Immunology of Aging: the Birth of Inflammaging.

The inflammaging concept was introduced in 2000 by Prof. Franceschi. This was an evolutionary or rather a revolutionary conceptualization of the immune changes in response to a lifelong stress. This conceptualization permitted to consider the lifelong proinflammatory process as an adaptation which could eventually lead to either beneficial or detrimental consequences. This dichotomy is influenced by both the genetics and the environment. Depending on which way prevails in an individual, the outcome may be healthy longevity or pathological aging burdened with aging-related diseases. The concept of inflammaging has also revealed the complex, systemic nature of aging. Thus, this conceptualization opens the way to consider age-related processes in their complexity, meaning that not only the process but also all counter-processes should be considered. It has also opened the way to add new concepts to the original one, leading to better understanding of the nature of inflammaging and of aging itself. Finally, it showed the way towards potential multimodal interventions involving a holistic approach to optimize the aging process towards a healthy longevity.

Sublingual gland neoplasms: clinicopathological study of 8 cases.

BACKGROUND: Sublingual gland neoplasms are very rare and the majority of them are malignant. The aim of this study was to evaluate the clinical course, treatment, and outcomes of these uncommon neoplasms based on the authors' experience and the recent literature. MATERIAL AND METHODS: The medical charts of 8 patients with primary epithelial sublingual gland tumors treated between 1994 and 2020 were reviewed. RESULTS: Malignant tumors comprised 75% (6/8) of cases. Adenoid cystic carcinoma was the most common (50%, 3/6) and characterized by high risk of local recurrence and lung metastasis. Pleomorphic adenoma was the only representative of benign tumors with no evidence of local recurrence in follow up. CONCLUSIONS: Treatment of choice of sublingual gland tumors is surgery. However, due to the fact that adenoid cystic carcinoma is the most common malignancy with poor prognosis, surgical treatment should be combined with postoperative radiotherapy. Benign sublingual tumors are less common and treatment of choice in these cases is tumor resection together with sublingual gland.

The frequency of interleukin-1ß-producing monocytes is significantly associated with varicella-zoster responses of nursing home residents.

Previous studies have demonstrated that the status of the T cell compartment and inflammation-related factors are associated with the immunogenicity of the varicella-zoster virus (VZV) vaccine in older adults; however, little is known about the roles of other immune cell subsets known to influence the generation and maintenance of immunological memory. Responses to a live-attenuated VZV vaccine were studied in relation to peripheral blood mononuclear cell (PBMC) composition and function in a sample of 30 nursing home residents (aged 80-99 years). Interferon-gamma enzyme-linked immunospot (ELISPOT) was used to measure VZV responses at baseline and 6 weeks following vaccination, and associations were sought with the frequencies of monocytes and T, B and natural killer (NK) cells and the production and secretion of cytokines following their ex-vivo stimulation with different agents. While only the frequency of interleukin (IL)-6+ CD14+ monocytes was inversely associated with post-vaccination VZV response, amounts of IL-1ß, IL-10, IL-17A and tumour necrosis factor (TNF) secreted by PBMCs and the frequency of IL-1ß+ CD14+ monocytes was positively correlated with pre-vaccination VZV response. Furthermore, both bivariate correlation and causal mediation analyses supported the notion that IL-1ß+ CD14+ monocytes were significant mediators of the associations between IL-1ß and TNF secretion by PBMCs and pre-vaccination VZV responses. Our findings implicate a strong cytokine response mediated by inflammatory IL-1ß+ monocytes in coordinating responses of long-lived VZV-reactive memory T cells, but with an opposing effect of IL-6+ CD14+ monocytes. Whether monocyte status promotes or inhibits the induction and/or maintenance of these memory T cells later in life has yet to be determined.

Exploratory study on immune phenotypes in Alzheimer's disease and vascular dementia.

BACKGROUND AND PURPOSE: The differentiation of Alzheimer's disease (AD) dementia from vascular dementia (VaD) and mixed-type dementia (mixed dementia) requires stepwise analysis and usually occurs late in the disease process. Early diagnosis and therapy monitoring would benefit greatly from the identification of biomarkers of neurodegeneration, especially blood biomarkers. To this end, the aim of the present pilot study was to investigate differences in the distribution of peripheral T-cell populations in patients with AD compared to VaD and mixed dementia. METHODS: Flow cytometry was performed on blood samples from 11 patients with AD, six with VaD and six with mixed dementia, as well as 17 healthy control subjects (HCs). CD4+ and CD8+ T cells were typed for expression of CD45, CD27, CD28, CD25, FoxP3, CCR4 and CCR6; the other leukocytes were also assessed. Functionally, immune cell uptake of the ß-amyloid (Aß) toxic fragment (Aß1-42 ) was also evaluated. RESULTS: A higher proportion of CD4+CD28- memory T cells and a reciprocal reduction of CD4+CD28+CD27+ naïve T lymphocytes was detected in all patient groups relative to controls. Significantly fewer CD4+CD25+FoxP3 regulatory T cells were present in patients with VaD, and significantly more CCR6+ and CCR4+ CD4+ T cells in those with AD. Higher CCR6+ T-cell frequencies were also present in patients with mixed dementia, potentially due to the inflammation and immune cell chemoattraction triggered by Aß. CONCLUSIONS: The present study was a comprehensive investigation comparing different kinds of dementia, revealing differentially expressed peripheral markers that are potentially useful for early AD, VaD and mixed dementia diagnoses, and that would assist in proper treatments for these disparate diseases. Validation is now required.

Primary epithelial salivary gland tumours in children and adolescents.

Primary epithelial tumours of the salivary glands are very rare in paediatric patients. The aim of this study was to evaluate the clinical course, treatment, and outcomes of these uncommon neoplasms based on the authors' experience and the recent literature. The medical charts of 12 female patients and seven male patients with primary epithelial salivary gland tumours were reviewed. All were under 19 years of age and underwent surgical treatment between 1994 and 2016. The results of this group of paediatric patients were compared with those of 621 adult patients. The two most common tumours in the paediatric patients were pleomorphic adenoma and mucoepidermoid carcinoma (89.4%; P=0.004). The incidence of facial nerve palsy following surgery of the parotid tumours was similar in the two groups (P=1.000). The most common primary cancer in the paediatric group was mucoepidermoid carcinoma (77.8%), while in the adult group, adenoid cystic carcinoma was most common (P<0.001). The paediatric group had only low-grade cancers in early stages (P<0.001), with an overall 5-year survival rate of 100%. These results show that the incidence of malignant salivary gland tumours is higher in paediatric patients than in adult patients. This should be taken into account during diagnosis and therapy.

Assessment of health status by molecular measures in adults ranging from middle-aged to old: Ready for clinical use?

In addition to measures already used in clinical practice, molecular measures have been proposed to assess health status, but these have not yet been introduced into clinical practice. We aimed to test the association of functional capacity measures used in current practice and molecular measures with age and health status. The cohort consisted of 178 middle-aged to old participants of the Leiden Longevity Study (range 42-82years). We tested associations between functional capacity measures (physical tests: grip strength, 4-meter walk, chair stand test; cognitive tests: Stroop test, digit symbol substitution test and 15-picture learning test) with age and with cardiovascular or metabolic disease as a measure of the health status. These associations with age and health status were also tested for molecular measures (C reactive protein (CRP), numbers of senescent p16INK4a positive cells in the epidermis and dermis and putative immunosenescence (presence of CD57+ T cells)). All functional capacity measures were associated with age. CRP and epidermal p16INK4a positivity were also associated with age, but with smaller estimates. Grip strength and the Stroop test were associated with cardiovascular or metabolic disease, as was epidermal p16INK4a positivity. All associations with cardiovascular or metabolic disease attenuated when adjusting for age. In conclusion, in middle-aged to old persons, the molecular measures tested here were more weakly associated with age and health status than functional capacity measures. Whether these molecular measures associate more closely with health status in the elderly or in specific groups of patients needs to be explored further.

Intracellular signalling pathways: targets to reverse immunosenescence.

Ageing is a very complex process, the result of the dysregulation of multiple systems interacting in many ways. A prominent change occurring with ageing is related to the architecture and functioning of the immune system, viewed commonly as detrimental and termed 'immunosenescence'. However, age-associated changes may also lead to increased function in certain respects, which can be viewed as adaptive. None the less, on balance it is well-recognized that immunosenescence is accompanied by the low-grade inflammation observed commonly in elderly people, which has been dubbed 'inflamm-ageing'. The exact cause and significance of all these changes is not clear, but there is a consensus that they are related to the occurrence of chronic non-infectious age-associated disease, as well as increased susceptibility to infections. Alterations to immune cell signalling may be a prominent cause of malfunctioning immunity. Emerging attempts to reverse immunosenescence have recently targeted the signalling pathways in various different cell types of the immune system. Here, we review and discuss alterations in the signalling pathways of immune cells with ageing and consider current targets and means to modulate altered functions. We discuss the potential dangers as well as the benefits of these interventions, and consider future approaches to this problem.

From inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation.

Aging is accompanied by many physiological changes including those in the immune system. These changes are designated as immunosenescence indicating that age induces a decrease in immune functions. However, since many years we know that some aspects are not decreasing but instead are increasing like the pro-inflammatory activity by the innate immune cells, especially by monocytes/macrophages. Recently it became evident that these cells may possess a sort of memory called trained memory sustained by epigenetic changes occurring long after even in the absence of the initiator aggressor. In this review we are reviewing evidences that such changes may occur in aging and describe the relationship between inflamm-aging and immunosenescence as an adaptation/remodelling process leading on one hand to increased inflammation and on the other to decreased immune response (immune-paralysis) mastered by the innate immune system. These changes may collectively induce a state of alertness which assure an immune response even if ultimately resulting in age-related deleterious inflammatory diseases.

Proliferative index activity in oral squamous cell carcinoma: indication for postoperative radiotherapy?

The predictive value of the Ki-67 labelling index and its relationship with radiosensitivity in oral squamous cell carcinoma (SCC) remains controversial. We sought to evaluate whether the expression of Ki-67 antigen found in SCC of the tongue and the floor of the mouth is an indication for postoperative radiotherapy (PORT). The first study group included 34 patients who were treated only with primary surgery, while the second group included 26 patients who underwent primary surgery combined with PORT. The correlation between Ki-67 expression and loco-regional recurrence, as well as the 5-year disease-specific survival, was assessed in the two groups. Cases of high-proliferative tumours showed a significantly higher risk of loco-regional recurrence (P=0.018) and a poorer prognosis (P=0.001) only in the 34 patients treated with surgery alone. In multivariate Cox regression analysis, high Ki-67 expression was an independent predictor of loco-regional recurrence (HR 5.42, P=0.029) and disease-specific survival (HR 9.02, P=0.004). The correlation between Ki-67 expression and the risk of loco-regional recurrence in SCC of the tongue and the floor of the mouth may be useful in the selection of patients at a higher risk of recurrence who would benefit from PORT, despite adequate margins of resection and early stage of the disease.

Minor salivary gland mucinous adenocarcinoma of buccal mucosa - case report and review of the literature.

Mucinous adenocarcinoma (MAC) is commonly found in the gastrointestinal tract but head and neck localisations are very rare. This article presents the case of a 67-year-old patient suffering from a minor salivary gland MAC of the left buccal mucosa, who was treated in the Department of Cranio-Maxillofacial Surgery in Krakow due to multiple recurrences of the tumour. The results of immunohistochemical staining, the course of surgical treatment and follow-up, as well as a review of literature are also discussed.

Human T cell aging and the impact of persistent viral infections.

Aging is associated with a dysregulation of the immune response, loosely termed "immunosenescence." Each part of the immune system is influenced to some extent by the aging process. However, adaptive immunity seems more extensively affected and among all participating cells it is the T cells that are most altered. There is a large body of experimental work devoted to the investigation of age-associated differences in T cell phenotypes and functions in young and old individuals, but few longitudinal studies in humans actually delineating changes at the level of the individual. In most studies, the number and proportion of late-differentiated T cells, especially CD8+ T cells, is reported to be higher in the elderly than in the young. Limited longitudinal studies suggest that accumulation of these cells is a dynamic process and does indeed represent an age-associated change. Accumulations of such late-stage cells may contribute to the enhanced systemic pro-inflammatory milieu commonly seen in older people. We do not know exactly what causes these observed changes, but an understanding of the possible causes is now beginning to emerge. A favored hypothesis is that these events are at least partly due to the effects of the maintenance of essential immune surveillance against persistent viral infections, notably Cytomegalovirus (CMV), which may exhaust the immune system over time. It is still a matter of debate as to whether these changes are compensatory and beneficial or pathological and detrimental to the proper functioning of the immune system and whether they impact longevity. Here, we will review present knowledge of T cell changes with aging and their relation to chronic viral and possibly other persistent infections.

A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies.

To monitor inflammation in a meaningful way, the markers used must be valid: they must reflect the inflammatory process under study and they must be predictive of future health status. In 2009, the Nutrition and Immunity Task Force of the International Life Sciences Institute, European Branch, organized an expert group to attempt to identify robust and predictive markers, or patterns or clusters of markers, which can be used to assess inflammation in human nutrition studies in the general population. Inflammation is a normal process and there are a number of cells and mediators involved. These markers are involved in, or are produced as a result of, the inflammatory process irrespective of its trigger and its location and are common to all inflammatory situations. Currently, there is no consensus as to which markers of inflammation best represent low-grade inflammation or differentiate between acute and chronic inflammation or between the various phases of inflammatory responses. There are a number of modifying factors that affect the concentration of an inflammatory marker at a given time, including age, diet and body fatness, among others. Measuring the concentration of inflammatory markers in the bloodstream under basal conditions is probably less informative compared with data related to the concentration change in response to a challenge. A number of inflammatory challenges have been described. However, many of these challenges are poorly standardised. Patterns and clusters may be important as robust biomarkers of inflammation. Therefore, it is likely that a combination of multiple inflammatory markers and integrated readouts based upon kinetic analysis following defined challenges will be the most informative biomarker of inflammation.

16(th) IHIW: immunogenetics of aging.

Ageing is a process characterised by progressive loss of function in multiple different organ systems, such as the nervous, endocrine and immune systems. Current data showing that ageing processes may be associated with alterations in the immune system suggest that some of the genetic determinants of senescence might be polymorphic genes that regulate immune responses. The 'Immunogenetics of Aging' programme was a component introduced in the 14th International HLA and Immunogenetics Workshop (IHIWS) and developed further within the 15th and 16th. The aim of this component was to determine the contribution of immune genes to successful ageing and an increased capacity to reach the extreme limits of lifespan. Within the 16th IHIWS, new populations were included, and the number of samples analysed was increased. Analysis was focused on innate immunity genes (KIR and MBL2) and their correlation with CMV serostatus. Collaborative studies suggested that both activating and inhibitory KIR and functionally relevant MBL2 haplotypes are important factors for control of CMV infection in the elderly and therefore for chronic low-grade inflammation. Results showed that these genes might be predictive biomarkers in ageing and longevity. Prevalence of MBL2 haplotypes determining absence of the protein (LYPB, LYQC and HYPD) was observed in elderly people with a higher CMV antibody titre. The high CMV titre was also associated with a decreased frequency of the activatory KIR2DS5 and A1B10 haplotypes in elderly. Due to the role of KIR and low or deficient MBL haplotypes in viral infections, these genetic markers could be considered as indicators of a need for CMV prophylaxis at younger age and therefore increased probability of longer lifespan.

Early-life environment influencing susceptibility to cytomegalovirus infection: evidence from the Leiden Longevity Study and the Longitudinal Study of Aging Danish Twins.

Human cytomegalovirus (CMV) is a common herpesvirus establishing lifelong persisting infection, which has been implicated in immunosenescence and mortality in the elderly. Little is known about how and when susceptibility to CMV infection is determined. We measured CMV seroprevalence in two genetically informative cohorts. From the Leiden Longevity Study (LLS) we selected long-lived sib-pairs (n=844) and their middle-aged offspring and the offspring's partners (n=1452). From the Longitudinal Study of Aging Danish Twins (LSADT) 604 (302 pairs) same-sex monozygotic (MZ) and dizygotic (DZ) twins aged 73-94 years were included (n=302 pairs). Offspring of the long-lived LLS participants had significantly lower seroprevalence of CMV compared to their partners (offspring: 42% vs. partners: 51%, P=0·003). Of 372 offspring living with a CMV-positive partner, only 58% were infected. The corresponding number for partners was 71% (P<0·001). In the LSADT, MZ and DZ twins had high and similar CMV-positive concordance rates (MZ: 90% vs. DZ: 88%, P=0·51) suggesting that shared family environment accounts for the similarity within twin pairs. Our findings suggest that susceptibility to CMV infection--even under continuous within-partnership exposure--appears to be more strongly influenced by early-life environment than by genetic factors and adult environment.

Immunogenetics of ageing.

The ageing process is very complex. Human longevity is a multifactorial trait which is determined by genetic and environmental factors. Twin and family studies imply that up to 25% of human lifespan is heritable. The longevity gene candidates have generally fallen into the following categories: inflammatory and immune-related factors, stress response elements, mediators of glucose and lipid metabolism, components of DNA repair and cellular proliferation and mitochondrial DNA haplogroups. Because of the central role of HLA molecules in the development of protective immunity and the extraordinary degree of polymorphism of HLA genes, many studies have addressed the possible impact of these genes on human longevity. Most of the data available so far demonstrated a possible role of HLA class II specificities in human longevity but definitive evidence has remained elusive. Although the data are limited and controversial, it has been hypothesized that longevity could be associated with cytokine gene polymorphisms correlating with different levels of cytokine production, thereby modulating immune responses in health and disease. Because of the essential role of cytokines in immune responses, the regulation of cytokine gene expression and their polymorphic nature, the genetic variations of these loci with functional significance could be appropriate immunogenetic candidate markers implicated in the mechanism of successful ageing and longevity. In addition, several other genes such as Toll-like receptor genes, Cycloxygenases (COX)/Lipoxygenases (LOX), CCR5, NK receptor genes and MBL2 have been assessed as a possible biomarkers associated with ageing. This review will summarize the data on the role of these immune genes in human longevity.

'Immunogenetics of Aging': report on the activities of the 15th International HLA and Immunogenetics Working Group and 15th International HLA and Immunogenetics Workshop.

'Immunogenetics of Aging' is a component that was first included in the 14th International HLA and Immunogenetics Workshop (IHIWS) and developed further within the 15th Workshop. The aim of this component was to assess the impact of human leukocyte antigen (HLA) genes, cytokine genes, and some innate immunity genes such as killer-cell immunoglobulin-like receptors (KIRs) and mannose-binding lectin 2 (MBL2) in successful aging and their contribution to the better understanding of immune dysfunction in old age. Within the 15th IHIWS new populations were included in the analysis. Additional cytokine gene polymorphisms were assessed and innate immunity genes were analyzed for possible relevance in longevity. The results showed that longevity might be associated with anti-inflammatory cytokine gene profiles, decreased frequency of interleukin-10 (IL-10) and transforming growth factor-B1 haplotypes associated with a low level of gene expression, and increased frequency of haplotypes determining a high level of expression. Extended tumor necrosis factor-A and IL-12B genotypes were also likely relevant to longevity. Data also showed that innate immunity genes are associated with susceptibility to infections in the elderly and showed that these genes might be an important genetic marker in aging. Decreased frequencies of KIR2DS5 and A1B10 haplotypes, and an increased proportion of MBL2-deficient haplotypes were found in the group with higher cytomegalovirus-specific IgG antibody levels. Together, these studies emphasize the relevance of genes regulating immune functions in maintaining human longevity and stress the importance of further clarifying their impact on successful aging.

Minimal information about T cell assays: the process of reaching the community of T cell immunologists in cancer and beyond.

Many assays to evaluate the nature, breadth, and quality of antigen-specific T cell responses are currently applied in human medicine. In most cases, assay-related protocols are developed on an individual laboratory basis, resulting in a large number of different protocols being applied worldwide. Together with the inherent complexity of cellular assays, this leads to unnecessary limitations in the ability to compare results generated across institutions. Over the past few years a number of critical assay parameters have been identified which influence test performance irrespective of protocol, material, and reagents used. Describing these critical factors as an integral part of any published report will both facilitate the comparison of data generated across institutions and lead to improvements in the assays themselves. To this end, the Minimal Information About T Cell Assays (MIATA) project was initiated. The objective of MIATA is to achieve a broad consensus on which T cell assay parameters should be reported in scientific publications and to propose a mechanism for reporting these in a systematic manner. To add maximum value for the scientific community, a step-wise, open, and field-spanning approach has been taken to achieve technical precision, user-friendliness, adequate incorporation of concerns, and high acceptance among peers. Here, we describe the past, present, and future perspectives of the MIATA project. We suggest that the approach taken can be generically applied to projects in which a broad consensus has to be reached among scientists working in fragmented fields, such as immunology. An additional objective of this undertaking is to engage the broader scientific community to comment on MIATA and to become an active participant in the project.

Aging, frailty and age-related diseases.

The concept of frailty as a medically distinct syndrome has evolved based on the clinical experience of geriatricians and is clinically well recognizable. Frailty is a nonspecific state of vulnerability, which reflects multisystem physiological change. These changes underlying frailty do not always achieve disease status, so some people, usually very elderly, are frail without a specific life threatening illness. Current thinking is that not only physical but also psychological, cognitive and social factors contribute to this syndrome and need to be taken into account in its definition and treatment. Together, these signs and symptoms seem to reflect a reduced functional reserve and consequent decrease in adaptation (resilience) to any sort of stressor and perhaps even in the absence of extrinsic stressors. The overall consequence is that frail elderly are at higher risk for accelerated physical and cognitive decline, disability and death. All these characteristics associated with frailty can easily be applied to the definition and characterization of the aging process per se and there is little consensus in the literature concerning the physiological/biological pathways associated with or determining frailty. It is probably true to say that a consensus view would implicate heightened chronic systemic inflammation as a major contributor to frailty. This review will focus on the relationship between aging, frailty and age-related diseases, and will highlight possible interventions to reduce the occurrence and effects of frailty in elderly people.