Nages Nagaratnam and Sai Adithya Nagaratnam
Historical Perspective
The prehistoric people interpreted disease through the spirits they believed in. The ancient Egyptians, the Greeks and the Romans also had supernatural approaches to disease and had strong belief in their gods [1].They believed that disease was a punishment by the gods for their sinful acts. Between then and the nineteenth century, disease was attributed to an imbalance or a change in one of the four humours, blood, phlegm, yellow bile and black bile [2]. In 430 BC the Athenian Thucydides described the plague of Athens and recorded that those who recovered from the disease attended to the sick and dying for they knew from their experience they will not be attacked a second time [3]. The word immunity was derived from the Latin words immunis and immunitas initially in Rome, mean- ing exemption from military service or duty [4]. Around 60 BC the poet Marcus Annaeus Lucanus used the term
‘immunes’ in his epic poem Pharsalia to describe the North African Psylli tribe’s resistance to snakebite venom [4, 5].
In the ninth century, an Islamic physician Al-Razi distin- guished smallpox from measles [1]. Modern scientific meth- ods were applied during the renaissance and thereafter, based on careful observation and recording of patient’s symptoms [1]. Edward Jenner (1749–1823) in 1796 inserted pus from a cowpox pustule into the arm of an 8-year-old boy, James Phipps. He subsequently proved that Phipps was immune to smallpox having been inoculated with cowpox. He later coined the word vaccine from the Latin word ‘vacca’ for cow [6]. Ilya Mechnikov was the first to recognise the contribu- tion of phagocytosis to the generation of immunity [7]. In 1908 he was awarded together with Paul Ehrlich the Nobel
Prize for Physiology or Medicine. Robert Koch a country physician identified the organism responsible for tuberculo- sis. Louis Pasteur’s work together with that of Koch’s led firmly to establishing the germ theory of diseases [7]. Pasteur created vaccinations for rabies and anthrax. The first realistic approach to the treatment of infectious diseases was the dis- covery of diphtheria toxin by Emil von Behring and Shibasaburō Kitasato in the 1890s [8]. Behring was awarded the Nobel Prize in Physiology or Medicine in 1901 for his work on serum therapy.
The earliest recognised attempt to induce immunity to an infectious disease was around 1000 AD in China by drying and inhaling crusts of smallpox lesions [3]. Mithridates VI, king of Pontus, lived between the second and first century BC, and the origin of active immunotherapy may have begun then. Mithridates consumed small doses of various types of poisons in order to develop immunity against them should someone try to kill him by this means [9].
General Considerations
The immune system is a complex process which responds to the invasion by viruses, bacteria and other pathogens by sys- temic inflammation. The immune system is divided into two categories, namely, innate and adaptive (Fig. 7.1), and more recently attention has been drawn to the interface between the two [10]. The former refers to non-specific mechanisms and includes physical barriers, physiological barriers and phagocytic cells. The natural killer cells (NK cells), neutro- phils and macrophages are components of the natural innate immune system [11]. The innate immune system does not require previous experience to carry out its functions [12].
When the innate immune defences are avoided or overpow- ered, the adaptive immune system responds [12].
The adaptive immunity is more complex and is comprised of T and B cells and consists of two arms, cellular immunity (mediated by T cells) and humoral immunity (mediated by
N. Nagaratnam (*)
Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
e-mail: [email protected] S. A. Nagaratnam
Westmead Hospital, Westmead, NSW, Australia e-mail: [email protected]
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Immune system
Innate (Non-specific: natural)
Adaptive (Specific: acquired)
Physical
barriers Humoral immunity
(B-cell immunity)
Cell-mediated immunity (T-cell immunity)
Exposure to
antigen Release of T-cells
Blood-borne
Lymphoblasts
Suppressor cells prevent organ-specific auto-immunity Plasma
cells
Helper cells (CD4) Cytotoxic
T-cells (CD8) kill viruses and
damaged cells Clonal
B-cells Death of
dangerous organisms
- Chemotaxis and inflammation
- Opsonization of pathogen - Membrane attack complex - Phagocytes
- Neutrophils - Basophils - Macrophages - Natural killer cells
Prevents infection entering the
body - Skin - Saliva - Mucous membranes - Gastric acid - Flushing action of tears and urine
Memory B-cells
Complement activation cascade (with activation of C3)
Alternative
pathway Mannan-binding
lectin pathway Classical
pathway
Th1 Macrophage
activation (cell-mediated)
Th 2 B-cell activation (humoral response)
and antibody production
Th 17 Neutrophil activation (cellular response to fungal
infection)
Fig. 7.1 The immune system. (Adapted with the permission of Virtual Medical Centre. Other sources Chaudhry [12], Troow and Daha [17], Rus et al. [18])
B cells) [12]. The T cells are specialised in the thymus gland and plays an important role in adaptive immunity via cellular immunity and B cell-mediated humoral immunity [13]. T cells have to be activated by functional antigen-presenting cells (APCs) to initiate adaptive immune response [10]. Both T and B cells are directed against specific antigens [12]. The T cells are released as cytotoxic T cells (CD8+), helper T cells (CD4+) and suppressor T cells. T cells play a signifi-
cant role in the prevention of organ-specific autoimmunity and allograft rejection [14]. The helper T cells activate B cells to secrete antibodies, activate macrophages to destroy ingested microbes and activate cytotoxic T cells to kill infected target cells [15]. Once activated to become an effec- tor cell, the helper cell helps to activate other cells, and it is the innate immune responses that determine what kind of helper T cell will develop into [15]. Th1, which secretes IL 2
N. Nagaratnam and S. A. Nagaratnam
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and IFN 8, play an important role in macrophage activation, Th2, which secretes IL 4,516d10, in B cell activation and antibody production and Th17 which secretes IL222d147, in fungal infections [12].
Two classes of major histocompatibility complex (MHC), the MHC I and MHC II, play vital roles in adaptive immu- nity [16]. Both present peptides on the cell surface for the recognition by T cells {16}. MHC I found on the surface of all nucleated cells allows cytotoxic CD8(+) T cells to destroy cells infected with virus or damaged cells. MHC II expressed by antigen-presenting cells (APCs) display an array of pep- tides to the T cell receptors of helper CD4(+) T cells [17] and initiate an antigen-specific response.
The mechanism mediated by the antibody called humoral immune response is brought about by antibodies that bind to the antigens and promote their destruction. The mature B cell when it leaves the bone marrow is not as yet exposed to self- antigen and requires signals from helper T cells (Th2) to make antibody. After activation of the B cells, they differenti- ate into plasma cells which secrete abundant amounts of anti- bodies [12]. Each plasma cell is specific for a specific antibody [12]. Following clonal expansion of an activated B cell is the memory B cell which functions in a similar way to that of memory T cells. Unlike the innate immune system, the adap- tive immune system requires prior experience. To make future responses against a specific antigen more effective, a relative amount will be retained as ‘memory’ which provides ade- quate immune protection against recurring pathogen in the domain [18]. The term repertoire is used to refer to the collec- tion of cells that respond to a specific pathogen [18].
During analysis of T cell responses to pathogens, T cell receptor (TCR) nucleotide sequences are created [18]. The capacity to distinguish the body’s own cells (self-antigen) from that produced by invaders (non-self-antigen) is made by way of the T cell receptors (TCR) or B cell receptors (BCR). The third complementary-determining region (CDR3) is the most significant region of the TCR and whose nucleotide sequence is unique to each cell clone [18].
The complement system heightens the strength and actions of innate immune response and is a major component of the innate immune system [19] defending against all for- eign pathogens via complement fragments that take part in chemotaxis, opsonisation and activation of the leucocytes [20]. The complement system is also involved in tissue regeneration and clearance of immune complexes and dead cells [19, 20]. It is also closely involved in the adaptive B and T cell responses [21]. There are three pathways through which complement can be activated on pathogen surfaces [12]. The three pathways are the classical pathway, the mannan- binding lectin pathway (MB-lectin pathway) and the alternative pathway. A protease called C3 convertase is generated in each of these pathways through a series of reac- tions and is bound covalently on the pathogen surface [22].
The C3 convertases cleave C3 to generate C3a a peptide mediator of inflammation and C3b. The C3b binds the C3 convertase to form C5 convertase to produce C5a, another peptide mediator of inflammation [22].
Immunosenescence
The ageing of the immune system is known as immunose- nescence. It affects both innate and adaptive immunity [23].
Immunosenescence affects the innate immunity, the NK cells, polymorphonuclear leucocytes and macrophages which are part of the natural immune system [11, 24, 25].
Adaptive immunity with ageing is characterised by a reduced humoral response as well as a decrease in cell-mediated immune function [26]. In the elderly alterations occur in the innate/natural and clonal-type immunity, and the former is largely preserved [11, 27], whereas the clonic compartment undergoes appreciable alterations [11, 27–29].
The alterations in the innate immune system associated with ageing have been shown to affect the natural killer (NK) cells. The natural killer (NK) cells whose role is to target virally infected, tumerogenic or other abnormal cells increase in numbers with increasing age [30] to compensate for their impaired function [10], but their toxicity and that of the antigen- presenting dendritic cells diminish with age [31–33]
with reduced production of cytokines and chemokines by the activated NK cells [26, 31, 34]. Similar increases are seen in the other NKT-related cells. NKT cells exhibit features of both T and NK cells. The function of the NK cells is con- trolled by diverse families of antigen receptors, the most prominent among them is the killer cell immunoglobulin- like receptor (KIR) [30]. There is a decline in their phagocytic capacity [24, 25]. Macrophages play an important role in the initiation of inflammatory responses, elimination of patho- gens, manipulation of adaptive immune response and repara- tion of damaged tissue [35]. Wound healing is impaired, but it is offset by relocation of young macrophages [10]. There seems to be a decline in the number of phagocytes in the aged host with reduction in their bacterial activity [36, 37].
The alterations to the clonal-type immunity are brought about by involution of the lymphoid tissue, continuous exposure to a variety of antigens, reduced number of den- dritic cells, debilitation of the naïve cells and accumula- tion of memory/effector T cells [27]. The accumulation of late differentiated effector T cells commonly associated with cytomegalovirus (CMV) infection results in a decline in their ability of the adaptive immune mechanism to respond to novel antigens [33]. The composition of T cell subsets is altered by CMV infection resulting in an increased number of CD8+ and CD57+ subsets in CMV- positive individuals [28], and the clonal expansion of CMV-specific CD8+ cells increases with age [28]. The
7 Immune System, Immunosenescence and Immunisation in the Elderly
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T cell activation and susceptibility to apoptosis are decreased in aged individuals and are due to CD28 which is an important receptor [28]. CD8+ and CD28- population is increased with age and CMV positivity [28].
In the aged, the age-dependent decline in immunity has been attributed to the functional activity of the haematopoietic stem cells (HSC) [38], and there is evidence to suggest that there is a decline in function with ageing [39]. HSC gives rise to all the components of the immune system, lymphoid as well as myeloid and with ageing an inclination towards myeloid lineage. Haematopoietic stem cells lose their capacity to self- renewal due to accumulation of oxidative damage to DNA by ageing [40] and are distinct from thymic changes [10].
Replicative senescence and degenerative changes associ- ated with involution of the thymus are two mechanisms whereby age has an effect on host immunity [10]. Replicative senescence suppresses tumorigenesis, and there is indirect evidence that it contributes to ageing [41]. The senescence of clonotypic immunity is mostly the result of the T cells [11].
The T cell function begins to decline from birth with involu- tion of the thymus and lifelong chronic antigenic stimula- tion. There is a progressive age-dependent decline of virgin T cells (CD 95), and the immune function of the elderly is weakened by exhaustion of the CD95- virgin cells and replaced by large clonal expansion of memory CD28- T cells [42]. In advanced age EBV and CMV induce different CD8+
T cells both in quality and in quantity [11]. The age- dependent expansion of CD28- T cells mostly positive for pro-inflammatory cytokines underscores the importance of chronic antigenic stimulation [43] in the pathogenesis of the main immunological changes with ageing (Box 7.1).
Age-Related Diseases
Most of the parameters are largely under genetic control [44]. The susceptibility of the elderly to infectious diseases, autoimmunity and cancer and in their decreased responsive- ness to vaccination is directly or indirectly related to age- related changes of the immune system [11]. It has been suggested that age-related diseases are due at least in part to dysregulation of the function of the immune system [45].
There is a high incidence of infection in the elderly, and the outcomes are severe [46]. Several pathologies such as dementia, atherosclerosis, and cancer all of which share an inflammatory pathogenesis may be the result of such immu- nological alterations with ageing [46].
The genetic component is involved in the achievement of longevity. In the course of evolution, the human organism is set to live 40–50 years [47]. Presently in a period not fore- seen by evolution, the immune system has to be active for longer periods of time. The genetic component appears to control the functioning of the innate/inflammatory and clo- notypic responses and necessarily the inflammatory state in later life [48, 49]. Although inflammatory genotypes are important in early life, excessive production of inflammatory molecules may be detrimental and cause immune-related inflammatory diseases [47].
The major driving force of immunosenescence seems to be the lifelong chronic antigen load [11, 39] which leads to chronic inflammatory status [28] resulting in damage to the organs later in life and is deleterious for longevity [11]. Chronic antigenic overload (virus, bacteria, fungi, toxins, mutated cells) results in a pro-inflammatory condition that continuously stimulates innate immunity and seems to incline towards the onset of age- related disease where immune and autoimmune factors play an important role [28]. The immune activity of the innate immune system in later life is evident by the presence of elevated mark- ers of inflammation such as TNF-alpha and interleukin-6 (IL- 6) [50]. The elevation of these markers of inflammation is associated with disability and death [51].
Immunisation in the Elderly
Nutrition including protein malnutrition and deficiency of vitamins and free elements may underlie many immune defi- cits attributed to ageing [52, 53]. The elderly have a greater susceptibility to infection due to age-related decline in immune responses [33]. The frequency and severity of infec- tious diseases are increased in the elderly [28].
Cytomegalovirus (CMV) is the leading cause of mortality in immunosuppressed individuals, and the immune system plays a vital role in controlling it by decreasing its effect on the individual [54]. The elderly have increased rates of infec- tion and multiple co-morbidities. An intact cell-mediated Box 7.1. Pathophysiology of Immunosenescence
Immunosenescence affects both innate and adaptive immunity.
Innate Immunity
Affects the natural killer (NK) cells; increase in num- bers to compensate for impaired function [21].
Dendritic cells diminish with age [29–31].
Reduced number of phagocytes with reduced phago- cytic capacity [34].
Decline in function of haematopoietic stem cells (HSC) with inclination towards myeloid lineage.
Adaptive Immunity
Reduced humoral response [24].
Decrease in cell-mediated functions [24].
Accumulation of memory/effector T cells [25].
CD8+ CD28− T cells increase with age [28].
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immunity is essential to generate the humoral response to vaccination which is distinctly diminished in some of the elderly [10]. The ability of the immune system to produce specific antibodies and memory cells in response to stimula- tion with an antigen is referred to as active immunisation.
The ability of the elderly to produce antibodies in response to vaccination is not clearly understood. Active immunisa- tion by vaccine administration in the elderly is safe and effective even in the presence of illness [55].
It is well documented that diseases such as tuberculosis, pneumonia and bacteraemia have an increased incidence and increased fatality rate in the elderly [55]. The elderly are at greater risk of vaccine-preventable diseases [56]. Vaccine- preventable diseases contribute significantly to increased mortality and morbidity among the elderly [57, 58]. And older adults with co-morbidities are at high risk of complica- tions [56]. Despite the beneficial effects of vaccination, vac- cination rates remain low among the elderly [57]. In the USA, the majority of deaths from influenza occur in over 60 years old, yet only 60% of the older adults are immunised against influenza [56].
Older adults require vaccination against the following diseases, namely, seasonal influenza, pneumococcal disease, shingles, tetanus, diphtheria and pertussis. It is recommended that adults above the age of 50 have influenza vaccination and every ten-yearly tetanus-diphtheria and adults above 65 for one-time pneumococcal vaccination who are either healthy or have medical conditions [56]. The elderly espe- cially the bedridden and those in institutions are at increased risk of severe disease. The oldest old in a recent study was shown to be 16 times more likely to die of influenza-related disease [59] and 32 times more likely to die of influenza- related pneumonia than those between the ages of 65 and 69.
In the USA, more than 90% of the influenza-related annual deaths occurred in those 65 years or older [60].
The influenza viruses have two external viral glycopro- teins, namely, haemagglutinin (HA) and neuraminidase (NA), which permit the virus to attach and infect the suscep- tible host [61]. There are three major subtypes of HA (H1, H2, H3) and two subtypes of NA (N1 and N2) [62]. Changes in the antigenicity occur annually with influenza. Mutations of HA and NA within the type of influenza virus are known as ‘antigenic drift’, a continuous process for both A and B viruses [61]. It can be substantial and has led to extensive epidemics and severe outbreaks. With increasing age there is decreasing vaccine effectiveness due to the decline in immune function resulting in waning of vaccine-induced immunity [63].
Influenza vaccination is recommended to (i) all elderly above the age of 65 years, (ii) to all those in residential and long-term care facilities and (iii) to all suffering from chronic pulmonary and immune-depressed patients. The only contra- indication to vaccination is hypersensitivity to hen’s eggs.
Yearly vaccination is recommended. A recent development of live attenuated influenza A virus given intranasally has shown promising results. Influenza vaccination is recom- mended for residents in aged care facilities and healthcare carers [56, 64].
To improve their efficacy, new vaccines are being devel- oped such as intradermal and high-dose vaccines for influenza [33]. Pneumonia in the oldest old often follows influenza.
Since influenza frequently causes secondary bacterial pneu- monia, it is recommended that patients who are at high risk should be encouraged to have pneumococcal vaccine. It includes elderly with chronic heart and lung disease, diabetes, asplenism and malignancy. Revaccination should be consid- ered after 6 years. Pneumococcal vaccine is given after 6 years with the current 20-valent polysaccharide [64] vaccine and to include all adults with asthma and all smokers [58]. For those above the age of 60, a single vaccination with current live her- pes zoster vaccine is recommended [58]. Herpes zoster affects 20–30% of adults with more than 50% occurring in those above the age of 60, and 40% develop post-herpetic neuralgia [64]. Hepatitis B vaccination should be encouraged in non- immune adults [65]. Tetanus vaccination and revaccination are recommended to older people exposed to the agent. It is fatal in at least 32% of people over the age of 80 years [55]. Certain subsets of the elderly may require vaccinations for hepatitis A, hepatitis B, meningococcal disease, varicella and measles, mumps and rubella (MMR) [56].
Clinical Relevance
The ageing of the immune system is known as immunosenescence.
With ageing there are alterations to the immune sys- tem [11, 25] and the capacity to respond to infection.
The elderly have a greater susceptibility to infection due to age-related decline in immune responses [31], and the elderly are at greater risk of vaccine- preventable diseases.
Active immunisation by vaccine administration in the elderly is safe and effective even in the presence of illness [53].
Older adults require vaccination against the follow- ing diseases, namely, seasonal influenza, pneumococ- cal disease, shingles, tetanus, diphtheria and pertussis.
Certain subsets of the elderly may require vaccina- tions for hepatitis A, hepatitis B, meningococcal dis- ease, varicella and measles, mumps and rubella (MMR).
All elderly above the age of 65 in residential and long-term facilities and those with chronic pulmonary, cardiovascular, malignant and metabolic diseases should be offered vaccination.
7 Immune System, Immunosenescence and Immunisation in the Elderly