Alterations in immune system that predispose to infection in old age

As we grow up, the aging of our body is an inevitable part of life. With this aging comes not only a wrinkly skin or more difficulty walking, but also an immune system with less ability to protect us against various infectious diseases. As can be read in another post of this weblog, immunosenescence and inflammaging are important terms related to the alterations that take place in our immune systems when we grow older. How can these processes influence the responses of our immune system to such an extent that the effectiveness of vaccines for protection against diseases, such as influenza, reduces? To answer this question, we need to understand what happens exactly when inflammaging and immunosenescence gradually start to influence our immune system and what organs and cells play a part in these age related alterations. 

Rajeeve. Age and Immune system function. https://t.co/M0gKbconrm pic.twitter.com/sgjtfjtyxw [Internet]. Twitter. 2020 [cited 2023 Oct 3]. Available from: https://twitter.com/rajivshivan/status/1233692472934531073

Thymus and lymph nodes

The thymus is the organ where T cells develop from naive T cells to differentiated mature T cells, and is thus indispensable for an accurate response of the adaptive immune system [1]. The differentiation that takes place in the thymus consists of processes such as producing the T cell receptor, which is needed for antigen specific binding and negative and positive selection. Negative selection involves the inducing of apoptosis if T cells have a high affinity to their own peptides, while positive selection maintains the T cells that have the ability to recognize non-self-antigens. After these selection processes, the naive T cells travel the circulation and can enter the lymph nodes, where they may encounter dendritic cells that present antigens taken up after an infection or vaccination. They provide the signal to activate antigen-specific T cells and once these T cells are proliferated, they can travel to the site of infection and instigate an inflammatory response [1]. Understanding this, we can conclude that the thymus and the lymph nodes are key to maintaining an effective adaptive immune system. However, as a study from Cakala-Jakimowicz et al. in 2021 mentioned, as we grow older, we often observe structural alterations in these lymphoid organs that collectively impact our adaptive immune response. Not only reduced cell migration to and within lymph nodes, but also misplacement of specific immune cell types and compromised intracellular communication are examples of these adjustments that take place with aging. Thymic involution is a process in which the thymus becomes smaller when we age, because we lose thymic epithelial cells [2]. Moreover, due to a decreased production of crucial cytokines, the growth, viability and function of immune cells will be disturbed [3]. The comprehension of these aging-related impairments will support us in preventing reduced response to vaccines in elderly in the future.

Thomas R, Wang W, Su D-M. Contributions of age-related thymic involution to immunosenescence and inflammaging. Immun Ageing [Internet]. 2020;17(1). Available from: http://dx.doi.org/10.1186/s12979-020-0173-8 

Immune responses to vaccines

Firstly, we need to understand how an immune response to a vaccine works, and why this helps us with the protection against various infections. When our body comes into contact with a pathogen, the immune system will respond by making antibodies that specifically target the antigen of the pathogen. In addition to this, the B cells will also produce memory cells, that remain in our body, in order to protect the body against a recurrent infection with a more efficient response [4]. Vaccines take advantage of this process by utilizing the production of memory cells after the first contact with a pathogen. The antigen of a pathogen in a vaccine can take form in multiple ways: a weakened/killed virus or bacteria, fragments of outer surface genetic material, mRNA or toxins treated and turned into non-toxic toxins [5]. When there are antibodies and memory cells produce against the antigen of the virus or bacterium, the body will be protected against the disease in case of reinfection.

Why does the effectiveness of vaccines reduce in older people?

With aging our immune system becomes less efficient in killing and removing pathogens from our body. This weakening of the immune system, called immunosenescence, results in less proper response of our immune system to not only pathogens, but also to vaccines. It was mainly thought that defects on T and B cell responses were the cause of a reduced vaccine efficacy in elderly. The different hallmarks of immunosenescence such as a reduction of T-cell production and the presence of senescent T-cells are associated with poor vaccine response as well as increased susceptibility to infectious pathogens [6]. A study from Gustafson et al. reports that a decrease in the quantity and effectiveness of T cells might be the explanation for the deteriorated vaccine responses in elderly. They found that the equilibrium between inflammatory T cells and T helper cells is disrupted, leading towards a stronger inflammatory response, while there is a diminished memory and T helper cell response [7]. As a consequence, a vaccine that is supposed to stimulate the production of memory cells, has a lot less impact.

Moreover, a review of Crooke et al. shows that due to the changes that take place in the thymus as we grow older, we endure a decrease in the output of new naive T cells [6]. This results in a diminished development of mature T cells and thus to an inaccurate immune response. Furthermore, the modifications in the innate immune system in elderly can have a vital impact on antigen presentation and therefore the initiation of the adaptive immune system [8]. In the review of Crooke et al., it is stated that multiple studies have shown that, for example, the efficacy of vaccines for influenza is drastically reduced in elderly compared to younger individuals [6].

Recent research suggests that also inflammaging can also be an explanation for the decline in response to vaccinations in elderly. Because of systematically increased levels of TNF-α, IL-6 and CRP, there is a chronic state of inflammation in the body which contributes to an alteration in the immune system, resulting in a decreased vaccine response. Post-translationally modified DNA or proteins are non-infectious agents that can cause continuous activation by stimulating the innate immunity, which will lead to the production of pro-inflammatory cytokines [9]. Due to this chronic overstimulation of the innate and adaptive immune system by pro-inflammatory mediators, the ability of the immune system to respond successfully to vaccines fails. Inflammation related genes were found to be negatively correlated to vaccine response, whereas signatures associated with T and B-cell function were positively correlated with antibody responses. This suggests that inflammaging negatively influences vaccine efficacy in elderly [8]. All of the reasons stated above are why we need to change our strategies when it comes to vaccinating elderly, so their immune system will respond more accurately and they will still be protected against all kinds of infections.

Literature

1. Thapa P, Farber DL. The role of the thymus in the immune response. Thorac Surg Clin [Internet]. 2019 [cited 2023 Sep 26];29(2):123–31. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446584/
2. Cai Z-J. Hypothalamic aging and hormones. In: Vitamins and Hormones. Elsevier; 2021. p. 15–37. https://www.sciencedirect.com/topics/immunology-and-microbiology/thymic-involution
3. Cakala-Jakimowicz M, Kolodziej-Wojnar P, Puzianowska-Kuznicka M. Aging-related cellular, structural and functional changes in the lymph nodes: A significant component of immunosenescence? An overview. Cells [Internet]. 2021 [cited 2023 Sep 26];10(11):3148. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8621398/
4. How do vaccines work? [Internet]. Who.int. [cited 2023 Sep 26]. Available from: https://www.who.int/news-room/feature-stories/detail/how-do-vaccines-work
5. CDC. Explaining how vaccines work [Internet]. Centers for Disease Control and Prevention. 2023 [cited 2023 Sep 26]. Available from: https://www.cdc.gov/vaccines/hcp/conversations/understanding-vacc-work.html
6. Crooke SN, Ovsyannikova IG, Poland GA, Kennedy RB. Immunosenescence and human vaccine immune responses. Immun Ageing [Internet]. 2019;16(1). Available from: https://immunityageing.biomedcentral.com/articles/10.1186/s12979-019-0164-9
7. Gustafson CE, Kim C, Weyand CM, Goronzy JJ. Influence of immune aging on vaccine responses. J Allergy Clin Immunol [Internet]. 2020 [cited 2023 Sep 26];145(5):1309–21. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198995/
8. Pereira B, Xu X-N, Akbar AN. Targeting inflammation and immunosenescence to improve vaccine responses in the elderly. Front Immunol [Internet]. 2020 [cited 2023 Sep 27];11. Available from: https://pubmed.ncbi.nlm.nih.gov/33178213/
9. Frasca D, Blomberg BB. Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology [Internet]. 2016 [cited 2023 Sep 27];17(1):7–19. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626429/