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Nursing Practice Keywords // T cells/B cells/ Systems of This article has been double-blind peer reviewed In this article... ● Age-related changes to the innate and adaptive immune responses ●  and ● Decreased production and impaired of immune cells

Anatomy and of ageing 9: the immune system

Key points Author Yamni Nigam is associate professor in biomedical science; John Knight is Almost all senior lecturer in biomedical science; both at the College of Health and components of Science, Swansea University. the immune system are adversely Abstract With advancing age, the body’s ability to respond to declines, affected by age and recovery from injury or microbial attack becomes delayed or ineffective. This is called immunosenescence. The innate immune response, the acquired immune One of the earliest response and the inflammatory response are all blunted, and the immune system and most drastic becomes less able to mount a rapid and complete defence against invading changes in the . Ageing also means older people respond less well to and immune system is are more prone to autoimmune conditions. This is the ninth article in an 11-part series thymic involution on the effects of ageing on the systems of the body.

The innate immune Citation Nigam Y, Knight J (2017) and physiology of ageing 9: the immune response, provided system. Times [online]; 113: 10, 42-45. by mechanical barriers, and cells with phagocytic urvival depends on the body’s innate defences change profoundly, but and killing abilities, ability to protect itself against the adaptive defences undergo an even is blunted environmental dangers, harmful more severe age-related deterioration. Ssubstances and pathogens. It The weapons of the does this using non-specific, natural Innate immune response adaptive immune (innate) defences such as the , secre- The has two lines response, T cells and tions, immune cells and chemicals. The of defence: B cells, undergo a innate immune system is bolstered by the l The skin, and the epithelial and decline in numbers inflammatory response (Box 1), which mucosal linings of internal organs; and function increases flow to damaged areas and l Non-specific white blood cells encourages phagocytic leucocytes to enter (leucocytes) and secreted , Better vaccines, a injured tissues and engulf pathogens. The including factors such healthy non-specific immune responses are as , which can pierce the of gut microbes, complemented by acquired (adaptive) membranes of pathogens. vitamin intake, immune responses, which develop more If a breaches the exterior, supplementation gradually but more robustly, targeting first-line barrier, the second-line internal and can individual pathogens and ridding the body defences come into play. The hallmark of support the ageing of malignant cells. the second line of innate defence is inflam- immune system Almost all components of the immune mation (Box 1). The innate defence also system are adversely affected by ageing, depends heavily on cells that can phago- resulting in an overall decline in immuno- cytise pathogens – , mono- competence. The system becomes less able cytes and . to mount an effective response and the mechanisms normally invoked to get rid Skin, mucous membranes and eye lashes of a foreign agent are disrupted; this The skin contains keratin, a waterproof decline is called immunosenescence. The and microbial-resistant . Lactic

Nursing Times [online] October 2017 / Vol 113 Issue 10 42 www.nursingtimes.net Copyright EMAP Publishing 2017 This article is not for distribution Nursing Practice Systems of life allow the skin to maintain a Box 1. Inflammation and inflammageing slightly acidic environment (pH5.5) and sebaceous and sweat glands produce secre- Inflammation isolates and protects the body from further injury and the spread of tions that can inhibit bacterial growth. invading pathogens. release causes an increase in blood flow to the injury With age, skin secretions diminish; the site, and allow white blood cells and plasma to migrate out of the skin becomes thinner, drier and less . A cascade of complement in the plasma kick-starts this elastic, and therefore more prone to cuts physiological process, which results in the classical symptoms of inflammation: and abrasions through which pathogens redness, heat, swelling and pain. can enter the body. Medical devices such as With age, in the presence of infection, both the complement pathway and the intravenous cannulas provide skin of inflammation are reduced (Navaratnarajah and Jackson, 2017). Ageing breaches, so should only be used when is also associated with a long-term, continuous state of low-grade inflammation absolutely necessary, removed as soon as (inflammageing), which can trigger other pathological mechanisms. This low-grade possible, and accompanied by tight infec- is considered the primary risk factor for major long-term tion prevention and control measures. conditions in older people (Isobe et al, 2017). Mucous membranes line cavities, tracts and structures throughout the body. The mechanical protection provided by their mediators, including and immune response usually kicks in a few tough is reinforced by the pro- , playing a key role in the days after the innate immune response. duction of that traps particulate inflammatory process (Box 1). When they matter and pathogens. With advancing encounter invading microbes, they initiate The thymus age, the integrity of the epithelial barrier inflammation – recruiting and activating Precursors of B and T cells are formed in and mucosal immune response are com- other phagocytes. Macrophages are also the marrow, but T cells mature into promised (Man et al, 2014). key to wound healing, producing growth immunocompetent in the Eyelashes keep debris out of eyes; like factors and secreting angiogenic and fibro- thymus gland. Located just above the hair, they grow through specialised folli- genic factors. With age, there is a sharp , this lymphoid is large and cles, but this process slows down with age, decline in the function of macrophages, active in early childhood and then rapidly and eyelashes become thinner. and their phagocytic, killing and wound- decreases in size, at a constant rate, until healing capacities are reduced (Linehan middle age. Atrophy (shrinking) of the Cells of the innate immune system and Fitzgerald, 2015; Solana et al, 2012). thymus is one of the earliest and most Neutrophils drastic changes in the immune system and The primary immune defence against rap- Dendritic cells this is thought to play a major role in idly proliferating , and fungi Dendritic cells are -presenting leu- immunosenescence. It results in a gradual are phagocytic neutrophils, which can kocytes found at the body’s frontiers such decrease in the output of naive T cells, destroy pathogens by rapid generation of as skin. They activate T-lymphocytes and which essentially stops between 50 and 60 potent reactive and nitrogen spe- play a pivotal role in the adaptive immune years of age (Muller and Pawelec, 2015). cies, as well as extrude extracel- response (see below). The production of various immunoregula- lular traps. Neutrophils are also important tory that differentiate T and B in wound healing: they arrive at the wound Natural killer cells cells also decreases: some are no longer site within minutes of an injury and con- Natural killer cells (NKCs) are non-specific detectable in the plasma of people over 60. tinue to do so for several days. cytotoxic white blood cells involved in early One role of the thymus is to mature T With advancing age, the number of defence. Known as the pitbulls of the cells that have not yet been exposed to anti- neutrophils remains constant but their immune system, they recognise and elimi- gens. These ‘naive’ T cells are quiescent, function is affected (Solana et al, 2012); nate a variety of -infected cells and and will only become active when exposed reduced (ability to ingest malignant cells by direct contact. Their to a foreign antigen. Another role of the microbes) may lead to an accumulation of ability to kill is seen as a biomarker of thymus is to ‘educate’ T cells to recognise debris, while reduced (move- healthy ageing, and low NKC activity is self-, so that they do not mount an ment in response to chemical stimulation) associated with the development of attack against self-cells and . Here, means neutrophils take longer to reach the and . Absolute numbers of NKCs maturing T cells are checked to ensure that site of infection. Neutrophils secrete pro- increase with age but their cytotoxic abili- they do not strongly respond to self body teases to aid their migration through tis- ties decrease (Shaw et al, 2010). Age-associ- proteins. Due to thymic atrophy, this sues: this also becomes less efficient with ated alterations in NKC function may result ‘thymic education’ is impaired by ageing, age. Tissue damage and inflammation are in part from changes in zinc homoeostasis; which may partly explain why we have therefore more frequent and more severe there is some evidence zinc supplements more as we age. in older people (Shaw et al, 2010). improve NKC function (Mariani et al, 2008). T cells and macrophages Adaptive immune response Matured naive T cells are exported to the Monocytes are white blood cells located in The main weapons of the adaptive immune secondary organs (lymph nodes the and blood. They respond to system are B and T cells (lymphocytes), and spleen), where they are more likely to inflammation by differentiating into which create and acquire to spe- encounter foreign antigens. T cells make antigen-presenting cells (APCs) such as cific antigens. Since the adaptive immune up 65-85% of blood lymphocytes and cir- macrophages and dendritic cells. Mac- response is antigen-specific, it needs to be culate through lymph, blood and back to rophages release a range of inflammatory primed by initial exposure, so the adaptive lymph nodes once a day, therefore

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Fig 1. Age-related changes to the immune system

Mucous membranes l Epithelium becomes less resilient Skin l Mucous production is compromised l Becomes thinner, drier, less elastic and more prone to injury l In situ devices provide portal of entry for pathogens l Number of dendritic cells Innate immune response decreases l Neutrophils: compromised phagocytosis, chemotaxis and intracellular killing l Macrophages: decreased phagocytic, killing and wound-healing abilities l Dendritic cells: dysregulated Thymus function l Thymus atrophies (thymic involution) Adaptive immune response l Output of naive T cells l T cells: decreased production declines and impaired function l B cells: decreased production and quality of response l Lower output of l Dendritic cells: lymphoid cells dysregulated function l Decreased production of mature B cells Inflammatory response l Inflammatory response is blunted l Chronic low-grade inflammation sets in

increasing their chances of encountering a Older people have vast numbers of (immunoglobulins) function variety of antigens. Once they have bound memory T cells, but almost no naive T by targeting extracellular pathogens and with an antigen, T cells proliferate and can cells, so they do not respond to new anti- neutralising antigen. Some B cells become differentiate into different types: cytotoxic gens as well as younger people. However, memory B cells, capable of remembering T cells (which mediate the direct killing of age-related loss of efficiency of the adap- the antigen that triggered antibody pro- target cells), helper T cells (which assist all tive immune system is thought to be duction. Both B and T memory cells are on other immune cells) and memory T cells mainly due to a decline in T receptors continuous patrol in the circulation (which remain dormant but will reactivate caused by the cytomegalovirus (CMV) (Marieb and Hoehn, 2016). on re-exposure to the same antigen). (Oishi and Manabe, 2016). This virus is With increasing age, the bone marrow The activation of T cells depends on highly prevalent in older people and asso- produces fewer mature B cells (Muller and their interaction with APCs, which ‘show’ ciated with increased rates of vascular dis- Pawelec, 2015). Antibody responses to them the antigen. APCs include dendritic ease and overall mortality (Parry et al, infectious agents – and vaccines – also cells: with their wispy extensions, these 2016). The capacity of T cells to respond to tend to decrease due to deficient T-helper will catch antigen, phagocytise it, and then infection is almost entirely absorbed by cells and intrinsic defects in B cells (Frasca enter a where they will present the CMV (Isobe et al, 2017), leaving older et al, 2011). In older people, the humoral bits of their caught antigen to T cells. people vulnerable to other infections. response is therefore of shorter duration Dendritic cells play a pivotal role in the and decreased specificity. adaptive immune response. Their age- B cells associated dysregulation not only compro- B cells originate and mature in the bone mises anti-pathogen defence, but also marrow and, like T cells, are activated by More than 90% of deaths from influenza wreaks havoc on general immunological antigens. Once activated they become anti- occur in people aged over 65 (Katz et al, function (Muller and Pawelec, 2015). body-secreting plasma cells. Secreted 2004). Older people are more susceptible to

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infections, especially flu and Healthy ageing Katz JM et al (2004) Immunity to influenza: the but also urinary tract infections. Hidden There is currently a lot of interest in the challenges of protecting an aging population. Immunologic Research; 29: 1-3, 113-124. infections such as varicella zoster virus gut bacterial population and its role in Linehan E, Fitzgerald DC (2015) Ageing and the infection (which can cause in maintaining healthy and immune system: focus on macrophages. European people who have had ) and immune function. Restoring gut micro- Journal of and ; 5: 1, 14-24. CMV are recurrent and can lead to life- bial balance by administering pre-biotics Man AL et al (2014) The impact of ageing on the threatening . In older people, shin- and appears to improve health intestinal epithelial barrier and immune system. Cellular Immunology; 289: 1-2, 112-118. gles is associated with a transient risk of and immunity in older people (Goronzy Mariani E et al (2008) Effect of zinc complications including stroke and myo- and Weyand, 2013); for example, the con- supplementation on plasma IL-6 and MCP-1 cardial infarction (Minassian et al, 2015). sumption of a drink containing Lactoba- production and NK cell function in healthy elderly: interactive influence of +647MT1a and –174IL-6 Nurses must encourage older patients cillus casei for four weeks had positive polymorphic alleles. Experimental Gerontology; 43: to have vaccines, even though it has been effects on the immune function of healthy 5, 462-471. reported that influenza vaccination is only older individuals (Dong et al, 2013). Marieb EN, Hoehn KN (2016) Human Anatomy and Physiology, 10th edn. Upper Saddle River, NJ: effective in 30-40% of the older population Good in older people is cru- Pearson. 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Seminars in number of autoantibodies increases sub- Andersen-Ranberg K et al (2004) High prevalence Immunology; 24: 5, 331-341. of autoantibodies among Danish centenarians. Vu T et al (2002) A meta-analysis of effectiveness stantially with age (Agrawal et al, 2012); Clinical and Experimental Immunology; 138: 1, of influenza vaccine in persons aged 65 years and studies have reported a higher prevalence of 158-163. over living in the . Vaccine; 20: 13-14, autoantibodies among healthy individuals Candore G et al (1997) Prevalence of organ- 1831-1836. specific and non organ-specific autoantibodies in Weinberger B, Grubeck-Loebenstein B (2012) aged 101-106 compared with people aged healthy centenarians. Mechanisms of Ageing and Vaccines for the elderly. Clinical Microbiology and 26-60 (Candore et al, 1997), while autoanti- Development; 94: 1-3, 183-190. Infection; 18 (Suppl 5): 100-108. bodies such as rheumatoid factor were Derhovanessian E, Pawelec G (2012) Vaccination in the elderly. 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