THE METABOLIC SYNDROME: IL-10 POLYMORPHISMS INFLUENCE ON SEROLOGICAL AND HAEMATOLOGICAL PARAMETERS IN TYPE 2 DIABETES.

Genetic risk profiles for Alzheimer's disease: Integration of APOE genotype and variants that up-regulate inflammation

BACKGROUND: A number of studies associate Alzheimer's disease with APOE polymorphism and alleles which favor the increased expression of immunological mediators such as cytokines or acute phase proteins. We integrated this information to better define risk and determine the relative importance of APOE and immunological mediators. METHODS: We investigated functional gene variants for APOE, IL-10 (3 loci), ACT (2 loci), HMGCR, IL-1alpha, IL-1beta, TNF-alpha, IFN-gamma, and IL-6 found for 260 AD patients and 190 controls enrolled in Northern Italy. A fuzzy latent classification approach, namely grade-of-membership analysis (GoM), was taken to identify extreme pure type risk sets, or profiles. …

Regulatory cytokine gene polymorphisms and risk of colorectal carcinoma.

It is well established that cancer arises in chronically inflamed tissue, and this is particularly notable in the gastrointestinal tract. Classic examples include Helicobacter pylori-associated gastric cancer, hepatocellular carcinoma, and inflammatory bowel disease-associated colorectal cancer. Growing evidence suggests that these associations might be not casual findings. Focusing on individual cytokines has generated evidence that anti-inflammatory cytokine interleukin (IL)-10 and transforming growth factor-beta1 (TGF-beta1) may have a complex role in gastrointestinal carcinogenesis. As an example, IL-10-deficient mice develop severe atrophic gastritis and a chronic enterocolitis, develo…

Search for genetic factors associated with susceptibility to multiple sclerosis.

Multiple sclerosis (MS) is a cell-mediated autoimmune disease characterized by type-1 cytokine production. Environmental and individual genetic background might influence this response particularly in cytokine gene polymorphisms. We evaluated whether polymorphisms of interleukin (IL)-10, IL-12, and tumor necrosis factor (TNF)-alpha genes, which might play a role in MS pathogenesis, are associated with MS susceptibility. Genotype frequencies for all the analyzed polymorphisms were not differently distributed between cases and controls. It is reasonable to suppose that the cytokine single-nucleotide polymorphisms (SNPs) studied must be considered against a larger genetic background involving …

Valutazione della “gene expression” di Citochine e loro recettori in soggetti dediti ad attività sportiva.

HLA, aging, and longevity: a critical reappraisal.

Despite a large number of studies, available data do not allow at present to reach definitive and clear conclusions on role of HLA on longevity, owing to major methodological problems, such as serological and molecular typing of different loci, insufficient sample sizes, different inclusion criteria and age cut-off, inappropriate mixing of data referred to people from 58 to over 100 years of age, inappropriate control matching, and neglected consideration of sex-related effects and the different genetic make-up of studied populations. However, within this confused scenario, some data emerge. First, two studies that do not fit the biases above discussed show that some HLA alleles are associa…

Analysis of HLA-DQA, HLA-DQB frequencies in a group of Sardinian centenarians

Human leukocyte antigen (HLA) alleles, regulating type and intensity of the immune response, might influence life expectancy. In previous case-control studies the authors have demonstrated that both HLA-DR and -DQ alleles are not associated with longevity in the Sardinian population. On the other hand, association studies are subjected (as part of the homogeneity of the population in terms of geographic origin) to a number of possible confounding factors. Therefore, the authors typed the HLA-DQA1 and HLA-DQB1 alleles in 24 sibs (age range 85 to 97) of 17 centenarians by PCR-SSP. Sib pair analysis showed non-significant differences between the observed and expected percentage of DQA* or DQB1…

Studio delle frequenze alleliche di +1188 A/C di IL12B (p40) in soggetti affetti da Sclerosi Multipla.

Genetic Background of Centenarians May Be Protective Against Cardiovascular Diseases.

Association between platelet glycoprotein Ib-alpha and myocardial infarction: results of a pilot study performed in male and female patients from Sicily.

Myocardial infarction (AMI) is a complex multifactorial disorder. Platelet adhesion and thrombosis are pivotal events in the development of atherosclerotic lesions. Occlusive thrombus is almost exclusively initiated by plaque rupture and adhesion of platelets to subendothelial von Willebrand factor (vWf) by its specific platelet receptor, the alpha-chain of glycoprotein (GP) Ib-IX-V complex of the human platelet-specific antigens (HPA). Two polymorphisms have been reported in the sequence of GPIb-alpha. The first, a C/T transition at nucleotide 1018 results in an amino acid dimorphism (Thr/Met) at residue 145 of GPIb-alpha, which is located within the vWF-binding domain of the receptor. The…

IL-10, genetic polymorphism and its relevance to age related diseases.

Centenarian offspring: A model for understanding longevity

Abstract: A main objective of current medical research is to improve the life quality of elderly people as priority of the continuous increase of ageing population. This phenomenon implies several medical, economic and social problems because of dramatic increase in number of non autonomous individuals affected by various pathologies. Accordingly, the research interest is focused on understanding the biological mechanisms involved in determining the positive ageing phenotype, i.e. the centenarian phenotype. In achieving this goal the choice of an appropriate study models is fundamental. Centenarians have been used as an optimal model for successful ageing. However, this model shows several …

IL-10 and TNF-α polymorphisms in a sample of sicilian patients affected by tuberculosis: implication for ageing and life span expectancy

Abstract Human longevity seems to be directly correlated with optimal functioning of the immune system, suggesting that some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses, in particular cytokine gene polymorphisms. In fact, modification of cytokine network is a constant report in studies on age related modification of immune response. Moreover cytokine polymorphisms studies are indicating their involvement in the reshaping of cytokines network as an integral part of the scenario related to a successful ageing. A particular role might be attributed to the influence of cytokine polymorphisms on the efficiency o…

Role of the pyrin M694V (A2080G) allele in acute myocardial infarction and longevity: a study in the Sicilian population

Abstract A proinflammatory genotype seems to contribute significantly to the risk of developing coronary heart disease (CHD). Conversely, the susceptibility alleles to inflammatory disease should be infrequent in the genetic background favoring longevity. In fact, in a modern environment, attainment of longevity is facilitated by an anti-inflammatory status. To evaluate whether inflammatory alleles of pyrin, the gene responsible for familial Mediterranean fever (FMF) may play an opposite role in CHD and in longevity, we examined three FMF-associated mutations, M694V (A2080G), M694I (G2082A), and V726A (T2177C), encoded by the FMF gene (MEFV) in 121 patients affected by acute myocardial infa…

Inflammation and Life-Span

In their Review “Inflammatory exposure and historical changes in human life-spans” (17 Sept., p. [1736][1]), C. E. Finch and E. M. Crimmins reinforce earlier suggestions that many diseases and disabilities of older age have their roots in previous exposures to infectious agents and other sources

Age-related changes in the expression of CD95 (APO1/FAS) on blood lymphocytes☆

Abstract Aging is associated with alterations of the immune system, thought to be related to an increased susceptibility to infectious diseases, and possibly to cancer and autoimmunity in the elderly. In the present paper we report data obtained on freshly collected blood from 148 healthy subjects of different ages (from cord blood to 102 years old). The subjects were divided into seven age classes (cord blood, 3–11 years, 15–39 years, 41–60 years, 61–74 years, 75–84 years, 85–102 years) and their lymphocyte subsets and the expression of the apoptosis-related molecule CD95 were evaluated. In respect of lymphocyte subsets, the major differences were found in the cord-blood samples compared w…

La diagnosi di Laboratorio della malattia di Alzheimer: ruolo dei markers infiammatori.

Acute Myocardial Infarction and Proinflammatory Gene Variants

We identified four genetic risk sets for acute myocardial infarction (AMI) from information on functional gene variants that favor inflammation or modulate cholesterol metabolism: IL6 -174 G/C, TNF -308 G/A, IL10 -1082 G/A, SERPINA3 -51 G/T, IFNG +874 T/A, HMGCR -911 C/A, and APOE ε2/3/4; 316 patients and 461 healthy subjects, all Italian. Putative risk alleles are shown underlined. The sets were identified using grade-of-membership analysis. Membership scores in the sets are automatically generated for individuals. The ''low intrinsic risk'' set had alleles that downregulate inflammation and cholesterol synthesis (IL6, TNF, ILl0, HMGCR). ''AMI across a broad age range'' carried multiple pr…

IL-10, Genetic Polymorphism and Its Relevance to Age-related Diseases

Association between the interleukin-1beta polymorphisms and Alzheimer's disease: a systematic review and meta-analysis.

Abstract The pro-inflammatory cytokine interleukin(IL)-1β is a main component in inflammatory pathways and is overexpressed in the brain of Alzheimer's disease (AD) patients. Several studies report associations between IL-1β polymorphisms and AD, but findings from different studies are controversial. Our aim was to verify the correlation between the single nucleotide polymorphisms (SNPs) of the IL-1β, at sites − 511 and + 3953, and AD by meta-analysis. Computerized bibliographic searches of PUBMED and AlzGene database ( http://www.alzgene.org ) were supplemented with manual searches of reference lists. There is evidence for association between IL-1β + 3953 SNP and AD, with an OR = 1.60 (95%…

Allele frequencies of +874T→A single nucleotide polymorphism at the first intron of interferon-γ gene in a group of Italian centenarians

Ageing is characterized by a pro-inflammatory status which could contribute to the onset of major age-related diseases such as cardiovascular diseases, neurodegeneration, osteoarthritis and osteoporosis, and diabetes. Thus, it can be hypothesized that genetic variations in pro- or anti-inflammatory cytokines might influence successful ageing and longevity. We have studied the distribution of +874T--A interferon-gamma (IFN-gamma) polymorphisms in a large number of Italian centenarians to evaluate if the two alleles might be differently represented in people selected for longevity. DNA samples were obtained from 174 Italian centenarians (99 years old, 142 women and 32 men) and from 24860-year…

Genetic Determined Downregulation of Both Type 1 and Type 2 Cytokine Pathways Might Be Protective against Pancreatic Cancer

Many cytokine polymorphisms have been studied for associations with susceptibility to breast, gastric, liver, lung, prostate, and ovarian cancer without conclusive results. The cytokine network, indeed, is characterized by complex interactions, and the final biological effect of a single genetic variation depends on the balance among different molecular signals. As is well known, Th1/Th2 cytokine unbalanced production might predispose to different pathologies, cancer included. In general, a prolonged type 1 inflammatory response might allow that cells accumulating enough "genetic hits" are promoted to neoplastic transformation. On the other hand, IL-13-producing cells through the IL-13/IL-4…

Gender-specific association between -1082 IL-10 promoter polymorphism and longevity.

Ageing is characterized by a pro-inflammatory status, which could contribute to the onset of major age-related diseases. Thus, genetic variations in pro- or anti-inflammatory cytokines might influence successful ageing and longevity. IL-10 is an appropriate candidate because it exerts powerful inhibitory effects on pro-inflammatory function. IL-10 production is controlled by several polymorphic elements in the 5' flanking region of IL-10 gene on 1q32 locus, involving alleles at two microsatellite regions and several polymorphisms in promoter region. We analysed in 190 Italian centenarians (99 years old, 159 women and 31 men) and in 26060 years old control subjects (99 women and 161 men), ma…

Systemic Immune Responses in Alzheimer's Disease: In Vitro Mononuclear Cell Activation and Cytokine Production

To investigate the systemic signs of immune-inflammatory responses in Alzheimer's disease (AD), in the present study we have analyzed blood lymphocyte subsets and the expression of activation markers on peripheral blood mononuclear cells (PBMCs) from AD patients and age-matched healthy controls (HC) activated in vitro by recombinant amyloid-beta peptide (rAbeta42). Our study of AD lymphocyte subpopulations confirms the already described decrease of the absolute number and percentage of B cells when compared to HC lymphocytes, whereas the other subsets are not significantly different in patients and controls. We report the increased expression of the activation marker CD69 and of the chemoki…

Inflammation, genes and zinc in Alzheimer's disease.

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 metal biological pathway. 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. Amyloid deposition, due to the accumulation of Abeta peptide, is the main pathogenetic mechanism. Inflammation clearly occurs in pathologically vulnerable regions of AD and several i…

Interleukin-10 promoter polymorphism in sporadic Alzheimer's disease.

Proinflammatory cytokines and acute-phase proteins play an important role in Alzheimer's disease (AD) neurodegeneration, and common polymorphisms of genes controlling their high production have been shown to be associated with AD. Thus, AD patients display a proinflammatory genotype and the control of inflammation might play a protective role in AD development. By sequence-specific probes, we have evaluated the role of anti-inflammatory cytokine interleukin(IL)-10 in AD, by analysing in 132 AD patients and 213 healthy controls the prevalence of three different haplotypes, involving three single-nucleotide polymorphisms (SNPs) at -1082 (G--A), -819 (C--T) and -592 (C--A) nucleotides of IL-10…

Cytokine serum profile in a group of Sicilian Nonagenarians

The aim of our study was to evaluate the possibility of using multiplex analysis of the cytokine profile as a marker for successful aging by comparing cytokine plasmatic levels of a group of Sicilian nonagenarians with those of young controls. We analyzed a panel of 17 cytokines, comprehensive of haematopoietic factors T helper 1 (Th1), Th2, inflammation regulatory cytokines, and chemokines. The assay was carried out using the Luminex system. Interleukin (IL)-6 levels (p = 0.01) were increased in nonagenarians, whereas no modifications of other proinflammatory cytokines and chemokines were observed. Interferon-gamma (IFN-gamma) and IL-2 levels are unmodified, suggesting a substantial mainte…

Are the leukocyte telomere length attrition and telomerase activity alteration potential predictor biomarkers for sporadic TAA in aged individuals?

A large variability in occurrence, complications, and age/gender manifestations characterizes individual susceptibility of sporadic thoracic aortic aneurysms (TAA), even in subjects with the same risk factor profiles. The reasons are poorly understood. On the other hand, TAA pathophysiology mechanisms remain unclear than those involved in abdominal aorta aneurysms. However, recent evidence is suggesting a crucial role of biological ageing in inter-individual risk variation of cardiovascular diseases, including sporadic TAA. Biological age rather than chronological age is a better predictor of vascular risk. Relevant assumptions support this concept. In confirming this evidence and our preli…

Production of T suppressor factor specific for the hapten picryl chloride requires both T suppressor cells and an antigen-specific, genetically restricted second signal

Summary We investigated the requirement for activation of T suppressor cells specific for the hapten picryl chloride and the release of hapten-specific T suppressor factor. Using an in vivo experimental system, we report that activation of T suppressor cells and the consequent release of T suppressor factor required two signals: one was provided by primed T suppressor cells, i.e. spleen cells from mice injected with the tolerogen picrylsulphonic acid, and the other was provided by the specific antigen in the context of H-2 gene products. Mechanisms by which the interaction between these two signals led to activation of T suppressor cells and the production of T suppressor factor, as well as…

HLA-DR phenotypes and blood levels of T cell subsets

Blood mononuclear cell and T cell subsets values were analyzed in 53 Sicilian individuals according to HLA-DR phenotypes. The results demonstrate that DR1-positive subjects show a significant increase of blood T cell subsets whereas DR3-positive subjects show a non-significant decrease of these values. These results suggest that gene(s) associated with HLA-DR could be one of the factors which affect blood levels of T cell subsets.

Training Effects on Laboratory Parameters Are Independent of Genetic Polymorphisms of IL-10 and TNF-alpha (TNF-α)

Background: It is well known that exercise has beneficial effects on health. Although intense exercise is experienced by the body as a condition of stress, a well designed training has long term beneficial effects on the organism of an athlete. Less is known about the effects that the genetic background might have on training adaptation and on the consequent modification of laboratory parameters. Methods: In our study we evaluated the blood chemistry parameters of a group of 41 athletes compared with a group of 45 amateur athletes, to assess whether the training has effects on their variation. In addition we typed our subjects for polymorphisms 308 A/G of the tumor necrosis factor-α (TNF-α)…

1267 HSP70-2 polymorphism as a risk factor for carotid plaque rupture and cerebral ischaemia in old type 2 diabetes-atherosclerotic patients.

Patients with type 2 diabetes mellitus (NIDDM) are at risk for macrovascular disease complications, such as myocardial infarction (MI) or stroke from plaque rupture. Cytokines play a key role in plaque vulnerability. IFN-gamma inhibits collagen synthesis thereby affecting plaque stability. High IL-6, TNF-alpha, and dyslipidemia are risk factors for thrombosis. Abnormal increments of HSP70 in atherosclerotic plaques might lead to plaque instability and rupture caused by chronic inflammation, which up-regulates the expression of pro-inflammatory cytokines (IL-6 and TNF-alpha) in human monocytes. Studies of a polymorphic PstI site lying in the coding region at position 1267 of the HSP70-2 gene…

Analisi dei Polimorfismi di Citochine Th2 nella Sclerosi Multipla.

Valutazione delle frequenze alleliche e genotipiche di citochine di tipo Th1 e Th2 in pazienti affetti da malattia di Behçet.

Inflammation, genetics, and longevity: further studies on the protective effects in men of IL-10 -1082 promoter SNP and its interaction with TNF-alpha -308 promoter SNP.

Ageing is associated with chronic, low grade inflammatory activity leading to long term tissue damage, and systemic chronic inflammation has been found to be related to mortality risk from all causes in older persons.1 Also, the genetic constitution of the organism interacting with systemic inflammation may cause defined organ specific illnesses. Thus, age related diseases such as Alzheimer’s disease (AD), Parkinson’s disease, atherosclerosis, type 2 diabetes, sarcopenia, and osteoporosis, are initiated or worsened by systemic inflammation, suggesting the critical importance of unregulated systemic inflammation in the shortening of survival in humans.1–3 Accordingly, proinflammatory cytokin…

Frequenza dei polimorfismi del peptide segnale del TGF-b1 in un gruppo di pazienti affetti da stenosi carotidea

Are Endothelial Progenitor Cells the Real Solution for Cardiovascular Diseases? Focus on Controversies and Perspectives

Advanced knowledge in the field of stem cell biology and their ability to provide a cue for counteracting several diseases are leading numerous researchers to focus their attention on “regenerative medicine” as possible solutions for cardiovascular diseases (CVDs). However, the lack of consistent evidence in this arena has hampered the clinical application. The same condition affects the research on endothelial progenitor cells (EPCs), creating more confusion than comprehension. In this review, this aspect is discussed with particular emphasis. In particular, we describe biology and physiology of EPCs, outline their clinical relevance as both new predictive, diagnostic, and prognostic CVD b…

Vascular Aging effect on Medial aorta degeneration: focus on blood keukocyte telomere lenght in Hypertensive and old patients with sporadic thoracic aortic aneurysm

Analysis of HLA-DRB1,DQA1,DQB1 haplotypes in Sardinian centenarians

Some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses. Many longevity association studies focused their attention on HLA (the human MHC) polymorphisms, but discordant results have been obtained. Sardinians are a relatively isolate population and represent a suitable population for association studies. Some HLA-DR and DQ alleles form very stable haplotypes with a strong linkage disequilibrium. In a previous study on Sardinian centenarians we have suggested that HLA-DRB1 *15 allele might be marginally associated to longevity. HLA-DR,DQ haplotypes are in strong linkage disequilibrium and well conserved playing a ro…

A study of serum immunoglobulin levels in elderly persons that provides new insights into B cell immunosenescence.

The literature on immunosenescence has focused mainly on T cell impairment. With the aim of gaining insight into B cell immunosenescence, we investigated the serum immunoglobulin levels in a cohort of 166 subjects (20-106 years). Serum IgG (and IgG subclasses) were quantified by the nephelometric technique, IgE by CAP system fluorescence enzyme immunoassay, and IgD by radial immunodiffusion (RID). There was an age-related increase of IgG and IgA; the IgG age-related increase was significant only in men, but IgG1 levels showed an age-related increase both in men and women, whereas IgG3 showed an age-related increase only in men. IgE levels remain unchanged, whereas IgD and IgM serum levels d…

Tumor necrosis-factor-alpha -308 A/G polymorphism is associated with age at onset of Alzheimer's disease.

Abstract Pro-inflammatory cytokines and acute-phase proteins play an important role in Alzheimer's disease (AD) neurodegeneration, and common polymorphisms of genes controlling their production have been shown to be associated with AD. Tumor necrosis factor (TNF)-α is an inflammatory cytokine involved in the local immune response occurring in the central nervous system of AD patients. Genetic variation could contribute to the risk of developing AD or influence the age at the onset of the disease. We genotyped 222 patients (152 women, 70 men; age range 60–87) and 240 non-demented age-matched healthy controls for TNF-α −308 G/A single nucleotide polymorphism (SNP). No significant differences …

Frequency of the HFE Gene Mutations in Five Italian Populations

Abstract ABSTRACT Genetic hemochromatosis is an autosomal recessive disorder characterized by iron overload and a variety of clinical manifestations such as liver cirrhosis and arthropathy. It is the most common genetic disease of northern European populations. The principal gene responsible for hereditary hemochromatosis, designated HFE, is located on chromosome 6 in the HLA region. The single point mutation 845A, changing cysteine at position 282 to tyrosine (C282Y), in this gene has been identified as the main genetic basis of hereditary hemochromatosis. Two other mutations, 187G, a histidine to aspartate at amino acid 63 (H63D), and 193T, a serine to cysteine at amino acid 65 (S65C), ap…

Febbre familiare mediterranea, longevità ed infarto del miocardio: uno studio nella popolazione siciliana

Immune-Inflammatory Responses and Oxidative Stress in Alzheimers 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) an…

CCR5 Proinflammatory Allele in Prostate Cancer Risk

Prostate cancer (PCa) is the most common malignant neoplasm in older men in Western countries. The number of affected older men is increasing. Therefore, strategies for prevention of prostate cancer are crucial. To this purpose it is essential to know the mechanisms involved in development and progression of this malignancy. Recently, an increasing body of genetic and epidemiological studies proposed new hypotheses for prostate carcinogenesis. It has been suggested that genetic factors as well as exposure to environmental factors such as infectious agents, dietary carcinogens, and hormonal imbalances participate in PCa development. Besides, chronic inflammation plays a key role in PCa. Taki…

B cell immunosenescence in the elderly and in centenarians.

The elderly suffer from an increased susceptibility to infectious disease and cancer. Aging of the immune system contributes to this state of affairs due to immunosenescence. Because repeated intermittent or chronic antigen exposure may lead to lymphocyte clonal exhaustion, chronic antigenic stress plays a part in the compromised immunity of the elderly, who have accumulated a lifetime's exposure to infectious agents, autoantigens, and cancer antigens. Literature on immunosenescence has focused mainly on T cell impairment, but B cell compartment is also affected. The age-dependent B cell changes documented by the present review indicate that advanced age per se is a condition characterized …

Polymorphisms of pro-inflammatory genes and Alzheimer's disease risk.

Polymorphisms of genes of TGF-beta pathway and susceptibility to colorectal cancer

Background: Genetic background implicated in cytokine network may have a key role in the susceptibility to colorectal cancer (CRC). The TGF-β pathway is involved in several biological processes, including cell proliferation, differentiation, migration and apoptosis. Methods: rs1800471 SNP polymorphism of TGF-ß1 rs334348 and rs334349 of TGF-βR1, rs900 of TGF-β2 and rs4522809 of TGF-β2R2 were typed in a group of 82 patients affected by sporadic CRC and in 237 age- and sex-matched healthy controls, using a competitive allele specific PCR assays (KASPar), developed by KBioscience (England). Results: No significant genetic contribution has been observed for 3 of the 5 SNPs tested. Indeed, a sign…

Cytokine profile of breast cell lines after different radiation doses

Purpose: Ionizing radiation (IR) treatment activates inflammatory processes causing the release of a great amount of molecules able to affect the cell survival. The aim of this study was to analyze the cytokine signature of conditioned medium produced by non-tumorigenic mammary epithelial cell line MCF10A, as well as MCF7 and MDA-MB-231 breast cancer cell lines, after single high doses of IR in order to understand their role in high radiation response. Materials and methods: We performed a cytokine profile of irradiated conditioned media of MCF10A, MCF7 and MDA-MB-231 cell lines treated with 9 or 23 Gy, by Luminex and ELISA analyses. Results: Overall, our results show that both 9 Gy and 23 …

B CELL IMMUNOSENESCENCE IN THE ELDERLY

Can the TLR-4-mediated signaling pathway be "a key inflammatory promoter for sporadic TAA"?

Thoracic aorta shows with advancing age various changes and a progressive deterioration in structure and function. As a result, vascular remodeling (VR) and medial degeneration (MD) occur as pathological entities responsible principally for the sporadic TAA onset. Little is known about their genetic, molecular, and cellular mechanisms. Recent evidence is proposing the strong role of a chronic immune/inflammatory process in their evocation and progression. Thus, we evaluated the potential role of Toll like receptor- (TLR-) 4-mediated signaling pathway and its polymorphisms in sporadic TAA. Genetic, immunohistochemical, and biochemical analyses were assessed. Interestingly, the rs4986790 TLR4…

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 …

Evaluation of CD1a polymorphism frequencies in patients with pancreatic cancer

A methodological strategy for PAH genotyping in populations with a marked molecular heterogeneity of hyperphenylalaninemia.

Abstract The elucidation of the molecular basis of hyperphenylalaninemia in various world populations (PKU Consortium Database: http://www.mcgill.ca/pahdb/) has revealed a remarkable molecular heterogeneity at the locus encoding for phenylalanine hydroxylase. As a consequence, genotyping of HPA patients has prompted the establishment of an impressive number of mutation detection protocols. In spite of the large variety of methods proposed so far, no comprehensive strategy has been yet developed for the detection of PAH gene mutations. Therefore, new approaches, combining the advantages of individual methods are required, especially in populations with a high number of PAH gene mutations. In…

Reazioni infiammatorie acute e croniche

Association between the Polymorphism of CCR5 and Alzheimer's Disease: results of a study performed on male and female patients from Northern Italy

In vitro treatment with interleukin-2 normalizes type-1 cytokine production by lymphocytes from elderly

The term immunosenescence is taken to mean the deterioration of immune function seen in elderly, which is manifested in increased susceptibility to infectious diseases, neoplasias, and autoimmune diseases. It is only recently that we have begun to understand the cellular and molecular changes involved. Of special interest in this regard are observations of a decline in synthesis of Type-1 cytokines which predisposes to diminished cell mediated immunity. We have evaluated the production of type 1 cytokines in old and young donors either in presence or in absence of recombinant interleukin-2 (rIL-2). Lymphocytes were stimulated with plastic bound anti-CD3 and after 48 h the supernatants were …

Association between longevity and cytokine gene polymorphisms. A study in Sardinian centenarians

Background and aims: Human longevity seems to be directly correlated with optimal functioning of the immune system, suggesting that some genetic determinants of longevity reside in those polymorphisms for the immune system genes which regulate immuneinflammatory responses, in particular cytokine gene polymorphisms. The frequency of − 174C single nucleotide polymorphism (SNP) in the promoter region of the interleukin(IL)-6 gene is increased in Italian male centenarians. Moreover, the frequency of − 1082G SNP at the 5′ flanking region of the IL-10 gene coding sequence is increased among male centenarians, and that of +874A SNP at the interferon (IFN)- γ gene was found more frequently in femal…

Looking for immunological risk genotypes

Pro-inflammatory genetic background and zinc status in old atherosclerotic subjects.

Inflammation and genetics are prominent mechanisms in the pathogenesis of atherosclerosis (AT) and its complications. In this review we discuss the possible impact on AT development of several genetic determinants involved in inflammation, oxidative stress and cytoprotection (IL-6, TNF-alpha, IL-10, CD14, TLR4, MT, HSP70). Genetic polymorphisms of these genes may affect a differential inflammatory response predisposing to AT. However, allelic polymorphisms of genes which increase the risk of AT frequently occur in the general population but, only adequate gene-environment-polymorphism interactions promote the onset of the disease. Zinc deficiency has been suggested as an environmental risk …

Involvement of -308 TNF-alpha and 1267 Hsp70-2 polymorphisms and zinc status in the susceptibility of coronary artery disease (CAD) in old patients.

Coronary artery disease (CAD) is characterized by an inflammatory status and it represents the major cause of death in elderly. Zinc deficiency and inflammatory genes within major histocompatibility complex (MHC) region are implicated in ischaemic heart diseases. TNF-alpha is present in coronary artery plaques and may provoke plaque instability. Hsp70 plays instead a pro-atherogenic role, via proinflammatory cytokine production, in atherosclerotic lesions contributing to plaque rupture. Contradictory data report the association between -308 TNF-alpha polymorphism and CAD, while no investigations exist on Hsp70-2 gene in CAD. In the current study, we analysed -308 TNF-alpha and 1267 Hsp70-2 …

Alpha1-antitrypsin heterozygosity plays a positive role in attainment of longevity.

Genes involved in cardiovascular diseases (CVD) play an opposite role in human longevity. The alpha1-antitrypsin (AAT) is a serine-protease inhibitor required for the prevention of proteolytic tissue damage, by neutrophil elastase. The role of AAT in CVD has not been definitively assessed and its effect on longevity has not yet fully been studied. To clarify these points, we have studied the distribution of AAT allele variants in 3 cohorts: 127 young patients affected by acute myocardial infarction (AMI), 255 young controls and 143 centenarians from Sicily. The Z allele frequency was most frequent in centenarians (13.3%), intermediate in healthy young controls (3.1%) and less frequent in AM…

TRafficking profile in naive and memory B cells in young and old subjects

G-protein-coupled receptor kinase 5 polymorphism and Takotsubo cardiomyopathy.

BACKGROUND: Takotsubo cardiomyopathy (TTC) is an increasingly reported clinical syndrome that mimics acute myocardial infarction without obstructive coronary artery disease and is characterized by transient systolic dysfunction of the apical and/or mid-segments of the left ventricle. The syndrome mainly occurs in postmenopausal women with high adrenergic state conditions. Nowadays, the pathophysiology of TTC is not yet known and the possibility of a genetic predisposition is controversial. AIMS: The purpose of this study was to assess the genetic susceptibility to TTC through analysis of the L41Q polymorphism of the G-protein-coupled receptor kinase 5 (GRK5). METHODS AND RESULTS: In a cohor…

Opposite role of CCR5 polymorphisms in cardiovascular diseases and longevity.

Alzheimer’s disease and genetics of inflammation: a pharmacogenomic vision

Inflammation plays a key role in Alzheimer disease, and dissecting the genetics of inflammation may provide an answer to the possible treatment. The next-generation therapy is based on a pharmacogenomics that will reconure new approaches to a drug used on definite people with specific dosage. The translation of pharmacogenomics into clinical practice will allow bold steps to be taken toward personalized medicine. In response to tissue injury elicited by trauma or infection, the inflammatory response sets in as a complex network of molecular and cellular interactions, directed to facilitate a return to physiological homeostasis and tissue repair. The role of an individual’s genetic backgroun…

Toll-like receptor-4 signaling pathway in aorta aging and diseases: “its double nature”

Recent advances in the field of innate immunity have revealed a complex role of innate immune signaling pathways in both tissue homeostasis and disease. Among them, the Toll-like receptor 4 (TLR-4) pathways has been linked to various pathophysiological conditions, such as cardiovascular diseases (CVDs). This has been interrogated by developing multiple laboratory tools that have shown in animal models and clinical conditions, the involvement of the TLR-4 signaling pathway in the pathophysiology of different CVDs, such as atherosclerosis, ischemic heart disease, heart failure, ischemia-reperfusion injury and aorta aneurysm. Among these, aorta aneurysm, a very complex pathological condition w…

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 trea…

Role of prothrombotic polymorphisms in successful or unsuccessful aging.

The study of the genetic profile of centenarians aims to identify the genes and allelic variants which may influence a greater life expectancy and that can be considered as predisposing factors associated to the aging diseases, such as Alzheimer. Centenarians, that represent a cohort of selected survivors, show an hypercoagulability state characterised by striking signs of high coagulation enzyme activity, as directly assessed by the tested higher plasma level of some important factors involved in the haemostasis balance. Anyway, these individuals seem to have a reduced susceptibility to dementia, as well as to cardiovascular events. In this study we analyze the frequencies of Leiden Factor…

Looking for Immunological Risk Genotypes

Several functional markers of the immune system may be used either as markers of successful aging or conversely as markers of unsuccessful aging. Particularly, a combination of high CD8 and low CD4 and poor T cell proliferation has been associated with a higher two-year mortality in very old subjects. Therefore, genetic determinants of longevity should reside in those polymorphisms for the immune system genes that regulate immune responses. Concerning these changes in T cell subpopulations, how much they depend on the immunogenetic background and how much they depend on individual antigenic load, such as chronic infections, should be assessed. As previously demonstrated in our population, t…

Analisi del Profilo genetico Th1/Th2 in soggetti allergici.

Gamma/delta T lymphocytes are affected in the elderly

gammadelta T lymphocytes are considered to represent a link between the inflammatory response and adaptive immunity. In the present paper we investigated whether these cells play any role in the remodeling of the immune system described in the elderly. We show that the absolute number of gammadelta T cells in peripheral blood of old and very old subjects is reduced. Moreover, gammadelta T cells from old people and centenarians show enhanced levels of the early activation marker CD69 both after culture in medium alone and in LPS-stimulated cells. Furthermore, they show a basal increased production of tumor necrosis factor (TNF)-alpha as evaluated at the single cell level. Additionally, the r…

Immunological and immunogenetic markers in sporadic Alzheimer’s disease

Background: Common polymorphisms of genes controlling inflammation-modulating cytokines and acute-phase proteins which play important roles in the pathogenesis of Alzheimer''s disease (AD) have been shown to be associated with AD. Aims: The immunological and immunogenetic markers potentially useful for the AD risk evaluation and diagnosis are briefly reviewed. Conclusion: The state-of-the-art of immunological and immunogenetic markers of AD indicates that new tools and strategies are necessary to identify gene products useful as diagnostic tools.

Gluten Stimulation Induces an in vitro Expansion of Peripheral Blood Tγδ Cells from HLA-DQ2-Positive Subjects of Families of Patients with Celiac Disease

The intestinal gluten sensitivity formally known as celiac disease (CD) is characterized by an evident involvement of local immune response and it is associated with the expression of HLA-DQ2 allele. The major role in the disease seems to be played by the T lymphocyte population bearing gamma delta T cell receptor (T gamma delta cells) which are increased both in peripheral blood and intestinal mucosae of celiac patients. In this paper data on the effects of in vitro gluten stimulation on lymphocytes expressing the T gamma delta phenotype are reported. Gluten seems to be able to induce the expansion of the T gamma delta cell population both in CD patients and their HLA-DQ2-positive asymptom…

MALATTIE INFIAMMATORIE CORRELATE ALL’ETÀ

IL-5 Enhances in Vitro and in Vivo Antigen-Specific IgA Production in MHC Genetically Determined Low IL-5 Responder Mice

Lymphonode cells from BALB/k mice, but not from BALB/c mice, immunized with picryl chloride (PCl) produce IL-5 when stimulated with the specific antigen in vitro and this correlates with picryl-specific IgA levels in vivo, which are 6 to 10 times higher in BALB/k mice. B lymphocytes from BALB/k mice cultured with PCl-immune T cells from BALB/k produce in vivo anti-PCl-IgA, while B lymphocytes from BALB/c mice, cultured with T cells from BALB/c mice, fail to produce appreciable amounts of anti-PCl IgA, unless IL-5 is added to cultures. B lymphocytes from both strains of mice produce similar amounts of total IgA antibodies when stimulated in vitro with lipopolysaccharide. In vivo administrati…

Apolipoprotein E Genotypic Frequencies Among Down Syndrome Patients Imply Early Unsuccessful Aging for ApoE4 Carriers

Down syndrome (DS) might be considered a model for unsuccessful and early aging, possibly accelerated for those who carry the APOE4 allele associated with common age-related diseases, e.g., Alzheimer's disease and a poor prognosis after acute myocardial infarction, causing lower ApoE4 frequencies among the very old in general populations. We compared ApoE genotypic frequencies found for healthy adults (n = 211, age 90) to those found for DS patients (n = 106, mean age 9 years), all living in western Sicily. We found that the frequency of the ApoE23 genotype increased with age among the healthy adults (8.5%, 6.4%, 19.7%; p = 0.024) while ApoE34 frequency decreased (16.1%, 12.6%, 4.1%; p = 0.…

CD14 C (-260)T polymorphism, atherosclerosis, elderly: Role of cytokines and metallothioneins.

Abstract Background CD14 receptor is a mediator of the inflammatory response to bacterial products. A functional polymorphism in the promoter of the CD14 gene (CD14 C-260T) was associated with coronary heart disease and atherosclerosis albeit with conflicting data. Methods To better clarify the role of CD14 in atherosclerosis, we typed CD14 C-260T polymorphism in old Italian (Central of Italy) atherosclerotic patients with carotid stenosis related to lipid assessment, inflammation (soluble CD14, IL-6 serum levels) and IL-6, TNF-α, IL-10, Metallothioneins (MT) gene expressions in carotid plaques. Results There was an increased frequency of TT homozygotes in patients when compared to controls…

Memory B Cell Subpopulations in the Aged

The literature on immunosenescence has focused mainly on T cell impairment. With the aim of gaining insight into B cell immunosenescence, the authors investigated the serum IgD levels in 24 young and 21 old people and analyzed their relationship with the number of CD19 CD27 memory cells. Serum IgD were quantified by the use of radial immunodiffusion and the lymphocyte population CD19 CD27 was identified by a FACScan flow cytometer. Serum IgD levels were significantly lower (p 0.0001) in old subjects, and the percentage of CD19 CD27 lymphocytes were significantly increased (p 0.01) in old subjects. Finally, a significant negative correlation was found (p 0.01) between serum concentrations of…

Study of the Association with -330T/G IL-2 in a Population of Centenarians from Centre and South Italy.

Immune response in elderly is characterised by a progressive loss of the ability to cope environmental stressors with a characteristic remodelling of cytokine network. One of the data constantly reported in literature is the decrease of IL-2 production. An IL-2 central role in the reconstitution of T cell function in vitro is largely documented. Studies on a T → G polymorphism at - 330 nt of IL-2 gene promoter region have demonstrated that T lymphocytes from 330GG homozygous subjects are able to produce in vitro higher amount of IL-2, than -330TG heterozygous or -330TT homozygous subjects. As a genetic background conditioning the maintaining of an efficient immune response would exert posit…

Modification of Peripheral Blood T-Lymphocyte Surface Receptors and Langerhans Cell Numbers in Hereditary Angioedema

Hereditary angioedema (HAE) is a disease related to a complement disorder, namely a deficiency of C1 esterase inhibitor. Complement-split products are implicated in the regulation of the immune response, and we have compared some immunologic parameters between HAE and normal individuals. T-lymphocytes with receptors for IgG were increased in HAE, but no difference in T-cell suppressor activity for B-cells was detected. Furthermore, increased IgG receptor expression was not accompanied by any significant changes in the ratios of OKT4- and OKT8-defined antigens. Numbers of peripheral mononuclear cells (MNC) detected by alpha-naphthyl acetate esterase (ANAE) staining positivity were not signif…

Association between the HLA-DR alleles and longevity: a study in Sardinian population

Human longevity may be correlated with optimal functioning of the immune system, suggesting that genetic determinants of longevity also resides in those polymorphisms for the immune system genes that regulate immune responses as histocompatibility (HLA) antigens. However, conflicting results have been obtained. Some well planned and designed association studies performed in Caucasians suggest that longevity is associated with positive selection of alleles (i.e. HLA-DR11) or haplotypes (i.e. HLA-B8,DR3) that confer resistance to infectious diseases, respectively, via peptide presentation or via antigen non-specific control of immune response. Association studies are subjected to a number of …

Association between +1059G/C CRP polymorphism and acute myocardial infarction in a cohort of patients from Sicily: a pilot study.

Inflammation plays a role in all the phases of atherosclerosis, and increased production of the acute-phase reactant, C-reactive protein (CRP), predicts future cardiovascular events. Furthermore, CRP has been claimed to play a role in the pathogenesis of atherosclerosis; therefore, CRP polymorphisms might be associated with acute myocardial infarction (AMI). We have analyzed male patients affected by AMI and healthy age-related male controls from Sicily for +1059G/C CRP single-nucleotide polymorphism (SNP). There was a significantly higher frequency of +1059C SNP (P = 0.0008; OR 3.86) in patients compared to controls. CRP serum levels were significantly higher in C+ healthy subjects rather …

Myocardial infarction marker levels are influenced by prothrombin and tumor necrosis factor-α gene polymorphisms in young patients.

Polymorphisms of genes encoding key factors for the control and activation of inflammatory response and coagulation cascade regulation may play a role in genetic susceptibility to acute myocardial infarction (AMI). This study sought to analyze the effect of TNF - 308G/A and pro-thrombin (FII) 20210G/A polymorphisms on the laboratory parameters of young patients affected by AMI. Results indicated that TNF - 308A positive genotype frequencies were increased in these patients and that a genetically determined higher production of TNF-alpha is associated in young subjects to a more severe cardiac damage as depicted by higher levels of troponin, Creatine kinase-MB Isoenzyme (mCK-MB) and a signif…

REGULATORY T CELLS IN FRAIL ELDERLY

Frequency of polymorphisms of signal peptide of TGF-beta1 and -1082G/A SNP at the promoter region of Il-10 gene in patients with carotid stenosis

The role of inflammation in atherosclerosis is well recognized. We have evaluated the allele frequencies of the +869T/C and +915G/C polymorphisms (SNPs) at the TGF-beta1 gene and -1082G/A SNP at IL-10 promoter sequence, two well-known immunosuppressive and anti-inflammatory cytokines, in patients with carotid stenosis. Our data suggest a lack of association between these SNPs and the susceptibility to atherosclerosis although other reports have demonstrated this association. These results may be due to the pleiotropic effects of the cytokines and/or differences in haplotype combination that should be investigated to elucidate the role of TGF-beta1 and IL-10 polymorphisms in atherosclerosis.

Opposite role of pyrin M694V allele in acute myocardial infarction and longevity: results of a pilot study performed in Sicily.

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…

Inflammation, longevity and cardiovascular diseases: role of polymorphisms of TLR4

Gender-Related Immune-Inflammatory Factors, Age-Related Diseases, and Longevity

This review discusses the role of estrogens as pro- or antiinflammatory players in immune-inflammatory responses. In particular, their role in Alzheimer’s disease (AD), an example of immune-inflammatory disease, is discussed briefly. AD is a progressive neurodegenerative disease, which in Western societies accounts for the majority of cases of clinical senile dementia. However, sexual dimorphism of diseases may also depend on factors independent of sex hormones (i.e., a gender effect), as demonstrated by our data on differential longevity in females and males. In fact, differences in mortality between men and women are not only a question of sex that refers to biological differences, but ra…

Role of Toll-like receptor 4 in acute myocardial infarction and longevity.

Biomarkers of aging

Aging is a complex process that negatively impacts the development of the different systems and its ability to function. Moreover, the Aging rate in humans is not the same, principally due to genetic heterogeneity and environmental factors. The aging rate is measured as the decline of functional capacity and stress resistance. Therefore, several attempts have been made to analyse the individual age, ( so-called biological age) compared to chronological age. The biomarkers of aging are age-related body function or composition, these markers aim to assess the biological age and predict the onset of age-related diseases and/or residual lifetime. Such biomarkers should help in one hand to chara…

IgG1 antiendomysium and IgG antitissue transglutaminase (anti-tTG) antibodies in coeliac patients with selective IgA deficiency

Background—In selective IgA deficiency (IgAD), there is no reliable screening test for coeliac disease (CD). Aim—To evaluate the usefulness of IgG1 antiendomysium and IgG antitissue transglutaminase tests for CD diagnosis in IgAD. Methods—IgA and IgG antigliadin antibodies (IgA- and IgG-AGA), IgA and IgG1 antiendomysium antibodies (IgA- and IgG1-EMA), and IgA and IgG antitissue

TLR4 polymorphisms and ageing: implications for the pathophysiology of age-related diseases.

Innate immunity provides a first line of host defense against infection by recognizing and killing microbes while simultaneously activating an instructive immune response. Toll-like receptors (TLRs) are principal mediators of rapid microbial recognition and function mainly by detection of pathogen-associated molecular patterns that do not exist in the host. Recognition of their ligands leads to a series of signaling events resulting in acute host responses, involved in killing pathogens. Discussion We describe the involvement of TLR4 polymorphisms in ageing, and in particular in age-related diseases, suggesting the crucial role of molecules of innate immunity in pathophysiology of these dis…

Evaluation of cytokine polymorphisms (TNFalpha, IFNgamma and IL-10) in Down patients with coeliac disease.

Abstract Background In Down syndrome there is an increased prevalence of coeliac disease, but the reasons for this association are yet unknown. Aims To evaluate a possible correlation between TNFα, IFNγ and IL-10 genotype polymorphisms with the susceptibility to coeliac disease in Down syndrome patients. Methods Single nucleotide polymorphisms of TNFα (−308G → A promoter region), IFNγ (+874T → A promoter region) and IL-10 (−1082G → A promoter region) have been studied in 10 Down patients with coeliac disease, in 40 Down patients without coeliac disease and in 220 healthy controls. Clinical features were also studied in coeliac disease–Down syndrome patients. Results The 10 coeliac disease–D…

Role of cyclooxygenae-2 and 5-lypoxygenase polymorphisms in Alzheimer's disease in a population from northern Italy:implications for pharmacogenomics

Alzheimer's disease (AD) is a neurodegenerative disorder clinically characterized by cognitive deficit with progressive worsening of memory. Recent data indicate that neurons, as well as other brain cells, can express enzymes such as cyclooxygenases (COXs) and 5-lipoxygenase (5-LO) which are considered important in inflammatory cells. Moreover, it has been demonstrated that COX-2 and 5-LO enzymes play a considerable role in the pathophysiology of AD. In order to assess the possible role of COX-2 and 5-LO single nucleotide polymorphisms (SNPs) in AD, we examined their distribution in 341 AD patients and 190 controls from Northern Italy. A significant difference was observed in the distributi…

Analysis of the Polymorphisms of Th1 and Th17 Cytokines in Mediterranean Spotted Fever

Background: We have recently reported that the susceptibility for Mediterranean spotted fever (MSF) caused by Rickettsia conorii, is influenced by the Th2 and Th1 cytokine genetic polymorphism profiles. Less it is known on the effect of gene polymorphisms of cytokine produced by the Th17. Methods: 70 Sicilian patients affected by MSF and 239 control subjects matched for age, gender, and geographic origin were typed for functionally relevant single nucleotide polymorphisms (SNPs) of IFN-γ (+874 T/A), IL-18 (-137 G/C and -607A/C ) and IL-17 (7488T/C) according to our laboratory procedures. Results: No significant differences in IL-18 -137 G/C, -607A/C and in IFN-γ +874 T /A genotype frequenci…

POLYMORPHISMS IN TYPE 1 AND TYPE 2 CYTOKINE GENES MIGHT PLAY COMPLEMENTARY ROLE IN PANCREATIC CANCER SUSCEPTIBILITY.

Correlation between clinical response and urinary interleukin levels using different doses and intravesical administration schedules of interferon-alpha-2b combined with epirubicin: a pilot study

A total of 62 patients at high risk for recurrence of superficial bladder cancer were selected for a study designed to compare the prophylactic efficacy of different doses and schedules of sequential intravesical instillations of epirubicin and interferon-alpha-2b and to evaluate which sequence could enhance the release of cytokines in the urine. Our investigations showed a significant increase in urinary concentrations of interleukins in patients who received the sequential intravesical administration of epirubicin and interferon-alpha-2b. Higher urinary concentrations of interleukins and a lower recurrence rate were detected in patients who received interferon-alpha-2b 24 h after epirubic…

Immunosenescence and anti-immunosenescence therapies: the case of probiotics.

ABSTRACT Aging is a complex process that negatively impacts the development of the immune system and its ability to function. Progressive changes in the T and B cell systems over the life span have a major impact on the capacity to respond to immune challenge. These cumulative age-associated changes in immune competence are termed immunosenescence. This process is mostly characterized by: (1) shrinkage of the T cell repertoire and accumulation of oligoclonal expansions of memory/effector cells directed toward ubiquitary infectious agents; (2) involution of the thymus and the exhaustion of naive T cells; and (3) chronic inflammatory status. Here we discuss possible strategies to counteract t…

Immunogenetics of longevity. Is major histocompatibility complex polymorphism relevant to the control of human longevity? A review of literature data.

Literature data suggest that human longevity may be directly correlated with optimal functioning of the immune system. Therefore, it is likely that one of the genetic determinants of longevity resides in those polymorphisms for the immune system genes that regulate immune responses. Accordingly, studies performed on mice have suggested that the Major Histocompatibility Complex (MHC), known to control a variety of immune functions, is associated with the life span of the strains. In the last 25 years, a fair number of cross-sectional studies that searched for the role of HLA (the human MHC) genes on human longevity by comparing HLA antigen frequencies between groups of young and elderly pers…

Autoantibody production in aging: effect of cytokine gene polymorphisms in Sicilian ultra-nonagenarians

Cytokine Polymorphism in Takotsubo Cardiomyopathy

IMIN11. Cytokine Polymorphism in Takotsubo Cardiomyopathy P. Di Gangi1, L. Scola1, S. Giambanco1, M. Bova1, G. Santini1, L. Vaccarino1, C. R. Balistreri1, D. Lio1, P. Assennato1, S. Novo1, G. Novo1 1University of Palermo, Palermo, Italy Background: Takotsubo (TT) cardiomyopathy is characterised by an acute left ventricular dysfunction triggered by emotional or physical stresses. Clinically, the syndrome is characterised by acute symptoms mimicking acute infarction without relevant electrocardiographic and biochemical markers of myocardial damage changes. Stressful events inducing an excess catecholamine release and myocardial β-adrenergic receptors (β-AR) seem to play a major role in TT. Ac…

Associazione dei polimorfismi dei geni INF-γ ed IL-10 con la suscettibilità alla Febbre bottonosa.

TGF-B pathway polymorphisms as markers for gender differential susceptibility to sporadic thoracic aortic aneurysm

CD4+CD25+ regulatory cells in aged people are related to IL-10 genetic background and have effect on CMV-specific CD8 lymphocytes

Relevance of gamma interferon, tumor necrosis factor alpha, and interleukin-10 gene polymorphisms to susceptibility to Mediterranean spotted fever.

Several studies have demonstrated that cellular immunity plays a critical role in the protective immune response against Rickettsia conorii. Immune CD4+ and CD8+ T cells are both involved in the control of rickettsial infection (38). Perivascular infiltrated CD4+ and CD8+ T lymphocytes, macrophages, and natural killer cells produce chemokines and cytokines that activate endothelial rickettsicidal activities. Infected human cells, including endothelial cells, hepatocytes, and macrophages, activated by gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β), kill intracellular rickettsiae by one or a combination of three mechanisms, involving nitric oxide syn…

Role of TLR Polymorphisms in Immunosenescence

Innate immunity provides a first line of host defense against infection through microbial recognition and killing while simultaneously activating a clonotypic immune response. Toll-like receptors (TLRs) are principal mediators of rapid microbial recognition and function mainly by detection of pathogen-associated molecular patterns (PAMPs) that do not exist in the host. The different members of TLRs recognize several PAMPs, such as peptidoglycan for TLR2, lipopolysaccharide (LPS) for TLR4, flagellin for TLR5, and CpGDNA-repeats for TLR9. Several endogenous ligands of various TLRs have been also identified in the host. In this chapter, we describe the involvement of TLR-4 polymorphisms in imm…

Genetic control of C3 production by the S region of the mouse MHC.

SUMMARY The present paper reports evidence indicating that the level of the third complement component (C3) is regulated by the S region of the murine H-2 complex. In fact, using congenic strains of mice we demonstrate that mice with the k haplotype at the S region show high C3 levels, whereas mice with the d haplotype at the S region show low C3 levels.

PROTECTIVE DETERMINANTS AGAINST CARDIOVASCULAR DISEASES ARE PRESENT IN GENETIC BACKGROUND OF CENTENARIANS.

On the Road to Accurate Biomarkers for Cardiometabolic Diseases by Integrating Precision and Gender Medicine Approaches

The need to facilitate the complex management of cardiometabolic diseases (CMD) has led to the detection of many biomarkers, however, there are no clear explanations of their role in the prevention, diagnosis or prognosis of these diseases. Molecules associated with disease pathways represent valid disease surrogates and well-fitted CMD biomarkers. To address this challenge, data from multi-omics types (genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiomics, and nutrigenomics), from human and animal models, have become available. However, individual omics types only provide data on a small part of molecules involved in the complex CMD mechanisms, whereas, here, we pr…

Cytokine genotyping (TNF and IL-10) in patients with celiac disease and selective IgA deficiency

Selective IgA deficiency (IgAD) and celiac disease (CD) are frequently associated and share the ancestral haplotype human leukocyte antigen (HLA)-8.1, which is characterized by a peculiar cytokine profile. The aim of this study was to evaluate the role of tumor necrosis factor (TNF) and interleukin (IL)-10 alleles in CD and CD-IgAD.The distribution of some biallelic polymorphisms of both cytokine promoters (-308G--A and -863C--A at TNF promoter sequence and -1082G--A, -819C--A, and -592C--T at IL-10 promoter) were typed using biotilinated specific probes in 32 celiac patients, in 34 CD-IgAD patients, and in 96 healthy controls.In CD and CD-IgAD, the -308A allele was significantly more frequ…

Role of TLR4 Receptor Polymorphisms in Boutonneuse Fever

The genetics of the interaction between host and microbes plays an essential role in the survival of the individual and attainment of longevity. The activation of toll-like receptor (TLR)4 plays a key role in natural and clonotypic immune responses. We evaluated whether TLR4 genotype is a component of genetic background protective versus rickettsiosis and whether this background influences longevity. We genotyped for +896A/G TLR4 polymorphism 78 patients affected by Boutonneuse fever, 78 age-matched controls and 78 advanced age individuals from Sicily. The +869G allele, that attenuates receptor signalling, was significantly overrepresented in patients in comparison with age-matched control…

IL-10 and TNF-α polymorphisms and the recovery from HCV infection

Hepatitis C virus (HCV) infection becomes chronic in about 85% of infected individuals, whereas only 15% of infected people clear spontaneously the virus. It is conceivable that the host immunogenetic background influences the course of infection in term of recovery. Thus, in this study we have evaluated the effect of functionally relevant polymorphisms at tumor necrosis factor-alpha (TNF-alpha, i.e., 2 biallelic polymorphisms at nt -863 and nt-308 of the promoter) and interleukin-10 (IL-10) loci (i.e., 1 biallelic polymorphism at nt -1082 of the promoter), on the clearance of HCV infection. To this purpose, we compared 18 Sicilian patients who had spontaneously recovered from previous HCV …

Single nucleotide polymorphisms (SNPs) of pro-inflammatory/anti-inflammatory and thrombotic/fibrinolytic genes in patients with acute ischemic stroke in relation to TOAST subtype.

Abstract Background The genetic basis of complex diseases like ischemic stroke probably consists of several predisposing risk factors, such as genes involved in inflammation and thrombotic pathways. On this basis the aim of our study was to evaluate the role of SNPs (single nucleotide polymorphisms) of some pro-inflammatory/anti-inflammatory and coagulation/fibrinolytic genes in patients with acute ischemic stroke. Methods The study population consisted of 144 consecutive Caucasian adult patients who were hospitalized in the Internal Medicine Department at the University of Palermo between November 2006 and January 2008, and who met inclusion criteria. The cases were patients admitted with …

Le cellule T regolatrici CD4+CD25+ negli anziani sono correlate al background genetico dell’Il-10 ed hanno effetti sui linfociti CD8-CMV specifici

Association Between the HLA-A2 Allele and Alzheimer Disease

In the elderly, the most common cause of dementia is Alzheimer disease (AD), which is responsible for the age-related progressive neurodegenerative inflammatory condition mediated by the disease. It has been seen that several genetic and environmental factors are involved in AD onset. Epidemiologic data suggest that some genetic determinants of AD might reside in those polymorphisms that regulate immune inflammatory responses, such as the major histocompatibility complex (MHC). Therefore, several MHC polymorphisms have been in the spotlight of a large number of AD association studies. A possible association of HLA-A2 allele with increased susceptibility to AD has been the subject of debate …

Major histocompatibility complex and sporadic Alzheimer's disease: a critical reappraisal

Epidemiological data suggest that some genetic determinants of Alzheimer's disease (AD) might reside in those polymorphisms for the immune system genes that regulate immune inflammatory responses, such as the major histocompatibility complex (MHC). Therefore, MHC polymorphisms have been the focus of a large number of AD association studies. Class Ia, Ib (hemochromatosis gene (HFE)), class II and class III (complement, tumour necrosis factor and heat shock proteins) alleles have been studied. Nearly every positive result has been followed by several studies that have failed to replicate it or that have contradicted it. Several factors, including methodological biases, might explain these dis…

Inflammation, ageing and cancer

Cancer is generally recognized as an age-related disease. In fact, incidence and mortality rates of most human cancers increase consistently with age up to 90 years, but they plateau and decline thereafter. A low-grade systemic inflammation characterizes ageing and this pro-inflammatory status underlies biological mechanisms responsible for age-related inflammatory diseases. On the other hand, clinical and epidemiological studies show a strong association between chronic infection, inflammation and cancer and indicate that even in tumours not directly linked to pathogens, the microenvironment is characterized by the presence of a smouldering inflammation, fuelled primarily by stromal leukoc…

Common polymorphisms in Th1 and Th2 cytokine genes and susceptibility to pancreatic adenocarcinoma

ACUTE PHASE RESPONSE IN OLDEST-OLD INDIVIDUALS AFTER SURGICAL STRESS

HLA and KIR Frequencies in Sicilian Centenarians

Several studies suggest that human longevity appears to be linked inextricably with optimal functioning of the immune system, suggesting that specific genetic determinants may reside in loci that regulate the immune response, as human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) genes. It has been suggested that longevity is associated with positive selection of alleles (i.e., HLA-DR11) or haplotypes (i.e., HLA-B8,DR3) that confer resistance to infectious disease(s). On the other hand, the cytolytic activity of natural killer (NK) cells is controlled by activating and inhibitory cell-surface receptors, including KIR. The genetic diversity of the KIR loci with r…

Genetic control of immune response in carriers of ancestral haplotype 8.1: the study of chemotaxis.

In all caucasian populations the association of an impressive number of autoimmune diseases with genes from the HLA-B8, DR3 hap- lotype that is part of the ancestral haplotype (AH) 8.1 HLA-A1, Cw7, B8, TNFAB∗a2b3, TNFN∗S, C2∗C, Bf∗s, C4A∗Q0, C4B∗1, DRB1∗0301, DRB3∗0101, DQA1∗0501, DQB1∗0201 has been reported by different research groups. This haplotype, which is more common in northern Europe, is also associated with a number of immune system dysfunctions in healthy subjects. Analyzing the data according to gender, some dysfunc- tions are observed in women but not in men, in agreement with the role of X-linked genes and/or estrogens in the development and progression of autoimmune diseases.…

CCR5 Receptor: Biologic and Genetic Implications in Age-Related Diseases

The CC chemokine receptor 5 (CCR5) is a member of CC-chemokine receptor family. CCR5 has the characteristic structure of a seven transmembrane G protein-coupled receptor (GPCR), which regulates trafficking and effector functions of memory/effector Th1 cells, macrophages, NK cells, and immature dendritic cells. CCR5 and its ligands are important molecules in viral pathogenesis. CCR5 represents the co-receptor for macrophage (M) and dual (T cell and M)-tropic immunodeficiency viruses. Recent evidence has also demonstrated the role of CCR5 in a variety of human diseases, ranging from infectious and inflammatory diseases to cancer. In this article, we describe the involvement of CCR5 in two age…

Analysis of Polymorphism C558T of MAL (TIRAP) in Mediterranean Spotted Fever

Analysis of Polymorphism C558T of MAL (TIRAP) in Mediterranean Spotted Fever M. Bova1, L. Scola1, C. Colomba1, L. Vaccarino1, P. Di Gangi1, G. Santini1, G. Giammanco1, C. R. Balistreri1, D. Lio1, L. Titone Lanza Di Scalea1 1University of Palermo, Palermo, Italy Background: In our previous studies, we have demonstrated that cytokine polymorphisms, such as IFNγ +874T/A or IL-17 SNP (7488T/C), might interfere with R. Conorii infection control. In addition, we have reported that +896A/G TLR4 SNP is a component of a genetic background that might influence the clinical outcome of Boutonneuse fever (Mediterranean spotted fever, MSF). The +869G allele, that attenuates receptor signaling, was actual…

MIF rs755622 and IL6 rs1800795 Are Implied in Genetic Susceptibility to End-Stage Renal Disease (ESRD)

Chronic kidney disease (CKD) is characterized by an increased risk of kidney failure and end-stage renal disease (ESRD). Aging and comorbidities as cardiovascular diseases, metabolic disorders, infectious diseases, or tumors, might increase the risk of dialysis. In addition, genetic susceptibility factors might modulate kidney damage evolution. We have analyzed, in a group of ESRD patients and matched controls, a set of SNPs of genes (Klotho rs577912, rs564481, rs9536314; FGF23 rs7955866; IGF1 rs35767; TNFA rs1800629; IL6 rs1800795; MIF rs755622, rs1007888) chosen in relation to their possible involvement with renal disease and concomitant pathologies. Analysis of the raw data did indicate …

Polymorphisms of Pro-Inflammatory IL-6 and IL-1β Cytokines in Ascending Aortic Aneurysms as Genetic Modifiers and Predictive and Prognostic Biomarkers

Background: Previous studies have demonstrated that polymorphisms involved in immune genes can affect the risk, pathogenesis, and outcome of thoracic ascending aortic aneurysms (TAAA). Here, we explored the potential associations of five functional promoter polymorphisms in interleukin-6 (IL-6), IL-1B, IL-1A, IL-18, and Tumor necrosis factor (TNF)A genes with TAAA. Methods: 144 TAAA patients and 150 age/gender matched controls were typed using KASPar assays. Effects on telomere length and levels of TAAA related histopathological and serological markers were analyzed. Results: Significant associations with TAAA risk were obtained for IL-6 rs1800795G&gt

1267 HSP70-2 POLYMORPHISM AS A RISK FACTOR FOR CAROTID PLAQUE RUPTURE AND CELEBRAL ISCHAEMIA IN OLD TIPE 2 DIABETES-ATHEROSCLEROTIC PATIENTS

ATHEROSCLEROSIS in: Cytokine gene polymorphisms in multifactorial conditions (K. Vandenbroeck ed.)

Role of proinflammatory alleles in longevity and atherosclerosis: results of studies performed on -1562C/T MMP-9 in centenarians and myocardial infarction patients from Sicily.

Centenarians are characterized by marked delay or escape from age-associated diseases that cause mortality at earlier ages. Jointly, atherosclerosis and its complications, such as myocardial infarction (AMI), significantly contribute to mortality in the elderly. Inflammation is a key component of atherosclerosis and inflammatory genes are good candidates for the risk of the development of atherosclerosis. Genetic traits contribute to the risk of AMI and allelic variations in inflammatory genes should boost the risk of disease. If proinflammatory genotypes significantly contribute to the risk of AMI, alleles associated with disease susceptibility should not be included in the genetic backgro…

Association between the HFE mutations and longevity: a study in Sardinian population

Hereditary hemochromatosis is an HLA-linked inherited disease characterised by inappropriately high absorption of iron by the gastrointestinal mucosa. The cysteine-to-tyrosine substitution at codon 282 of the HFE encoding gene sequence is responsible for the disease, although other variants, as H63D and S65C, may modify the affinity of the protein for transferrin receptors. We have recently reported that C282Y mutation is significantly increased in very old (>90 years) Sicilian women, suggesting a role in attainment of longevity. In addition, an increase of H63D polymorphism was also observed in these women but the difference was not significant. To validate and extend these results we inve…

Major histocompatibility complex regulation of interleukin-5 production in the mouse.

Lymph node cells of CBA (H-2k), but not of BALB/c (H-2d) mice immunized epicutaneously with picryl chloryde secrete interleukin (IL)-5 when stimulated with the specific antigen in vitro. The low IL-5 production in BALB/c mice persists when either picryl chloride or the unrelated antigen oxazolone are used, when the amount of antigen in vitro is varied and when a secondary response is studied. The difference in IL-5 production maps to the major histocompatibility complex (MHC) in the congenic BALB/b, BALB/c and BALB/k mice. Furthermore, lymph node cells from (k × d) F1 mice produce IL-5 when stimulated by antigen presented on H-2k but not on H-2d antigen-presenting cells. Finally, the low IL…

Evidences of +896 A/G TLR4 Polymorphism as an Indicative of Prevalence of Complications in T2DM Patients

T2DM is today considered as world-wide health problem, with complications responsible of an enhanced mortality and morbidity. Thus, new strategies for its prevention and therapy are necessary. For this reason, the research interest has focused its attention on TLR4 and its polymorphisms, particularly the rs4986790. However, no conclusive findings have been reported until now about the role of this polymorphism in development of T2DM and its complications, even if a recent meta-analysis showed its T2DM association in Caucasians. In this study, we sought to evaluate the weight of rs4986790 polymorphism in the risk of the major T2DM complications, including 367 T2DM patients complicated for th…

Does Down's syndrome support the homocysteine theory of atherogenesis?

Abstract Down syndrome (DS) is generally considered as an “atheroma-free model”. In this preliminary study, we investigated homocysteine, folate and Vitamin B 12 levels in 13 DS patients (male, average age 60 years) and 20 age-matched individuals. We also studied lipid fractions, and polymorphisms for Cystothionine β-synthase (CBS), 5,10-methyl-tetrahydro-folate reductase (MTHFR) and apolipoprotein E (Apo-E) genes. However, DS patients with the MTHFR TT genotype showed an increased of plasma homocysteine (tHcy). Our results indicate that this group of “healthy old” Down syndrome patients, although showing some classical biochemical risk factors for atherosclerosis, did not suffer clinical c…

Compendio di Patologia Generale

Longevity in: Cytokine Gene Polymorphisms in multifactorial conditions. (K. Vandenbroeck ed.)

Role of Cytokine Polymorphisms in the Rhinitis-Asthma Evolution

AAD1. Role of Cytokine Polymorphisms in the Rhinitis-Asthma Evolution G. Santini1, L. Scola1, S. La Piana1, P. Di Gangi1, L. Vaccarino1, M. Bova1, C. R. Balistreri1, D. Lio1, G. Di Lorenzo1 1University of Palermo, Palermo, Italy Background: Several epidemiological studies demonstrate that a timeline from rhinitis to asthma exists, and that rhinitis is a risk factor for asthma. In particular, rhinitis increases the chance of development of asthma by about three times. In addition to environmental factors, genetic factors play an important role in the development of atopic airway diseases. The aim of this study is to analyse the role of cytokine polymorphism in the evolution of rhinitis-asthm…

TNFalfa,IFN gamma, IL-10 gene polymorphisms in a sample of Sicilian patients with coeliac disease

Association between the HFE mutations and unsuccessful ageing: a study in Alzheimer's disease patients from Northern Italy

Mutations in the class I-like Major Histocompatibility Complex gene HFE are associated with hereditary hemochromatosis (HH), a disorder caused by excessive iron uptake. Three common mutations have been found: C282Y, H63D, and S65C. Moreover, several studies have suggested that HFE mutations may be involved in several age-related chronic diseases such as Alzheimer's disease (AD) and coronary heart disease, but apparently paradoxically also with longevity. In particular, in AD, patients carrying the H63D allele have been suggested to have a mean age at onset of 72 vs. 77 years for those who were homozygous for the wild-type allele. Thus, it seems that H63D mutations may anticipate sporadic AD…

Polymorphisms of pro-inflammatory genes and Alzheimer's disease risk: A pharmacogenomic approach.

Clinically and pathologically Alzheimer's disease (AD) represents a sequential progressive neurodegenerative disorder. AD is etiologically heterogeneous and accounts for a majority of dementia in western societies. Inflammation clearly occurs in pathologically vulnerable regions of the AD brain and the search for genetic factors influencing the pathogenesis of AD has lead to the identification of numerous gene polymorphisms that might act as susceptibility modifiers. Accordingly, several reports have indicated that the risk of AD is substantially influenced by several genetic polymorphisms in the promoter region, or other untranslated regions, of genes encoding inflammatory mediators, altho…

Association between the polymorphism of CCR5 and Alzheimer's disease: results of a study performed on male and female patients from Northern Italy.

Alzheimer's disease (AD) is the most common cause of dementia in Western society. The prevalence of AD is greater in women than in men, largely due to longevity and survival differences favoring women. However, some studies suggest that incidence rates may really be increased in women. One possible factor influencing AD incidence in women is the loss of ovarian estrogens production after menopause, which might be involved in AD pathogenesis. Estrogens seem to influence some neuronal functions. Many of these actions appear beneficial (i.e., neuroprotective action against a variety of insults, as oxidative stress, and reduction of beta-amyloid plaques formation). Furthermore, several studies …

Effect of interleukin-6 polymorphisms on human longevity: a systematic review and meta-analysis.

Udgivelsesdato: 2009-Jan Several studies have assessed changes in frequency of -174 interleukin (IL)-6 single nucleotide polymorphism (SNP) with age. If IL-6 tracks with disability and age-related diseases, then there should be reduction, in the oldest old, of the frequency of homozygous GG subjects, who produce higher IL-6 levels. However, discordant results have been obtained. To explore the relationship between this polymorphism and longevity, we analyzed individual data on long-living subjects and controls from eight case-control studies conducted in Europeans, using meta-analysis. There was no significant difference in the IL-6 genotype between the oldest old and controls (Odds Ratio […

Role of environmental and genetic factor interaction in age-related disease development: the gastric cancer paradigm.

The association of Helicobacter pylori (Hp) infection with gastric cancer is well known and might be considered a paradigmatic example of the role that interaction among environmental factors and individual background might play in inducing age-associated disease. To evaluate the role of interaction of Hp infection with genetic background, gastric cancer and chronic gastritis patients as well as random selected controls were typed for five inflammation-related polymorphisms of IL-1 and IL-10 cytokine genes. No association among IL-10 or IL-1 variants with an increased risk of gastric cancer was found, whereas an Hp-independent association of IL-1beta -511T positive genotypes to an increased…

Laboratory parameters in centenarians of Italian ancestry

Studies aimed at collecting reference parameters for haematochemical analysis in the elderly are scarce and for the oldest old subjects even more rare. In order to establish the reference values for the most common laboratory text in long living individuals, we measured haematochemical parameters in >100 years old subjects and in aged subjects as control. Six hundred and two centenarians accepted to be enrolled in the study. A case history containing the complete anamnesis, clinical examinations, evaluation of the clinical cognitive and functional tests, was prepared for each centenarian. Blood samples from 120 > 100 years old subjects free of chronic or acute Illness (i.e. Alzheimer’s dise…

Inflammation, Cytokines, Immune Response, Apolipoprotein E, Cholesterol, and Oxidative Stress in Alzheimer Disease: Therapeutic Implications

Alzheimer disease (AD) is a heterogeneous and progressive neurodegenerative disease, which in Western society mainly accounts for senile dementia. Today many countries have rising aging populations and are facing an increased prevalence of age-related diseases, such as AD, with increasing health-care costs. Understanding the pathophysiology process of AD plays a prominent role in new strategies for extending the health of the elderly population. Considering the future epidemic of AD, prevention and treatment are important goals of ongoing research. However, a better understanding of AD pathophysiology must be accomplished to make this objective feasible. In this paper, we review some hot to…

Polymorphisms of pro-inflammatory genes and prostate cancer risk: a pharmacogenomic approach.

In this paper, we consider the role of the genetics of inflammation in the pathophysiology of prostate cancer (PCa). This paper is not an extensive review of the literature, rather it is an expert opinion based on data from authors' laboratories on age-related diseases and inflammation. The aim is the detection of a risk profile that potentially allows both the early identification of individuals at risk for disease and the possible discovery of potential targets for medication. In fact, a major goal of clinical research is to improve early detection of age-related diseases, cancer included, by developing tools to move diagnosis backward in disease temporal course, i.e., before the clinical…

Susceptibility to Heart Defects in Down Syndrome Is Associated with Single Nucleotide Polymorphisms in HAS 21 Interferon Receptor Cluster and VEGFA Genes

Background: Congenital heart defects (CHDs) are present in about 40&ndash

Ruolo delle mutazioni del gene della febbre mediterranea familiare nel raggiungimento dell’invecchiamento con successo.

Age-Related Inflammatory Diseases: Role of Genetics and Gender in the Pathophysiology of Alzheimer's Disease

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western societies mainly accounts for clinical dementia. A high proportion of women are affected by this disease, especially at a very advanced age, which might to a large extent be associated with the fact that women live longer. However, some studies suggest that incidence rates may be really increased in women. For this reason the influence of estrogens on the brain and the decrease of it during menopause are of special interest. After menopause, circulating levels of estrogens markedly decline, influencing several brain processes predicted to influence AD risk. The control of estrogens on oxid…

Frequenze degli aplotipi-1082GA/819CT/592CA della regione promoter del locus IL-10 in campioni di DNA ottenuti da pazienti affetti da Diabete mellito di tipo II.

Studio delle frequenze alleliche del polimorfismo +1902A/G del gene IL4R in soggetti affetti da sclerosi multipla .

GENETICS OF INFLAMMATION IN CARDIOVASCULAR DISEASES AND LONGEVITY.

Plasma cytokine profiles in patients with celiac disease and selective IgA deficiency

Celiac disease (CD) and selective IgA deficiency (IgAD) are frequently associated, and share the same genetic background. The aim of the present study was to evaluate both Type 1 and 2 plasma cytokine levels in CD and in CD-IgAD. IL-2, TNF-alpha, IL-10, IL-4 and IL-13 plasma levels were measured both at diagnosis and after a gluten-free diet (GFD) in 32 CD patients, in 27 CD-IgAD patients and in 30 healthy controls. IFN-gamma levels were significantly higher in CD and CD-IgAD than in controls, TNF-alpha displayed significantly higher levels in CD-IgAD when compared both with controls and with CD, and IL-2 was in CD-IgAD significantly increased respect to controls. Kinetics of the Type 1 cyt…

LPS-mediated production of pro/anti-inflammatory cytokines and eicosanoids in whole blood samples: Biological effects of +896A/G TLR4 polymorphism in a Sicilian population of healthy subjects

Toll-like receptors (TLRs) are the principal mediators of rapid microbial recognition: the lipopolysaccharide (LPS) receptor TLR4 seems to have a paradigmatic role. Single nucleotide polymorphisms (SNPs) in the TLR4 gene, such as +896A/G, known to attenuate receptor signaling, have been described. The +896A/G SNP is significantly less frequent in patients with myocardial infarction, Alzheimer's disease or prostate cancer, whereas it is overrepresented in centenarians. To clarify and confirm the biological effects of +896A/G SNP and its role in the pathophysiology of age-related diseases and longevity, we assessed the levels of IL-6, TNF-α, IL-10 and eicosanoids (LTB4 and PGE2) in LPS-stimul…

Role of environmental and genetic factor interaction in the aging related disease development: The gastric cancer paradigm.

Inflammation, genes and zinc in ageing and age-related diseases.

Lifelong antigenic burden determines a condition of chronic inflammation, with increased lymphocyte activation and pro-inflammatory cytokine production. A large number of studies have documented changes in Zn metabolism in experimental animal models of acute and chronic inflammation and in human chronic inflammatory diseases. In particular, modification of zinc plasma concentration as well as intracellular disturbance of antioxidant intracellular pathways have been found associated to age-related inflammatory diseases, like atherosclerosis. Zinc deficiency is extremely diffused in aged people that are educated to avoid meat and other high Zn-content foods due to fear of cholesterol. Rather,…

Familial mediterranean fever, longevity and cardiovascular diseases: a pilot study in the Sicilian population

Genotype frequencies of the +874T→A single nucleotide polymorphism in the first intron of the interferon-γ gene in a sample of Sicilian patients affected by tuberculosis

In the light of the key role played by interferon (IFN)-gamma in the control of tuberculosis, in the present paper we have evaluated the distribution of the functional +874T --> A IFN-gamma single nucleotide polymorphism (SNP) in Sicilian patients affected by tuberculosis. Our aim was to determine whether there is an association between the TT genotype, which has been suggested to be linked to an increased production of IFN-gamma, and resistance to chronic tuberculosis. DNA samples were obtained from 45 patients and 97 healthy controls. Polymorphism at +874 was identified using amplification refractory mutational system methodology. The +874T SNP was less frequent in patients than in contro…

Senescence Markers

Background: Evolutionary theory and empirical evidence suggest that aging is a process of gradual accumulation of damage in cells and tissues of the body. The progressive loss of ability to interact effectively with environmental stimuli is accompanied by progressive modification and adaptations that are influenced by lifestyle and genetic background of the individual. These affect the ability to age successfully, defined both as longevity and/or escaping the major age-related diseases. Some of the most important characteristics of adaptive immunity in aging are compatible with this assumption. Actually, the antigenic load results in the progressive generation of a chronic low grade inflamm…

The Homocysteine System

Association between platelet endothelial cellular adhesion molecule 1 (PECAM-1/CD31) polymorphisms and acute myocardial infarction: a study in patients from Sicily

Summary Adhesion of circulating cells to the arterial surface is among the first detectable events in atherogenesis. Cellular adhesion molecules, expressed by the vascular endothelium and by circulating leucocytes, mediate cell recruitment and their transendothelial migration. Platelet endothelial cellular adhesion molecule 1 (PECAM-1/CD31), involved in this migration, has been associated with the developmental course of atherosclerosis. A few studies have investigated an association between coronary heart disease and single nucleotide polymorphisms (SNPs) located in functionally important domains of the PECAM-1/CD31 gene. In particular, Ser563Asn and Gly670Arg SNPs have been described as s…

Major Histocompatibility Complex Polymorphisms and Ageing.

ASTRACT Longevity seems to be directly correlated with optimal functioning of the immune system, suggesting that some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses. Accordingly, mouse lifespan is influenced by MHC (major histocompatibility complex) genotype. The HLA (the human MHC) region encompasses over 4 Mb of DNA on the chromosome band 6p21.3 and its extensive characterisation has recently culminated in the determination of the nucleotide sequence of the entire region, confirming the presence of ~ 220 genes. The MHC is traditionally divided into the class I, class II and class III regions. Most HLA genes …

Immunological and immunogenetic markers of successful and unsuccessful ageing

Age and Cytokine Gene Variants Modulate the Immunogenicity and Protective Effect of SARS-CoV-2 mRNA-Based Vaccination

The introduction of anti-SARS-CoV-2 vaccines in late 2020 substantially changed the pandemic picture, inducing effective protection in the population. However, individual variability was observed with different levels of cellular response and neutralizing antibodies. We report data on the impact of age, gender, and 16 single nucleotide polymorphisms (SNPs) of cytokine genes on the anti-SARS-CoV-2 IgG titers measured 31 and 105 days after administration of the second dose of BNT162b2 vaccine to 122 healthy subjects from the health care staff of the Palermo University Hospital, Italy. The higher titers at 31 days were measured in the younger subjects and in subjects bearing T-positive genotyp…

Immunogenetics, Gender, and Longevity

In this article we discuss relevant data on aging, longevity, and gender with particular focus on inflammation gene polymorphisms which could affect an individual's chance to reach the extreme limit of human life. The present review is not an extensive revision of the literature, but rather an expert opinion based on selected data from the authors' laboratories. In 2000-2005 in the more developed regions, the life expectancy at birth is 71.9 years for men (78.3 in Japan) and 79.3 years for women (86.3 in Japan). Indeed, gender accounts for important differences in the prevalence of a variety of age-related diseases. Considering people of far-advanced age, demographic data document a clear-c…

Biomarkes of aging

Ageing is a complex process that negatively impacts the development of the different systems and its ability to function. On the other hand, the rate of ageing in humans is not uniform, due to genetic heterogeneity and the influence of environmental factors. Thus, the ageing rate, measured as the decline of functional capacity and stress resistance, seems to be different in every individual. Therefore, attempts have been made to analyse this individual age, the so-called biological age, in comparison to chronological age. Age-related changes in body function or composition that could serve as a measure of biological age and predict the onset of age-related diseases and/or residual lifetime …

Is human immunosenescence clinically relevant? Looking for ‘immunological risk phenotypes’

Abstract The 3rd ImAginE Conference on ‘Basic Biology and Clinical Impact of Immunosenescence' was held at Palermo University, Italy from 10–13 April 2002.

Immunogenetic Markers and Sporadic Alzheimer's Disease Diagnostic Knot.

AGE6. Skin Ageing: Focus on the Role of Inflammatory Genetic Factors in Cutaneous Neoplasia

AGE6. Skin Ageing: Focus on the Role of Inflammatory Genetic Factors in Cutaneous Neoplasia C. M. Gambino1, F. Crapanzano1, G. Accardi1, A. Aiello1, C. Virruso1, G. Pistone1, M. R. Bongiorno1, D. Lio1, C. R. Balistreri1, G. Candore1 1University of Palermo, Palermo, Italy Background: Skin aging is a complex process that involves intrinsic and exogenous causes. Photo-oxidative damage caused by UV is the leading cause of extrinsic aging of the skin, known as photo-ageing. UV damages can be linked mostly to overproduction of ROS that induces a complex molecular cascade able to accelerate physiological aging, determining a typical dermal/epidermal inflammation with an increased risk of getting s…

Associations of rs3918242 and rs2285053 MMP-9 and MMP-2 polymorphisms with the risk, severity, and short- and long-term complications of degenerative mitral valve diseases: A 4.8-year prospective cohort study

Abstract Background Degenerative forms of mitral valve diseases (MVDs) are very complex pathologies. Thus, it is difficult to make generalizations about the disease pathways or genetic risk factors contributing to these diseases. However, a key role of metalloproteinases (MMPs) in their pathophysiology is emerging. Thus, we performed for the first time a perspective study to assess eventual associations of some functional single nucleotide polymorphisms (SNPs) in MMP-2 and MMP-9 genes with the MVD risk, symptom severity, and short- and long-term (4.8 years) complications. Materials and methods For this purpose, 90 patients and two control groups were genotyped for rs3918242, rs243865, and r…

Inflammation, Longevity, and Cardiovascular Diseases: Role of Polymorphisms of TLR4

The total burden of infection at various sites may affect the progression of atherosclerosis, the risk being modulated by host genotype. The role of lipopolysaccaride receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative bacteria; and TLR4 polymorphisms, as ASP299GLY, suggested to attenuate receptor signaling, have been described. We demonstrated that TLR4 ASP299GLY polymorphism shows a significantly lower frequency in patients affected by myocardial infarction compared to controls, whereas centenarians show a higher frequency. Thus, people genetically predisposed to developing weak inflammatory activity, seem to have fewer chances of developing cardio…

Altered cytokine production in leukocyte obtained from Alzheimer’s disease patients.

SARS CoV2 infection _The longevity study perspectives

Graphical abstract

Opposite role of pro-inflammatory alleles in longevity and atherosclerosis: results of studies performed in male centenarians and male myocardial infarcion patients from Sicily

Analysis of polymorphisms Leiden Factor V G1691A and prothrombin G20210A as risk factors for acute myocardial infarction.

Thrombotic risk increases in elderly, therefore, the understanding of the genetic predisposition of hypercoagulability could make the difference in the prevention of venous and/or arterial thrombotic events. Laboratory evaluation of hyperfibrinogenemia, increased Factor VII levels, antiphospholipid antibodies presence and hyperhomocysteinemia are considered to have a consistent high predictivity for arterial thrombophilic diseases. Anyway, a large debate exists on the validity of testing Leiden Factor V (FV) G1691A and/or prothrombin (FII) G20210A polymorphisms in patients affected by arterial thrombotic diseases, despite of the several observations described. Here we report data strongly s…

TNFalpha, IFNgamma and IL-10 gene polymorphisms in a sample of Sicilian patients with coeliac disease.

Coeliac disease is associated with DQ2 and DQ8 alleles, but other genes also confer an additional genetic risk.Defining whether the genetic profiles of interleukin-10, tumour necrosis factor alpha and interferon gamma are associated with an increased coeliac disease risk.The functionally gene polymorphisms of tumour necrosis factor alpha (-308G/A), interferon gamma (+874T/A) and interleukin-10 (-1082G/A) were typed using sequence specific primer-polymerase chain reaction in 110 Sicilian coeliac disease patients and in 220 Sicilian healthy controls.No differences in genotype frequencies of interleukin-10 polymorphisms were found between coeliac disease patients and healthy controls. A signif…

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/inflamma…

FREQUENZA DEGLI ALLELI DEL POLIMORFISMO -330T-->G IL-2 IN UNA POPOLAZIONE DI CENTENARI ITALIANI

Cytokine Gene Polymorphisms and Breast Cancer Susceptibility

Human breast cancer (BC) is characterized by a considerable clinical heterogeneity. Steroid hormone receptor expression and growth factor receptor expression have been considered suitable diagnostic and prognostic markers, whereas mutations of oncosuppressor and gatekeeper genes have been found associated with an increased risk for this malignancy. To evaluate the role that polymorphisms of genes involved in the regulation of inflammatory response might play in BC susceptibility, we investigated associations between cytokine functionally relevant polymorphisms in 84 BC patients compared to 110 age- and sex-matched controls. TNF-alpha (-308G/A), TGF-beta1 (+869C/T), IL-10 (-1117G/A; -854C/T;…

Valutazione Dei Linfociti T Regolatori CD4+CD25+ (Treg) Nell’anziano

Age-related inflammatory disease: role of genetics and gender in the pathophisiology of Alzheimer’s disease

Pathophysiology of age-related diseases

Abstract A Symposium regarding the Pathophysiology of Successful and Unsuccessful Ageing was held in Palermo, Italy on 7-8 April 2009. Three lectures from that Symposium by G. Campisi, L. Ginaldi and F. Licastro are here summarized. Ageing is a complex process which negatively impacts on the development of various bodily systems and its ability to function. A long life in a healthy, vigorous, youthful body has always been one of humanity's greatest dreams. Thus, a better understanding of the pathophysiology of age-related diseases is urgently required to improve our understanding of maintaining good health in the elderly and to program possible therapeutic intervention.

Association between HFE mutations and acute myocardial infarction: a study in patients from Northern and Southern Italy.

There is interest in the role of iron in age-related diseases such as atherosclerosis. Tissue iron deposition could be harmful, because Fe(2+) can react with H(2)O(2) to form OH(-) radicals and Fe(2+) can react with O(2) to form reactive oxygen species. Free radicals react with cell membranes and cell organelles and could lead to the development of atherosclerosis by initiating lipid peroxidation. Hereditary hemochromatosis provides an opportunity for studying the effects of iron on cardiovascular disease. Some studies have shown that individuals who carried HFE mutations may be at greater risk of developing coronary heart disease than those without the mutations. In contrast, a large numbe…

Taking Advantage of Viral Immune Evasion: Virus-Derived Proteins Represent Novel Biopharmaceuticals

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 biopharmaceut…

B cells in the aged: CD27, CD5, and CD40 expression.

Ageing is characterized by numerous changes in lymphocyte subpopulations. In the present paper we have focused on B cells carrying the surface markers CD27, CD5 and CD40. CD27 is considered a marker of primed (memory) cells and its engagement promotes the differentiation of memory B cells into plasma cells. CD5 is expressed on B1 cells, which are considered to be responsible for T cell-independent antibody production other than autoantibodies. The CD40 molecule binds CD40L (CD154) and is necessary for T-dependent antibody responses. Here we show that the absolute number of CD5+ and CD40+ B cells is decreased in the elderly, while CD27+ B lymphocytes only marginally decrease in centenarians.…

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 …

Ageing, longevity, inflammation and cancer

Variazioni delle frequenze degli alleli di ApoE in soggetti anziani ed in pazienti affetti da sindrome di Down.

Analysis of IL-6, IL-10 and IL-17 genetic polymorphisms as risk factors for sepsis development in burned patients.

Abstract Infection risk, sepsis and mortality after severe burn are primarily determined by patient age, burn size, and depth. Whether genetic differences contribute to otherwise unexpected variability in outcomes is unknown. We sought to determine whether there was an association between IL-6, IL-10 and IL-17 polymorphisms with cytokine production and development of sepsis. We evaluated 71 patients with burns ≥15% TBSA and 109 healthy subjects. The genotypes of IL-6 (−174C/G), IL-10 (−819C/T and −1082A/G) and IL-17 (7488T/C) polymorphisms were identified applying polymerase chain reaction protocols. The cytokine levels in serum were determined with enzyme-linked immunoabsorbent assays. Our…

Analisi dei polimorfismi funzionali dei geni IL-10 e TNF e della produzione di citochine in pazienti affetti da Malattia di Alzheimer di tipo sporadico.

Biology of Longevity: Role of the Innate Immune System

Genetic factors play a relevant role in the attainment of longevity because they are involved in cell maintenance systems, including the immune system. In fact, longevity may be correlated with optimal functioning of clonotypic and natural immunity. The aging of the immune system, known as immunosenescence, is the consequence of the continuous attrition caused by chronic antigenic overload. The antigenic load results in the progressive generation of inflammatory responses involved in age-related diseases. Most of the parameters influencing immunosenescence appear to be under genetic control, and immunosenescence fits with the basic assumptions of evolutionary theories of aging, such as anta…

Portrait of inflammatory response to ionizing radiation treatment

Ionizing radiation (IR) activates both pro-and anti-proliferative signal pathways producing an imbalance in cell fate decision. IR is able to regulate several genes and factors involved in cell-cycle progression, survival and/or cell death, DNA repair and inflammation modulating an intracellular radiation-dependent response. Radiation therapy can modulate anti-tumour immune responses, modifying tumour and its microenvironment. In this review, we report how IR could stimulate inflammatory factors to affect cell fate via multiple pathways, describing their roles on gene expression regulation, fibrosis and invasive processes. Understanding the complex relationship between IR, inflammation and …

A Typical Immune T/B Subset Profile Characterizes Bicuspid Aortic Valve: In an Old Status?

Bicuspid valve disease is associated with the development of thoracic aortic aneurysm. The molecular mechanisms underlying this association still need to be clarified. Here, we evaluated the circulating levels of T and B lymphocyte subsets associated with the development of vascular diseases in patients with bicuspid aortic valve or tricuspid aortic valve with and without thoracic aortic aneurysm. We unveiled that the circulating levels of the MAIT, CD4+IL−17A+, and NKT T cell subsets were significantly reduced in bicuspid valve disease cases, when compared to tricuspid aortic valve cases in either the presence or the absence of thoracic aortic aneurysm. Among patients with tricuspid aortic…

Association between +1059G/C CRP polymorphism and acute myocardial infarction in a cohort of patients from Sicily: a pilot study.

Inflammation genes and Alzheimer’s disease.

The -308G/A polymorphism of TNF-alpha influences immunological parameters in old subjects affected by infectious diseases.

Abnormal increments of pro-inflammatory cytokines (IL-6 and TNF-alpha) characterize the outbreak of infectious diseases, which are the major cause of death in the elderly. A counterbalance to the inflammation is exerted by IL-10 with an inhibitory role on TNF-alpha production. As is well known, some cytokine gene polymorphisms influence the cytokine production, playing a role as susceptibility or resistance factors against immune-mediated and infectious disease. Genetic variations in the -308A/G locus for TNF-alpha seems to affect the clinical outcome of some infectious diseases. In fact, the -308A allele is associated with severe septic shock and death. On this basis, we have screened heal…

INNATE IMMUNITY AND INFLAMMATION IN AGEING: A KEY FOR UNDERSTANDING AGE-RELATED DISEASES.

Abstract The process of maintaining life for the individual is a constant struggle to preserve his/her integrity. This can come at a price when immunity is involved, namely systemic inflammation. Inflammation is not per se a negative phenomenon: it is the response of the immune system to the invasion of viruses or bacteria and other pathogens. During evolution the human organism was set to live 40 or 50 years; today, however, the immune system must remain active for much a longer time. This very long activity leads to a chronic inflammation that slowly but inexorably damages one or several organs: this is a typical phenomenon linked to ageing and it is considered the major risk factor for a…

IL-1 Superfamily Member (IL-1A, IL-1B and IL-18) Genetic Variants Influence Susceptibility and Clinical Course of Mediterranean Spotter Fever

Mediterranean Spotted Fever (MSF) is one of the most common spotted fever Rickettsioses. Most cases of MSF follow a benign course, with a minority of cases being fatal. The severity of the infection depends on bacterial virulence, dose and host factors such as effective immune response and genetic background. Herein, we reported data on typing by competitive allele-specific PCR of functionally relevant polymorphisms of genes coding for MyD88 adapter-like (Mal/TIRAP) protein (rs8177374), interleukin(IL)-1 cluster (IL-1A rs1800587, IL-1B rs16944 and rs1143634) and IL-18 (rs187238), which might be crucial for an efficient immune response. The results enlighten the role that IL-1 gene cluster v…

Role of TLR4 polymorphisms in inflammatory responses: implications for unsuccessful aging.

The total burden of infection at various sites may affect the progression of atherosclerosis and Alzheimer's disease (AD), the risk being modulated by host genotype. The role of lipopolysaccharide (LPS) receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative bacteria, and TLR4 single nucleotide polymorphisms (SNPs), such as +896A/G, known to attenuate receptor signaling, have been described. This SNP shows a significantly lower frequency in patients affected by myocardial infarction or AD. Thus, people genetically predisposed to developing lower inflammatory activity seem to have less chance of developing cardiovascular disease (CVD) or AD. In the presen…

Immune-inflammatory responses in successful and unsuccessful ageing

A dramatic increase in mean life span and life expectancy, coupled with a significant reduction in early mortality, has lead to a large increase in number of elderly people in modern societies. This demographic phenomenon has been paralleled by an epidemic of chronic diseases associated with advancing age. Both innate and instructive immunity are implicated in almost all age-related diseases. The modifications of the immune system in the elderly are evaluated as a deterioration of the immune system, the so-called immunosenescence, which is thought to be mostly the result of the declining effectiveness of T cells and it is responsible for the increased susceptibility of elderly to infectious…

NF-κB pathway activators as potential ageing biomarkers: targets for new therapeutic strategies

Chronic inflammation is a major biological mechanism underpinning biological ageing process and age-related diseases. Inflammation is also the key response of host defense against pathogens and tissue injury. Current opinion sustains that during evolution the host defense and ageing process have become linked together. Thus, the large array of defense factors and mechanisms linked to the NF-κB system seem to be involved in ageing process. This concept leads us in proposing inductors of NF-κB signaling pathway as potential ageing biomarkers. On the other hand, ageing biomarkers, represented by biological indicators and selected through apposite criteria, should help to characterize biologica…

Analysis of functionally Relevant Single nucleotide polymorphisms of TNFα and of IFN-gamma in Celiac Disease

Impairment of gamma/delta T lymphocytes in elderly: implications for immunosenescence

Gamma/delta T lymphocytes cells recognize the antigen in a non-classical way and are considered the third branch of the immune system devoted to defend the integrity of the body. Ageing is characterized by an impairment of the main way of protection (the adaptive branch) but, successfully aged people show compensatory mechanisms of defense such as proneness to inflammation. Moreover, very old subjects show an increased number of NK cells. We have previously demonstrated that gamma delta T lymphocytes are reduced in elderly. In the present paper we have studied some characteristics of these cells to evaluate the possibility that these cells might balance the decreased action of the adaptive …

A genetically determined high setting of TNF-alpha influences immunologic parameters of HLA-B8,DR3 positive subjects: implications for autoimmunity.

The 8.1 ancestral haplotype (AH) is a common Caucasoid haplotype carried by most people who type for HLA-B8,DR3. It seems unique in its association with a wide range of immunopathologic diseases. Healthy subjects bearing this haplotype demonstrate several alterations of immune response. This article will focus on the identification of the mechanism(s) of disease susceptibility of 8.1 AH. In 13 carriers of 8.1 AH, and 43 negative patients, enzyme immune assays serum levels of tumor necrosis factor (TNF)-alpha, soluble endothelial leukocyte adhesion molecule-1 (sELAM-1), cortisol, and interleukin(IL)-10 were determined. In addition, quantification of cytokine produced in vitro after mitogen s…

The role of IL-1 gene cluster in longevity: a study in Italian population.

In this study, we analysed the polymorphic variants of IL-1alpha (C-T transition at position -889), IL-1beta (C-T transition at position -511) and IL-1 receptor antagonist (Ra) (86-bp repeated sequence in intron 2) in 1131 subjects (453 females and 678 males) from Northern and Central Italy, including 134 centenarians, to evaluate whether IL-1 cluster alleles might be differently represented in people selected for longevity. In addition, IL-1Ra and IL-1beta plasma levels were quantified by ELISA in 130 randomly selected subjects. No significant differences in the genotype and allele frequency distributions were observed between young, elderly and centenarian subjects. IL-1Ra plasma levels s…

Frequency of polymorphisms of signal peptide of TGF-β1 and –1082G/A SNP at the promoter region of IL-10 gene in a group of patients with carotid stenosis.

Age at onset of Alzheimer disease and Tumor Necrosis Factor-Alpha -308A/G Polymorphism. Alzheimer’s and Parkinson diseases:

Genetics of longevity. Data from the studies on Sicilian centenarians

Abstract The demographic and social changes of the past decades have determined improvements in public health and longevity. So, the number of centenarians is increasing as a worldwide phenomenon. Scientists have focused their attention on centenarians as optimal model to address the biological mechanisms of "successful and unsuccessful ageing". They are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases, such as cardiovascular diseases and cancer. Thus, particular attention has been centered on their genetic background and immune system. In thi…

Marcatori di danno tissutale

Association between C1019T polymorphism of connexin37 and acute myocardial infarction: a study in patients from Sicily

Abstract During atherogenesis, a critical role is played by intercellular communication via gap junctions, cell membrane channels linking the cytoplasmic compartments of adjacent cells. The component protein subunits of these channels, called connexin (Cx), belong to a multigene family. Cx37 is involved in growth, regeneration after injury and ageing of the endothelial cells, suggesting its role in atherosclerosis. The C1019 single nucleotide polymorphism (SNP) of Cx37 gene was associated with thickening of the carotid intima in Swedish men and was also associated with coronary artery disease in a Taiwanese population. On the other hand, in two more recent studies performed in male Japanese…

Analysis of functionally relevant single nucleotide polymorphisms of TNF alfa and IFN gamma genes in celiac diseases

Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: effect of multiple gene interactions.

Genetic studies have shown that individuals with certain HLA alleles have a higher risk of specific autoimmune disease than those without these alleles. Particularly, the association in all Caucasian populations of an impressive number of autoimmune diseases with genes from the HLA-B8,DR3 haplotype that is part of the ancestral haplotype (AH) 8.1 HLA-A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201 has been reported by different research groups. This haplotype, the more common one in northern Europe, is also associated in healthy subjects with a number of immune system dysfunctions. It has been proposed that a small number of genes withi…

Opposite Role of Pro-Inflammatory Alleles in Acute Myocardial Infarction and Longevity: Results of Studies Performed in a Sicilian Population

The major trait characterizing offspring in centenarians is a reduction in the prevalence of cardiovascular disease. Because a pro-inflammatory genotype seems to contribute significantly to the risk of coronary heart disease, alleles associated with disease susceptibility would not be included in the genetic background favoring longevity, as suggested by our previous studies on inflammatory cytokines. To confirm whether genotypes of inflammatory molecules play an opposite role in atherosclerosis and longevity, we are studying the role of other proinflammatory alleles, such as pyrin and CCR5, in acute myocardial infarction and longevity. The results support the hypothesis that the genetic ba…

Connexin37 1019 gene polymorphism in myocardial infarction patients and centenarians

The molecular basis of the low hemolytic activity of C4 molecules from low-C4 mice with IgM-coated erythrocytes.

This study investigated the origin of the different hemolytic activity of two allotypes of murine C4, C4H (C4-high) and C4L (C4-low) in the presence of IgM-coated erythrocytes. C4H displayed a threefold higher hemolytic titer (expressed in hemolytic units/microgram protein) than C4L. No difference was found between c4H and C4L either in stability at 37 degrees C at different pH values and in the rate of C4H and C4L hydrolysis by activated Cl. The major functional difference was found in the covalent binding capacity to IgM-coated erythrocytes, with the amount of C4H bound being about threefold higher than that of C4L. A marked difference in the reactivity of the C4b fragment of C4H and C4L …

Parametri immunologici e infiammatori in patologia In: Compendio di Patologia Generale (Caruso C., Licastro F eds.)

Impact of CMV and EBV seropositivity on CD8 T lymphocytes in an old population from West-Sicily.

Abstract Herpes viruses (particularly CMV and to some extent EBV) might play a role in accelerating the deterioration of immune functions with age. Indeed, it has been demonstrated that chronic infection with CMV causes an expansion of specific CD8 T lymphocytes and that this is related to a shrinkage of the T cell repertoire in very elderly people, predicting mortality. We have analysed CD8 T cells in young and old healthy Sicilians who were both CMV- and EBV-seropositive. Our data confirm expansions of T cells specific for the HLA-A2-restricted pp65 (495–503) CMV epitope up to nearly 14% of total peripheral CD8 cells in certain elderly individuals (range 0–14%). However, the mean percenta…

Aging, longevity, inflammation, and cancer.

Cancer rates increase sharply with age in both sexes, and the majority of cases of cancer occur in patients over the age of 65 years. However, the incidence and mortality for cancer level off around 85-90 years of age, followed by a plateau, or even a decline in the last decades of life. Therefore, it seems reasonable to conclude that centenarians are endowed with a peculiar resistance to cancer. Tumor progression is a complex process that depends on interactions between tumor and host cells. One aspect of the host response, the inflammatory response, is of particular interest because it includes the release of proinflammatory cytokines, some of which may promote tumor growth and hence infl…

Inflammatory Response to a High Radiation Dose in Breast Cancer

Background: Radiation therapy (RT) is an essential treatment modality used for breast cancer (BC) care. Radiations can stimulate the immune system via the early activation of cytokine cascades, which can greatly affect cellular radio-sensitivity. Our aim is to analyze inflammatory response induced by high ionizing radiation (IR) doses, generated by intraoperative radiotherapy (IORT) treatment, to identify several potential targets that may influence cell radio-response. Methods: MCF10, MCF7 and MDA-MB231 BC cell lines have been exposed to high IR (23 Gray and 9 Gray), delivered by IORT treatments. Conditioned media (CM) were assayed at the time points: 0’, 30’, 1, 3, 6, 24, 48, and 72 hours…

Hemostasis and ageing

Abstract On March 19, 2008 a Symposium on Pathophysiology of Ageing and Age-Related Diseases was held in Palermo, Italy. The lecture of D. Mari on Hemostasis and ageing is summarized herein. Physiological ageing is associated with increased plasma levels of many proteins of blood coagulation together with fibrinolysis impairment. This may be of great concern in view of the known association between vascular and thromboembolic diseases and ageing. On the other hand, centenarians are characterized by a state of hypercoagulability and possession of several high-risk alleles and well-known atherothrombotic risk markers but this appears to be compatible with longevity and/or health. Parameters c…

Interleukin-5 production by mononuclear cells from aged individuals: implication for autoimmunity.

It is well known that in the elderly a deterioration of immune functions may occur. Particularly, stimulation of T cells from aged individuals leads to different kind and/or size of responses if compared with the responses obtained from T cells from young individuals. At the same time, an increase in prevalence of autoantibodies occurs in elderly. The altered production of certain cytokines might explain this paradox of decreased responsiveness to foreign antigens in the face of an increased response to self-antigens. We and others have suggested that this kind of immune response might depend on an age-associated impairment of Th-1 type function that selectively affects production of cytoki…

Analysis of functionally relevant single nucleotide polymorphisms of TNF alfa and of IFN gamma in celiac disease

Proposta di protocollo per la determinazione dei valori normali di riferimento per i comuni test di routine nella popolazione anziana

“Analysis of interleukin 10 (IL-10)-1082 G/A single nucleotide polymorphism (SNP) genotypes in breast cancer (BC) patients (pts) and in >95 years old cancer free women"

Age-related Diseases: Key Role of Insulin Resistance for the Association Between Type II Diabetes and Alzheimer’s Disease

Background: Alzheimer’s disease (AD) and Type 2 diabetes mellitus (T2DM) present many relationships. Insulin resistance (IR) plays a key role in neuronal degeneration and death. Reduced energy makes neurons more sensible to oxidation causing mitochondrial damages. Moreover AD brain has lower insulin utilization, reduced expression of its receptors and of IGF 1 and 2, all necessary for neuronal survival and learning and memory processes. Hyperinsulinemia is correlated with increase of hyerphosphorilated tau-protein. SHIP2, a phosphatase, is an antagonist of PI3K. Since the PI3K plays a key role in the biological effects of insulin, its attenuation could be associated with IR in T2DM. Methods…

TLR2 and age-related diseases: potential effects of Arg753Gln and Arg677Trp polymorphisms in acute myocardial infarction.

ABSTRACT Inflammation is a key component of immune system. It is involved in both defense and pathophysiological events maintaining the dynamic homeostasis of host organism. Its function is controlled by innate immunity genes. Both their polymorphisms and environmental conditions give rise to different phenotypes in human population. Proinflammatory genotype may be beneficial in early life but not in old people. With advancing age, indeed, it increases the vulnerability and the intensity to inflammatory reactions responsible for the chronic inflammatory diseases, such as atherosclerosis and myocardial infarction (MI). Several studies have looked for detecting a genetic risk profile that mig…

The nACHR4 594C/T polymorphism in Alzheimer disease

Alzheimer disease (AD) is the most common form of dementia with complex etiology and multifactorial origin. Although several neurochemical deficits have been described in AD patients, explanation of the nature of the cognitive disturbance is focused on the "cholinergic hypothesis." The neuronal nicotinic acetylcholine receptor (neuronal nAChR) belongs to the superfamily of ionic channel activated by ligand. This paper presents a population-based population association study, testing the hypothesis that variants of the nAChR gene confer genetic susceptibility to AD. The authors analyzed two cohorts constituted by 60 controls and 80 AD patients in which significant increase of 594T polymorphi…

Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: a genetically determined defect of C4 influences immunological parameters of healthy carriers of the haplotype.

Abstract Subjects with certain HLA alleles have a higher risk of specific autoimmune diseases than those without these alleles. The 8.1 ancestral haplotype (AH) is a common Caucasoid haplotype carried by most people who type for HLA-B8,DR3. It is unique in its association with a wide range of immunopathological diseases. To gain insight into the identification of the mechanism(s) of disease susceptibility of 8.1 AH carriers, we have investigated the prevalence of circulating immune complexes and non-organ-specific autoantibodies in healthy carriers of the haplotype. The results show that carriers of 8.1 AH display both a significant increased prevalence of immune complexes and higher titers…

Linkage of HFE with HLA antigens: a study in Sicilian population.

PECAM-1/CD31 in infarction and longevity.

: Inflammation has recently proven to be associated with the pathogenesis of atherosclerosis and inflammatory genes are good candidates for the risk of developing atherosclerosis. The early phase of atherosclerosis involves the recruitment of inflammatory cells from the circulation and their transendothelial migration. This process is mainly mediated by cellular adhesion molecules, which are expressed by the vascular endothelium and by circulating leukocytes in response to several inflammatory stimuli. Adhesion of circulating cells to the arterial surface is among the first detectable events in atherogenesis. Cellular adhesion molecules, expressed by the vascular endothelium and by circulat…

Analysis of interleukin 10 (IL-10) -1082G/A single nucleotide polymorphism (SNP) genotypes in breast cancer (BC) patients (pts) and in >95 years old cancer free women

9656 Background:the anti-inflammatory IL-10 -1082 (G/A) SNP might be associated with different risk for breast tumor development. The -1082GG homozygous genotype is associated with an higher IL-10 ...

Genetics, gender and longevity

Polymorphism of cytochrome P450 (CYP) genes and response to chemiotherapy in patients with colorectal cancer (CRC)

Background: Genes coding for the cytochrome P450 (CYP) enzyme system implied in antineoplastic drug metabolism pathways are highly polymorphic. This may influence both carcinogen metabolism and drug pharmacodynamics modifying their therapeutic efficacy and side effects. Methods: We investigated the influence of genetic polymorphisms of CYP enzymes: rs1799853 (CYP2C9), rs35742686 (CYP2D), rs5030655 (CYP2D6/3), rs2740574 (CYP3A4/1) rs776746 (CYP3A5) on the response of chemotherapy and clinical outcomes, in a group of 56 patients affected by sporadic CRC, treated with the standard protocols. A total of 44 patients were in complete remission after treatment, 12 had persistence of the disease. P…

Characterization of two alternative Interleukin(IL)-10 5′UTR mRNA sequences, induced by lipopolysaccharide (LPS) stimulation of peripheral blood mononuclear cells

Abstract IL-10 production shows a broad-spectrum of individual response, suggesting a genetic component of approximately 75%. Different polymorphisms located close to, or within the IL-10 gene has been demonstrated to influence its transcription rate whereas the post-transcriptional regulation of IL-10 production has not well elucidated. The main responsible elements at this control level are both the 5′- and 3′-untranslated regions (UTR's) of mRNAs, and as the 3′-UTR regions are mainly involved in the stability and decay rate of mRNAs, the 5′-UTR regions mediate the binding rate of the molecule with ribosomal 40S subunit as a cis-acting element. Herein are report data on the identification…

A double-negative (IgD−CD27−) B cell population is increased in the peripheral blood of elderly people

The T cell branch of the immune system has been extensively studied in the elderly and it is known that the elderly have impaired immune function, mainly due to the chronic antigenic load that ultimately causes shrinkage of the T cell repertoire and filling of the immunologic space with memory T cells. In the present paper, we describe the IgD(-)CD27(-) double-negative B cell population which (as we have recently described) is higher in the elderly. Most of these cells were IgG(+). Evaluation of the telomere length and expression of the ABCB1 transporter and anti-apoptotic molecule, Bcl2, shows that they have the markers of memory B cells. We also show that these cells do not act as antigen…

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 accord…

In vitro reactivity of peripheral blood mononuclear cells from subjects with different genetic background to amyloid b (Ab42) peptide: implication for cancer an immunotherapy.

Opposite effects of interleukin 10 common gene polymorphisms in cardiovascular diseases and in successful ageing: genetic background of male centenarians is protective against coronary heart disease

Many aspects of ageing involve inflammatory processes. We evaluated the association with longevity of alleles of IL10 and TNFa, known to have opposite functions in inflammatory reactions, IL-10 acting predominantly as an anti-inflammatory and TNF-a as a proinflammatory factor. The number of male centenarians homozygous for the –1082G genotype, suggested to be associated with high IL-10 production, was significantly increased in comparison with younger control subjects. No significant differences were observed between women and controls. The genotypic frequencies of the TNFa promoter SNPs 308G and 308A, suggested to be associated with low and high TNF-a production respectively, were not sign…

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 immunosen…

Biological Basis of the HLA-B8,DR3-Associated Progression of Acquired Immune Deficiency Syndrome

The factors influencing the evolution of human immunodeficiency virus (HIV) infection are not fully known, but the host genotype undoubtedly plays a role in determining the outcome of the disease by affecting the immune response to HIV. The role of the host human leukocyte antigen (HLA) genotype in the regulation of susceptibility to HIV infection and expression has been studied extensively in different major risk groups. Certain HLA alleles and haplotypes, being associated with aberrant immune responses independently from HIV infection, have been reported to facilitate the rapid progression of disorders related to HIV infection. Particularly, the association of rapid acquired immunodeficie…

Genetics of Inflammation in Age-Related Atherosclerosis: Its Relevance to Pharmacogenomics

In response to tissue injury elicited by trauma or infection, the inflammatory response, as a complex network of molecular and cellular interactions, sets an answer directed to facilitate a return to physiological homeostasis and tissue repair. The role of the genetic background and the subsequent predisposition toward the extent of the inflammatory response is determined by gene variability encoding endogenous mediators involved in the inflammatory pathway. Due to its clinical relevance, the genetics of inflammation in aging will be studied using an inflammatory disease like atherosclerosis as an example. Several studies have reported a significant difference in distribution, between patie…

“Analysis of serum HER-2/neu levels (S-HER2) in breast cancer (BC) patients (pts)”

Association between Platelet Glycoprotein Ib-α and Myocardial Infarction: results of a pilot study performed in male and female patients from Sicily

Construction of a reference panel for IGF-1 gene expression: strategies for the identification of “genetic doping” practices.

Analysis of Candidate Genes in Celiac Disease: A Tool to Identify Life-Threatening Associated Genes?

The authors have recently reported that celiac patients show a proinflammatory cytokine genetic profile characterized by the contemporaneous presence of both the tumour necrosis factor-alpha-308A and the interferon-gamma +874T allele-positive genotypes. The same alleles are considered risk factors for aging associated disease, whereas an anti-inflammatory cytokine genotype profile might be associated with an extended life expectancy. This paper reports data on the 1249-1250InsACAA/Non-Ins transforming growth factor (TGF)-beta2, a multifunctional anti-inflammatory cytokine, polymorphism distribution in 88 celiac disease (CD) patients, 99 age- and sex-matched controls, and 2895-year-old healt…

Role of TGF-β Pathway Polymorphisms in Sporadic Thoracic Aortic Aneurysm: rs900 TGF-β2 Is a Marker of Differential Gender Susceptibility

Thoracic aortic aneurysm (TAA) is a progressive disorder involving gradual dilation of ascending and/or descending thoracic aorta with dissection or rupture as complications. It occurs as sporadic or defined syndromes/familial forms.Genetic, molecular and cellular mechanims of sporadic TAA forms are poorly characterized and known. Thus, our interest has been focused on investigating the role of genetic variants of transforming growth factor-β(TGF-β) pathways in TAA risk. On the other hand, no data on the role of genetic variants of TGF-βpathway in sporadic TAA exist until now. In addition, other cytokines, including IL-10, orchestrate TAA pathophysiology. Their balance determines the ultima…

Valutazione della “gene expression” di IGF-1 ed IGF-1R in soggetti dediti ad attività sportiva: costruzione di un panel di riferimento utile all’identificazione di casi di “doping genico”

Sharing pathogenetic mechanisms between acute myocardial infarction and Alzheimer's disease as shown by partially overlapping of gene variant profiles.

Abstract Gene variants that promote inflammation and cholesterol metabolism have been associated with acute myocardial infarction (AMI) and Alzheimer's disease (AD). We investigated a panel of relevant polymorphisms to distinguish genetic backgrounds for AMI and AD: IL10 -1082G/A, IL6 -174G/C, TNF -308G/A, IFNG +874T/A, SERPINA3 -51G/T, HMGCR -911C/A, APOE e2/3/4 (280 AMI cases, 257 AD cases, and 1307 population controls, all Italian (presumed risk alleles are shown in bold). Six genetic risk sets I to VI were identified by fuzzy latent classification: I had low risk; II and III had low risk before age 65 (II, III); low risk sets lacked pro-inflammatory alleles for HMGCR-TNF-APOE. Pro-infla…

TGF-&beta;/VEGF-A Genetic Variants Interplay in Genetic Susceptibility to Non-Melanocytic Skin Cancer

Differential genetically determined expression of transforming growth factor-&beta; (TGF-&beta; pathway and of vascular endothelial growth factor-A (VEGF-A) might modulate the molecular &ldquo;milieu&rdquo; involved in the etio-pathogenesis of non-melanoma skin cancer (NMSC). We have evaluated the frequency of some functionally relevant SNPs of TGF-&beta; and VEGF-A genes in 70 NMSC patients and 161 healthy controls, typed for TGF-&beta;1 rs1800471, TGF-&beta;2 rs900, TGF-&beta;R1 rs334348 and rs334349, TGF-&beta;R2 rs4522809 and VEGF-A rs3025039 SNPs. TGF-&beta;R2 rs1800629G allele and related genotypes were found to be associated with a possible protective role against NMSC, whereas VEGF-…

Association between the MHC class I gene HFE polymorphisms and longevity: a study in Sicilian population.

Classes I and II human leukocyte antigens (HLA) genes encode highly polymorphic heterodimeric glycoproteins involved in the control of immune responses. The HLA class I gene HFE seemingly no longer participates in immunity because it has lost its ability to bind peptides and it has acquired the ability to form complex with the receptor for iron-binding transferrin by regulating iron uptake by intestinal cells. Thus, it indirectly regulates immune responses too, because iron availability plays a role in specific and non-specific immune responses. The distribution of HFE polymorphisms in Sicilian centenarians and nonagenarians was studied to evaluate if HFE alleles might be represented differ…

Acute phase response in oldest-old individuals after surgical stress.

Systematic review by meta-analyses on the possible role of TNF-alpha polymorphisms in association with Alzheimer's disease.

It has been hypothesized that polymorphisms of Tumor Necrosis Factor (TNF)-alpha gene affect the risk of developing Alzheimer's disease (AD). However, results of different studies are often inconsistent. Our aim was to investigate by meta-analysis the association of the common polymorphisms comprehensively defining the genetic variability of the TNF-alpha gene with AD risk. Hence, the results being stated are of a meta-analysis across studies, and that this meta-analysis does not invalidate the results of the individual studies previously performed. Seventeen studies that investigated the association between 5 TNF-alpha polymorphisms (-850, -308, -863, -238, and -1031) and AD were retrieved…

Trafficking phenotype and production of granzyme B by double negative B cells (IgG(+)IgD(-)CD27(-)) in the elderly.

The impairment of humoral immune response in elderly humans has been extensively demonstrated. We have reported the increase of memory B cells (IgG(+)IgD(-)CD27(-), double negative, DN) population in the elderly, in which there is also a typical inflammatory micro-environment. In order to evaluate whether this pro-inflammatory status could influence the trafficking phenotype of naïve/memory B cells, we have assessed the expression of CCR7, CCR6, CXCR3, CXCR4, CXCR5 and CD62L on naïve/memory B cell subpopulations in young and elderly subjects. Moreover, the combination of pro-inflammatory interleukin-21 (IL-21) and B cell receptor (BCR) stimulation enables B cells to produce and secrete gran…

Genotyping strategy of SMAD-3 rs3825977 gene variant for a differential management of ascending aorta aneurysm in women people: Gender oriented diagnostic tools

Abstract Background and objectives The research of opportune strategies for facilitating the management of complex pathologies, such as ascending aorta aneurysm (AAA), currently represents the principal object of clinicians, clinical pathologists included. Herein, we propose genotyping of gene variants related to TGF-β pathway as useful strategy to improve the complex AAA management, exclusively based on imaging evaluations. Precisely, we investigated four functional SNPs in SMAD and VEGF genes, encoding molecules able to modulate functions and cross-talks of TGF-β pathway. Populations and methods Our study included 92 individuals (70 men (76%) and 22 (24%) women; mean age: 71.4 ± 2.6 years…

Interleukin-12 release by mitogen-stimulated mononuclear cells in the elderly.

Abstract Defects involving cellular expression of activation molecules, cell mediated immune response and natural killer (NK) activity are commonly observed in the elderly. Herein, data are reported on the evaluation of IL-12 production by old subjects. IL-12 is, actually, considered the key molecule for the induction of a T helper 1 (Th1) -type and NK response. IL-12 production from old subjects peripheral blood mononuclear cells (PBMNC) was evaluated using T-independent (bacterial lipopolysaccharide, LPS) or -dependent (phytoemagglutinin, PHA; immobilized anti-CD3 monoclonal antibodies, anti-CD3) mitogens. The IL-12 production after LPS stimulation was not reduced in cultures from old sub…

Ruolo del recettore TLR4 nell’infarto e nella longevità

Inflammatory networks in ageing, age-related diseases and longevity

Inflammation is considered a response set by the tissues in response to injury elicited by trauma or infection. It is a complex network of molecular and cellular interactions that facilitates a return to physiological homeostasis and tissue repair. The individual response against infection and trauma is also determined by gene variability. Ageing is accompanied by chronic low-grade inflammation state clearly showed by 2-4-fold increase in serum levels of inflammatory mediators. A wide range of factors has been claimed to contribute to this state; however, the most important role seems to be played by the chronic antigenic stress, which affects immune system thorough out life with a progress…

Interleukin-6 gene polymorphism is an age-dependent risk factor for myocardial infarction in men.

Summary Several studies show that inflammatory components may contribute to atherosclerosis and increase the risk for myocardial infarction (MI). Interleukin-6 (IL-6) is a key pro-inflammatory and immune-modulatory cytokine of relevance for cardiovascular diseases. In this case-control study, 200 patients with MI and 257 healthy controls were genotyped for the polymorphism present in −174 promoter region of the IL-6 gene. Plasma concentrations of IL-6 and C-reactive protein (CRP) in a group of patients and controls were measured. The −174 C allele was associated with an increased risk of developing MI (OR = 2.886, c.i. = 1.801–4.624, P = 0.0001) in older patients, while no association was f…

Analisi della frequenza del polimorfismo 1249-1250insACAA del gene TGF-beta2 in un gruppo di pazienti affette da carcinoma della mammella.

Pathophysiological implications of inflammation and genetic inflammatory factors in hypertensive and old patients affected by sporadic thoracic aortic aneurysm

Early activation of γδ T lymphocytes in the elderly

T cell function is altered in vivo and in vitro in elderly compared with young subjects, and this alteration is believed to contribute to morbidity and mortality in man due to the greater incidence of infection, as well as autoimmunity and cancer in elderly. The majority of T cells express TCRalphabeta whereas TCRgammadelta is expressed on a minority of T cells. Moreover, it is known that gammadelta T lymphocytes display major histocompatibility complex (MHC)- unrestricted cytotoxicity that is reminiscent of natural killer (NK) activity. In view of earlier findings on both T cells and NK cells in the elderly, we hypothesised a different behaviour of gammadelta T lymphocytes from old subject…

FREQUENZA DEI POLIMORFISMI DEL PEPTIDE SEGNALE DEL TGF-β1 IN UN GRUPPO DI PAZIENTI AFFETTI DA STENOSI CAROTIDEA

Genetic determined downregulation of both type 1 and type 2 cytokine pathways might be protective against pancreatic cancer

PROTECTIVE DETERMINANTS AGAINST CARDIOVASCULAR DISEASES ARE PRESENT IN GENETIC BACKGROUND OF CENTENARIANS

IL-2 HIGH PRODUCER GENETIC BACKGROUND IS NEGATIVELY ASSOCIATED TO LONGEVITY

Ruolo del polimorfismo –308 A/G del gene del Tumor Necrosis Factor-a nell’età di insorgenza della malattia di Alzheimer

OPPOSITE ROLE OF TRL4 RECEPTOR IN ACUTE MYOCARDIAL INFARCTION AND LONGEVITY

RUOLO DELLA CITOCHINA PRO-INFIAMMATORIA TNF NELL’INVECCHIAMENTO SENZA SUCCESSO E NELLA LONGEVITÀ

Prevalenza degli autoanticorpi in una coorte di soggetti anziani e centenari

ANALISI DEI POLIMORFISMI DEL PEPTIDE SEGNALE DEL TGF-β1 IN GRUPPO DI PAZIENTI AFFETTI DA MALATTIA DI BEHÇET

ANALYSIS OF HLA-DQA, HLA-DQB FREQUENCIES IN A GROUP OF SARDINIAN CENTENARIANS

GENETIC BACKGROUND OF CENTENARIANS MAY BE PROTECTIVE AGAINST CARDIOVASCULAR DISEASES

Ruolo del recettore nACHR4 nella malattia d’Alzheimer: associazione con il polimorfismo C594T

LONGEVITY AND MYOCARDIAL INFARCTION: ROLE OF ALPHA1-ANTITRYPSIN DEFICENCY

SEARCHING FOR PRO-INFLAMMATORY GENOTYPE IN ACUTE MYOCARDIAL INFARCTION: A STUDY IN THE SICILIAN POPULATION

Analisi della frequenza del polimorfismo -330T/G della regione promoter del gene IL-2 in una coorte di centenari italiani