1.4. Changes in the Immune System Related to Immunosenescence

The cells of the immune system are constantly renewed from pluripotent hematopoietic progenitors (HSC) that reside in the bone marrow. These cells differentiate into lymph organs and can move freely. In the presence of inflammatory signalers, they interact with organs to capture cell debris or invading elements.

‌ Due to several factors (e.g., telomere shortening) due to aging, there is a decrease in the capacity of immune cells to renew, leading to a decrease in the total amount of hematopoietic tissue and its myeloid progenitors. The thymus undergoes a physiological involution process, with a reduction in volume and replacement by adipose tissue in functional parts such as the cortex and medulla. This process starts early in life and is completed around the age of 40-50.

‌ 1.4.1 Changes to the Adaptive Immune System

‌ T cells are matured in the thymus, where they differentiate into cell subtypes according to their receptors, and then migrate to the peripheral system. The main subtypes are called CD4+ and CD8+ and show some changes during aging relative to their proportions, in which the number of CD8+ cells tends to increase. The insertion of naïve T cells gradually decreases, as well as their subsequent divisions, represented by the decay of TRECs (TCR excision circles) in peripheral T lymphocytes. This reduction may be a consequence of both thymic involution and chronic antigen stimulation (HAYNES et al., 2003), which could help explain the reduced ability of the elderly to resist new infections (VALLEJO, 2005). Furthermore, naïve T cells in the elderly show multiple alterations, such as telomere shortening, reduced IL-2 production, and diminished ability to differentiate into effector cells. The loss in number and function of naïve T cells can be compensated for through the expansion of CD8+, CD45RO+ and CD25+ T cells, which are capable of producing IL-2, and with a humoral protective capacity for a vaccination with the expansion of effector memory cells ( SCHWAIGER et al., 2003).

‌ Regulatory T cells (Tregs) are a subset characterized by high expression of CD25 and FOXP3, a transcription factor for Treg cell function and differentiation. At older ages, the number of CD4+ FOXP3+ lymphocytes increases, and the accumulation of these cells in the elderly plays an important role in the reactivation of chronic infections and the change in the Th17/Treg ratio can cause changes in the immune response, which can lead to the development of autoimmune and inflammatory diseases (LAGES et al., 2008).

‌ The reservoir of B cells is also influenced by aging, leading to both quantitative and qualitative changes in humoral immunity (COLONNA-ROMANO et al., 2008). B cells are important antigen presenters and can be key regulators in the development of T cells (COLONNA-ROMANO et al., 2008).

‌ In the elderly, there is a reduced level of IgM and IgD, certainly connected to the transformation of naïve B cells into memory cells (WEKSLER; SZABO, 2000). During immunosenescence, there is an increase in the level of IgA and IgG. This imbalance may be responsible for the reduction of Peyer's plaques at the level of the gastrointestinal mucosa concerning IgA2, while the increase in IgA1 may be secondary to the deficiency in the activity of the suppressor T cell subset and the consequent hyperfunction of B lymphocytes (VENTURA, 1991).

‌ 1.4.2 Changes to the Innate Immune System

‌ Innate immunity plays a crucial role in the body's defence and undergoes important changes during aging, starting with the reduction of epithelial, gastrointestinal and respiratory mucosal barriers (NOMELLINI; GOMEZ; KOVACS, 2008). The high incidence of infectious events in the elderly may be secondary to alterations in the phagocytic system (ANTONACI et al., 1984). Deficits in the elderly are mainly caused by infectious events, particularly in the gastrointestinal and respiratory systems. The reduced number of plasma cells in the bone marrow of the elderly (PRITZ et al., 2015) can cause a lack of antibody production, a reduced ability to respond to viruses and bacteria (BUFFA et al., 2013) and an altered response to vaccines, as previously demonstrated in elderly patients immunized with hepatitis B vaccine (ROSENBERG et al., 2013).

‌ Dendritic cells, one of the main responsible for the first recognition of pathogens in the skin, show clear mitochondrial dysfunctions that interfere with their protective role (SIMON; HOLLANDER; MCMICHAEL, 2015). In particular, there is a loss in antigen absorption and apoptotic function. When comparing the antigen absorption capacity of plasmacytoid dendritic cells (PCD) of the elderly compared to the young, it is possible to observe a reduction in the ability to induce proliferation and stimulate the secretion of IFN-gamma in CD4+ and CD8+ cells [(PRAKASH et al., 2013).

‌ Macrophages are cells with the function of processing and presenting antigens to T cells, and are capable of producing pro-inflammatory cytokines such as TNF-alpha, IL-1, IL-6 and IL-9. During immunosenescence, there is a decrease in macrophage precursors, even though the number of monocytes remains unchanged (Della Bella et al. 2007). The shortening of telomeres results in a reduction in the production of GS-CSF, as well as cytokines such as TNF-alpha and IL-6 (Davalos et al. 2010). The phagocytic function appears to be reduced, whereas chemotaxis appears to remain conserved, especially in the presence of certain C5a complement-stimulating factors. The presence of these factors reduces the production of lymphocytes derived from chemotactic (LDCF) and chemotoxins. In this case, the inhibitory mechanisms seem to be related to prostaglandins that are produced in high amounts during immunosenescence, and that exerts an inhibitory action (Ventura et al. 1994). The reduced production of LDCF may be related to the small percentage of lymphocytes involved in cytokine synthesis.

‌ The number of neutrophils seems to be preserved in the elderly, however, the expression of the CD16 Fc gamma receptor is reduced, making both the generation of superoxides mediated by the Fc receptor and phagocytosis to be involved. This suggests that the decline in the Fc receptor effector response is particularly important for neutrophil dysfunction in the elderly (Butcher et al. 2001). In the elderly, the reduced response of these cells to Streptococcus Aureus is of fundamental clinical importance, as this event increases the susceptibility to pulmonary infections. The same was observed in elderly rats, where neutrophil migration to the lungs is reduced, increasing the risk of lung infections and recurrences (Chen et al. 2014). In addition, an alteration in pathogen-mediated destruction of neutrophil extracellular traps (NETs) has recently been described, which also implies an increase in infections in the elderly (Brinkmann and Zychlinsky 2007).

‌ The high incidence of immunoproliferative diseases in the elderly suggests the possibility of a deficiency in important mechanisms for immune supervision, such as the activity of NK cells. These cells intervene in the elimination of tumours, virus-infected cells and also in innate and adaptive immune regulation, through the production of cytokines and chemokines (Brinkmann and Zychlinsky 2007). Recent studies indicate that high NK toxicity is associated with longevity, while low NK function is associated with an increase in infections, arteriosclerosis and neurodegenerative diseases. NK cells, by producing cell lysis, could cause the release of perforins and granzymes, which, in turn, activate caspases and cause apoptosis of target cells. During immunosenescence, there is a reduction of lymphokines important for the lymphocyte activation process, such as IL-2, and also for the death of NK-resistant cell lines in response to IL-2. This contributes to their impaired function, even in the presence of a normal number of NK cells (Borrego et al. 1999). Furthermore, there is a redistribution of NK cells with a decrease in CD56 cells, characterized by a high density of CD56 surface antigens. In contrast, there is an increase in CD56-CD16 NK cells [64]. This results in a reduction in IFN secretion for the elderly compared to the young (Krishnaraj 1997).