28 research outputs found
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.Alarge 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. Inflammageing
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
Immunoproteasome LMP2 60HH Variant Alters MBP Epitope Generation and Reduces the Risk to Develop Multiple Sclerosis in Italian Female Population
Background: Albeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cells
involvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in the
production of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation and
regulation of autoreactive CD8+ T cells in Multiple Sclerosis.
Methodology/Principal Findings: Immunoproteasomes and PA28-ab regulator are present in MS affected brain area and
accumulated in plaques. They are expressed in cell types supposed to be involved in MS development such as neurons,
endothelial cells, oligodendrocytes, macrophages/macroglia and lymphocytes. Furthermore, in a genetic study on 1262
Italian MS cases and 845 controls we observed that HLA-A*02+ female subjects carrying the immunoproteasome LMP2
codon 60HH variant have a reduced risk to develop MS. Accordingly, immunoproteasomes carrying the LMP2 60H allele
produce in vitro a lower amount of the HLA-A*0201 restricted immunodominant epitope MBP111\u2013119.
Conclusion/Significance: The immunoproteasome LMP2 60HH variant reduces the risk to develop MS amongst Italian HLAA*
02+ females. We propose that such an effect is mediated by the altered proteasome-dependent production of a specific
MBP epitope presented on the MHC class I. Our observations thereby support the hypothesis of an involvement of
immunoproteasome in the MS pathogenesis
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 TLR4ASP299GLY 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 cardiovascular diseases (CVD) and, subsequently, live longer if they do not become affected by serious infectious diseases. These results are in agreement with our other data demonstrating how genetic background may exert the opposite effect with respect to inflammatory components in CVD and longevity. In the present report, to validate this hypothesis, the levels of interleukin (IL)-6, a pro-inflammatory cytokine involved in atherosclerosis and longevity, were determined by an enzymelinked immuno-sorbent assay (ELISA) in supernatants from a whole blood assay after stimulation with subliminal doses of lipopolysaccaride (LPS) from Escherichia coli (E. coli). The samples, genotyped for the ASP299GLY polymorphism, were challenged with LPS for 4, 24, and 48 h. What we found was that Il-6 values were significantly lower in carriers bearing TLR4 mutation. Therefore, the pathogen burden, by interacting with host genotype, determines the type and intensity of the immune-inflammatory responses accountable for pro-inflammatory status, CVD, and unsuccessful aging. On the other hand, our present data seem to explain the inconclusive results obtained in case-control studies taking into account the role of functional IL-6 polymorphisms in successful and unsuccessful aging. In fact, IL6levels seem to depend, in addition, on IL-6 polymorphisms and on innate immunity gene polymorphisms as well