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-1 beta 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.

Many studies have been conducted on the effects of red wine polyphenols on certain diseases, primarily, coronary heart disease (CHD) and, in this respect, evidence has been demonstrated that intake of red wine is associated with a reduction of CHD symptomatology. In this framework, the purpose of this review is to illustrate the effects of polyphenols on immune cells from human healthy peripheral blood. Data will show that polyphenols are able to stimulate both innate and adaptive immune responses. In particular, the release of cytokines such as interleukin (IL)-12, interferon (IFN)-gamma, and IL-10 as well as immunoglobulins may be important for host protection in different immune related disorders. Another important aspect pointed out in this review is the release of nitric oxide (NO) from peripheral blood mononuclear cells (PBMC), stimulated by red wine polyphenols despite the fact that the majority of studies have reported NO production only by endothelial cells. Release of NO from PBMC may play an important role in cardiovascular disease, because it is known that this molecule acts as an inhibitor of platelet aggregation. On the other hand, NO exerts a protective role against infectious organisms. Finally, some molecular cytoplasmatic pathways elicited by polyphenols able to regulate certain immune responses will also be discussed. In particular, it seems that p38, a molecule belonging to the MAPK family, is involved in the release of IFN-gamma and, therefore, in NO production. All these data confirm the beneficial effects of polyphenols in some chronic diseases.

Red wine represents a source of polyphenols which exhibit a number of biological effects on various systems. In this respect, there is evidence that red wine polyphenols constitute one of the ingredients of the Mediterranean diet which is associated to a reduced risk of coronary heart disease according to current literature. Here, we have evaluated in vitro the molecular mechanisms elicited by polyphenols from red wine (Negroamaro) on human healthy mononuclear cells. In particular, we have investigated the involvement of polyphenols in the activation of p38 and ERK1/2 molecules belonging to the MAPK kinase family and on the expression of I kappaB alpha and p65/NF kappaB. Results will demonstrate that in cells both the expression of p38 and ERK1/2 augments in the presence of red wine polyphenols, but their expression drops in the presence of polyphenols plus lipopolysaccharides (LPS). This indicates that in Gram-negative infections polyphenols may attenuate triggering of inflammatory mediators as a response to LPS stimulation. Finally, the regulatory role of polyphenols on I kappaB alpha and p65/NF kappaB expression is discussed, pointing out that red wine might favor anti-atherogenic mechanisms in the course of cardiovascular disease.

Hereditary Haemorrhagic Telangiectasia (HHT) or Rendu-Osler-Weber syndrome is an autosomal dominant disease characterized by local angiodysplasia affecting different organism districts. From a clinical viewpoint, HHT patients suffer from epistaxis, mucocutaneous telangiectases and arteriovenous malformations in various organs. Mutations in two known genes (ENG and ALK1) account for the majority of HHT patients. Additional loci are predicted, but the underlying genes are still to be identified. Moreover, SMAD4 mutations have been reported to cause JP-HHT combined syndrome. Both endoglin and ALK-1 bind to various growth factors in the context of the Transforming Growth Factors (TGF)-beta superfamily and their expression is restricted to vascular endothelial cells and very few other cell types, such as activated monocytes. Endoglin and ALK1 mutations are thought to affect endothelial cell metabolism, angiogenesis and vascular remodelling, even if the precise mechanism leading to the HHT lesions is still obscure. Endoglin is also overexpressed in smooth muscle cells of atherosclerotic plaques, suggesting a role for this protein in atherogenesis and plaque progression, as well as in other cardiovascular diseases. Recently, we demonstrated that HHT adult patients display several deficits of both innate and adaptive immune system. Here, we investigated the function of immune cells in HHT pediatric patients. Our results clearly show that HHT children have a normal functionally immune system, and suggest that HHT patients become immunocompromised host during their lifetime, likely due to a precocious immunosenescence. Moreover, the relationship between immune responsiveness in HHT and atherosclerosis are discussed.

Evidence has been provided that red wine possesses antiatherogenic activities in virtue of its content in polyphenols (flavonoids and non-flavonoids substances). Here, some red wines (Negroamaro, Primitivo and Lambrusco) were tested for their ability to trigger nitric oxide (NO) production from human healthy peripheral blood mononuclear cells (PBMC). Negroamaro was the strongest inducer of NO from PBMC and deprivation of polyphenols did not influence its NO generation capacity. This fact supports the involvement of polyphenols in the NO production even in the absence of alcohol, which also per se does not exert any significant activity. These results are also corroborated by the evidence that PBMC inducible-nitric oxide synthase expression occurred by the effect of samples containing polyphenols but this expression was very weak when polyphenols were removed from the whole Negroamaro. In synthesis, flavonoids and resveratrol, major constituents of red wine, once absorbed at intestinal level, enter circulation and trigger monocytes for NO production. To the best of our knowledge, this is the first demonstration of a direct effect of red wine on monocytes for NO release to occur. On the other hand, also the macrophage contingent from gut-associated lymphoid tissue can contribute to NO generation, besides the aliquot produced by endothelial cells, as previously demonstrated by various authors. Taken together, these results support the concept that moderate intake of red wine can prevent atherosclerosis via production of NO, a potent vasodilator of terminal vessels.

Obesity represents a chronic inflammatory status and adipocytes release either cytokines or an array of adipokines such as leptin, endowed with immunomodulating and systemic activities. The involvement of cytokines in obesity as well as of the adipokine leptin is supported by the notion that weight reduction normalizes mediators of inflammation. In this framework, we will demonstrate that in obese children, subjected for a period of six months to a hypocaloric diet, reduction of major biochemical and anthropometric parameters correlates with a normalization of immune status. In fact, absolute numbers of CD4+ cells and CD4/CD8 ratio increase, while leptin values fluctuate within normal ranges, being this adipokine involved in the modulation of either innate or adaptive immune responses. In the discussion, the immune abnormalities detected in obesity will be pointed out and emphasis will be placed on the increased frequency of infectious episodes occurring in obese adolescent and adults. Finally, the infectious etiology of obesity will be illustrated in the sense that adipocytes interacting with infectious agents may cause obesity. Taken together, the bulk of available data indicate that childhood obesity should be prevented or reduced to avoid more serious complications in adulthood.

Nowadays, calprotectin, a cytoplasmatic protein, released by activated neutrophilic polymorphonuclear cells (PMN) and/or monocytes-macrophages (MØ), is considered a good indicator of inflammation in several diseases. Accordingly, fecal calprotectin represents a good predictor of clinical relapse in ulcerative colitis (UC) patients, whereas conflicting results have been reported in Crohn's disease (CD) patients. In our study, in 76 IBD patients (29 CD and 47 UC) fecal calprotectin has been evaluated by a commercial ELISA kit. Results demonstrate that levels of this protein in the stool are significantly more elevated in active CD and UC patients than in normal volunteers. In quiescent CD and UC a trend to higher levels of calprotectin than in the normal counterpart is, however, evident. These data suggest that a low-grade inflammation of the intestinal wall is always present in CD and UC patients, which may predict a clinical relapse risk. In the same group of patients calprotectin levels also were analyzed according to sex and age. A trend to higher values of calprotectin was present in male patients with active or quiescent CD than in their female counterparts. Only in UC patients in remission a trend to calprotectin increase was more marked in the male group than in the female counterpart. When CD and UC patients were divided up according to age, calprotectin positivity peaked between 30-39 years in active CD patients, while in quiescent CD maximum positivity was between 40 and 49 years. However, in both active and quiescent UC patients, calprotectin positivity increased with age. The more precocious detectability of fecal calprotectin in CD patients, as a marker of intestinal mucosa inflammation, may be related to the different histopathology of the two diseases (CD versus UC). However, reduced PMN and/or MØ trafficking from peripheral blood to intestinal mucosa with age by effects of chronic treatment should not be ignored in CD patients.

Nowadays, infections with Candida albicans (C.a.) are very frequent, mostly in the so-called immunocompromised host. Therefore, research has been focused on the types of immune response elicited by C.a., with the aim to develop novel therapeutic strategies. Neutrophils and macrophages (MØ) are deeply involved in the host defense against C.a., and also dendritic cells (DCs) seem to be very active in the host protection. In particular, DCs display an array of surface receptors able to interact with fungal components, even including Toll-like receptors. Here, we will illustrate the in vitro immune response of human monocyte-derived DCs infected with C.a. In this test system, DCs exert phagocytic and killing activities with a magnitude similar to that of MØ. Moreover, in the presence of autologous CD4(+) cells, DCs produce T-helper (h) 1 type cytokines. This Th1 polarizing activity is mediated by interleukin-12 released by infected CDs in the presence of CD4(+) cells. Taken together, these data suggest a protective role played by DCs in the course of C.a. infection and the possibility to develop new strategies of immune intervention.

In healthy individuals, natural and adaptive immune responses are able to control virus entry into the host. In particular, CD8(+)-mediated cytotoxicity, sustained by the intervention of CD4+ cells, represents the major key event leading to virus eradication. On the other hand, viruses are able to evade from host immune response via several mechanisms, and special emphasis will be placed on hepatitis C virus and chronic Epstein-Barr infections also in view of personal data. Virokines, viroreceptors, and serpins greatly contribute to viral immune escape, and, among virokines, interleukin (IL)-10 has been object of intensive studies. Finally, all these products have been used as biopharmaceuticals. and, for instance, viral IL-10, chemokine-binding proteins, and serpins exhibit in animal models immunosuppressive, anti-inflammatory, and antiatherogenic activities. As far as their use in human trials is concernded, many cautions are required in order to avoid deleterious side effects and, in particular, the purity of the product, its route and frequency of administration, as well as the immune status of the patient should be taken into serious account.

Dendritic cells (DCs) represent a bridge between innate and adaptive immunity, being the maturation process dependent on the binding of pathogen-associated molecular patterns (PAMPs) to Toll-Like Receptors (TLRs) expressed on their surface. TLRs associated to adaptor proteins, following binding to PAMPs, are able to skew specific immune responses towards the T helper (h)(1)- or the Th(2)-type according to the antigenic stimulation involved. Of note, other receptors different from TLRs are expressed on DCs which are also able to recognize PAMPs. Among them, one should mention the DC-specific ICAM-3-grabbing nonintegrin, the mannose receptor, Dectin-1 (the major beta-glucan receptor) and NOD2. Finally, the possibility to interfere therapeutically with the TLR-dependent and -independent signaling pathways in DCs is reviewed. According to current literature, DC activation, their antigen uptake capacity and migration can be enhanced with different experimental procedures whose use in humans is still under evaluation. However, just recently a probiotic cocktail VSL3, successfully used in patients with pouchitis, seems to act on DCs, promoting abundant release of Interleukin-10 in the gut. These novel therapeutic strategies based on the modulation of the signaling pathways in DCs seem to be encouraging for the treatment of inflammatory and autoimmune diseases.

Dendritic cells (DCs), instructed by the priming signals from microbial factors, can produce interleukin (IL)-12p70 and promote T helper (Th)1 proliferation and interferon (IFN)-gamma production. This event seems to be critical for the containment of infections caused by intracellular pathogens, even including Leishmania infection. In the present in vitro study we have investigated: 1) phagocytic capacities and IL-12 production by human monocyte-derived DCs and macrophages (MØs), infected with Leishmania infantum promastigotes; 2) IFN-gamma production by human CD4+ T cells co-incubated with DCs or macrophages pulsed with live promastigotes. Monocyte-derived myeloid DCs and MØs from healthy donors were infected with live metacyclic Leishmania infantum (MON-1) promastigotes, previously opsonized with 5% autologous serum, at 1:4 cell/parasite ratio. Percentage and index of phagocytosis were calculated after 2, 24 and 48 h of incubation. IL-12 production was evaluated by an ELISA in supernatants from 48 h Leishmania-infected or lipopolysaccharides (LPS)-stimulated DCs and MØs, also in the presence of phytohemagglutinin-activated or inactivated CD4+ T cells. For IFN-gamma production, CD4+ T cells were repeatedly stimulated with DCs or MØs, pulsed with live Leishmania promastigotes or activated with LPS. The number of IFN-gamma-secreting cells was evaluated by an ELISpot assay. Results showed that MØs have a higher phagocytic capacity towards L. infantum promastigotes than DCs. Moreover, unlike MØs, Leishmania-infected DCs were able to release IL-12p70; this production significantly increased in the presence of activated CD4+ T cells. Finally, DCs pulsed with live parasites and added to autologous CD4+ T cells induced a higher number of IFN-gamma-secreting cells than MØs, thus indicating their ability to polarize Th cells toward the Th1 subset. These data indicate that DCs are able to promote protective Th1 immune responses in our experimental model of Leishmania infantum infection, thus representing the grounds for initiating immunoterapeutic and vaccinal strategies.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by vessel alterations such as dilatation of postcapillary venules and arterio-venous communications, which account for the major clinical manifestations of the disease. Two types of HHT have been characterized HHT-1 and HHT-2, respectively, depending the former on endoglin mutations and the latter on activin receptor-like kinase 1 (ALK-1) mutations. Both endoglin and ALK-1 bind to the transforming growth factor (TGF) superfamily which, physiologically, regulates the activities of endothelial cells and also those related to the extracellular matrix. In this review, the salient features of TGF-beta will be outlined with special reference to its activity on the immune system and on tumorigenesis. Furthermore, the involvement of TGF-beta in the pathogenesis of some gastrointestinal diseases will be discussed and, in particular, in the course of liver disease, Helicobacter pylori infection and inflammatory bowel disease. In the light of these data and of animal model of HHT, the potential risk of developing other diseases in HHT patients will be discussed.

Nervous and immune systems mutually cooperate via release of mediators of both neurological and immunological derivation. Adrenocorticotropin hormone (ACTH) is a product of the hypothalamus-pituitary adrenal axis (HPAA) which stimulates secretion of corticosteroids from adrenals. In turn, corticosteroids modulate the immune response in virtue of their anti-inflammatory activity. On the other hand, catecholamines, products of the sympathetic nervous system (SNS), regulate immune function by acting on specific beta-adrenergic receptors. Conversely, cytokines released by monocytes/macrophages and lymphocytes, upon antigenic stimulation, are able to cross the blood-brain-barrier, thus modulating nervous functions (e.g., thermoregulation, sleep, and appetite). However, cytokines are locally produced in the brain, especially in the hypothalamus, thus contributing to the development of anorexic, pyrogenic, somnogenic and behavioural effects. Besides pathogens and/or their products, the so-called stressors are able to activate both HPAA and SNS, thus influencing immune responses. In this respect, many studies conducted in medical students taking exams have evidenced an array of stress-induced immune alterations. Phobic disorders and migraine without aura (MWA) represent examples of stress-related disorders in which phagocytic immune deficits, endotoxemia and exaggerated levels of proinflammatory cytokines [Tumor Necrosis Factor-alpha (TNF- alpha), and interleukin- 1 beta] have been detected. Quite interestingly, administration of a thymic hormone could ameliorate clinical symptoms in phobic patients. In MWA patients, a beta-blocker, propranolol, could mitigate migraine, whose cessation coincided with a drop of TNF-alpha serum concentration. In phobic disorders and in MWA, benzodiazepines are very often administered and, in this respect, some of them, such as diazepam, inhibit immune functions, while others, e.g., alprazolam, enhance immune responses. Alprazolam could improve clinical symptoms in MWA patients. Chronic Fatigue Syndrome (CFS) is a disorder whose etiology and pathogenesis are still unknown. In this syndrome both abnormalities of nervous and immune systems have been reported. Despite many immune parameters evaluated in CFS no specific biomarkers of disease have been found. Our own data are in agreement with current literature in that we found decreased levels of serum (IFN)-gamma in these patients, thus indicating a predominance of T helper (h)1 response in CFS. Also leptin, a hormone which regulates food intake, fluctuates within normal ranges in CFS individuals. Quite interestingly, in depressed patients, used as controls, leptinaemia was more elevated than in CFS. Finally, in a series of recent therapeutic trials several immunomodulating agents have been used, such as staphypan Berna, lactic acid bacteria, kuibitang and intravenous immunoglobulin. In conclusion, it seems that major drug targets in stress-related disorders are immune cells in terms of inhibition of proinflammatory cytokines and modulation of Th responses. In particular, according to recent evidences, antidepressants seem to exert beneficial effects in experimental autoimmune neuritis in rats by decreasing IFN- beta release or augmenting NK activity in depressed patients.

It is well known that inappropriate nutrient intake accounts for the maintenance of the immunological equilibrium, in humans and animals. Vitamins, elements, lipids, proteins and nucleic acids play an important role in the regulation of cellular and humoral immune responses since single or multiple deficits of these food components have been shown to cause immune abnormalities. For instance, in the course of protein-calorie malnutrition bacterial and/or viral infections represent the major cause of death. Ageing is characterized by a decline of many immune functions, and this process is called immunosenescence. Here, we report novel findings on the inability of superantigens to activate old CD8+, natural killer and B cells, as an expression of cell amnesia. In the elderly, this lack of activation could lead to lethal effects in the case of severe staphylococcal infections. Quite interestingly, recent findings outlined some similarities between human immune deficiency virus (HIV)-1 infection and ageing in terms of immune changes. The model of HIV-infection may be useful for the interpretation of ageing mechanisms and possible therapeutical interventions. Finally, the role of nutrition in different pathological conditions and the use of medical foods for correcting of immune deficits will be described.

Several lines of evidence support a mutual relationship between the nervous system and the immune system. Therefore, it is not surprising that some neuropsychiatric disorders are also characterized by immune abnormalities. In patients with phobic disorders and in patients with migraine without aura some common immune abnormalities have been detected and, in particular, natural immunity deficits, exaggerated release of proinflammatory cytokines and circulating bacterial endotoxins have been found. In other neurological disease, some etiologic factors have been detected as in the case of Guillain-Barrè syndrome in which molecular mimicry between Campylobacter jejuni endotoxin and GM1 ganglioside may cause an acute inflammatory polyneuropathy. On the other hand, attempts to identify an antigen have been made in patients with Alzheimer's disease and schizophrenia. Finally, the chronic fatigue syndrome, an old illness in search for an antigen, risk factors and precipitating agents have been described but evidence for a specific antigen is still lacking.

Naloxone acts as an opioid antagonist, displacing opioid drugs from cellular receptors. Among opioid substances, P-endorphins are able to bind to several cell receptors, even including those expressed by immune cells. In this respect, evidence has been provided that in the course of viral infections, as well as in patients with ulcerative colitis high levels of beta -endorphins are detectable. Here, peripheral blood lymphocytes (PBL) from 21 HCV infected patients and 14 patients with IBD, respectively, were incubated with Naloxone and Naloxone + Ca2+ in order to evaluate a putative modulation of PBL-mediated antibacterial activity. In fact, previous studies have demonstrated a reduction of this T-cell activity in HCV and IBD patients.In general terms, the above treatment led to a recovery of the depressed antibacterial activity. In some cases, increase in T lymphocyte function was obtained with Naloxone alone, while in other cases the combination Naloxone -e Ca2+ gave rise to a restorative effect. Of note, in some instances, lymphocytes were unresponsive to pharmacological modulation.The overall results suggest that beta -endorphins may down modulate T-cell antibacterial response in HCV and in IBD patients by saturating peripheral receptors on immune cells. Therefore, it is likely that Naloxone and/or Nalox-one + Ca2+ may displace opioid drugs, thus antagonizing their effects.

The study analyzes the prevalence of cardiovascular risk factors in 1343 patients with severe headache (399 men and 944 women), aged 15 to 64 years; analyses were controlled for sex, age, and type and frequency of headache. Prevalence of various forms of headache was different between men and women. Age and days per year with headache were significantly different among various forms of headache. For men and women with headache, age directly related to prevalence of hypertension, hypercholesterolemia, and obesity. Due to low prevalence, analyses by age were not done for diabetes mellitus. For cigarette smoking, prevalence was not related to age in men, but was inversely related to age in women. With control for age, prevalence of cardiovascular risk factors was not significantly different among patients with different forms of headache, except for cluster headache. Among men with cluster headache, prevalence was high for cigarette smoking, but low for hypercholesterolemia. With control for age, days per year with headache did not relate to prevalence of cardiovascular risk factors except for cigarette smoking in men. Compared to data for a population sample used as control, patients with headache had higher prevalence of hypertension in both sexes, independent of age (odds ratio 1.51, 95% confidence interval 1.28 to 1.80); the difference between patients with headache and the control population was lower with increasing age. The high prevalence of hypertension among patients with headache was not due to overweight. The data indicate that headache is significantly associated with hypertension, but not with other cardiovascular risk factors.

Stress-related behaviors are accompanied by modification of a large number of neurotransmitters in the brain. Moreover, the binding to GABA(A) receptors does not account for all the effects of benzodiazepines. In this study we investigated the effect of repeated restraint stress and alprazolam treatment (1 mg/day os) on dopamine receptors (Bmax and Kd) in the striatum of adult rats by means of quantitative receptor autoradiography. After chronic restraint stress dopamine D1 receptors (Bmax value) decreased in the accumbens nucleus, whereas dopamine D2 receptors were not modified in any investigated area. After alprazolam treatment, a considerable increase in both dopamine D1 and D2 receptors in the striatum was observed. Chronic immobilization stress together with alprazolam treatment re-established dopamine D1 receptor density to control values in the accumbens nucleus and olfactory tubercle, whereas it resulted in an increase in dopamine D2 receptors comparable to that elicited by alprazolam treatment alone.