Immunosenescence

The term "immunosenescence" (lat. from immunis "free, 'pure" and senescere = "to grow old") describes the slow aging of the immune system in the course of life. Immunosenescence is thus on the one hand a "physiological" side effect of chronological aging. It affects both the innate and the acquired immune system (Gruver Al et al. 2007). On the other hand, it leads to a limitation of the functionality of the humoral immune response (Pera A et al. 2015) and is one of the causes for an increased susceptibility to infections in older people as well as for the increase in tumours (Pawelec G 2017) - and autoimmune diseases.

The large number of infectious or inflammatory events ("multiple hits") in the course of life cause inflammatory stress ("inflammatory/pathogenic burden"). This contributes significantly to the increase in inflammatory parameters and further to the increase in diseases with pro-inflammatory pathogenesis such as atherosclerosis, arthritis, Alzheimer's disease and others (Chalan P et al. 2015). Immunosenescence is thus partly responsible for the increase in morbidity and mortality in old age (inflammatory ageing; inflammation).

The following changes characterize the (physiological) changes of the immune system in advanced age:

Involution of the thymus: This begins with sexual maturity and is completed between the ages of 40 and 50. After this time, the maturation of T-lymphocytes is no longer possible; as a result, the immune system is dependent on the pool of T-lymphocytes formed up to this point. However, the thymus shows residual activity throughout life, recognizable by CD31-labeled lymphocytes. Only CD4-naive lymphocytes that have freshly left the thymus carry the CD31 marker on their surface (thymic reserve).

Age-related leukopenia: In adolescence, the organism has a high proportion of naive -T lymphocytes, a low proportion of memory cells and hardly any effector cells. In old age, the effector cells dominate.

Involution of lymph nodes (age-related decrease in germinal centers, lipomatous atrophy) (Luscieti P et al. 1980); decrease in the number of B cells. Antibody production decreases (Listì F et al 2006). Individual B-cell clones proliferate and produce AK specificity (incidence of monoclonal gammopathies of unclear significance = MGUS increases; it is 20-25% in 70-year-olds); autoantibodies (and autoimmune diseases) increase.

Reduction in the lifespan of activated neutrophil granulocytes (decreased apoptosis protection).

Increase in the number of cytotoxic NK cells; their cell function decreases. Increase in regulatory T cells (Treg). Inhibition of Th1 immune response (immune brake).

Macrophages: Reduced chemotaxis and phagocytosis - Inhibited response to growth factors - Reduced nitrite oxide/H2O2 production.

Increase in inflammatory cytokines (inflammaging); decrease in release of interleukin-2 and interleukin-4

Fever and leukocytosis are less frequentand less pronounced ("the older, the colder"). Cause: Altered production of cytokine spectrum -decreased temperature control of hypothalamic receptors.

Increase of tumor and autoimmune diseases; general increase of morbidity and mortality in old age (see also inflammatory aging).

Increased susceptibility to infections, often with oligosymptomatic and severe, even septic courses (Martín S et al 2017):

• Lung: pneumonia (aspiration pneumonia: anaerobes! early tachypnea as the only symptom); urinary tract infections (often nonspecific symptoms); tuberculosis (reactivation).
• Intestine: gastric anacidity, increased enteritis rate (C. difficile colitis); diverticulitis; appendicitis
• Heart: endocarditis (nonspecific symptoms such as weakness, weight loss, thrombosis, joint pain, preexisting heart murmurs)
• CNS: herpes zoster; meningitis/meningoencephalitis -listeria-: confusion, clouding of consciousness, absence of fever/meningismus).
• Urinary tract: decreased diuresis, increased risk of urinary tract infections.

Immunosenescence further leads to attenuation of vaccine response (Gruver Al et al 2007). As a result, antibody formation is attenuated after vaccination. This has led to the development of new, more immunogenic vaccines. This is achieved, for example, in influenza vaccination by adding an adjuvant (e.g. MF59) or else by increasing the antigen content fourfold. In order to minimize the clinically relevant negative effects of immune senescence during vaccination, the concept of lifelong vaccination seems to be recommendable.

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