokines after ex vivo stimulation of peripheral leukocytes with T-cell agonists. Specifically, we measured participants' use of cognitive reappraisal, an adaptive emotion regulation strategy in many contexts, and expressive suppression, a less adaptive emotion regulation strategy that involves actively inhibiting emotions after already experiencing them. RESULTS: Bereaved spouses who self-reported frequently using expressive suppression as an emotion regulation strategy tended to have a more pronounced inflammatory response, as indexed by higher levels of a composite cytokine index consisting of interleukin (IL) 17A, IL-2, IL-6, tumor necrosis factor α, and interferon-γ (b = 0.042), as well as tumor necrosis factor α (b = 0.083) and interferon-γ (b = 0.098) when analyzed individually. Notably, these associations were observed in both unadjusted and adjusted models, with the latter including known covariates of inflammation and other potential confounding variables. CONCLUSIONS: These findings suggest that bereaved spouses' use of emotion regulation strategies is associated with altered immune functioning, and such a link may be an important biological pathway by which interventions targeting affect may improve immune system-related health outcomes.

Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis.

Development of central nervous system (CNS) is regulated by both intrinsic and peripheral signals. Previous studies have suggested that environmental factors affect neurological activities under both physiological and pathological conditions. Although there is anatomical separation, emerging evidence has indicated the existence of bidirectional interaction between gut microbiota, i.e., (diverse microorganisms colonizing human intestine), and brain. The cross-talk between gut microbiota and brain may have crucial impact during basic neurogenerative processes, in neurodegenerative disorders and tumors of CNS. In this review, we discuss the biological interplay between gut-brain axis, and further explore how this communication may be dysregulated in neurological diseases. Further, we highlight new insights in modification of gut microbiota composition, which may emerge as a promising therapeutic approach to treat CNS disorders.

Synthetic Biology Approaches in Immunology.

Breakthroughs in gene synthesis has allowed synthetic biologists the ability to design any DNA sequence of interest, enabling the possibility to create complex systems inside cells with novel functions to tackle problems in immunology. Synthetic immunology of mammalian cells expressing natural or synthetic genes can guide and induce immune responses in patients. Through recent developments in engineering chimeric receptors, it is now feasible to customize control over engineered cells to target the disease sites with specificity. These cells can avoid immune rejection if derived from expandable cell types (e.g., stem cells or T cells) and then can be grown in abundance before implantation. However, safety concerns of engineered cells in circulation necessitates the development of a wide range of mechanisms to kill cells after their therapeutic life ends. This therapeutic effect is still predominantly the secretion of therapeutic proteins, but novel therapeutic interventions have been explored by synthetic biologists. In the pursuit of engineering new cell functions for synthetic immunology, it is possible that many problems previously thought intractable may actually be possible.

Dissecting FcγR Regulation through a Multivalent Binding Model.

Many immune receptors transduce activation across the plasma membrane through their clustering. With Fcγ receptors (FcγRs), this clustering is driven by binding to antibodies of differing affinities that are in turn bound to multivalent antigen. As a consequence of this activation mechanism, accounting for and rationally manipulating immunoglobulin (Ig)G effector function is complicated by, among other factors, differing affinities between FcγR species and changes in the valency of antigen binding. In this study, we show that a model of multivalent receptor-ligand binding can effectively account for the contribution of IgG-FcγR affinity and immune complex valency. This model in turn enables us to make specific predictions about the effect of immune complexes of defined composition. In total, these results enable both rational immune complex design for a desired IgG effector function and the deconvolution of effector function by immune complexes.

Regulatory functions of γδ T cells.

γδ T cells share characteristics of innate and adaptive immune cells and are involved in a broad spectrum of pro-inflammatory functions. Nonetheless, there is accumulating evidence that γδ T cells also exhibit regulatory functions. In this review, we describe the different phenotypes of regulatory γδ T cells in correlation with the identified mechanisms of suppression.

Acute Retroviral Syndrome Is Associated With High Viral Burden, CD4 Depletion, and Immune Activation in Systemic and Tissue Compartments.

Background: Many individuals with acute human immunodeficiency virus infection (AHI) experience acute retroviral syndrome (ARS), which is associated with adverse long-term clinical outcomes. Methods: Participants presenting for voluntary human immunodeficiency virus (HIV) testing were enrolled during AHI in Bangkok, Thailand. ARS was defined by ≥3 qualifying signs/symptoms. HIV burden, immunophenotypes, and biomarkers were stratified by ARS diagnosis at enrollment and after up to 96 weeks of antiretroviral therapy (ART). Results: From 212382 samples screened, 430 participants were enrolled during AHI, including 335 (78%) with ARS. Median age was 26 years and 416 (97%) were men. Sixty (14%) underwent sigmoid biopsy and 105 (24%) underwent lumbar puncture during AHI. Common symptoms included fever (93%), fatigue (79%), pharyngitis (67%), and headache (64%). Compared to those without ARS, participants with ARS were in later Fiebig stages with higher HIV RNA in blood, colon, and cerebrospinal fluid; higher total HIV DNA in blood; CD4 depletion in blood and colon; and elevated plasma tumor necrosis factor alpha (TNF-α), C-reactive protein, and D-dimer (all P < .05). Subgroup analyses of Fiebig I/II participants (95 with ARS, 69 without) demonstrated similar findings. After 96 weeks of ART, TNF-α and interleukin 6 were elevated in the ARS group (P < .05) but other biomarkers equilibrated. Conclusions: ARS was associated with high viral burden, CD4 depletion, and immune activation across multiple body compartments during AHI and prior to ART. Persistent inflammation despite suppressive ART could contribute to increased morbidity in individuals who experience ARS.

[Evolutionary medicine: A new look on health and disease]. / La médecine évolutionniste : un nouveau regard sur la santé et les maladies.

Evolutionary medicine represents an innovative approach deriving from evolutionary biology. It includes the initial Darwin's view, its actualization in the light of progresses in genetics and also dissident theories (i.e. non gene-based) particularly epigenetics. This approach enables us to reconsider the pathophysiology of numerous diseases, as for instance, infection, and our so-called diseases of civilization especially obesity, type 2 diabetes, allergy or cancer. Evolutionary medicine may also improve our knowledge regarding inter-individual variation in susceptibility to disease or drugs. Furthermore, it points out the impact of our behaviors and environment on the genesis of a series of diseases.

Therapeutic hyperthermia: The old, the new, and the upcoming.

Hyperthermia has long been used for cancer treatment, either alone or in combination with chemotherapy, radiation therapy, or both. Its efficacy and versatility continue to be well demonstrated in randomized trials across a number of primary cancers, but barriers to its widespread adoption persist including effective delivery and verification systems. This article describes hyperthermia, details its biological mechanisms of action and immunological effects, and summarizes select preclinical data and key clinical trials combining hyperthermia with standard cancer treatments. Current challenges and emerging technologies that have the potential to make this translational therapy more accessible to a greater number of patients are also described.

[Immune and genetic markers revealed in women working in technical rubber goods production].

Medical examination covered female workers engaged into chemical production of technical rubber goods, under combined exposure to chemicals (nitrogen oxides, carbon oxide) and noise exceeding MAC by 3.7-27.5%. Findings are increased phagocytary activity, lower level of serum IgM and IgG, suppressed expression of CD25 and CD95 T-cell receptors, and slower apoptosis induced via Fas receptor--all those indicators associated with work conditions. The disorders revealed are actualized on a basis of genetic variability features of the females, that is characterized by prevalence of mutant allels of FAS and TNFR genes with minor homozygous phenotype.

[The ageing immune system]. / Das alternde Immunsystem.

The aging of the immune system, also called immunosenescence, contributes to the increased morbidity and mortality from infections, autoimmune diseases and cancer as well as to the low efficacy of vaccination in elderly persons. Immunosenescence is characterized by a decrease in cell-mediated immune function and by reduced humoral immune responses caused by age-related changes in the innate immune system and age-dependent defects in T-and B-cell function. This paper gives an overview of the most important modifications in the different compartments of the immune system during the ageing process.

Cell exhaustion in HIV-1 infection: role of suppressor cells.

PURPOSE OF REVIEW: Suppressor cells regulate immune responses during chronic viral infection by limiting immunopathology associated with inflammation and immune activation. This dampening of adaptive immune responses can be harmful in HIV-1 infection as it also prevents the immune system from clearing the virus, leading to viral persistence and prolonged antigen expression that often leads to immune exhaustion. A current priority is to find the best strategy to target and manipulate key molecules such as CD39 that suppress anti-HIV-1 immune responses. RECENT FINDINGS: New suppressor cell subsets and cellular markers have been identified and characterized in the past years. We are able to identify and measure regulatory T cells, regulatory B cells and myeloid-derived suppressor cells in HIV-1-infected patients. We can also measure antigen-specific regulatory T cells in patients, which is a valuable step forward. Targeting HIV-1-specific regulatory T cells could be beneficial if we aim to manipulate key inhibitory molecules such as CTLA-4 and/or PD-1 that have already proven their efficacy in cancer. New other possible targets to take into account are CD39 and Tim-3-Gal9 pathways that have recently attracted attention in the field. These new findings offer the possibility to recognize suppressor cells as future targets in therapeutic vaccines because it became obvious that good vaccines candidates should concurrently generate robust effector responses and inhibit specific pathways that lead to immune suppression and exhaustion. SUMMARY: The recent advances on suppressor cells and the availability of new markers or assays will certainly open up new avenues for targeting molecules that are involved in immune suppression pathways, thus avoiding viral persistence and immune exhaustion.