Guide Questions:
As a guide for the reader, we have posted this guide questions to help in the understanding of the topic and the focus of the subject.
1. Ageing and COPD:
a. Discuss the immunological events in the elderly make it harder for them to fight infection as opposed to a young adult.
2. Thymic Involution:
a. Discuss and propose a theory on how thymic involution might compromise our immune system as we age.
3. Smoking and Ageing:
a. Discuss another example of how smoking indirectly affects immunosenescence.
Immunology and Ageing
The number of people aged 60 years or older exceeded 635 million in 2002, and is expected to grow to nearly 2 billion by 2050.1 These numbers have great repercussions on the importance of the immune system as it ages. The immune system loses its ability to fight off infections, as an individual grows older. This increases the risk of getting sick, and may make immunizations less effective. The immune system's ability to detect and correct cell defects also declines. Later in life, the immune system seems to become less tolerant of the body's own cells and sometimes an autoimmune disorder develops.2
A marked difference has been observed between young and old subjects in the subpopulations of naive (mature cells, part of the immune system that has not yet had their first encounter) and memory T cells (cells of the immune system, that have already had their first encounter, and thus are more competent to a specific antigen). The elderly have almost no naive T cells at all, since as the thymus (region of the body where T cells mature) progressively deteriorates with age. Consequently, the population of naive T cells becomes depleted and the aged immune system cannot respond as well as a young person to a "new" antigen.3
Aged T cells do not display the CD28 antigen, a molecule critical for signal transduction (cascade of events that lead to proper function) and T cell activation, on the cell surface. Without this protein, T cells remain quiescent and do not respond to foreign pathogens.3
This reduced function of T cells in the elderly also affects B cell function because T cells act in concert with B cells to regulate the production of antibodies. T cells induce B cells to hypermutate immunoglobulin genes, which in turn create the antibody diversity necessary to recognize a wide range of antigens. Aged helper T cells cannot interact as effectively with B cells, and so in the elderly, the potential antibody repertoire is more restricted than the antibody repertoire of younger people.3
During infection, IgM is the first class of antibodies to respond. The inability to ward off infections could be linked to the diminishing IgM response characteristic of elderly. Ageing B cells show decreased gene expression in the areas of lineage commitment and differentiation, resulting in reduced clonotypic diversity.4 Having fewer mature B cells contributes to the observed decrease in the amount of antibody produced in response to infection. As a repercussion, antibody responses to vaccines are slower and not as strong as in younger people, (vaccine efficacy 17-53% in elderly population).5
Aged T cells are more susceptible to apoptosis, or programmed cell death, due in part to the gradual loss of telomeres that cap the ends of the chromosomes to prevent DNA degradation, thus it seems that T cells have a limited lifespan, and immunosenescence (changes in the immune system associated with age) is genetically programmed.6
Thymic Involution
Thymic epithelial cells constitute the major subcomponent of the thymic stroma that encourages T-cell development but, with age, there is a decrease in the thymic epithelial space with reduced T-cell output. CD8+ as well as CD4+ T-cells have a low count believed to be due to shorter telomeres in older individuals.7 Treatments with IL-7, IL-15, IGF-1, and GH have shown to develop thymopoiesis but not to the point of fully recovering the thymus.8 Regeneration is also observed in the absence of sex hormones, although this was shown by castration or ovariectomy of mice. Thymic transplantation is another alternative in restoring immune function but tissue rejection has to be kept in mind, too, due to the limited tissue transplantation. Even though these treatments are at an early stage, it should be noted that more research in this matter could permit the restoration of the thymus in immuno-impaired individuals.9
When an individual ages, the immune system starts to lose its ability to carry out phagocytosis and chemotaxis, as well as maintain the robust population of leukocytes from earlier years. When examining the effects on lung tissue, as shown in the figure above, Sharma compares the effects of ageing to chronic obstructive pulmonary disease (COPD), and shows how in both there is a rise in CD 4, CD 8 T-cells, and pro-inflammatory cytokines such as IL-6, IL-8 and TNF-α. Physical changes noted in ageing, which parallel COPD include hyperinflation, loss of both lung function and elastic recoil.10
Ageing is affected both genetically and environmentally. Smoking is considered an ageing accelerator both directly, though triggering inflammatory responses, and indirectly through favoring diseases in which smoking is a risk factor.
One possible direct mechanism is oxidative stress caused by the free radicals in cigarette smoke that activate inflammatory cells with inflammatory mediator production and further oxidative damage. Another mechanism is thought to be that tobacco smoking enhances telomere shortening in circulating lymphocytes, which increases immunosenescence. This occurs at a critical minimum length of telomeres, which triggers cell cycle arrest, or senescence of the cell.11
Indirectly, smoking increases the deterioration of the immune system by making the body more susceptible to disease. For example, the oxidative damage causes endothelial dysfunction, which induces arteriosclerosis. This is caused by changes in cellular redox status and the production of high levels of pro-inflammatory cytokines.12
Even though ageing is multifactorial, the environmental aspect has a profound effect on the change in immunosenescence characteristics that are seen in ageing. In order to attain longevity, smoking cessation is encouraged to delay the ageing process and appearance of diseases.13
Assessment quiz:
1. Which of the following is NOT a result of the involution of the thymus?
a) Impairment of chemotaxis
b) Stimulation naïve CD4 T cells
c) Immunosuppression
d) Impairment of phagocytosis
Answer is B. The inhibition, not stimulation, of naïve CD4 T cells is a result of the involution of the thymus.
2. Thymic involution is thought to result from high levels of:
a. Low levels of circulating CD4 cells in plasma during puberty
b. High levels of circulating CD8 cells in plasma during puberty
c. Circulating sex hormones in particular during puberty, lower population of precursor cells from the bone marrow and changes in thymic microenvironment.
d. Amount of free radicals as we begin to age.
e. Reactive C-proteins causing damage to the thymus as we age.
Answer is C.
3. How does tobacco smoking activate the inflammatory response?
a. Destroys T cells receptors
b. Decreases macrophages
c. Releases free radicals
d. Reduces IgG response
e. Increases complement system
Answer: C. The free radicals in cigarette smoke activate inflammatory cells with inflammatory mediator production and further oxidative damage.
Works Cited
1. Editorial. Aging in the 21st Century: A Call for Papers . Arch Neurol. 2002;59:518-519.
2. Langan M. Aging Changes in immunity. MedlinePlus Medical Encyclopedia. Available at:
3. Whitman DB. The Immunology of Aging. ProQuest. Available at: http://www.csa.com/discoveryguides/archives/immune-aging.php#g23. Accessed April 28, 2010.
4. Dicarlo, Al., et al. Aging in the context of immunological architecture, function and disease outcomes. Trends. Immunol. 2009; 7:293-297.
5. Goodwin K, Vibound C, and Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine. 2006;24:1159-1228.
6. Vasto S, Malavolta M and Graham P. Age and immunity. Immunology & Ageing. 2006;3:1186-1196.
7. Dorshkind K, Montecino-Rodriguez E and Singer RA. The ageing immune system: is it ever too old to become young again? NatRev Immunol. 2009; 9:57-62.
8. Caruso C, Buffa S, Candore G, et al. Mechanisms of immunosenescence. Immunity & Ageing. July 22, 2009:6-10.
9. Danielle AW, Silva AB and Palmer DB. Immunosenescence: emerging challenges for an ageing population. Immunology. 2007; 120:435-446.
10. Sharma G, Hanania NA. and Shim YM. The Aging Immune System and Its Relationship to the Development of Chronic Obstructive Pulmonary Disease. The Proceedings of the American Thoracic Society. 2009;6:573-580.
11. Kaszubowska L. Telomere shortening and ageing of the immune system. J Physiol Pharmacol. 2008;9:169-86.
12. Wilson, S. and Mazzatti DJ. Current status and future prospects in the search for protein biomarkers of immunosenescence. Expert Rev Proteomics. 2008;5:561-570.
13. Nicita-Mauro V, Basile G, Maltase G, et al. Smoking, health and ageing. Immunity & Ageing. Available at: http://www.immunityageing.com/content/5/1/10. Accessed April 28, 2010.
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