Advancements in the field of biomedicine, including the control of infectious diseases through antibiotics and vaccination practices and the prevention of chronic disorders, have led to reduced mortality, increased life expectancy and, as such, growth of the older population. Ageing is accompanied by profound morphological and physiological alterations. In particular, the immune system undergoes a complex series of remodeling/restructuring events, involving almost all compartments - both the innate and the adaptive system. This process is termed immunosenescence or immune dysregulation and, basically, includes 3 events: a reduction in immune response, an increase in the inflammatory and oxidation background (inflammaging and oxi-inflammaging), and a production of autoantibodies. While there is an increase in autoimmunity in the elderly, this does not always translate into an increase in autoimmune diseases, which represent an important cause of morbidity and mortality and affect 5-10% of the world population. Each disease involves a specific age group. Generally speaking, most autoimmune diseases have a decreased peak age of onset, except for very few diseases such as giant cell arteritis and primary biliary cirrhosis, which are more prevalent among the elderly, or inflammatory bowel disease, which has 2 peaks of onset, the first one in young subjects and the other in those older than 60 years. Autoimmune disorders in the elderly have unique clinical presentations, and insidious and atypical symptoms may constitute a challenge for the physician. They are generally milder than in adults and can be controlled by a proper therapeutic treatment. However, despite advancements both in basic and clinical sciences, further studies and investigations are warranted and should be carried out in order to dissect the molecular framework induced by ageing.

Ageing can be defined as “a progressive, generalized impairment of function resulting in a loss of adaptive response to stress and an increasing probability of death” [1]. The last decades have been characterized by remarkable advancements in the field of biomedicine, including the control of infectious diseases through antibiotics and vaccination practices, as well as the prevention and the improved management and treatment of chronic-degenerative disorders, such as cancer, through the achievements of higher life standards and the delivery of better health care.

These changes have led to reduced mortality, increased life expectancy and, as such, growth of the older population, among others. According to some estimates, 1 in 4 Europeans is projected to be aged 65 years or older by 2030 [2]. Worldwide, the old population is expected to reach 1.5 billion subjects in 2050, the increase being particularly relevant in developing countries [3]. Therefore, understanding the physiological and physiopathological mechanisms underlying ageing is of crucial importance, given both the societal and clinical impact of ageing.

Ageing is accompanied by profound morphological and physiological alterations, concerning cellularity, hormonal profile, and, in particular, insulin responsiveness, cognitive functions, and immune system, among others. If not properly counteracted, the decline in these domains can lead to frailty, physical limitations, development of chronic-degenerative diseases, and mortality [4].

Since ageing is a complex, multifactorial process, different theories of ageing have been formulated, which vary according to the perspective used - biological, sociological, or psychological. The major ones are biological and belong to the family of damage or error theories and include the Dr. August Weismann's wear and tear theory (“human body wears out due to use and time”). Another conceptual framework is given by Dr. Johan Bjorksten's cross-linking theory, according to which senescence is a process characterized by an impairment of proteostasis (a portmanteau of the words “protein” and “homeostasis”) and accumulation of cross-linked proteins and structural molecules. Dr. Max Rubner, Dr. Raymond Pearl, and Dr. Rollo's rate of living theory states that “larger animals outlive smaller ones, and the larger animals have slower metabolisms” or, in other words, “the faster an organism's metabolism, the shorter its lifespan.” The idea of a putative correlation between the size of animals and their lifespan has been pioneered by Dr. Andrzej Bartke [5]. Dr. Alexander, Dr. Gensler, and Dr. Bernstein's somatic DNA damage theory attributes a major role to the accumulation of genetic mutations, which the human body fails to repair. In conclusion, Dr. Rebeca Gerschman and Dr. Denham Harman's free-radical and mitochondrial theories claim that ageing is characterized, respectively, by free radical-induced DNA damages and mutations, as well as by impairment and disruption of cellular processes, and by the loss of the mitochondrial ability to produce and stock energy [6,7].

The other competing family of theories described ageing as a programmed series of biological events, which are regulated by a fine tuning of genes, being switched on and off, and by the existence of “endocrinological clocks” that modulate the hormonal release [6,7].

For further details concerning these and further ageing theories, including the psychosocial ones, the reader is referred to Table 1.

Table 1

An overview of the main theories of ageing

An overview of the main theories of ageing
An overview of the main theories of ageing

Of particular importance for us, given the specific topic of the current mini-review, is the immunological theory. Cellular senescence, with the immune cell infiltration and the subsequent release of proinflammatory cytokines and chemokines and chronic sterile inflammation, results in senescence-associated secretory phenotype [8]. Immunological theory claims to explain not only the increased rate of infectious diseases and vulnerability among elderly people, but also a variety of disorders, including cardio-vascular diseases, Alzheimer disease and chronic-degenerative disorders, such as atherosclerosis and cancer.

During ageing, the immune system undergoes a complex series of remodeling/restructuring events involving almost all compartments - both the innate and the adaptive system, even though the latter is affected to a greater extent [9]. This process is termed as “immunosenescence,” “immunopause,” or “immune dysregulation” and, basically, includes 3 events: (a) a reduction in immune response, (b) an increase in the inflammatory and oxidation background (inflammaging - a term coined by Dr. Claudio Franceschi [10] - and oxi-inflammaging), and (c) a production and release of autoantibodies [11,12].

For example, among the elderly, immunosenescence has been associated with an increased incidence of blood tumors and lymphomas due to immune deficiency and immune surveillance changes. Age-related changes at the level of the immune system are summarized in Table 2. It should be emphasized that changes in lymphoid populations with age are selective; in other words, not all subpopulations are equally affected: the degree of changes can vary between people and can occur at different ages.

Table 2

Overview of the main biological changes of immunosenescence at the level of the human immune system

Overview of the main biological changes of immunosenescence at the level of the human immune system
Overview of the main biological changes of immunosenescence at the level of the human immune system

Ageing, T Cells, and Autoimmunity

T lymphocytes represent an important subset of the adaptive immunity compartment. Ageing is characterized by an absolute decrease in CD3+ T cells. Basically, this is due to 2 main events: (a) thymus atrophy and (b) alterations at the level of hematopoietic stem cells (HSCs).

The supply of T cell progenitors from bone marrow to thymus is compromised by genetic/epigenetic modifications of HSCs, including telomere shortening and impaired enzymes. Further, it seems that a depletion in lymphoid-biased HSC pool with an enrichment of the myeloid-biased HSC compartment occurs [13].

Thymic involution involving reduction in the size of the organ and increase in adipocyte content leads to a decrease in naïve CD45RA+ CD45RO- T cell output and, therefore, to a reduced T cell diversity, a restricted T cell repertoire and a shrinkage of peripheral T cell pool [14,15]. The molecular bases of thymic involution are still unclear in details: however, it seems that molecules, like IL-6, leukemia inhibitory factor, oncostatin M, stem cell factor, and some hormones, including corticosteroids, could play a role [16]. Ageing, as such, causes the accumulation of terminally differentiated αβCD8+ T cells, which can quickly act as effectors, despite their limited proliferative potential, acquiring the phenotype of innate-like T cells or natural killer (NK) cells receptors and losing co-stimulatory receptors [17]. In this way, a peculiar convergence between innate and adaptive immunity is realized [17]. Moreover, age-related FoxN1 (transcription factor) decline causes disruption of medullary thymic epithelial cells (mTECs), which are fundamental for the generation of a proper central tolerance. mTECs, indeed, eliminate self-reactive T cell clones together with thymic dendritic cells (via expression of the autoimmune regulator gene and thymic negative selection) and contribute to the development of natural regulatory T cells. An impairment of these biological processes could result in autoimmune phenotypes [18].

Thymic involution represents only one of the factors, impacting on T output, since thymic T cell generation only contributes to approximately 15% of T cell generation even in young adults. T cell generation in the adult tends to occur through homeostatic proliferation.

Another effect of ageing impacting on T cells is the loss of CD28, a molecule responsible for the proper activation of T cells: this event, indeed, requires the proper interaction between molecules such as the T cell receptor, IL-2R, and CD28. While the loss of CD28 is a typical feature of effector cells, during ageing the loss of the CD28 is accompanied with an impairment of biochemical pathways and cascades, as well as with the formation of altered second messengers, such as the nuclear factor of activated T cells and the nuclear factor kappa-light-chain-enhancer of activated B cells. Further, altered lipid rafts accumulate, leading to the formation of an improper immunological synapse (interface between antigen-presenting cell, APC, or target cell and T lymphocyte). The major biochemical pathways and cascades are altered too, leading to an alteration of phosphorylation mechanisms, kinase activation, chromatin remodeling and proteasome functioning, among others [19]. Age-related loss of CD28 occurs both in CD4+ and CD8+ T cells; however, it seems that this biological event happens more commonly and rapidly among CD8+ T cells. Moreover, CD4 as well as CD8 effector senescent T cells begin to de novo express receptors such as the killer immunoglobulin-like receptor, the natural-killer activating receptor group 2, member D, as well as other inhibitory receptors, whilst senescent T cells begin to mount the lymphocyte function-associated antigen 1. These molecules are usually not found on nonsenescent T cells. They, then, acquire cytolytic capability, become resistant to apoptosis, release high titers of interleukins and cytokines, have shorter telomeres and reduced proliferative capacity, and may expand to large clonal populations, including also autoreactive T cells [20,21,22]. Autoreactivity can be explained considering loss of CD28 and de novo receptors (most of which inhibitory) expression: the first molecular event results in an accumulation of self-reactive cells in secondary lymphoid organs, whilst the second molecular event leads to an impaired threshold for antigen-specific activation and the ability to be activated independently of the antigen. However, it should be noticed that loss of CD28 seems to occur in humans but not in murine models.

Ageing causes a shift in the predominance of activated naïve CD4+ T-cell pools, too. For example, there is an expansion of the Th17 subset. These cells produce and release IL-17; in more detail, they are able to produce only IL-17A and IL-17F, 2 of the 6 IL-17 isoforms (A-F) currently known [23]. There is also impairment in the differentiation of T CD4+ cells in Th1 and Th2 pools [19].

The compartment of regulatory CD4+ CD25+ T cells (Tregs) tends to decrease, even though studies show contrasting findings in this regard. Treg cells have suppressive functions, and, as such, are able to counteract the insurgence of autoimmune events. A decline in their number could favor the insurgence of autoimmune disorders. However, other studies have failed to replicate such results [24].

Finally, another age-related relevant change is given by the increase in memory T cells, CD4+ CD45RO+ and CD8+ CD45RO+, which are, in the elderly people, preferentially located in tissues [19].

Besides thymic involution, chronic antigenic stimulation contributes to the above-mentioned changes. Persistent viral infections, including cytomegalovirus (CMV), human papillomavirus, varicella-zoster virus, herpes-simplex virus type 1, herpes-simplex virus type 2, Epstein-Barr virus, and measles virus, among others, can cause chronic stress and exhaust the human immune system over time.

Finally, the role of CD4+ CD28- T cells in atherosclerosis should be stressed since they are commonly found in patients with chronic inflammatory diseases including systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis (RA), progressive systemic sclerosis, multiple sclerosis, ankylosing spondylitis, Crohn disease, granulomatosis with polyangiitis (Wegener's), Graves' disease, and autoimmune myopathies, among others. CD4+ CD28- T cells grow and develop in a majority of people as they age. Importantly, they invade atherosclerotic plaques and contribute to their growth and rupture.

Ageing, B Cells, and Autoimmunity

Ageing causes deep transformations of bone marrow, leading to reduced B cell generation. In more detail, this is due to several factors, including defects in HSCs, such as altered telomeres or epigenetic modifications, reduced transition of pro-B cells into pre-B cells, decreased IL7 production and release, and impairment in V-DJ rearrangements, which consists in heavy chain gene recombination [25,26], as can be inferred from murine models.

Ageing can cause alterations in activation-induced cytidine deaminase and E2A/E47 concentration, reduced activation and expression of phosphotyrosine kinases and protein kinase C, resulting in impairment of immunoglobulin class switching (isotype switching or class-switch recombination) [27,28]. Further, a reduction in the number and/or an impairment of the function of immature transitional B cells with a CD19+ CD24hi CD38hi phenotype is accompanied by an increased concentration of autoantibodies [29].

A subset of B cells with unique phenotypic and functional features termed age-associated B cells (ABCs), bearing CD11b and CD11c, but not CD21, has recently been identified in both mice and humans. These cells are characterized by a T-BET-driven transcriptional program, a robust responsiveness to Toll-like receptor 7 (TLR7) and TLR9 ligands, and a propensity for immunoglobulin G 2a/2c (IgG2a/c) allotype production [30,31]. The evidence for a role of ABCs in the etiopathogenesis of autoimmune diseases comes from the observation that ABCs depletion in animal models leads to a reduced auto-antibody titer [32]. However, further research is needed to shed light on the precise role of ABCs and their molecular mechanisms.

Ageing, NK Cells, and Autoimmunity

NKs are crucial in the defense against tumor and virus-infected cells. While ageing seems not to alter the antibody-dependent cell-mediated cytotoxicity, which remains relatively preserved, a decline in NK-mediated direct cytotoxicity and IL-2- and IL-12-mediated secretion of immunoregulatory cytokines and chemokines, such as interferon-γ (IFN-γ), has been described [33]. Expression of important molecules, such as CD69, which represents one of the earliest inducible cell surface glycoproteins mounted during lymphoid activation, and which is involved in tissue retention interacting with sphingosine 1-phosphate receptor-1 (S1P1), or HLA-DR, DNAM-1 (CD226), CD57, CD95, NKp30 (CD337), and NKp46 (CD335), seems to be decreased [19,34]. Conversely, production and release of IL-1, IL-4, IL-6, IL-8, and TNF-α are increased [34]. Further, ageing causes an increase in absolute NK cell number; while remodeling NK population, there is, indeed, an age-related redistribution of NK subsets. In particular, there is a decrease in the CD56bright pool, and an increase in the CD56dim CD57+ population [34].

Ageing, Monocytes/Macrophages, and Autoimmunity

Age-related impairment in macrophage activity and functioning results in alterations in the TLR biochemical cascade (in particular, TLR1 and TLR4), expression of MHC class II following IFN-γ stimulation, polarization, differentiation, phagocytosis, release of reactive oxygen species and of IL-6 and TNF-α, wound healing, and tissue regeneration, among others [35]. Further, the decline in the proteasome-mediated autophagy and mitophagy pathways progressively leads to accumulation of altered molecules, resulting into an autoreactive/autoimmune profile [35]. However, most human studies focus on monocytes, and further research on macrophages is warranted.

Ageing, Neutrophils, and Autoimmunity

Neutrophils, an important part of the innate immune system, represent the largest pool of granulocytes. While not changing the total number of polymorphonuclear leukocytes, ageing, in contrast, causes several alterations in neutrophil functioning and activities, impairing calcium mobilization, actin polymerization, granulocyte-macrophage colony-stimulating factor (GM-CSF) release, oxidative burst, and the ability to develop a proper antioxidant shield (for example, releasing superoxide anion radical), microbicidal capacity, phagocytosis, and chemotaxis, among others. Also, adhesion and responses to soluble factors (including GM-CSF), bacteria - N-formylmethionyl-leucyl-phenylalanine, lipopolysaccharide, or endotoxin - or to phorbol 12-myristate 13-acetate are altered. Molecule recruitment into lipid raft, apoptosis, and signal transduction are impaired, too [36].

However, there is a dearth of information concerning the relationship between senescent neutrophils and autoimmunity [36]. The major function of neutrophils in autoimmunity is net formation. Further, it could be speculated that since polymorphonuclear leukocytes act as APCs to lymphocytes via major histocompatibility complex class I and release important mediators like IFN-γ, IL-12, and IL-18, their impairment could result in an inappropriate T cell response. Further, neutrophils act also as accessory cells in superantigen-mediated T cell activation [36]. Potentially, also this factor could play a role in the formation of autoantibodies.

Ageing, Dendritic Cells, and Autoimmunity

Dendritic cells, being APCs, are fundamental for ensuring self-tolerance. With ageing, they exhibit decreased propensity to migration, impaired production and release of IL-12 and of IFN-α [19]. Moreover, antigen processing and presenting capacity, micropinocytosis, endocytosis, phagocytosis, and TLR functioning seem to be impaired [19]. Further, dendritic cells can react to apoptotic cells and intracellular self-antigens, leading to autoimmune events [13].

Protective Factors

However, there are also factors and mechanisms that may exert an antiageing effect. For example, some studies found that the increased production of peripheral T-regulatory cells, such as CD4+ CD25highFoxP3+ Treg cells, can counteract the formation of autoantibodies, protecting against the insurgence of autoimmune diseases [30].

The existence of these protective factors is very important in that it can explain, at least partially, the apparent paradoxes, i.e. an autoimmune disorder occurs despite the weakened immune system and the epidemiological/clinical incidence rate among elders, which is lower than expected, taking into account the high autoantibody levels [37]. On the other hand, the incidence and, above all, the burden of autoimmune disorders appear to be higher in the elderly, with some diseases, like polymyalgia rheumatica and temporal arteritis, being practically nonexistent in younger people [37].

Autoimmune diseases are a considerable cause of morbidity and mortality, and affect 5-10% of the world population. However, each disease involves a specific age group (Table 3) [38].

Table 3

Comparison of the age-related onset of autoimmune diseases among the elderly and young to middle-aged subjects

Comparison of the age-related onset of autoimmune diseases among the elderly and young to middle-aged subjects
Comparison of the age-related onset of autoimmune diseases among the elderly and young to middle-aged subjects

Giant cell arteritis (GCA) is a rare disease with an incidence of 200 cases per 100,000 people [39]. GCA often affects individuals aged >50 years differently from most autoimmune diseases. Its prevalence is approximately 0.2%, with a peak incidence occurring among subjects aged 70-80 years.

Systemic lupus erythematosus affects more often women in the range of 30-40 years [38]. Its age-specific incidence rate among males has a maximum of 2.2 (95% CI 1.0-3.4) per 100,000 person-years at the age of 65-70 years, while in women, the incidence is peaking at the rate of 3.6 cases per 100,000 person-years at the age of 20-25 years, having also a second local maximum of 2.6 cases per 100,000 at menopausal age [40]. RA is highly prevalent among women aged between 40 and 60 years. Its overall prevalence in adults is of 0.81% (1.16% for women and 0.44% for men, with a female:male ratio of 2.7:1) [41]. Estimates from the “Global Burden of Disease 2010” study suggest that, while the global prevalence of RA of 0.24% did not substantially change from 1990 to 2010, the overall burden as measured in disability-adjusted life years increased from 3.3 million in 1990 to 4.8 million. This increase was due to both a growth in population and increase in ageing [42]. Pemphigus vulgaris (PV) is an autoimmune blistering disease that involves the skin and mucous membranes with a mortality rate of 5-15%. The mean age at onset of PV is usually between 40 and 60 years, with an incidence that varies from 0.5 to 3.2 cases per 100,000 population [43]. Myasthenia gravis (MG) has a prevalence of about 20 cases per 100,000 subjects [44]. The mean age at onset of MG is between 20 and 40 years, involving females in 60% of cases, whilst in late-onset MG, the female:male ratio is 1:1 [45]. Worldwide incidence of autoimmune hypothyroidism ranges from 27 to 448 cases per 100,000 subjects with the peak age at onset for women being between 30 and 50 years [46]. The incidence of Graves' disease is 21-120 cases per 100,000 people, with a peak age at onset usually before the age of 40 years [46]. Multiple sclerosis incidence is 3.6 and 2 cases per 100,000 subjects in females and males, respectively, and usually affects the ages between 20 and 50 years [47]. Systemic sclerosis has an incidence ranging from 3.7 to 22.8 cases per million subjects and a prevalence from 31 to 658.6 cases per million people, with a peak age at onset between 20 and 50 years [48]. Concerning the inflammatory bowel diseases (IBDs), the incidence of ulcerative colitis ranges from 0 to 24.3 cases per 100,000 subjects, with a prevalence varying from 4.9 to 505 cases per 100,000 subjects. The incidence of Crohn disease varies from 0 to 20.2 cases per 100,000 population [49]. The age at onset of IBD has 2 peaks, the first and the largest peak among subjects of 20-40 years old and the other among those >60 years old. Another disease is primary biliary cirrhosis (PBC) which affects mainly women aged 50-65 years. However, it has been reported that antimitochondrial antibodies, which are very sensitive and specific for PBC, may appear many years before the clinical presentation [50]. The fact that there is a very long period of incubation in some autoimmune diseases, such as PBC, gives rise to the hypothesis that also other autoimmune diseases may start many years before the clinical presentation. However, in GCA subjects, the lack of specific autoantibodies makes this hypothesis very difficult to be proven.

Autoimmune disorders in the elderly have unique clinical presentations. As already mentioned, serological profiles are characterized by high auto-antibody (including rheumatoid factor or RF, antinuclear antibodies, antiphospholipid antibodies, antithyroglobulins, and antiparietal cell antibodies) levels. However, while there is an increase in autoimmunity in the elderly, this does not always translate into an increase in autoimmune diseases. Moreover, insidious and atypical symptoms may constitute a challenge for the physician [51].

Ageing implies a complex array of changes and remodeling in homeostatic mechanisms that control the immune system, both in terms of numbers and functions of the different cellular subsets. Rather than being a mere process of immunosenescence, age-related transformations redesign the immune architecture and the balance between proinflammatory and anti-inflammatory protective factors, as well as between proapoptotic and antiapoptotic signals.

However, despite advancements in both basic and clinical sciences, further studies and investigations are warranted and should be carried out in order to dissect the molecular framework induced by ageing. Some details still remain unclear or overlooked in the extant literature, such as, for example, the role of senescent neutrophils in autoimmunity. Scholars, like Dr. Sergio Giunta, have postulated some specific mechanisms at the base of the so-called auto-innate-immunity syndromes [52]. Also, the role of gender differences in autoimmune disorders should be better explored.

Even though some notable longitudinal studies, such as the Swedish OCTO and the NONA trials [53], have contributed to a better understanding of age-related immune transformations, future research in the field of immunogeriatrics is warranted.

Smith M: Review lectures on senescence. I. The causes of aging. Proc R Soc Lond 1962;B157:115-127.
Ferrucci L, Giallauria F, Guralnik JM: Epidemiology of aging. Radiol Clin North Am 2008;46:643-652.
Freundlich B, Altman C, Snadorfi N, Greenberg M, Tomaszewski J: A profile of symptomatic patients with silicone breast implants: a Sjogrens-like syndrome. Semin Arthritis Rheum 1994;24:44-53.
Stout MB, Justice JN, Nicklas BJ, Kirkland JL: Physiological aging: links among adipose tissue dysfunction, diabetes, and frailty. Physiology 2016;32:9-19.
Brown-Borg HM, Borg KE, Meliska CJ, Bartke A: Dwarf mice and the ageing process. Nature 1996;384:33.
Jin K: Modern biological theories of aging. Aging Dis 2010;1:72-74.
Tosato M, Zamboni V, Ferrini A, Cesari M: The aging process and potential interventions to extend life expectancy. Clin Interv Aging 2007;2:401-412.
Coppé J-P, Desprez P-Y, Krtolica A, Campisi J: The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol Mech Dis 2010;5:99-118.
Castelo-Branco C, Soveral I: The immune system and aging: a review. Gynecol Endocrinol 2013;30:16-22.
Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S: Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 2007;128:92-105.
De la Fuente M, Miquel J: An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging. Curr Pharm Des 2009;15:3003-3026.
Ramos-Casals M, García-Carrasco M, Brito MP, López-Soto A, Font J: Autoimmunity and geriatrics: clinical significance of autoimmune manifestations in the elderly. Lupus 2003;12:341-355.
Lindstrom TM, Robinson WH: Rheumatoid arthritis: a role for immunosenescence? J Am Geriatr Soc 2010;58:1565-1575.
Aw D, Palmer DB: The origin and implication of thymic involution. Aging Dis 2011;2:437-443.
Pfister G: Naive T cells in the elderly: are they still there? Ann NY Acad Sci 2006;1067:152-157.
Sempowski GD, Hale LP, Sundy JS, Massey JM, Koup RA, Douek DC, Patel DD, Haynes BF: Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy. J Immunol 2000;164:2180-2187.
Pereira BI, Akbar AN: Convergence of innate and adaptive immunity during human aging. Front Immunol 2016;7:445.
Xia J, Wang H, Guo J, Zhang Z, Coder B, Su DM: Age-related disruption of steady-state thymic medulla provokes autoimmune phenotype via perturbing negative selection. Aging Dis 2012;3:248-259.
Ponnappan S, Ponnappan U: Aging and immune function: molecular mechanisms to interventions. Antioxid Redox Signal 2011;14:1551-1585.
Goronzy JJ, Weyand CM: Ageing, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity - catalysts of autoimmunity and chronic inflammation. Arthritis Res Ther 2003;5:225-234.
Sansoni P, Vescovini R, Fagnoni F, Biasini C, Zanni F, Zanlari L, Telera A, Lucchini G, Passeri G, Monti D, Franceschi C, Passeri M: The immune system in extreme longevity. Exp Gerontol 2008;43:61-65.
Weyand CM, Fulbright JW, Goronzy JJ: Immunosenescence, autoimmunity, and rheumatoid arthritis. Exp Gerontol 2003;38:833-841.
Tabarkiewicz J, Pogoda K, Karczmarczyk A, Pozarowski P, Giannopoulos K: The role of IL-17 and Th17 lymphocytes in autoimmune diseases. Arch Immunol Ther Exp 2015;63:435-449.
Mellanby RJ, Thomas DC, Lamb J: Role of regulatory T-cells in autoimmunity. Clin Sci (London) 2009;116:639-649.
Mehr R, Melamed D: Reversing B cell aging. Aging 2011;3:438-443.
Szabo P, Shen S, Telford W, Weksler ME: Impaired rearrangement of IgH V to DJ segments in bone marrow Pro-B cells from old mice. Cell Immunol 2003;222:78-87.
Frasca D, Riley RL, Blomberg BB: Humoral immune response and B-cell functions including immunoglobulin class switch are downregulated in aged mice and humans. Semin Immunol 2005;17:378-384.
Weiskopf D, Weinberger B, Grubeck-Loebenstein B: The aging of the immune system. Transplant Int 2009;22:1041-1050.
Duggal NA, Upton J, Phillips AC, Sapey E, Lord JM: An age-related numerical and functional deficit in CD19+CD24hiCD38hiB cells is associated with an increase in systemic autoimmunity. Aging Cell 2013;12:873-881.
Naradikian MS, Hao Y, Cancro MP: Age-associated B cells: key mediators of both protective and autoreactive humoral responses. Immunol Rev 2015;269:118-129.
Vadasz Z, Haj T, Kessel A, Toubi E: Age-related autoimmunity. BMC Med 2013;11.
Rubtsov AV, Rubtsova K, Fischer A, Meehan RT, Gillis JZ, Kappler JW, Marrack P: Toll-like receptor 7 (TLR7)-driven accumulation of a novel CD11c+ B-cell population is important for the development of autoimmunity. Blood 2011;118:1305-1315.
Hazeldine J, Lord JM: The impact of ageing on natural killer cell function and potential consequences for health in older adults. Ageing Res Rev 2013;12:1069-1078.
Montoya-Ortiz G: Immunosenescence, aging, and systemic lupus erythematous. Autoimmune Dis 2013;2013:1-15.
Linehan E, Fitzgerald D: Ageing and the immune system: focus on macrophages. Eur J Microbiol Immunol 2015;5:14-24.
Fortin CF, McDonald PP, Lesur O, Fülöp T: Aging and neutrophils: there is still much to do. Rejuvenation Res 2008;11:873-882.
Grolleau-Julius A, Ray D, Yung RL: The role of epigenetics in aging and autoimmunity. Clin Rev Allergy Immunol 2009;39:42-50.
Ramos-Casals M, Brito-Zerón P, Kostov B, Sisó-Almirall A, Bosch X, Buss D, Trilla A, Stone JH, Khamashta MA, Shoenfeld Y: Google-driven search for big data in autoimmune geoepidemiology: analysis of 394,827 patients with systemic autoimmune diseases. Autoimmun Rev 2015;14:670-679.
Berti A, Campochiaro C, Cavalli G, Pepe G, Praderio L, Sabbadini MG, Dagna L: Giant cell arteritis restricted to the limb arteries: an overlooked clinical entity. Autoimmun Rev 2015;14:352-357.
Brinks R, Hoyer A, Weber S, Fischer-Betz R, Sander O, Richter JG, Chehab G, Schneider M: Age-specific and sex-specific incidence of systemic lupus erythematosus: an estimate from cross-sectional claims data of 2.3 million people in the German statutory health insurance 2002. Lupus Sci Med 2016;3: e000181.
Symmons D: The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology 2002;41:793-800.
Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L: The global burden of rheumatoid arthritis: estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis 2014;73:1316-1322.
Ahmed AR, Shetty S: A comprehensive analysis of treatment outcomes in patients with pemphigus vulgaris treated with rituximab. Autoimmun Rev 2015;14:323-331.
Phillips LH: The Epidemiology of myasthenia gravis. Ann NY Acad Sci 2003;998:407-412.
Pekmezovic T, Lavrnic D, Jarebinski M, Apostolski S: Epidemiology of myasthenia gravis (in Serbian). Srp Arh Celok Lek 2006;134:453-456.
McLeod DSA, Cooper DS: The incidence and prevalence of thyroid autoimmunity. Endocrine 2012;42:252-265.
Alonso A, Hernan MA: Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology 2008;71:129-135.
Barnes J, Mayes MD: Epidemiology of systemic sclerosis. Curr Opin Rheumatol 2012;24:165-170.
Ananthakrishnan AN: Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol 2015;12:205-217.
Mousa HS, Carbone M, Malinverno F, Ronca V, Gershwin ME, Invernizzi P: Novel therapeutics for primary biliary cholangitis: toward a disease-stage-based approach. Autoimmun Rev 2016;15:870-876.
Ramos-Casals M, Brito-Zerón P, López-Soto A: Autoimmune diseases in the elderly: systemic lupus erythematosus and Sjögren's syndrome. Aging Health 2008;4:389-397.
Giunta S: Is inflammaging an auto(innate)immunity subclinical syndrome? Immunity Ageing 2006;3:12.
Wikby A, Ferguson F, Forsey R, Thompson J, Strindhall J, Lofgren S, Nilsson BO, Ernerudh J, Pawelec G, Johansson B: An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J Gerontol A Biol Sci Med Sci 2005;60:556-565.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.