The aim of the present review is to provide an update of the current research into the pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype. This is a common Caucasoid ...haplotype carried by most people who type for HLA‐B8, DR3. Numerous genetic studies reported that individuals with certain HLA alleles have a higher risk of specific autoimmune disorders than those without these alleles. However, much remains to be learned about the heritability of autoimmune conditions. Recently, progress and advances in the field of genome‐wide‐association studies have revolutionized the capacity to perform large, economically feasible, and statistically robust analyses of HLA within 8.1 ancestral haplotype, and understand its contribute to autoimmune events.
In this paper, the characteristic features of this haplotype that might give rise to diverse autoimmune phenotypes are reviewed, focusing on the contribution of the HLA‐DRB1 gene, the most polymorphic sequence within the HLA II region.
Nowadays, people are living much longer than they used to do, however they are not free from ageing. Ageing, an inexorable intrinsic process that affects all cells, tissues, organs and individuals, ...is a post-maturational process that, due to a diminished homeostasis and increased organism frailty, causes a reduction of the response to environmental stimuli and, in general, is associated to an increased predisposition to illness and death. However, the high incidence of death due to infectious, cardiovascular and cancer diseases underlies a common feature in these pathologies that is represented by dysregulation of both instructive and innate immunity. Several studies show that a low-grade systemic inflammation characterizes ageing and that inflammatory markers are significant predictors of mortality in old humans. This pro-inflammatory status of the elderly underlies biological mechanisms responsible for physical function decline and age-related diseases such as Alzheimer's disease and atherosclerosis are initiated or worsened by systemic inflammation. Understanding of the ageing process should have a prominent role in new strategies for extending the health old population. Accordingly, as extensively discussed in the review and in the accompanying related papers, investigating ageing pathophysiology, particularly disentangling age-related low grade inflammation, is likely to provide important clues about how to develop drugs that can slow or delay ageing.
A typical feature of ageing is a chronic, low-grade inflammation characterized by a general increase in the production of pro-inflammatory cytokines and inflammatory markers ("inflamm-ageing"). This ...status may slowly damage one or several organs, especially when unfavorable genetic polymorphisms and epigenetic alterations are concomitant, leading to an increased risk of frailty together with the onset of age-related chronic diseases. The contribution of different tissues (adipose tissue, muscle), organs (brain, liver), immune system and ecosystems (gut microbiota) to age-related inflammation ("inflamm-ageing") will be discussed in this review in the context of its onset/progression leading to site-restricted and systemic effects. Moreover, some of the possible strategies and therapies to counteract the different sources of molecular mediators which lead to the age-related inflammatory phenotype will be presented.
Summary
Killer immunoglobulin‐like receptors (KIRs) regulate the activation of natural killer cells through their interaction with human leucocyte antigens (HLA). KIR and HLA loci are highly ...polymorphic, and certain HLA‐KIR combinations have been found to protect against viral infections. In this study, we analysed whether the KIR/HLA repertoire may influence the course of hepatitis B virus (HBV) infection. Fifty‐seven subjects with chronic hepatitis B (CHB), 44 subjects with resolved HBV infection and 60 healthy uninfected controls (HC) were genotyped for KIR and their HLA ligands. The frequency of the HLA‐A‐Bw4 ligand group was higher in CHB (58%) than subjects with resolved infection (23%) (crude OR, 4.67; P<.001) and HC (10%) (crude OR, 12.38; P<.001). Similar results were obtained for the HLA‐C2 ligand group, more frequent in CHB (84%), than subjects with resolved infection (70%) (crude OR, 2.24; P<.10) and HC (60%) (crude OR, 3.56; P<.01). Conversely, the frequency of KIR2DL3 was lower in CHB (81%) than in subjects with resolved infection (98%) (crude OR, 0.10; P<.05). These results suggest a detrimental role of HLA‐A‐Bw4 and HLA‐C2 groups, which are associated with the development of CHB, and a protective role of KIR2DL3. A stepwise variable selection procedure, based on multiple logistic regression analysis, identified these three predictive variables as the most relevant, featuring high specificity (90.9%) and positive predictive value (87.5%) for the development of CHB. Our results suggest that a combination of KIR/HLA gene/alleles is able to predict the outcome of HBV infection.
Summary
T helper 9 (Th9) cells and interleukin (IL)‐9 are involved in the pathogenesis of several autoimmune diseases. The exact role of IL‐9 and Th9 cells in patients with systemic sclerosis (SSc) ...have not yet been studied adequately. IL‐9, IL‐9R, transcription factor PU.1 (PU.1), IL‐4, thymic stromal lymphopoietin (TSLP) and transforming growth factor (TGF)‐β expression were assessed in skin and kidney biopsies of SSc patients and healthy controls (HC) by immunohistochemistry (IHC). The cellular source of IL‐9 was also analysed by confocal microscopy analysis. Peripheral IL‐9‐producing cells were also studied by flow cytometry. The functional relevance of IL‐9 increased expression in SSc was also investigated. Our results demonstrated a strong expression of IL‐9, IL‐9R, IL‐4, TSLP and TGF‐β in skin tissues of patients with both limited and diffuse SSc. IL‐9 expression was observed mainly in the context of skin infiltrating mononuclear cells and keratinizing squamous epithelium. IL‐9 over‐expression was also observed in renal biopsies of patients with SSc. IL‐9 producing cells in the skin were identified as Th9 cells. Similarly, Th9 cells were expanded and were the major source of IL‐9 among SSc peripheral blood mononuclear cells (PBMC), their percentage being correlated directly with the modified Rodnan skin score. Infiltrating mononuclear cells, mast cells and neutrophils expressed IL‐9R. In in‐vitro studies stimulation with rIL‐9 significantly induced NET (neutrophil extracellular traps) release by dying cells (NETosis) in neutrophils, expansion of mast cells and increase of anti‐systemic scleroderma 70 (Scl70) production by B cells. Our findings suggest that Th9 cells and IL‐9 could be implicated in the pathogenesis of SSc.
IL‐9 and Th9 cells are expanded in the skin, kidney and peripheral blood of SSc patients.
IL‐9 pathway may play an important role in SSc and should be considered as potential therapeutic target in SSc.
OBJECTIVES
The involvement of different factors in the onset of thoracic aortic aneurysm (TAA) in patients with a bicuspid aortic valve (BAV) vs those with a tricuspid aortic valve (TAV) is well ...recognized. However, the molecular, genetic and cellular mechanisms driving TAA remain unclear. The aim of this study was to identify the different mechanisms involved in TAA development in patients with BAV vs TAV.
METHODS
Aorta specimens and DNA samples were collected from 24 BAV (18 men and 6 women; mean age: 54.2 ± 14.39 years) and 110 TAV (79 men and 31 women, mean age: 66 ± 9.8 years) patients. A control group of 128 subjects (61 men and 67 woman, mean age: 61.1 ± 5.8 years) was also enrolled. Histopathological and immunoistochemical analyses were performed, as well as genotyping of 10 polymorphisms.
RESULTS
In BAV-associated ascending aortas, significant severe plurifocal apoptosis of smooth muscle cells and matrix metalloproteinase-9 (MMP-9) amounts were detected. In contrast, TAV-associated ascending aortas were characterized by a significant severity of elastic fragmentation, cystic medial necrosis, medial fibrosis and inflammation. In addition, in BAV cases, the −1562TMMP-9 and −735TMMP-2 alleles represent independent risk factors for TAA. The effects of these genotypes combined with hypertension and smoking in BAV cases result in an increase in both the apoptosis (P = 0.0001) and levels of MMP-9 (P = 0.001). In TAV cases, the D angiotensin-converting enzyme and +896A Toll-like receptor-4 alleles seem to be the predictive factors for TAA risk. They, combined with hypertension and age, significantly increase both the microscopic lesions and inflammation.
CONCLUSIONS
Our data seem to suggest that TAA in BAV and TAV patients arises from different molecular, cellular and genetic mechanisms. They might help to identify the potential molecular and genetic biomarkers that are useful to detect BAV subjects at high TAA risk, to monitor and treat them differently from those with TAV, with approaches such as the complete removal of the ascending aorta, including the aortic root with or without dilatation.
Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. AD has been linked to inflammation and oxidative ...stress. Neuro-pathological hallmarks are senile plaques, resulting from the accumulation of several proteins and an inflammatory reaction around deposits of amyloid, a fibrillar protein, Abeta, product of cleavage of a much larger protein, the beta-amyloid precursor protein (APP) and neurofibrillary tangles. Inflammation clearly occurs in pathologically vulnerable regions of AD and several inflammatory factors influencing AD development, i.e. environmental factors (pro-inflammatory phenotype) and/or genetic factors (pro-inflammatory genotype) have been described. Irrespective of the source and mechanisms that lead to the generation of reactive oxygen species, mammalian cells have developed highly regulated inducible defence systems, whose cytoprotective functions are essential in terms of cell survival. When appropriately activated, each one of these systems has the possibility to restore cellular homeostasis and rebalance redox equilibrium. Increasing evidence, support the notion that reduction of cellular expression and activity of antioxidant proteins and consequent augment of oxidative stress are fundamental causes for ageing processes and neurodegenerative diseases., including AD. The better understanding of different molecular and cellular inflammatory mechanisms is crucial for complete knowledge of AD pathophysiology, hence for its prevention and drug therapy. Accordingly, two lines of preventive therapeutics can be outlined, the first based on anti-inflammatory drugs, the second one on anti-oxidative properties.
Immunosenescence is considered a major contributory factor to the increased frequency of morbidity and mortality among elderly. On the other hand centenarians are considered the best example of ...successful ageing. To gain insight into mechanisms of immunosenescence and its clinical relevance, a possible model is represented by centenarians and/or their offspring. Nowadays centenarians are not more a curiosity, but in Europe are 1/8000 inhabitants and it has been demonstrated that the centenarian offspring, who are typically in their 70s and 80s, have a survival advantage when compared with age-matched controls whose parents died at an average life expectancy. Then again, studies on immunosenescence focus mainly on T cell impairment, although B cells are also affected. So, in the present preliminary report, we have studied B cell compartment in two classes of individuals, old people and centenarian offspring. B cell compartment was analysed using IgD and CD27 antibodies which characterize naïve B cells (IgD(+) CD27(-)), memory unswitched B cells (IgD(+)CD27(+)), memory switched B cells(IgD(-)CD27(+)) and double negative B cells (DN) (IgD(-)CD27(-)), i.e. exhausted memory cells. As expected, in both cohorts we observed a decreased B cell count. However, in centenarian offspring, naïve B cells are more abundant whereas exhausted memory cells (DN B cells, IgD(-)CD27(-)) do not show the increase that we have previously demonstrated in healthy elderly donors. These data are similar to that found in previously experiments on young subjects. So, our preliminary results show that centenarian offspring do not have the typical trend of memory/naive B cell subsets observed in elderly people and this is in agreement with the higher levels of IgM in the serum of centenarian offspring in comparison with data obtained in age-matched controls. This reservoir of naive B cell might be one of the causes that make centenarian offspring able to keep fighting off new infections, hence prolonging their life. So, B cell subset changes could represent a hallmark of successful or unsuccessful ageing and could be used as a biomarker of human life span, potentially useful for the evaluation of anti-ageing treatment.
Many studies have been conducted on the effects of red wine polyphenols on certain diseases, primarily, coronary heart disease (CHD) and, in this respect, evidence has been demonstrated that intake ...of red wine is associated with a reduction of CHD symptomatology. In this framework, the purpose of this review is to illustrate the effects of polyphenols on immune cells from human healthy peripheral blood. Data will show that polyphenols are able to stimulate both innate and adaptive immune responses. In particular, the release of cytokines such as interleukin (IL)-12, interferon (IFN)-gamma, and IL-10 as well as immunoglobulins may be important for host protection in different immune related disorders. Another important aspect pointed out in this review is the release of nitric oxide (NO) from peripheral blood mononuclear cells (PBMC), stimulated by red wine polyphenols despite the fact that the majority of studies have reported NO production only by endothelial cells. Release of NO from PBMC may play an important role in cardiovascular disease, because it is known that this molecule acts as an inhibitor of platelet aggregation. On the other hand, NO exerts a protective role against infectious organisms. Finally, some molecular cytoplasmatic pathways elicited by polyphenols able to regulate certain immune responses will also be discussed. In particular, it seems that p38, a molecule belonging to the MAPK family, is involved in the release of IFN-gamma and, therefore, in NO production. All these data confirm the beneficial effects of polyphenols in some chronic diseases.
Several pathologies affect human prostate, such as prostate cancer (PC), which is the most common non-skin malignant cancer in Western male populations. A complex interaction between genetic and ...environmental factors (i.e. infectious agents, dietary carcinogens) and hormonal imbalances has been reported to have a fundamental role in PC pathophysiology by evoking chronic inflammation. Thus, chronic inflammation drives prostate carcinogenesis and neoplastic progression. No adequate biomarkers exist until now to guide PC prognosis and treatment. Accordingly, the research has particularly focused its attention on genetic variants in genes, codifying molecules of signaling innate immune/inflammatory and steroid metabolism pathways, which are able to modify the PC genetic susceptibility and clinical disease outcome. Single-nucleotide polymorphisms (SNPs) may operate in combination to create a 'risk profile'. Combinations of several inflammatory and sex steroid hormone pathway SNPs are found in PC patients. Thus, their combinations might be used as promising biomarkers in a pre- and post-treatment clinical PC setting. Indeed, their identification may hold promise for the realization of a personalized PC medicine. Many of these aspects are summarized in this report through the elucidation of literature data and the results of our studies.
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