Age-related aging of the immune system (5)
Between the death of immune cells and the activation of cytokine synthesis
Immuno senescence in aging: between immune cells depletion and cytokines up-regulation
Maria Teresa Ventura et al., Clinical and Molecular Allergy, 2017.
Translated by Evgenia Ryabtseva
The beginning of the article is here.
For links, see the original article.
Hematopoietic bone tissue and thymus
The cells of the immune system are constantly being updated due to hematopoietic stem cells, but this ability fades during physiological aging, accompanied by a decrease in the total volume of hematopoietic tissue. Apparently, this process correlates with telomere shortening. The changes also affect the progenitor cells of the myeloid and erythroid series, including B lymphocytes, which leads to a decrease in the number of mature B cells. The precursors of T-lymphocytes are less susceptible to the detrimental effect of this process. However, age-related changes in the thymus also entail changes in T-cell populations. The thymus undergoes a process of physiological involution, manifested by a decrease in volume and replacement of the tissue of the functional part of the thymus gland with adipose tissue, which leads to a reduction in the production of soluble factors and hormones. This process begins already at the early stages of life and is completed by the age of 40-50.
Moreover, the immune system has an important function of protecting the body from any damaging agents (chemical, traumatic and infectious). There are two types of immunity, the functioning of which is strictly coordinated: natural (innate) and adaptive (acquired) immunity. Innate immunity provides rapid protection of the body, the disadvantages of which are non-specificity and inferiority. This line of immune response is mainly represented by monocytes, natural killer cells and dendritic cells that exert their effect before the formation of an adaptive immune response. The latter develops much more slowly, but is characterized by high specificity and durability. The cellular substrate of the acquired immune response is represented by T- and B-lymphocytes.
T-lymphocytes
T-lymphocytes are formed as a result of selection in the thymus and, depending on the presence of co-receptor molecules on the membrane, are divided into CD4+ and CD8+ cells. The percentage of these cellular subtypes changes somewhat during aging due to an increase in the number of CD8+. CD4+ and CD8+ cells express mutually exclusive CD45RA and CD45RO phenotypes. The first phenotype allows to recognize naive T cells, while the second allows to identify memory cells and activated T lymphocytes. A decrease in the number of naive T-lymphocytes can be both a consequence of thymus involution and the result of chronic antigenic stimulation. This phenomenon helps explain the age-related decline in the ability to resist new infections.
Moreover, naive T-lymphocytes of elderly people show many anomalies, including shortening of telomeres, decreased production of interleukin-2 and the extinction of the ability to differentiate into effector cells. The decline in the number and functions of naive T-lymphocytes in about 30% of elderly people is compensated by the expansion of CD8+, CD45RO+, CD25+ T-cell clones capable of producing interleukin-2 and having the ability to a protective humoral reaction to vaccination, manifesting the expansion of effector memory cells. In particular, in the elderly, vaccination induces the accumulation of CD8+ effector cells with phenotypic changes, such as the loss of co-stimulatory CD8 molecules.
CD28 cells are responsible for the production of pro-inflammatory cytokines and are resistant to apoptosis. The origin of CD28 cells has not yet been fully established, however, it is generally assumed that they are cells undergoing replicative aging, which is the result of telomere shortening and a decrease in proliferative capacity. Inversion of the quantitative ratio of CD4+ and CD8+ cells, an increased number of effector memory cells and a seropositive reaction to cytomegalovirus constitute the phenotype of immunological risk for the elderly. At the same time, the elderly are characterized by increased production of interleukins-2, -4, -6 and interferon-gamma cytokines regulating B–cell differentiation.
Further changes concern the disruption of the reaction to oxidative stress, which leads to an increased predisposition to damage-induced cell death, and the dynamics of calcium metabolism. Recently, an association between these disorders and physiological aging, as well as a decrease in the amount of Mir 181 (a precursor of microRNA), which disrupts the ability of T-lymphocytes to recognize antigens, has been revealed.
Regulatory T-lifocytes are a subtype of cells expressing CD25 and FOXP3, a transcription factor that ensures the functioning and differentiation of these cells. The number of CD4+ FOXP3+ lymphocytes increases in old age. The accumulation of these cells in an aging body plays an important role in reactivating chronic infections and changing the ratio between subtypes of T-lymphocytes, which can lead to impaired immune responses, manifested as inflammatory or autoimmune diseases.
B-lymphocytes
The population of B-lymphocytes, representing humoral immunity, is also subject to age-related changes, manifested both quantitatively and qualitatively.
It was believed that the functionality of B cells in the development of T-dependent reactions is reduced due to the extinction of the functionality of T-helpers. On the other hand, not all B-cell functions depend on the activity of T-lymphocytes. One example is the reaction to a polysaccharide, which is critical for the formation of protection against bacteria and also loses effectiveness as it ages.
In addition, a number of data indicate that B-lymphocytes themselves are important antigen-presenting cells and can perform regulatory functions key to the maturation of T-lymphocytes. Therefore, it is obvious that partial dysfunction of T-cells may be due to insufficient activity on the part of B-lymphocytes. At the same time, quantitative changes in the B-cell population are described. In the elderly, there is also a decrease in the levels of immunoglobulins M and D, which are uniquely involved in the maturation of naive cells into memory B cells. In the process of physiological aging, on the contrary, there is an increase in the level of immunoglobulin G (IgG), especially its subtypes G1, G2 and G3, as well as immunoglobulin A (IgA). The level of the latter undergoes particularly noticeable changes, manifested by a significant increase in the concentration of IgA1 monomer in both serum and saliva, as well as a decrease in the levels of the polymer form of IgA2, especially in sputum. This imbalance may be the cause of a decrease in the number of lymphoid nodules on the mucous membrane of the gastrointestinal tract, occurring due to a decrease in IgA2 levels, while an increase in IgA1 concentration may be a secondary manifestation of insufficient activity of suppressor T-lymphocytes (T-suppressors), accompanied by hyperfunction of B-lymphocytes. The lack of activity of immune cells in this case is mainly due to episodes of infection of the elderly, especially diseases of the digestive tract and respiratory organs. A decrease in the number of plasma cells in the bone marrow of elderly people leads to a decrease in the production of antibodies, a deterioration in the ability to respond to viruses and bacteria, as well as a violation of the response to vaccination against hepatitis B virus.
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