Separately or combined, these two processes are at the base of autoimmune diseases Manestar-Blazic and Volf With advancing age the body is unable to defend itself from pathogens and results in a detrimental harm van Deursen , Childs et al. Clinical evidence indicates that with advancing age, immune responses against recall antigens may still be conserved, but the ability to mount primary immune responses against novel antigens declines significantly.
The impaired ability to mount immune responses to new antigens may result in a high susceptibility to infectious diseases Fagnoni et al. The immune responses to novel antigens rely on the availability of naive T cells Fagnoni et al.
Ageing is associated with various changes in immune parameters, therefore many authors have postulated that these age-related diseases could be explained, at least in part, by an overall deregulation in the immune system response McElhaney and Effros , Franceschi et al. This is supported by an age-associated disruption to the balance of alternatively expressed isoforms for selected genes, suggesting that a modification of the mRNA processing may be a feature of human aging Harries et al. The observed down regulation of toll-like receptors TLRs and nod-like receptors NLRs during the aging process may contribute to the lack of effective recognition of invading pathogens or the commensal flora.
This effect results in aberrant secondary immune cell activation and could significantly contribute to morbidity and mortality at an advanced age Rosenstiel et al. Response mechanisms associated with the immune system are divided into innate and adaptive immunity Dunkelberger and Song , Iwasaki and Medzhitov The first relates to anatomical and biochemical barriers, unspecific cellular responses that are mediated by monocytes, natural killer NK and dendritic cells Vesely et al.
The second relates to the fact that the response to specific antigens is mediated by B and T lymphocytes Denson Both are involved in immune senescence, where the adaptive response is affected the most in this process Franceschi et al. The innate immune system is the first line of host defense against pathogens. We will describe the effect of aging on the function of innate immunity Figure 1.
These are the first line of defense of our body against pathogens, with age the replacement of skin cells decreases, sweat production is reduced, changes at the structural level of epithelial cells are produced, depletion of Langerhans and melanocyte cells occurs and subcutaneous tissue atrophy Kottner et al. In skin, aging is associated with overall epidermal thinning, decreased barrier function, pro-inflammatory state and gradual deterioration of the epidermal immune response Kinn et al.
The mucus membranes of hair cells, which play an important role in removing pathogens, are reduced in quantity and movement, as well as presenting ultra structural changes Kim et al. Immunoglobulin Ig A, the main constituent in secretions, levels increase up to 60 years old and thereafter a significant reduction in levels begins Jafarzadeh et al. Therefore, structural and physiologic changes occur as a consequence of intrinsic aging combined with the environment can produce a marked susceptibility to dermatologic disorders in the elderly.
For example, immunologic senescence in the elderly also sets the stage for potential reactivation of the Varicella zoster virus, in which initial dermatologic involvement expands into the major sensory ganglia Farage et al. Dendritic cells DC Rainham et al. Thus DC are a bridge between innate and adaptive immunity and with age a group of them can decrease such as the Langerhans cells in skin and plasmocytes Agrawal and Gupta Therefore, DC in aging appears to be functionally impaired with regard to the response to uptake of antigens, phagocytosis of apoptotic cells and migration Gupta Other altered DC elements during aging are associated with the function of TLR Inappropriate persistence of TLR activation in specific systems , in addition to the antigen processing and cell migration, which is associated with an alteration of phosphoinositide 3 kinase pathway Panda et al.
The NK cells are a key component of innate immunity involved not only in the elimination of virus-infected or tumor cells but also in the regulation of the immune response by producing cytokines and chemokines that can activate other cellular components of innate and adaptive immunity Gayoso et al. Aged nonhematopoietic environment is an important contributor to the impaired maturation and function of NK cells in aging Shehata et al.
Human NK cells can be subdivided into two populations based on the density of cell surface CD56 antigen.
Under normal conditions, exposure to exogenous IL-2 induces tenfold greater proliferation of CD56bright cells compared to CD56dim lymphocytes Baume et al. Neutrophils are recruited to the infection site by cytokine and chemokine mainly by IL-1 and IL-8 Sica et al.danardono.com.or.id/libraries/2020-01-21/bupi-how-i.php
Immune system - Wikipedia
When involved in phagocytosis, the generation of ROS, degranulation releasing enzymes and antimicrobial peptides and neutrophil extracellular traps NETs , in order to eliminate the pathogen from our organism Zawrotniak and Rapala-Kozik , Borregaard In addition, they facilitate the maturation and migration of DC that will initiate the adaptive immune response Solana et al. Neutrophil has a short half-life, presenting a spontaneous apoptosis, which is augmented by pro-inflammatory cytokines such as INF-1 and stimulating factor granulocyte-monocyte colony of G-CSF , this effect is diminished as we age since there is an alteration in the activation of the Jak-STAT Fortin et al.
In addition, the marked decline in TCRL n repertoire diversity in old age identifies a novel mechanism of immunosenescence in neutrophils Fuchs et al. Neutrophil migration into the lungs is impaired in aged mice 24h after intratracheal infection despite elevated chemokine levels, suggesting that immunosenescence is impairing neutrophil migration Chen et al. Inaccurate migration was causally associated with increased constitutive phosphoinositide 3-kinase PI3K signaling; untreated neutrophils from old donors demonstrated significant PI3K activation compared with cells from young donors.
In addition, phagocytosis also altered, for example a reduction in receptor expression is observed CD16 Fulop et al. Recently an alteration in pathogen destruction mechanism mediated by neutrophil extracellular traps NETs was demonstrated, which it is one of the results of increased infections in older individuals Brinkmann and Zychlinsky Activated macrophages are now broadly classified into two subsets; pro-inflammatory M1 or an anti-inflammatory M2 phenotype.
M1 and M2 cells differentially express a range of chemokines and also have distinct metabolic programmes Fuentes et al. In this context, expression of both M1 and M2 markers was reduced in adherent splenocytes from old mice, indicating that ageing did not cause a skew towards M1 or M2 phenotype Mahbub et al. Macrophages from aged mice showed increased susceptibility to oxidants and an accumulation of intracellular reactive oxygen species Sebastian et al.
Also, macrophages from older animals lost the capacity to respond to pharmacological 10 -3 M concentrations of norepinephrine NE.
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The lower capacity of response to NE by macrophages from older animals possibly contributes to immunosenescence Ortega et al. The changes observed in the macrophages stronger generation of nitric oxide NO and ROS isolated from the elderly indicate that these cells could contribute to the development of metabolic disorders like atherosclerosis and diabetes Suchy et al. Meanwhile, activated macrophages which function as antigen presenting cells were decreased in aged rats Kizaki et al. Significant up regulation of miRb and miRb effectively prevented LPS-induced excessive expression of cyclooxygenase Odden et al.
Meanwhile, histone deacetylase suppressed the expression of miRb and miRb in the LPS-treated macrophages of aged mice and contributed to the aging process Liu et al. The dysregulated expression of miRa results in the age-associated dysfunction of macrophages, and miRa may be a good target for the treatment of age-related inflammatory diseases Jiang et al.
In addition, autophagy modulation may prevent excess inflammation and preserve macrophage function during aging, improving immune responses and reducing the morbidity and mortality associated with inflamm-aging Stranks et al. Microglia cells are unique from neurons, oligodendrocytes, and astrocytes in that they are not derived from the neuroectoderm Dheen et al. Microglia cells play an important role in CNS homeostasis during development, adulthood and ageing.
Microglia function is tightly regulated by the CNS microenvironment, and increasing evidence suggests that disturbances, such as neurodegeneration and ageing, can have profound consequences for microglial phenotype and function Perry and Teeling Under physiological conditions, the number and function of microglia is tightly controlled by the local microenvironment.
In response to neurodegeneration and the accumulation of abnormally folded proteins, however, microglia multiply and adopt an activated state - a process referred to as priming. Priming makes the microglia susceptible to a secondary inflammatory stimulus, which can then trigger an exaggerated inflammatory response. The secondary stimulus can arise within the CNS, but in elderly individuals, the secondary stimulus most commonly arises from a systemic disease with an inflammatory component Perry and Holmes The cause of this amplified microglial activation may be related to impairments in several key regulatory systems with age that make it more difficult to resolve microglial activation Norden and Godbout In addition, there are clear age associated deficits in memory and learning and neuronal plasticity Henry et al.
The adaptive immune system depends on the generation of a diverse repertoire of antigen receptors on T and B lymphocytes and subsequent activation and clonal expansion. The induction of adaptive immunity, not only depends on the recognition of the particular antigen receptor, but is also based on essential signals that are delivered by the innate immune system Schenten and Medzhitov A well-described age-related alteration of the immune system is the decrease of de novo generation of T and B cells Stervbo et al.
We will describe the effect of aging on the function of B and T lymphocytes Figure 1.
The primary function of B lymphocytes is the production of antibodies in response to infection from a pathogen Tedder et al. The B cell arm of adaptive immunity undergoes significant modifications with age.
Predisposition to Infection in the Elderly
Elderly people are characterized by impaired B cell responses and defective antibody production reflected in a reduced ability to effectively respond against viruses and bacteria Buffa et al. Thus, the formation of antibodies in response to vaccination against hepatitis B virus infection was significantly reduced for donors with a mean age of 61 years compared with a group with a mean age of 33 years Rosenberg et al. Immunosenescence in the B-lineage is not irreversible and depletion of the long-lived B cells in old mice rejuvenates the B-lineage and enhances immune competence Keren et al.
Plasma cells are terminally differentiated elements derived from B lymphocytes. Plasma cell numbers decrease in the bone marrow of old patients Pritz et al. This reduction of clonal expansion of plasma cells results in a low affinity of antibodies to antigens Dunn-Walters et al. Aging is associated with an increased susceptibility to infection and disease. It is also associated with reduced functionality and altered distribution of the immune cells, especially T cells Vasudev et al. This is thought to contribute to the reduction in T cell diversity seen in older individuals and linked with increased susceptibility to infection, autoimmune disease and cancer Palmer Oxidative stress and chronic antigenic load increases with age reduced lymphocyte susceptibility to damage-induced cell death and enhances proinflammatory status leading to increased activation induced cell death Sikora Altered lymphocyte potassium channel inhibitory patterns, regulators of calcium influx kinetics, might contribute to the development of age-related changes of T cell function Kollar et al.
It also presents a reduction of membrane receptors such as CD28 important in lymphocyte activation and CD27 limited proliferative capacity by T lymphocytes Vallejo , Parish et al. In addition to a decrease in intracellular calcium levels and alterations in the signal transduction pathways NF kB and MAPK have been observed Deruy et al. Recently decreased miRa has been associated with age, this controls lymphocyte activation via their T cell receptor this decline results in poor cell activation and also recognizing autoantigens Li et al.
CD4 T cell lymphopenia is an important T cell defect associated to ageing Martinet et al. Meanwhile, menin binding at Bach2 locus and Bach2 expression are decreased in the senescent CD4 T cells.
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T cell-specific Menin deficiency results in the premature senescence of CD4 T cells, which is accompanied by the senescence-associated secretory phenotype after antigenic stimulation and dysregulated cytokine production Kuwahara et al. This indicates a higher susceptibility to develop inflammatory diseases with increasing age Schmitt et al.