Blood antiphospholipid antibody levels are influenced by age, sex and HLA-B8,DR3 phenotype.

Antiphospholipid antibodies (APA) are known to be associated with a number of seemingly heterogeneous pathological conditions that are part of the antiphospholipid syndrome, formerly called anticardiolipin syndrome. Recent studies on the mechanism of action of these autoantibodies suggest that we are dealing with a new autoimmune syndrome which may occur either in a primary form or in the context of other autoimmune diseases, mainly systemic lupus erythematosus (SLE). Moreover, increased levels of APA have been found in elderly subjects, who are known to display increased frequency of autoimmune phenomena. It is well known that many autoimmune diseases, including SLE, are associated with HLA antigens, particularly with HLA-B8,DR3 phenotype. In our study, APA serum levels were analyzed in 26 old subjects and in 56 young ones. The results demonstrate that HLA-B8,DR3-positive young females display significantly higher levels of APA than HLA-B8,DR3-negative ones. Interestingly, the same is true for elderly subjects on the whole with respect to young individuals. These data are consistent with previous findings demonstrating that HLA-B8,DR3-positive subjects (mainly female) as well as old subjects display (also in the absence of any clinical manifestation), multiple immune dysfunctions that may underlie the predisposition to autoimmunity.     

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 investigated the distribution of these three common HFE gene mutations in Sardinian centenarians and controls. DNA samples, obtained from 61 controls and 57 Centenarians, were typed for HFE polymorphisms using sequence specific primers. Among the controls, none was heterozygous for the C282Y mutation, 15 were heterozygous for H63D mutation and one for S65C. Among the centenarians, none was heterozygous for the C282Y mutation whereas 25 were heterozygous for H63D mutation and four for the S65C mutation. No significant differences were observed in frequencies of the different alleles between young and centenarians both on the whole and when the data were analysed according to gender. However, there was a trend for an increased frequency of H63D allele in centenarian women (24 vs. 17%, i.e. 19/80 vs. 13/78). It is noteworthy that the cumulative frequency of H63D mutations in Centenarian and very old women from Sardinia and Sicily is 22 vs. 11%, i.e. 30/136 vs. 23/210, P=0.008. These findings are consistent with the hypothesis that there may be a survival difference for centenarian women, among carriers and non-carriers of alleles involved in iron sparing.     

Impact of different texture of polypropylene mesh on the inflammatory response

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

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

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 might allow a pharmacogenomic approach to prevent and treat age-related diseases such as MI. We have evaluated the possible association between two polymorphisms of TLR2 gene-Arg677Trp and Arg753Gln-and MI. However, we found no association between TLR2 polymorphisms and MI.     

Inflammation,genetic background and longevity

Ageing is an inexorable intrinsic process that affects all cells, tissues, organs and individuals. Due to a diminished homeostasis and increased organism frailty, ageing causes a reduction of the response to environmental stimuli and, in general, is associated to an increased predisposition to illness and death. Actually, it is characterized by a state of reduced ability to maintain health and general homeodynamics of the organism. A large part of the ageing phenotype is explained by an imbalance between inflammatory and anti-inflammatory networks, which results in the low grade chronic pro-inflammatory status of ageing, “inflamm-ageing”. It is strictly linked to immunosenescence, and on the whole they are the major contributory factors to the increased frequency of morbidity and mortality among elderly. Inflamm-ageing is compatible with longevity; even if centenarians have an increased level of inflammatory mediators in comparison to old subjects and they are very frail, they also have high level of anti-inflammatory cytokines together with protective genotypes. Actually, data on case control studies performed in Italian centenarians suggest that a pro-inflammatory genotype is unfavourable to reach extreme longevity in good health and likely favours the onset of age-related diseases such as cardiovascular diseases and Alzheimer’s disease, the leading causes of mortality and disability in the elderly. However, many associations between gene variants and longevity have been found only in Italian population. This should not be unexpected, since ageing and longevity are complex traits resulting not only and not exclusively from genetics, but rather from the interactions between genetics, environment and chance.     

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 α1-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 AMI patients (1.2%) (P = 0.0000001). The heterozygous MZ genotype was significantly over represented in centenarians (38/143) and under represented in AMI patients (3/127) with intermediate values in young controls (16/255) (P = 0.0000001). After adjustment for well-recognized AMI risk factors, the MZ genotype still predicted a significant negative risk factor for developing AMI in the Sicilian population. Thus, our data show a positive role of MZ heterozygosity in attainment of successful ageing linked to the positive effects of this genotype versus the cardiovascular ischemic diseases.     

Human longevity within an evolutionary perspective: the peculiar paradigm of a post-reproductive genetics

The data we collected on the genetics of human longevity, mostly resulting from studies on centenarians, indicate that: (1) centenarians and long-living sib-pairs are a good choice for the study of human longevity, because they represent an extreme phenotype, i.e., the survival tail of the population who escaped neonatal mortality, pre-antibiotic era illnesses, and fatal outcomes of age-related complex diseases. (2) The model of centenarians is not simply an additional model with respect to well-studied organisms, and the study of humans has revealed characteristics of ageing and longevity (geographical and sex differences, role of antigenic load and inflammation, role of mtDNA variants) which did not emerge from studies in laboratory model systems and organisms. (3) All the phenotypic characteristics of nonagenarians and centenarians fit the hypothesis that ageing is a remodelling process where the body of survivors progressively adapts to internal and external damaging agents they are exposed to during several decades, largely unpredicted by evolution. (4) Such a remodelling process, which can be considered a Darwinian process occurring at the somatic level within the framework of the evolutionary constraints, established by evolution for Homo sapiens as a species, may explain why the same gene polymorphism can have different (beneficial or detrimental) effects at different ages. (5) Geographic and demographic evidence suggest that longevity can be achieved by different combinations of genes, environment, and chance quantitatively and qualitatively different in many geographic areas, and that population-specific genetic factors, play a role on the longevity trait. (6) The concomitant and integrated use of new in silico and high throughput strategies will greatly accelerate the identification of new longevity genes in humans.