Autoimmune diseases and 8.1 ancestral haplotype: An update.

The aim of the present review is to provide an update of the current research into the pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype. This is a common Caucasoid haplotype carried by most people who type for HLA-B8, DR3. Numerous genetic studies reported that individuals with certain HLA alleles have a higher risk of specific autoimmune disorders than those without these alleles. However, much remains to be learned about the heritability of autoimmune conditions. Recently, progress and advances in the field of genome-wide-association studies have revolutionized the capacity to perform large, economically feasible, and statistically robust analyses of HLA within 8.1 ancestral haplotype, and understand its contribute to autoimmune events. In this paper, the characteristic features of this haplotype that might give rise to diverse autoimmune phenotypes are reviewed, focusing on the contribution of the HLA-DRB1 gene, the most polymorphic sequence within the HLA II region.

Interleukin-9 over-expression and T helper 9 polarization in systemic sclerosis patients.

T helper 9 (Th9) cells and interleukin (IL)-9 are involved in the pathogenesis of several autoimmune diseases. The exact role of IL-9 and Th9 cells in patients with systemic sclerosis (SSc) have not yet been studied adequately. IL-9, IL-9R, transcription factor PU.1 (PU.1), IL-4, thymic stromal lymphopoietin (TSLP) and transforming growth factor (TGF)-ß expression were assessed in skin and kidney biopsies of SSc patients and healthy controls (HC) by immunohistochemistry (IHC). The cellular source of IL-9 was also analysed by confocal microscopy analysis. Peripheral IL-9-producing cells were also studied by flow cytometry. The functional relevance of IL-9 increased expression in SSc was also investigated. Our results demonstrated a strong expression of IL-9, IL-9R, IL-4, TSLP and TGF-ß in skin tissues of patients with both limited and diffuse SSc. IL-9 expression was observed mainly in the context of skin infiltrating mononuclear cells and keratinizing squamous epithelium. IL-9 over-expression was also observed in renal biopsies of patients with SSc. IL-9 producing cells in the skin were identified as Th9 cells. Similarly, Th9 cells were expanded and were the major source of IL-9 among SSc peripheral blood mononuclear cells (PBMC), their percentage being correlated directly with the modified Rodnan skin score. Infiltrating mononuclear cells, mast cells and neutrophils expressed IL-9R. In in-vitro studies stimulation with rIL-9 significantly induced NET (neutrophil extracellular traps) release by dying cells (NETosis) in neutrophils, expansion of mast cells and increase of anti-systemic scleroderma 70 (Scl70) production by B cells. Our findings suggest that Th9 cells and IL-9 could be implicated in the pathogenesis of SSc.

KIR2DL3 and the KIR ligand groups HLA-A-Bw4 and HLA-C2 predict the outcome of hepatitis B virus infection.

Killer immunoglobulin-like receptors (KIRs) regulate the activation of natural killer cells through their interaction with human leucocyte antigens (HLA). KIR and HLA loci are highly polymorphic, and certain HLA-KIR combinations have been found to protect against viral infections. In this study, we analysed whether the KIR/HLA repertoire may influence the course of hepatitis B virus (HBV) infection. Fifty-seven subjects with chronic hepatitis B (CHB), 44 subjects with resolved HBV infection and 60 healthy uninfected controls (HC) were genotyped for KIR and their HLA ligands. The frequency of the HLA-A-Bw4 ligand group was higher in CHB (58%) than subjects with resolved infection (23%) (crude OR, 4.67; P<.001) and HC (10%) (crude OR, 12.38; P<.001). Similar results were obtained for the HLA-C2 ligand group, more frequent in CHB (84%), than subjects with resolved infection (70%) (crude OR, 2.24; P<.10) and HC (60%) (crude OR, 3.56; P<.01). Conversely, the frequency of KIR2DL3 was lower in CHB (81%) than in subjects with resolved infection (98%) (crude OR, 0.10; P<.05). These results suggest a detrimental role of HLA-A-Bw4 and HLA-C2 groups, which are associated with the development of CHB, and a protective role of KIR2DL3. A stepwise variable selection procedure, based on multiple logistic regression analysis, identified these three predictive variables as the most relevant, featuring high specificity (90.9%) and positive predictive value (87.5%) for the development of CHB. Our results suggest that a combination of KIR/HLA gene/alleles is able to predict the outcome of HBV infection.

Prostate cancer: from the pathophysiologic implications of some genetic risk factors to translation in personalized cancer treatments.

Several pathologies affect human prostate, such as prostate cancer (PC), which is the most common non-skin malignant cancer in Western male populations. A complex interaction between genetic and environmental factors (i.e. infectious agents, dietary carcinogens) and hormonal imbalances has been reported to have a fundamental role in PC pathophysiology by evoking chronic inflammation. Thus, chronic inflammation drives prostate carcinogenesis and neoplastic progression. No adequate biomarkers exist until now to guide PC prognosis and treatment. Accordingly, the research has particularly focused its attention on genetic variants in genes, codifying molecules of signaling innate immune/inflammatory and steroid metabolism pathways, which are able to modify the PC genetic susceptibility and clinical disease outcome. Single-nucleotide polymorphisms (SNPs) may operate in combination to create a 'risk profile'. Combinations of several inflammatory and sex steroid hormone pathway SNPs are found in PC patients. Thus, their combinations might be used as promising biomarkers in a pre- and post-treatment clinical PC setting. Indeed, their identification may hold promise for the realization of a personalized PC medicine. Many of these aspects are summarized in this report through the elucidation of literature data and the results of our studies.

Pathological implications of Th1/Th2 cytokine genetic variants in Behçet's disease: Data from a pilot study in a Sicilian population.

Cytokines act as pleiotropic polypeptides able to regulate inflammatory/immune responses and to provide important signals in physiological and pathological processes. Several cytokines (Th1, Th2, and Th17) seem to be involved in the pathophysiology of Behçet's disease, a chronic immune-mediated disease characterized by oral and genital lesions and ocular inflammation. Its individual susceptibility seems to be modulated by genetic variants in genes codifying these cytokines. Th1 and Th17 seem to be involved in the disease's active phases, and Th2 seems to affect the development or severity of the disease; however, contrasting data are reported. In this study, some genetic variants of the Th1/Th2 cytokine genes were investigated in Sicilian patients and age- and gender-matched controls. Three very significant associations with Behçet's disease were detected, and combined genotypes associated with increased disease risk were identified. Results obtained point to the key role of Th1/Th2 cytokine genetic variants in disease susceptibility.

Role of genetic polymorphisms in myocardial infarction at young age.

Acute myocardial infarction (AMI) in young adult presents a typical pattern of risk factors, clinical, angiographic and prognostic characteristics. In the last years we demonstrated that hemorheological profile is altered in these patients in a persistent way and independently of the number of risk factors and of the extent of coronary lesions. Thus, the hyperviscosity syndrome following AMI could be considered an intrinsic characteristic of these patients. Consequently it is possible to hypothesise the presence of a genetic background at the origin of this predisposition. If this background is able to influence the risk of ischemic heart disease, this should be particularly evident in young subjects. Since inflammatory mechanisms play a central role in mediating all phases of atherosclerosis, genes encoding for inflammatory or anti-inflammatory molecules are candidates for the risk of developing atherosclerosis. As atherosclerosis is the first cause of mortality in Western countries and if pro-inflammatory genotypes contribute to risk of coronary heart disease, alleles associated to disease susceptibility should not be included in the genetic background favouring longevity: People genetically predisposed to a weak inflammatory activity have fewer chances to develop cardiovascular disease and, therefore, have better chance for a long-life. According to this hypothesis, we studied in our population of young patients with AMI, the distribution of some polymorphisms influencing a inflammation and found an higher prevalence of pro-inflammatory polymorphisms (SNP A2080G of pyrin gene, SNP Gly670Arg of PECAM gene, C1019T of Cx 37 gene, SNP G1059C of PCR gene) and a lower prevalence of anti-inflammatory polymorphisms (Asp299Gly of TLR4 gene, SNP -1082 G/A of IL10 gene, CCR5Δ32). Results of these studies show that early myocardial infarction could be associated with a genetic predisposition to an intense inflammatory response, associated also to an hyperviscosity syndrome.

Low grade inflammation as a common pathogenetic denominator in age-related diseases: novel drug targets for anti-ageing strategies and successful ageing achievement.

Nowadays, people are living much longer than they used to do, however they are not free from ageing. Ageing, an inexorable intrinsic process that affects all cells, tissues, organs and individuals, is a post-maturational process that, due to a diminished homeostasis and increased organism frailty, causes a reduction of the response to environmental stimuli and, in general, is associated to an increased predisposition to illness and death. However, the high incidence of death due to infectious, cardiovascular and cancer diseases underlies a common feature in these pathologies that is represented by dysregulation of both instructive and innate immunity. Several studies show that a low-grade systemic inflammation characterizes ageing and that inflammatory markers are significant predictors of mortality in old humans. This pro-inflammatory status of the elderly underlies biological mechanisms responsible for physical function decline and age-related diseases such as Alzheimer's disease and atherosclerosis are initiated or worsened by systemic inflammation. Understanding of the ageing process should have a prominent role in new strategies for extending the health old population. Accordingly, as extensively discussed in the review and in the accompanying related papers, investigating ageing pathophysiology, particularly disentangling age-related low grade inflammation, is likely to provide important clues about how to develop drugs that can slow or delay ageing.

B cells compartment in centenarian offspring and old people.

Immunosenescence is considered a major contributory factor to the increased frequency of morbidity and mortality among elderly. On the other hand centenarians are considered the best example of successful ageing. To gain insight into mechanisms of immunosenescence and its clinical relevance, a possible model is represented by centenarians and/or their offspring. Nowadays centenarians are not more a curiosity, but in Europe are 1/8000 inhabitants and it has been demonstrated that the centenarian offspring, who are typically in their 70s and 80s, have a survival advantage when compared with age-matched controls whose parents died at an average life expectancy. Then again, studies on immunosenescence focus mainly on T cell impairment, although B cells are also affected. So, in the present preliminary report, we have studied B cell compartment in two classes of individuals, old people and centenarian offspring. B cell compartment was analysed using IgD and CD27 antibodies which characterize naïve B cells (IgD(+) CD27(-)), memory unswitched B cells (IgD(+)CD27(+)), memory switched B cells(IgD(-)CD27(+)) and double negative B cells (DN) (IgD(-)CD27(-)), i.e. exhausted memory cells. As expected, in both cohorts we observed a decreased B cell count. However, in centenarian offspring, naïve B cells are more abundant whereas exhausted memory cells (DN B cells, IgD(-)CD27(-)) do not show the increase that we have previously demonstrated in healthy elderly donors. These data are similar to that found in previously experiments on young subjects. So, our preliminary results show that centenarian offspring do not have the typical trend of memory/naive B cell subsets observed in elderly people and this is in agreement with the higher levels of IgM in the serum of centenarian offspring in comparison with data obtained in age-matched controls. This reservoir of naive B cell might be one of the causes that make centenarian offspring able to keep fighting off new infections, hence prolonging their life. So, B cell subset changes could represent a hallmark of successful or unsuccessful ageing and could be used as a biomarker of human life span, potentially useful for the evaluation of anti-ageing treatment.

Age-related inflammation: the contribution of different organs, tissues and systems. How to face it for therapeutic approaches.

A typical feature of ageing is a chronic, low-grade inflammation characterized by a general increase in the production of pro-inflammatory cytokines and inflammatory markers ("inflamm-ageing"). This status may slowly damage one or several organs, especially when unfavorable genetic polymorphisms and epigenetic alterations are concomitant, leading to an increased risk of frailty together with the onset of age-related chronic diseases. The contribution of different tissues (adipose tissue, muscle), organs (brain, liver), immune system and ecosystems (gut microbiota) to age-related inflammation ("inflamm-ageing") will be discussed in this review in the context of its onset/progression leading to site-restricted and systemic effects. Moreover, some of the possible strategies and therapies to counteract the different sources of molecular mediators which lead to the age-related inflammatory phenotype will be presented.

Immune-inflammatory responses and oxidative stress in Alzheimer's disease: therapeutic implications.

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. AD has been linked to inflammation and oxidative stress. Neuro-pathological hallmarks are senile plaques, resulting from the accumulation of several proteins and an inflammatory reaction around deposits of amyloid, a fibrillar protein, Abeta, product of cleavage of a much larger protein, the beta-amyloid precursor protein (APP) and neurofibrillary tangles. Inflammation clearly occurs in pathologically vulnerable regions of AD and several inflammatory factors influencing AD development, i.e. environmental factors (pro-inflammatory phenotype) and/or genetic factors (pro-inflammatory genotype) have been described. Irrespective of the source and mechanisms that lead to the generation of reactive oxygen species, mammalian cells have developed highly regulated inducible defence systems, whose cytoprotective functions are essential in terms of cell survival. When appropriately activated, each one of these systems has the possibility to restore cellular homeostasis and rebalance redox equilibrium. Increasing evidence, support the notion that reduction of cellular expression and activity of antioxidant proteins and consequent augment of oxidative stress are fundamental causes for ageing processes and neurodegenerative diseases., including AD. The better understanding of different molecular and cellular inflammatory mechanisms is crucial for complete knowledge of AD pathophysiology, hence for its prevention and drug therapy. Accordingly, two lines of preventive therapeutics can be outlined, the first based on anti-inflammatory drugs, the second one on anti-oxidative properties.

A pilot study on prostate cancer risk and pro-inflammatory genotypes: pathophysiology and therapeutic implications.

Host genetic factors are crucial risk determinants for many human cancers. In this framework, an interesting model is represented by prostate cancer (PC), which is featured by a complex pathophysiology with a strong genetic component. Multiple genes seem to influence PC risk and several single nucleotide polymorphisms (SNPs) of candidate genes modifying PC susceptibility have been identified. It is noteworthy the potential association of common SNPs in pro-inflammatory genes with PC risk, since chronic inflammation is assumed to play a key role in prostate carcinogenesis. With the aim to identify candidate genes as an experimental basis to develop new strategies for both prevention and treatment of PC, we have investigated the potential role of common SNPs of a gene cluster (TLR4, TLR2, PTGS2 and 5-Lo), involved in innate and inflammatory response, in PC cases, age-matched controls and centenarians from Sicily. Six SNPs were genotyped and their association with PC risk determined. Statistical analysis evidenced a significant association of some pro-inflammatory gene SNPs with an increased risk of PC. Furthermore, significant differences were observed comparing the three groups in the combined presence of a "high responder" pro-inflammatory profile. Overall, the present results suggest the likely association of these SNPs and PC risk, clearly motivating the need of larger studies to confirm the role of these genes in PC development and/or progression.

Administration of a synbiotic to free-living elderly and evaluation of serum cytokines. A pilot study.

Ten free-living elderly were administered with a synbiotic [fermented milk containing Lactobacillus rhamnosus Gorbach and Goldin (LGG)] and oligofructose as a prebiotic for one month. Serum cytokines were evaluated before (T(0)) and after (T(1)) synbiotic administration. At T(0), values of Interleukin (IL)-12, IL-6, IL-10, IL-1beta and Tumor Necrosis Factor (TNF)-alpha were lower than normal controls, with the exception of IL-8, thus confirming previous results on the impairment of both innate and adaptive responses in elderly. At T(1), the synbiotic was able to significantly increase, depressed values of IL-1, IL-6 and IL-8 with a trend to a modest increase for the restant cytokines. In conclusion, the synbiotic used in this study seems to be very beneficial to elderly for its capacity to maintain the immune homeostasis, even if an increase in dosage and prolongation of administration time are required for a better modulation of the aged adaptive immune response.

Risk profiles in type 2 diabetes (metabolic syndrome): integration of IL-10 polymorphisms and laboratory parameters to identify vascular damages related complications.

Recently it has been reported that low serum IL-10 levels are associated with an increased susceptibility for metabolic syndrome and type 2 diabetes mellitus (T2DM). We investigated whether the -1087G/A (rs1800896), -824C/T (rs1800871), -597C/A (rs1800872) IL-10 polymorphisms were associated with type 2 diabetes in a study on a cohort of Italian Caucasians comprising 490 type 2 diabetic and 349 control subjects. Stratifying the data according to IL-10 genotypes, trends for the progressive increase of glucose and neutrophil levels were observed in -1087GG vs. -1087GA vs. -1087AA positive diabetic patients (-1087GG<-1087GA<-1087AA). In addition, evaluating the laboratory parameters according to the -597/-824/-1087 derived haplotypes a significant increase of neutrophils was found in diabetic vs. non-diabetic -597A/ -824T/-1087A positive subjects (Student t test = 3.707, p<0.01). In an attempt to integrate clinical laboratory and immunogenetic data to determine whether these factors taken together define sufficient risk sets for type 2 diabetes we performed the grade-of-membership analysis (GoM). GoM allowed to identify a population of subjects negative for IL-10 -824T allele, 74.4% of which were diabetic patients characterised by vascular damages (Chronic kidney failure and/or Myocardial Infarction), reduction of haematocrit, increase of blood urea nitrogen, creatinin and monocyte levels. These data seem to suggest that -597A/-824T/-1087A negative subjects are more prone to the major type 2 diabetic vascular damages and allow to hypothesise that the contemporary evaluation of some simple hematochemical parameters and IL-10 SNPs may allow identifying diabetic patients with the worse prognostic profile, needing both better complication prevention planning and therapeutic strategies.

Association between the polymorphisms of TLR4 and CD14 genes and Alzheimer's disease.

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. Inflammation plays a key role in AD and dissecting the genetics of inflammation may provide an answer to the possible treatment. Hence, the better understanding of different molecular and cellular inflammatory mechanisms is crucial for complete knowledge of AD pathophysiology, and for its prevention and drug therapy. Accordingly, in the present study we evaluated whether the pro-inflammatory polymorphisms of lipopolysaccaride-receptors, +896A/G Toll-Like Receptor (TLR4) and -260C/T CD14, are risk factors for AD. The study included both 626 AD patients (427 women and 199 men; age range: 53-98 years; mean age: 74.88+/-8.44) from Northern Italy and age and gender matched controls. Our results demonstrate that the +896A/G TLR4 single nucleotide polymorphism (SNP) is associated with AD, whereas no association has been observed with -260C/T CD14 SNP. Furthermore, no differences have been observed evaluating the combined presence of +896A+TLR4/-260T+CD14 "high responder"(proinflammatory-profile). However, our results showing the involvement of TLR4 in AD pathophysiology, strengthen the suggestion that systemic inflammation plays a key role in AD. Carriers of high responder SNP, affected by mild cognitive impairment might, be the ideal target for a preventive treatment with biologics as monoclonal antibodies directed against the pro-inflammatory cytokines to decrease the level of systemic inflammation involved in AD pathophysiology.

A scientific approach to anti-ageing therapies: state of the art.

A lasting dream of human beings is to reverse or at least postpone ageing. During the last years, an increasing number of scientific meetings, articles, and books have been devoted to anti-ageing therapies. This subject, full of misleading, simplistic, or wrong ideas, is very popular among the general public, whose imagery has been fascinated by all possible tools to delay ageing, getting immortality. Here, we discuss anti-ageing strategies aimed not to rejuvenate but to slow ageing and delay the onset of age-related diseases. These approaches should be able to substantially slow down the ageing process, extending our productive, youthful lives.

Pro-inflammatory gene variants in myocardial infarction and longevity: implications for pharmacogenomics.

Inflammation and genetics play an important role in the pathogenesis of coronary heart disease (CHD). However, despite the increasing appreciation of the role of genetics in CHD and myocardial infarction (MI) pathogenesis, pharmacogenomic approaches to uncover drug target have not been extensively explored. Cyclo-oxygenases (COXs) and 5-lipoxygenase (5-LO) are the key enzymes in the conversion of arachidonic acid to prostaglandins (PG) and leukotrienes (LT) and are implicated in a wide variety of inflammatory disorders, including atherosclerosis. In fact, PGE2 activates Matrix Metallo-proteinases whereas LTB4 is a chemoactractant for monocytes and activates gene expression in inflammatory cells. We have tested the hypothesis that anti-inflammatory variants of these genes confer genetic resistance to MI and conversely favour longevity. So, we analyzed MI patients, age-related controls and centenarians. The pro-inflammatory alleles of COX-2 and 5-LO were overrepresented in MI and under-represented in centenarians whereas age-related controls displayed intermediate values. MI is a multifactorial disease, hence MI might be the result of a cumulative effect which contributes with different timing to achieve a threshold where the chance to develop the diseases is very high. In particular, differences in inflammatory status can contribute to the chance of developing a risk phenotype. However, these studies might contribute to the determination of a risk profile which may allow both the early identification of individuals susceptible to disease and the possible discovery of potential targets for drug.

Polyphenols from red wine modulate immune responsiveness: biological and clinical significance.

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.

Impact of different texture of polypropylene mesh on the inflammatory response.

Over the past decade, hernia surgery has undergone a considerable transformation with the use of prosthetic materials. The most used polypropylene meshes induce a rapid acute inflammatory response followed by chronic foreign body reaction. Many factors influence this response such as density, size, physical characteristics, different texture and porosity of each biomaterial. The aim of this study is to assess whether the implant of monofilament or multifilament meshes, in the inguinal hernioplasty, determine a different inflammatory response. Thirty-two male patients were included in the study and were randomly divided into two groups. In the first group (MO) inguinal hernioplasty was performed using monofilament polypropylene mesh, while in the second one (MU) multifilament prosthesis was used. Peripheral venous blood samples were collected 24 hours before surgery and then 6, 24, 48 and 168 hours post-operatively. Modifications in leukocyte count, C-reactive protein (CRP), alpha-1 antitrypsin (alpha1-AT), interleukin (IL)-1, IL-6, IL-1 ra and IL-10 serum levels were recorded at all sampling times. We present evidence that serum levels of CRP, (alpha1-AT), leukocytes and cytokines were significantly increased post-operatively in both groups, returning to basal values 168 hours afterwards. In particular, the production of all pro-inflammatory mediators was higher in the MU group, whereas the anti-inflammatory cytokine (IL-10, IL-1ra) production was higher in MO patients. Our results indicate that polypropylene multifilament mesh allows a higher intense acute inflammatory response as compared to monofilament mesh implantation.