Immunosenescence

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Immunosenescence

The aging of the immune system, or immunosenescence, is manifested by an increased susceptibility to infections with increased morbidity and mortality. The most impressive change is the involution of the thymus, starting soon after puberty with decreasing size of the organ progressively with age and resulting in a replacement of thymic tissue by fat. Most striking changes of immunosenescence are a shift in the expression of CD45 isoforms from the CD45RA+CD45RO– to the CD45RA–CD45RO+ subsets in humans within CD4+ and CD8+ T cell pools. Much of this shift is attributed to chronic antigenic stimulation and a depletion of naive T cells with involution of the thymus. IL-7 has been shown to be a key cytokine in the early stages of thymocyte development with IL-7 expression levels greatly reducing with age. Primary antibody responses in aged humans are often weak and short-lived with lower affinity. Decline of the immune response to vaccinations in the aged population is of high clinical relevance. The innate immune system in higher age appears to be less affected by aging than the clonotypical, more advanced immune defenses.

The loss of CD28 expression has been well documented in CD4+ as well as CD8+ T cells in the elderly. CD28 mediates the major co-stimulatory signal complementing T cell receptor derived signals and amplifying T cell proliferation, IL-2 production, and IFN-g production. The loss of CD28 expression, typical for T cells that have excessively replicated, should also affect the functional profile of T cells. Telomere shortening in the CD28– T cells is more pronounced than in CD28+ T cells indicating that the former have undergone more rounds of cell division than the latter.

Aging can affect both the innate and adaptive arms of the immune response. The clinical implications of age-related dysregulation of the immune system include increased risk of infections, malignancy, autoimmune disorders, atherosclerosis, and neurodegenerative changes. Incidence of autoimmune disorders appears to be higher in older humans, although they show a decline in their immunological response to antigenic stimulus with age. Autoimmunity may increase with aging by activation of memory B cells presented with “neoantigens” that form during aging process. As self-tolerance is lost at later age with a detection bias, decreased apoptosis and increased oligoclonal activation of T cells.