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Background and objectives Dietary habits strongly influence our health status, mostly, in terms of maintenance of the inflammatory/anti-inflammatory homeostasis. High fat and high sugar diets account for the development of a low-grade inflammation which is the pathogenic common denominator of various chronic disease. Severe Acute Respiratory Syndrome Coronavirus (SARS)-CoV2 (COVID-19) infection affects all ages and especially frail elderly people and a nutri-tional intervention seems to be crucial in the course of this pandemic. The present review describes the properties of some vegetal products and their derivatives, such as Lupin sp., garlic, salvia and extra virgin olive oil (EVOO) that can be exploit-ed for their beneficial effects, as preventive and/or nutritional treatment of coronavirus disease SARS-CoV2. Discussion Lupin, salvia, garlic and EVOO share overlapping properties, such as anti-oxidant, anti-inflammatory and anti-viral activities. Quite importantly, these products and their derivatives are able to recover the expression of angiotensin con-verting enzyme expression 2 on cell membrane, otherwise suppressed by COVID-19 binding and entry into cytoplasm. Conclusion Dietary administration of the above nutraceuticals or their extracts may play a preventive or nutritional role in the course of SARS-CoV2 infection, even including the effects of the lockdown and the condition of inflamm-ageing.

Background & Objectives: In old people, both innate and adaptive immune responses are impaired, thus leading to a condition of systemic inflamm-ageing, even including the involvement of the central nervous system (CNS). Aims: Here, main mechanisms of the immune ageing and neuro-inflammation will be discussed along with the dietary approaches for the modulation of age related diseases. Discussion: Neuroinflammation is caused by the passage of inflammatory mediators through the brain blood barrier to CNS. Then, in the brain, antigenic stimulation of microglia and/or its activation by peripheral cytokines lead to a robust production of free radicals with another wave of proinflammatory cytokines which, in turn, causes massive neuronal damage. Also, infiltrating T cells [T helper (h) and T cytotoxic cells] contribute to neuronal damage. Additionally, a peripheral imbalance between inflammatory Th17 cells and anti-inflammatory T regulatory cells seems to be prevalent in the aged brain, thus leading to a proinflammatory profile. Alzheimer’s disease, Parkinson’s disease and multiple sclerosis will be described as typical neurodegenerative diseases. Finally, modulation of the immune response thanks to the anti-oxidant and anti-inflammatory effects exerted by dietary products and nutraceuticals in ageing will be discussed. Special emphasis will be placed on polyunsaturated fatty acids, polyphenols, micronutrients and pre-probiotics and synbiotics. Conclusion: Ageing is characterized by an imbalance subversion of the immune system with a condition of inflamm-ageing. Neuroinflammation and neurodegenerative diseases seem to be a central manifestation of a peripheral perturbation of the immune machinery. Dietary products and nutraceuticals may lead to a down-regulation of the oxidative and pro-inflammatory profile in ageing.

Background: Heavy metals [arsenic, aluminium, cadmium, chromium, cobalt, lead, nickel (Ni), palladium and titanium] are environmental contaminants able to impact with host human cells, thus, leading to severe damage. Objective: In this review, the detrimental effects of several heavy metals on human organs will be discussed and special emphasis will be placed on Ni. In particular, Ni is able to interact with Toll-like receptor-4 on immune and non-immune cells, thus, triggering the cascade of pro-inflammatory cytokines. Then, inflammatory and allergic reactions mediated by Ni will be illustrated within different organs, even including the central nervous system, airways and the gastrointestinal system. Discussion: Different therapeutic strategies have been adopted to mitigate Ni-induced inflammatoryallergic reactions. In this context, the ability of polyphenols to counteract the inflammatory pathway induced by Ni on peripheral blood leukocytes from Ni-sensitized patients will be outlined. In particular, polyphenols are able to decrease serum levels of interleukin (IL)-17, while increasing levels of IL- 10. These data suggest that the equilibrium between T regulatory cells and T helper 17 cells is recovered with IL-10 acting as an anti-inflammatory cytokine. In the same context, polyphenols reduced elevated serum levels of nitric oxide, thus, expressing their anti-oxidant potential. Finally, the carcinogenic potential of heavy metals, even including Ni, will be highlighted. Conclusion: Heavy metals, particularly Ni, are spread in the environment. Nutritional approaches seem to represent a novel option in the treatment of Ni-induced damage and, among them, polyphenols should be taken into consideration for their anti-oxidant and anti-inflammatory activities.

Background:Sepsis is a clinical condition due to an infectious event which leads to an early hyper-inflammatory phase followed by a status of tolerance or immune paralysis. Hyper-inflammation derives from a massive activation of immune (neutrophils, monocytes/macrophages, dendritic cells and lymphocytes) and non-immune cells (platelets and endothelial cells) in response to Gram-negative and Gram-positive bacteria and fungi.Discussion:A storm of pro-inflammatory cytokines and reactive oxygen species accounts for the systemic inflammatory response syndrome. In this phase, bacterial clearance may be associated with a severe organ failure development. Tolerance or compensatory anti-inflammatory response syndrome (CARS) depends on the production of anti-inflammatory mediators, such as interleukin-10, secreted by T regulatory cells. However, once triggered, CARS, if prolonged, may also be detrimental to the host, thus reducing bacterial clearance.Conclusion:In this review, the description of pathogenic mechanisms of sepsis is propaedeutic to the illustration of novel therapeutic attempts for the prevention or attenuation of experimental sepsis as well as of clinical trials. In this direction, inhibitors of NF-κB pathway, cell therapy and use of dietary products in sepsis will be described in detail.

Platelets are cellular fragments derived from bone-marrow megacaryocytes and they are mostly involved in the haemostasis and coagulation. However, according to recent data, platelets are able to perform novel immune functions. In fact, they possess a receptorial armamentarium on their membrane for interacting with innate and adaptive immune cells. In addition, platelets also secrete granules which contain cytokines and chemokines for activating and recruiting even distant immune cells. The participation of platelets in inflammatory processes will also be discussed in view of their dual role in terms of triggering or resolving inflammation. Involvement of platelets in disease will be illustrated, pointing to their versatile function to either up- or down-regulate pathological mechanisms. Finally, despite the availability of some anti-platelet agents, such as aspirin, dietary manipulation of platelet function is currently investigated. In this regard, special emphasis will be placed on dietary omega-3 polyunsaturated fatty acids (PUFAs) and polyphenol effects on platelets. Platelets play a dual role in inflammatory-immune-mediated diseases either activating or deactivating immune cells. Diet based on substances, such as omega-3 PUFAs and polyphenols, may act as a modulator of platelet function, even if more clinical trials are needed to corroborate such a contention.

Background: Eosinophils are primitive myeloid cells derived from bonemarrow precursors and require the intervention of interleukin (IL)-5 for their survival and persistence in blood and tissues. Under steady-state conditions, they contribute to immune regulation and homeostasis. Under pathological circumstances, eosinophils are involved in host protection against parasites and participate in allergy and inflammation. Discussion: Mostly, in asthma, eosinophils provoke airway damage via the release of granule contents and IL-13 with mucus hypersecretion and differentiation of goblet cells. Then, tissue remodeling follows with the secretion of transforming growth factor-β. Eosinophils are able to kill helminth larvae acting as antigen-presenting cells with the involvement of T helper (h)-2 cells and subsequent antibody response. However, they also exert pro-worm activity with the production of suppressive cytokine (IL- 10 and IL-4) and inhibition of nitric oxide. Eosinophils may play a pathogenic role in the course of chronic and autoimmune disease, e.g., inflammatory bowel disease and eosinophilic gastroenteritis, regulating Th2 responses and promoting a profibrotic effect. In atopic dermatitis, eosinophils are commonly detected and may be associated with disease severity. In cutaneous spontaneous urticaria, eosinophils participate in the formation of wheals, tissue remodeling and modifications of vascular permeability. With regard to tumor growth, it seems that IgE can exert anti-neoplastic surveillance via mast cell and eosinophil-mediated cytotoxicity, the so-called allergo-oncology. From a therapeutic point of view, monoclonal antibodies directed against IL-5 or the IL-5 receptors have been shown to be very effective in patients with severe asthma. Finally, as an alternative treatment, polyphenols for their anti-inflammatory and anti-allergic activities seem to be effective in reducing serum IgE and eosinophil count in bronchoalveolar lavage in murine asthma. Conclusion: Eosinophils are cells endowed with multiple functions and their modulation with monoclonal antibodies and nutraceuticals may be effective in the treatment of chronic disease.

Mast cells (MCs) bear many receptors which allow them to respond tAs far as treatment of MC-derived diseases is concerned, allergen immunotherapy as well as other attempts to reduce MC-activation will be outlined according to the recent data. Finally, in agreement with current literature and our own data polyphenols have been demonstrated to attenuate type I allergic reactions and contact dermatitis in response to nickel. The use of polyphenols in these diseases will be discussed also in view of MC involvement.o a variety of exogenous and endogenous stimuli. However, MC function is dual since they can initiate pathological events or protect the host against infectious challenges.:The role of MCs in disease will be analyzed in a broad sense, describing cellular and molecular mechanisms related to their involvement in auto-inflammatory diseases, asthma, autoimmune diseases and cancer. On the other hand, their protective role in the course of bacterial, fungal and parasitic infections will also be illustrated.:Mast cells (MCs) bear many receptors that allow them to respond to a variety of exogenous and endogenous stimuli. However, MC function is dual since they can initiate pathological events or protect the host against infectious challenges.

Fish despite their low collocation in the vertebrate phylum possess a complete immune system. In teleost fish both innate and adaptive immune responses have been described with melanomacrophage centers (MMCs) equivalent to mammalian germinal centers. Primary lymphoid organs are represented by the thymus and kidney, while spleen and mucosa-associated lymphoid tissues act as secondary lymphoid organs. Functions of either innate immune cells (e.g., macrophages and dendritic cells) or adaptive immune cells (T and B lymphocytes) will be described in detail, even including their products, such as cytokines and antibodies. In spite of a robust immune arsenal, fish are very much exposed to infectious agents (marine bacteria, parasites, fungi, and viruses) and, consequentially, mortality is very much enhanced especially in farmed fish. In fact, in aquaculture stressful events (overcrowding), microbial infections very frequently lead to a high rate of mortality. With the aim to reduce mortality of farmed fish through the reinforcement of their immune status the current trend is to administer natural products together with the conventional feed. Then, in the second part of the present review emphasis will be placed on a series of products, such as prebiotics, probiotics and synbiotics, β-glucans, vitamins, fatty acids and polyphenols all used to feed farmed fish. With special reference to polyphenols, results of our group using red grape extracts to feed farmed European sea bass will be illustrated. In particular, determination of cytokine production at intestinal and splenic levels, areas of MMCs and development of hepatopancreas will represent the main biomarkers considered. All together, our own data and those of current literature suggests that natural product administration to farmed fish for their beneficial effects may, in part, solve the problem of fish mortality in aquaculture, enhancing their immune responses.

Background: T cell tolerance both at thymic and peripheral levels is a mechanism of protection finalized to eradicate autoreactive T cell clones and/or to maintain immune homeostasis, especially, postnatally. Central tolerance occurs in the thymic medulla via a mechanism of negative selection which leads to the eradication of autoreactive T cell clones. Mechanisms of Action: Such a tolerogenic event relies on Fas-mediated apoptosis of autoreactive T cell clones operated by thymic dendritic cells (DCs), on the one hand. On the other hand, activated thymic T regulatory (Treg) cells in cooperation with medullary thymic epithelial cells and DCs suppress autoreactive T cell clones. Peripherally, different types of Treg cells exert the so-called peripheral tolerance towards autoreactive T cell clones which may have escaped from negative selection mechanisms. At the same time, peripheral Treg cells activated by tolerogenic DC have antiinflammatory activities, especially in the intestine towards food and microbial antigens. Drug Targeting: Various natural and dietary products, such as vitamins (A, C, D), lactobacilli and polyphenols will be described for their tolerogenic capacity to attenuate the inflammatory pathway, as observed in preclinical and clinical studies.

Background: Secondary lymphoid organs (SLO) are distributed in many districts of the body and, especially, lymph nodes, spleen and gut-associated lymphoid tissue are the main cellular sites. On the other hand, tertiary lymphoid organs (TLO) are formed in response to inflammatory, infectious, autoimmune and neoplastic events. Developmental Studies: In the present review, emphasis will be placed on the developmental differences of SLO and TLO between small intestine and colon and on the role played by various chemokines and cell receptors. Undoubtedly, microbiota is indispensable for the formation of SLO and its absence leads to their poor formation, thus indicating its strict interaction with immune and non immune host cells. Furthermore, food antigens (for example, tryptophan derivatives, flavonoids and byphenils) bind the aryl hydrocarbon receptor on innate lymphoid cells (ILCs), thus promoting the development of postnatal lymphoid tissues. Also retinoic acid, a metabolite of vitamin A, contributes to SLO development during embryogenesis. Vitamin A deficiency seems to account for reduction of ILCs and scarce formation of solitary lymphoid tissue. Translational Studies: The role of lymphoid organs with special reference to intestinal TLO in the course of experimental and human disease will also be discussed. Future Perspectives: Finally, a new methodology, the so-called “gut-in-a dish”, which has facilitated the in vitro interaction study between microbe and intestinal immune cells, will be described.

Antimicrobial Peptides (AMPs) are produced by a variety of human immune and non immune cells in health and disease. In virtue of their antimicrobial activity, AMPs have been exploited in human disease and here this aspect will extensively be described. AMPs in comparison to antibiotics possess a larger spectrum of antimicrobial activity without inducing microbial resistance. Therefore, their use in the course of antibiotic-resistant infections is justified. AMP activity in early life, in the airways, in the oral and gastro-enteric system, in the skin and in the female reproductive tract, respectively, will be elucidated. In addition, the use of AMPs in sepsis will be discussed due to the frequency of this pathological condition characterized by multiple organ dysfunctions. Finally, the evidence that AMPs represent valid substitutes of antibiotics will be provided and a series of novel substances able to reinforce the innate immune response in different clinical settings will be discussed.

Background:Drugs of abuse affect both central nervous system (CNS) and peripheral immune function. Besides the involvement of dopamine and glutamate systems, chronic exposure to drugs of abuse alters immune homeostasis, promoting a pro-inflammatory status. At the same time, impaired peripheral immunity leads to an increased susceptibility to infections in drug abusers.Discussion:There is evidence that certain drugs, such as opioids, activate microglial cells and astrocytes which, in turn, provoke central neuroinflammation. Particularly, opioids bind the Toll-like receptor (TLR)-4 with increased expression of nuclear factor kappa-light-chain-enhancer of activated B cells and release of pro-inflammatory cytokines. Peripheral mediators released by immune cells also contribute to aggravate central neuroinflammation.Conclusion:These are based either on the inhibition of TLR-4 activation by drugs of abuse or on the correction of dopamine and glutamate pathways. Finally, a hypothetic nutraceutical intervention with polyphenols in view of their anti-inflammatory and anti-oxidant properties will be outlined as an adjuvant treatment for drugs of abuse-related disorders.

BACKGROUND Nickel (Ni) is widely distributed in the environment and continuous exposure to this metal may lead to pathological manifestations, such as the human allergic contact dermatitis. METHODS The in vitro effects of Ni on human healthy non allergic peripheral blood mononuclear cells (PBMCs) in the absence or presence of red grape polyphenols have been evaluated. In the culture supernatants, levels of cytokines have been determined by ELISA, while nitric oxide (NO) concentration has been evaluated by a colorimetric procedure. RESULTS Ni per se did not affect release of interferon-γ, interleukin (IL)-4 and IL-10. Instead, this metal dramatically reduced production of IL-17 which was restored by the supplementation of polyphenols. Finally, while Ni significantly increased generation of NO, polyphenols reduced production of this compound. CONCLUSION Taken together, all these data may indicate a preventative role of polyphenols against Ni exposure in non allergic to Ni individuals, also confirming the immunomodulating role of these natural products. The interaction Ni/polyphenols/lipopolysaccharides will also be discussed.

It is well known that cocoa and dark chocolate possess polyphenols as major constituents whose dietary consumption has been associated to beneficial effects. In fact, cocoa and dark chocolate polyphenols exert anti-oxidant and anti-inflammatory activities switching on some important signaling pathways such as Toll-like receptor 4/Nuclear factor B/Signal transducer and activator of transcription. In particular, cocoa polyphenols induce release of nitric oxide (NO) through activation of endothelial nitric oxide synthase which, in turn, accounts for vasodilation and cardioprotective effects. In the light of the above described properties, a number of clinical trials based on the consumption of cocoa and dark chocolate have been conducted in healthy subjects as well as in different categories of patients, such as those affected by cardiovascular, neurological, intestinal and metabolic pathologies. Even if data are not always concordant, modifications of biomarkers of disease are frequently associated to improvement of clinical manifestations. Quite interestingly, following cocoa and dark chocolate ingestion cocoa polyphenols also modulate intestinal microbiota, thus leading to the growth of bacteria which trigger a tolerogenic anti-inflammatory pathway in the host. Finally, many evidences encourage the consumption of cocoa and dark chocolate by aged people for the recovery of the neurovascular unit.

Immune decline with ageing accounts for the increased risk of infections, inflammatory chronic disease, autoimmunity and cancer in humans. Both innate and adaptive immune functions are compromised in aged people and, therefore, attempts to correct these dysfunctions represent a major goal of modern medicine. In this review, special emphasis will be placed on the aged innate immunity with special reference to polymorphonuclear cell, monocyte/ macrophage, dendritic cell and natural killer cell functions. As potential modifiers of the impaired innate immunity, some principal nutraceuticals will be illustrated, such as micronutrients, pre-probiotics and polyphenols. In elderly, clinical trials with the above products are scanty, however, some encouraging effects on the recovery of innate immune cells have been reported. In addition, our own results obtained with symbiotics and polyphenols extracted from red wine or fermented grape marc suggest the potential ability of these substances to modulate the innate immune response in ageing, thus reducing the inflammaging which characterizes immune senescence.

The innate lymphoid cells (ILCs) have been grouped into three main categories: ILC1s [T helper (h)1-like cells], ILC2s (Th2-like cells) and ILC3s (Th17-like cells), respectively. In particular, ILC3s are responsible for the secretion of both interleukin (IL)-17 and IL-22, which play either protective (antimicrobial and repairing activities) or harmful (inflammation and tumor growth) roles into the host. Here, some putative interventional studies will be hypothesized, taking into account that activation of innate cell receptors, arylhydrocarbon receptor and gut microbiota, respectively, contribute to both differentiation and function of ILC3s. A series of biological and natural compounds may represent putative regulators of these cells in the gut. In this respect, the modulating effects of agonist and antagonists of Toll-like receptors and nucleotide binding oligomerization domain-like receptors, polyphenols and probiotics will be described in detail.

Polyphenols contained in FGM from Negroamaro (N) and Koshu (K) Vitis vinifera have been shown to exhibit several immunomodulating activities. For instance, mice affected by experimental colitis when administered with K-FGM showed an attenuation of the inflammatory process. In murine asthma, K-FGM reduced IgE production and eosinophil number in bronchial alveolar lavage fluid. In vitro, both N- and K-FGM were able to induce T regulatory cells in terms of Foxp-3 molecule expression and release of interleukin-10. In another set of experiments both N- and K-FGM were able to balance rate of proliferation/apoptosis/necrosis of normal human peripheral lymphocytes, thus indicating the property of these compounds to maintain immune homeostatic mechanisms in the host. On the other hand, N- and K-FGM inhibited human basophil degranulation, thus, confirming our previous results obtained with rat basophilic leukemia cells. Finally, N- and K-FGM also decreased oxidative burst of human polymorphonuclear cells and monocytes.Taken together, these findings imply the potential clinical usefulness of FGM administration in inflammatory/allergic conditions, such as chronic asthma.

Human ageing is characterized by several abnormalities of both innate and adaptive immune responses, thus leading to an increased frequency of infectious, inflammatory, allergic and autoimmune diseases. In elderly patients, among allergic diseases, asthma is a very common pathological event which complicates the dysfunction of many systems. Among a variety of natural products used to modulate the altered immune response, polyphenols have been shown to exert antiinflammatory activities in both young and aged persons. Here, special emphasis will be given to the the immune-modulating effects of Leucoselect® Phytosome® (a dietary supplement enriched in the flavonoid epigallocatechin) administered to frail elderly patients. Leucoselect® Phytosome® was able to upregulate the T helper (Th)1 response [increase in serum concentrations of interleukin (IL)-2 and interferon-γ]. On the other hand, IL-4 serum levels, as an index of Th2 function, fluctuated within normal ranges. Quite interestingly, in this cohort of frail aged patients from South Italy the balance between inflammation (IL-17) and anti-inflammation (IL-10) was preserved, thus suggesting that the Mediterranean diet might have been involved in the observed effects. In conclusion, these data support the ability of Leucoselect® Phytosome® to induce up-regulation of Th1 responses in frail elderly patients which may be beneficial in those patients affected by chronic allergic disorders.

Cigarette smoke (CS) accounts for the outcome of several pathologies, even including lung cancer, cardiovascular disease and chronic obstructive pulmonary disease (COPD). Under healthy conditions, lung immune system becomes tolerant in response to various external stimuli. CS exposure alters the pulmonary immune equilibrium, thus leading to a condition of hyper activation of the local innate and adaptive immunity. COPD is one of the major complications of chronic CS exposure where a pro-inflammatory profile of the pulmonary and systemic immunity is predominant. In this review, alternative treatments with natural products to mitigate CS-mediated pulmonary inflammation are proposed. In particular, polyphenols, a class of natural compounds largely present in fruits and vegetables, have been shown to act as anti-inflammatory agents. Accordingly, recent experimental and clinical evidences support polyphenol-mediated potential health benefits in smokers. For instance, pomegranate juice is able to attenuate the damage provoked by CS on cultured human alveolar macrophages. In addition, maqui beery extract has been proven to normalize H2O2 and interleukin-6 levels in exhaled breath condensate in healthy smokers. However, some limitations of alternative treatments are represented by a better knowledge of the mechanism(s) of action exerted by polyphenols and by the lack of animal models of COPD. In any case, the potential targets of polyphenols in the course of COPD will be outlined with special reference to the activation of T regulatory cells as well as to the inhibition of the polymorphonuclear cell and monocyte respiratory burst and of the NF-κB pathway, respectively.

Background Chronic upper respiratory tract infections (cURTI) are very frequent illnesses which occur at any age of life. In elderly, cURTI are complicated by immunosenescence, with involvement of lung immune responsiveness. Results In the present study, 51 elderly (age range: 66–86) and 51 young (age range 24–58) cURTI patients underwent a single cycle (two weeks) of inhalatory therapy with salt-bromide-iodine thermal water in the thermal station “Margherita di Savoia” (Margherita di Savoia, BAT, Italy). Peripheral blood serum cytokines and clinical assessment were performed before therapy (T0) and after six months (T1) and 12 months (T2) from inhalatory treatment. In both elderly and young patients, at baseline an increased release of T helper (h)1-related cytokines [interleukin (IL)-2 and interferon-γ] and of Th2-related cytokine (IL-4) was documented. Inhalatory treatment reduced the excessive secretion of all the above-cited cytokines. IL-10 values were above normality at all times considered in both groups of patients. In addition, an increase in IL-17 and IL-21 serum levels following therapy was observed in both groups of patients. Pro-inflammatory cytokine (IL-1β, IL-6, IL-8 and tumor necrosis factor-α) baseline values were lower than normal values at T0 in both elderly and young cURTI patients. Their levels increased following inhalatory treatment. Clinically, at T2 a dramatic reduction of frequency of upper respiratory tract infections was recorded in both groups of patients. Conclusion Thermal water inhalation is able to modulate systemic immune response in elderly and young cURTI patients, thus reducing excessive production of Th1 and Th2-related cytokines, on the one hand. On the other hand, increased levels of IL-21 (an inducer of Th17 cells) and of IL-17 may be interpreted as a protective mechanism, which likely leads to neutrophil recruitment in cURTI patients. Also restoration of pro-inflammatory cytokine release following inhalatory therapy may result in microbe eradication. Quite importantly, the maintenance of high levels of IL-10 during the follow-up would suggest a consistent regulatory role of this cytokine in attenuating the pro-inflammatory arm of the immune response.

Western diets seem to be responsible for the development of metabolic diseases, atherosclerosis, neurodegeneration, and cancer. All these pathologies are characterized by an inflammatory status, on one hand, and on the other hand, by an alteration of the gut microbiota. Synbiotics are a combination of prebiotics and probiotics endowed with the ability to reduce inflammation and keep equilibrium in the microbiota components. In human trials, synbiotics have successfully been administered in different pathologies, including aging. The elderly exhibit multiple deficits of innate and adaptive immunity and also have an altered microbiota which polarizes the immune response toward inflammation. Microbiota-induced modification of the immune response in the elderly may prevent or attenuate winter infections. However, clinical trials with synbiotics are still incomplete because assessment of the microbiota composition and monitoring of the peripheral immune response should proceed in parallel to identify the best synbiotic combination.

Farmed fish are exposed to a continuous antigenic pressure by microbial and environmental agents, which may lead to a condition of chronic inflammation. In view of the notion that polyphenols, largely contained in fruits and vegetables, are endowed with antioxidant and anti-inflammatory activities, farmed sea bass (Dicentrarchus labraxL.) have been administered with red grape polyphenol-enriched feed. Polyphenols were extracted from the seeds ofCanosinaNero di TroiaVitis viniferaand mixed with conventional feed at two different concentrations (100 and 200 mg/kg, resp.). Fish samples collected at days 223 and 273, respectively, were evaluated for intestinal and spleen cytokine release as well as for spleen macrophage (MØ) and melanomacrophage center (MMC) areas and distribution. Data will show that in treated fish decrease of intestinal interleukin- (IL-) 1βand IL-6 and increase of splenic interferon- (IFN-)γoccur. On the other hand, in the spleen reduction of MØ number seems to parallel increase in MMCs. Collectively, these data suggest that polyphenol-administered sea bass generate lower levels of intestinal proinflammatory cytokines, while producing larger amounts of spleen IFN-γ, as an expression of a robust and protective adaptive immune response. Increase of MMCs corroborates the evidence for a protective spleen response induced by feed enriched with polyphenols.

Gut immune system is daily exposed to a plethora of antigens contained in the environment as well as in food. Both secondary lymphoid tissue, such as Peyer's patches, and lymphoid follicles (tertiary lymphoid tissue) are able to respond to antigenic stimuli releasing cytokines or producing antibodies (secretory IgA). Intestinal epithelial cells are in close cooperation with intraepithelial lymphocytes and possess Toll-like receptors on their surface and Nod-like receptors (NLRs) which sense pathogens or pathogen-associated molecular patterns. Intestinal microbiota, mainly composed of Bacteroidetes and Firmicutes, generates tolerogenic response acting on gut dendritic cells and inhibiting the T helper (h)-17 cell anti-inflammatory pathway. This is the case of Bacteroides fragilis which leads to the production of interleukin-10, an anti-inflammatory cytokine, from both T regulatory cells and lamina propria macrophages. Conversely, segmented filamentous bacteria rather induce Th17 cells, thus promoting intestinal inflammation. Intestinal microbiota and its toxic components have been shown to act on both Nod1 and Nod2 receptors and their defective signaling accounts for the development of inflammatory bowel disease (IBD). In IBD a loss of normal tolerance to intestinal microbiota seems to be the main trigger of mucosal damage. In addition, intestinal microbiota thanks to its regulatory function of gut immune response can prevent or retard neoplastic growth. In fact, chronic exposure to environmental microorganisms seems to be associated with low frequency of cancer risk. Major nutraceuticals or functional foods employed in the modulation of intestinal microbiota are represented by prebiotics, probiotics, polyunsaturated fatty acids, amino acids and polyphenols. The cellular and molecular effects performed by these natural products in terms of modulation of the intestinal microbiota and mostly attenuation of the inflammatory pathway are described.

Pre-, pro-, and symbiotics are endowed with a broad spectrum of beneficial effects when administered to animals and humans. A series of experimental and clinical studies have clearly demonstrated that prebiotics, probiotics, or their combination are very effective in attenuating chronic inflammatory conditions such as inflammatory bowel disease or obesity. In addition, these natural products are able to prevent or arrest tumor development, acting on the intestinal microbiota as well as potentiating the immune response.Aging is characterized by a dramatic reduction of both innate and adaptive immune responses, the so-called immunosenescence. This leads to an increased incidence of infections, autoimmune diseases, and cancer in the elderly. Pre-, pro-, and symbiotic administration has been shown to ameliorate the immune response in aging. In particular, administration of a symbiotic to free-living elderly was able to potentiate the release of interleukin-8, thus increasing neutrophils in the host, perhaps explaining the reduced frequency of winter infections in the elderly.

Over recent years, neutrophil functions have extensively been reevaluted. For instance, it has been found that extracellular traps generated by activated neutrophils are able to perform a very effective antimicrobial activity against a plethora of microorganisms. In addition, neutrophils possess the ability to interact with monocytes/macrophages either via release of their granule content or via efferocytosis. Efferocytosis is based on neutrophil clearance by macrophages, which, in turn, exert pro- or antinflammatory effects. Furthermore, alarmins released by neutrophils have been shown to mobilize and activate dendritic cells as well as macrophages for antigenpresentation to occur. Finally, other researchers have demonstrated that neutrophils act as suppressor cells by deprivation of arginine in T cells. From a clinical point of view, it is well known that neutrophils are present as activated effector cells in a number of diseases such as infectious disease, sepsis, autoimmune disease, cardiovascular disease and tumors. They play pro-inflammatory and angiogenetic effects in some cases, while in other cases they depress host immune response. In this review, also emphasis will be placed on neutrophil functional deficits which seem to participate to the pathogenesis of various diseases, e.g., viral hepatitis C infection and inflammatory bowel disease. Finally, novel therapeutic measures able to modulate neutrophil functions will be described with special reference to both immune agents and natural products.

Parkinson disease (PD) and Alzheimer disease (AD) are neurodegenerative processes whose frequency is dramatically increasing in the western world. Both diseases share a common pathogenic denominator characterized by an exaggerated activation of the systemic and cerebral immune system, respectively. For instance, lipopolysaccharides in PD and amyloid beta in AD trigger microglia and astrocytes to release reactive oxygen species (ROS) and proinflammatory cytokines. Infiltrating peripheral T cells once activated in the central nervous system also contribute to the neurodegenerative process. Besides innovative biotherapy, nutraceuticals or functional foods are currently investigated for their neuroprotective activities. Especially, vitamin D and polyphenols, seem to be promising therapeutic tools for inhibiting ROS formation and arresting cytokine-mediated neuroinflammation in PD and AD.

The continuous antigenic triggering has greatly contributed to the evolution of the immune system and, therefore, animals have developed cells able to cope with a broad variety of microbial antigens and or their toxins, e.g., endotoxins. At the same time, intestinal commensals have evolved along with human progress and introduction of new foods, thus empowering both regional and systemic immune response. In this review, some important steps in the evolution of the immune system will be analyzed such as organization of lymphoid organs, formation of germinal centers, leukocyte attraction to tissue function of Toll like receptors and role of antimicrobial peptides. In particular, the major phylogenetic acquisitions of living organisms in the assessment of the immune machinery will be emphasized. Finally, fish will be taken into consideration as animal models of human diseases also in view of drug design strategies. Special attention will be focused on vaccinated salmon and zebrafish models.

The environmental impact as well as malnutrition are responsible for an increased incidence of inflammatory diseases with a consequential loss of immune homeostasis. Therefore, administration of nutraceuticals is aimed at reconstituting the immune balance in terms of the so-called immune nutrition. Among many known nutraceuticals, more recently, donkey's and goat's milks have been used as good alternatives to human and bovine milk in various clinical conditions such as allergy, atopy and inflammatory diseases. In fact, both milks possess immunomodulating capacities and release nitric oxide, a potent vasodilator endowed with anti-atherogenic properties. In this review, emphasis will be placed on the consumption of fermented milk and, in particular, on its ability to modulate the aged immune system, even including the intestinal mucosal immune response in elderly. Therefore, for their specific properties donkey's and goat's milk administration to aged people should be encouraged.

Anisakiasis is a zoonosis due to infection with the nematode Anisakis (A.) simplex. Humans represent an accidental host after ingesting raw fish infected with A. simplex. A. simplex larvae lead to a robust host immune response mostly at gastro-intestinal level and, usually, T helper (h)2 lymphocytes play a protective against this nematode. However, larvae can elude immunity triggering activation of T regulatory (Treg) cells, which, in turn, suppress Th2 responses via production of interleukin (IL)-10. According to our own experience in the area of Bari (south Italy) where anisakiasis is endemic, chronic urticaria (CU) is very often associated to A. simplex infection. The cytokine profile in CU patients with Anisakis infection is characterized by an elevated release of interferon-γ and IL-17, while IL-10 production is very low. This pattern of pro-inflammatory cytokine response was consistently detectable in patients who underwent a raw fish free diet regimen over a period of six months. In the light of the above considerations, we hypothesize that treating these patients with polyphenols it may be beneficial in terms of activation of Treg cell function. In fact, polyphenols have the capacity to expand Treg cell response in vitro. In this regard, activation of human Treg cells, by analogy to other helminthiasis, may lead to a reduction of allergic/inflammatory reaction in the course of human anisakiasis.

Childhood obesity is characterized by a low-grade inflammation status depending on the multicellular release of cytokines, adipokines, and reactive oxygen species. In particular, the imbalance between anti-inflammatory T regulatory cells and inflammatory T helper 17 cells seems to sustain such a phlogistic condition. Alterations of gut microbiota since childhood also contribute to the maintenance of inflammation. Therefore, besides preventive measures and caloric restrictions, dietary intake of natural products endowed with anti-oxidant and anti-inflammatory activities may represent a valid interventional approach for preventing and/or attenuating the pathological consequences of obesity. In this regard, the use of prebiotics, probiotics, polyphenols, polyunsaturated fatty acids, vitamins, and melatonin in human clinical trials will be described.

The liver plays an important physiological role in lipopolysaccharide (LPS) detoxification and, in particular, hepatocytes are involved in the clearance of endotoxin of intestinal derivation. In experimental shock models, tumor necrosis factor (TNF)-alpha induces hepatocyte apoptosis and lethal effects are due to secreted TNF-alpha and not to cell-associated TNF-alpha. An exaggerated production of TNF-alpha has been reported in murine viral infections, in which mice become sensitized to low amounts of LPS and both interferon (IFN)-gamma and IFN-alpha/beta are involved in the macrophage-induced release of TNF-alpha. The prominent role of LPS and TNF-alpha in liver injury is also supported by studies of ethanol-induced hepatic damage. In humans, evidence of LPS-induced hepatic injury has been reported in cirrhosis, autoimmune hepatitis, and primary biliary cirrhosis and a decreased phagocytic activity of the reticulo-endothelial system has been found in these diseases. The origin of endotoxemia in hepatitis C virus (HCV) infected patients seems to be multifactorial and LPS may be of exogenous or endogenous derivation. In endotoxemic HCV-positive patients responsive to a combined treatment with IFN-alpha/ribavirin (RIB), endotoxemia was no longer detected at the end of the therapeutic regimen. By contrast, 48% of the non-responders to this treatment were still endotoxemic and their monocytes displayed higher intracellular TNF-alpha and interleukin (IL)-1beta levels than responders. Moreover, in responders, an equilibrium between IFN-gamma and IL-10 serum levels was attained. In the non-responders, serum levels of IL-10 did not increase following treatment. This may imply that an imbalance between T helper (Th)1 and Th2 derived cytokines could be envisaged in the non-responders.

The balance between T helper (h)1 and Th2 responsiveness seems to represent a key event in the evolution of hepatitis C virus (HCV) infection. In particular, Th1 cytokines [interleukin (IL-2) and interferon (IFN-γ)] have been demonstrated to mediate the antiviral immune response. Serum levels of Th1 cytokines (IL-2 and IFN-γ) as well as of Th2 products (IL-4 and IL-10) were determined in a group of HCV-positive patients before and after treatment with IFN-α and Ribavirin (RIB). Results indicate that responder patients exhibited increased levels of IFN-γ and IL-10, while this enhancement was not observed in non-responder patients. In this respect, the major effect exerted by the combined therapy with IFN-α / RIB could be represented by the attainment of a re-equilibrium between inflammatory (Th1) and antiinflammatory (Th2) mechanisms. In this framework, according to current literature, novel therapeutical approaches to treat HCV infection are represented by administration of recombinant IL-2 and IL-10.

Human peripheral blood mononuclear cells (PBMCs) were treated with Helicobacter pylori (Hp) organisms alone or with Hp-stimulated AGS cells (a gastric adenocarcinoma cell line). Hp organisms were able per se to increase the percentage of CD8 +/- CD95 +/- cells, while number of CD25+ cells and HLA-DR molecule expression increased following pretreatment with Hp-stimulated AGS cells. A comparison was made with a test system in which PBMCs were stimulated with Escherichia coli (Ec) organisms and colo-cells (a colon carcinoma cell line). In this case, CD95+ cells and CD25+ cells increased when the combination Ec organisms/colo-cells was present in the culture. On the other hand, Hp bacteria in combination with colo-cells were not able to induce activation and/or apoptotic surface markers on PBMCs, while Ec-stimulated AGS cells increased the expression of CD95 on PBMC. Finally, the direct interaction of AGS cells with Hp was able to induce higher expression of CD95 on gastric epithelial cells than Hp-stimulated PBMCs. Taken together, these data support the interplay between bacteria and epithelial cells in the course of Hp-mediated gastropathy.

Ulcerative colitis (UC) and Crohn's disease (CD) [inflammatory bowel disease (IBD)] are both characterized by an exaggerated immune response at the gut associated lymphoreticular tissue level. Such an abnormal and dysregulated immune response may be directed against luminal and/or enteric bacterial antigens, as also supported by murine models of inflammatory bowel disease (IBD) caused by organisms such as Citrobacter rodentium and Helicobacter hepaticus.Bacterial endotoxins or lipopolysaccharides (LPS) have been detected in the plasma of IBD patients and an abnormal microflora and/or an increased permeability of the intestinal mucosa have been invoked as cofactors responsible for endotoxemia. At the same time, the evidence that phagocytosis and killing exerted by polymorphonuclear cells and monocytes and the T-cell dependent antibacterial activity are decreased in IBD patients may also explain the origin of LPS in these diseases.In IBD, pro-inflammatory cytokines and chemokines have been detected in elevated amounts in mucosal tissue and/or in peripheral blood, thus suggesting a monocyte/macrophage stimulation by enteric bacteria and/or their constituents ( e.g. LPS).On these grounds, in experimental models and in human IBD, anti-cytokine monoclonal antibodies and interleukin receptor antagonists are under investigation for their capacity to neutralize the noxious effects of immune mediators. Finally, the administration of lactobacilli is beneficial in human IBD and, in murine colitis, this treatment leads to a normalization of intestinal flora, reducing the number of colonic mucosal adherent and translocated bacteria.

Nowadays, donkey's and goat's milk consumption has been reevaluated for its potential benefits to human health. For example, in infants with intolerance to cow's milk, donkey's milk represents a good alternative due to its chemical characteristics similar to those of human milk. On the other hand, goat's milk in virtue of its higher content in short chain, medium chain, mono and polyunsaturated fatty acids than that of cow's milk, is more digestible than the bovine counterpart. From an immunological point of view, donkey's milk is able to induce release of inflammatory and anti-inflammatory cytokines from normal human peripheral blood lymphomononuclear cells, thus maintaining a condition of immune homeostasis. Similarly, goat's milk has been shown to trigger innate and adaptive immune responses in an in vitro human system, also inhibiting the endotoxin-induced activation of monocytes. Finally, in these milks the presence of their own microbiota may normalize the human intestinal microbiota with a cascade of protective effects at intestinal mucosal sites, even including triggering of intestinal T regulatory cells. In the light of the above considerations, donkey's and goat's milk should be recommended as a dietary supplement in individuals with inflammatory and allergic conditions, even including elderly people.

The increased incidence of allergic disease seems to rely on many factors. Among them, the association between genetic variations of the immune response and environmental pressure by allergens, infectious agents and pollutants should be taken into consideration. In alternative to conventional treatments with corticosteroids and antihistaminics, nutraceuticals have been shown to act on allergic disease either during allergic sensitisation or on consolidated disease. In this review, special emphasis is placed on the effects of dietary polyphenols on three major allergic diseases, namely atopic eczema, food allergy and asthma. Interference of polyphenols with T-helper 2 activation seems to be the main mechanism of their inhibitory effects on allergy development. Moreover, deficits of T-regulatory cells seem to play a pathogenic role in allergic disease and, therefore, these cells may represent a major target of polyphenol activity.

The onset of neurodegenerative diseases has become more frequent than in the past also in relation to inappropriate dietary habits adopted in the western world. Nutraceuticals are currently investigated in order to prevent or retard the outcome of the so-called diet-related diseases, even including neurodegenerative pathologies. Here, we have in vitro studied the ability of fermented grape marc (FGM) from Negroamaro (N) and Koshu (K) Vitis vinifera to modulate the function of human peripheral blood mononuclear cells (PBMCs). Actually, both FGMs were able to increase the release and the intracellular content of inflammatory and anti-inflammatory cytokines, the induction of FoxP3 (a biomarker of T regulatory cells) and reduce the production of Granzyme B from PBMCs. Since these FGM-induced effects tend to polarize the immune response toward an anti-inflammatory pathway, the potential use of FGMs may represent a valid therapeutic measure to mitigating neuroinflammation in pathologies such as Parkinson disease and Alzheimer disease.

It is well known that the consumption of dietary polyphenols leads to beneficial effects for human health as in the case of prevention and/or attenuation of cardiovascular, inflammatory, neurodegenerative and neoplastic diseases. This review summarizes the role of polyphenols from red wine in the immune function. In particular, using healthy human peripheral blood mononuclear cells, we have demonstrated thein vitroability of Negroamaro, an Italian red wine, to induce the release of nitric oxide and both pro-inflammatory and anti-inflammatory cytokines, thus leading to the maintenance of the immmune homeostasis in the host. All these effects were abrogated by deprivation of polyphenols from red wine samples. We have also provided evidence that Negromaro polyphenols are able to activate extracellular regulated kinase and p38 kinase and switch off the NF-κB pathway via an increased expression with time of the IκBα phosphorylated form. These mechanisms may represent key molecular events leading to inhibition of the pro-inflammatory cascade and atherogenesis. In conclusion, according to the current literature and our own data, moderate consumption of red wine seems to be protective for the host in the prevention of several diseases, even including aged-related diseases by virtue of its immunomodulating properties.

Atherosclerosis is an inflammatory disease characterized by lipid accumulation as well as vascular injury due to a massive infiltration of immune cells in the endothelial wall. Microbial and self- antigens are responsible for a persistent activation of immune and non-immune cells, thus leading to a condition of arterial chronic inflammation with plaque formation and rupture in complicated cases. In particular, the effects of bacteria, viruses and their toxic products as well as of glycated lipoproteins will be illustrated with special reference to the main inflammatory pathways triggered by a persistent antigenic load in the host. Taking into consideration this broad variety of antigens implicated in the pathogenesis of atherosclerosis, therapeutic approaches such as antibiotics, dietary intervention and immune therapies will be discussed.

The intestinal mucosa contains a highly specialized immune system which plays a central role in the induction of immune reactions. In the small bowel, Gut-Associated Lymphoid Tissue (GALT) is organized in lymphoid aggregates which are known as Peyer's Patches (PP). Even though human PP involvement in systemic immunity has been described, little is known about their anatomy and morphology and viability. The aim of this study was to examine PP according to their macroscopic anatomy, distribution and cell viability after death. Specimens from the distal ileum were obtained from 72 serial autopsy cases: PP were identified and, parts of them were analyzed for histological examination. Moreover, viability of recovered PP cells was assessed by the trypan blue exclusion test. Most of the PP (90%) were situated on the antimesenteric border of ileum, and the greatest density of PP occurred in the most distal segment. The number of PP varied with age, with the maximum number observed in 21- to 30-years old cadavers. Histological examination showed their remarkable architectural preservation at different post-mortem intervals (PMI), while the mucosal surface underwent autolysis. In 56% of cases PP cells were still viable, especially at PMI < 24 hours after death. These data confirm that human PP are still well preserved in a remarkable percentage of cadavers also several hours after death, and their availability may be helpful in various fields of research.

Pro-inflammatory mediators hold important functions in human body in response to infection, trauma and vascular disease. However, their action is down regulated by the release of anti-inflammatory cytokines, thus restoring a balance which reflects the immune status of a given individual. Recent studies have stressed out the importance of circulating levels of cytokines for forensic purposes even if there is a lack of studies regarding the role of post-mortem mucosa-associated lymphoid tissue. In this respect, Peyer's patches (PP), represent one of the most important immunological site of the body and the major component of the gut -associated lymphoid tissue. The aim of this study was to evaluate post-mortem PP immune response in 40 serial autopsy cases of people who died from natural and traumatic death. The study examined spontaneous release of the following cytokines by fresh isolated PP cells: interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, IL-10, IL-6, IL-1 beta, and IL-8. Results will show that higher levels of TNF-alpha, IL-6, IL-1 beta, and IL-8 are statistically correlated with the traumatic death group. From a forensic point of view these data demonstrate that fundamental lymphoid organs, such as PP, may have a potential in diagnosing the cause of death.

Polyphenols contained in red wine possess a broad array of properties which seem to be beneficial to human and animal health. We have investigated the ability of red wine polyphenols to promote the in vitro release of both proinflammatory and antiinflammatory cytokines from human healthy mononuclear cells, as well as of immunoglobulins from B cells. Following red wine (Negroamaro) pretreatment of lymphomonocytes, results will show a production of regulatory [Interleukin( IL)-12], proinflammatory (IL-1β and IL-6), and anti-inflammatory (IL-10) cytokines, as well as of IgA and IgG. The fine balance between inflammation and antiinflammation, as well as the role of humoral immune response either systemic or mucosal will be discussed as a consequence of red wine intake. Finally, since ageing is characterized by a decline of many immune functions, our results suggest that moderate use of red wine may be beneficial in age-related disorders where the host immune response is very often not effective against a variety of antigens.