Hindawi Publishing Corporation
Autoimmune Diseases
Volume 2013, Article ID 267078, 15 pages
http://dx.doi.org/10.1155/2013/267078
Review Article
Immunosenescence, Aging, and Systemic Lupus Erythematous
Gladis Montoya-Ortiz
Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario,
Carrera 24 No. 63C-69, Bogota, Colombia
Correspondence should be addressed to Gladis Montoya-Ortiz; gladis.montoya@gmail.com
Received 30 June 2013; Accepted 18 August 2013
Academic Editor: Yehuda Shoenfeld
Copyright © 2013 Gladis Montoya-Ortiz. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Senescence is a normal biological process that occurs in all organisms and involves a decline in cell functions.This process is caused
by molecular regulatory machinery alterations, and it is closely related to telomere erosion in chromosomes. In the context of the
immune system, this phenomenon is known as immunosenescence and refers to the immune function deregulation. Therefore,
functions of several cells involved in the innate and adaptive immune responses are severely compromised with age progression
(e.g., changes in lymphocyte subsets, decreased proliferative responses, chronic inflammatory states, etc.). These alterations make
elderly individuals prone to not only infectious diseases but also to malignancy and autoimmunity. This review will explore the
molecular aspects of processes related to cell aging, their importance in the context of the immune system, and their participation
in elderly SLE patients.
1. Introduction 2. Aging Molecular Mechanisms
Aging can be defined as the progressive decay of tissue func- One of the most striking features of cell aging is its close rela-
tions which eventually results in organ dysfunction and tionshipwith telomere length [3].There is an inverse relation-
death.This declinemay be the result of the loss of postmitotic ship between telomere length and cellular aging; for example,
cell function or the lack of replacement of such cells due very short telomeres force their cells to enter senescence.
to a decreased stem cell ability to maintain cell division Human telomeres contain guanine-rich repetitive sequences
and replication [1]. If the organism suffers damage and it is (i.e., TTAGGG) which are gradually lost in each mitotic
irreparable, the senescence or aging process will take place division. This occurs by the fact that the DNA polymerase is
by limiting the cells’ proliferative potential. Some control unable to replicate linear chromosomes in a process known as
mechanisms include differential gene expression which may telomere erosion (Figure 1) [4–6].This process functions as a
be detrimental [2]. However, there is a renewal mechanism mitotic clock for which the length of the telomeres represents
that ensures damaged cell replacement. This singular mecha- the number of cell divisions sustained by the cells [7].
nism corresponds to a set of proliferating precursor cells that There is also a significant variability with respect to the
provide a source of cell replacement within the tissues. The speed and quality of aging between and within populations
immune system provides an interesting case of replacement: [8]. This heterogeneity results from interaction between
cells that die by apoptosis are replaced by new ones, a genetic, environmental, and stochastic factors. In this regard,
process which is essential for immune system longevity and several epigenetic alterations have been associated with aging
for adequate functionality. This review will describe main and diseases caused by aging (e.g., DNA methylation state,
molecular mechanisms implicated in immunosenescence histone modification, miRNA, etc.) [9]. Several studies about
and their relationship with autoimmune disease, particularly DNA methylation have shown loss of methylcytosines with
related to systemic lupus erythematous (SLE). age, especially in CpG islands within Alu repetitive sequences
2 Autoimmune Diseases
Defects in replication/repair machinery 3. Immunosenescence
One characteristic of elderly people is their inability to
respond properly to vaccines and infections. This condition
could be the result of their low immune system efficiency
[14] and occurs because of thymic involution in which
Genetic defects Chronic viral infections the thymus loses its ability to produce and replace näıve
T cells on the periphery. As a result, thymic dysfunction
produces a decrease in cell-mediated response to foreign
Telomere antigens, self-tolerance, and näıve T-cell population. In
erosion turn, it could increase the autoproliferation of T cells and
eventually the induction of premature T-cell maturation
which would also conduce to tolerance reduction [15]. These
alterations lead to not only modifications in lymphocyte
subsets but also to functional changes in cell population
subsets. For instance, longitudinal studies have demonstrated
an association between immunosenescence and an increase
in cytomegalovirus (CMV) anergic CD8 T cells [16].
One of the main characteristics of the immune system is
the constant renewal of its cells. At the same time, this renewal
Aging Environmental, emotional, is highly dependent on the efficiency of telomere mainte-
and psychological stresses nance. Immune system cells are derived from hematopoietic
progenitor cells that come from myeloid and lymphoid lin-
eages. These cells are constantly dividing and differentiating
Figure 1: Factors related to telomere erosion. The mechanisms throughout their lifespan and that leads to changes in their
contributing to the loss of telomere length include genetic defects, telomere length. Note that a high rate of telomere loss in the
chronic viral infections, defects in repair machinery, aging, and first years of life has been observed, perhaps because of their
stress. high rate of mitotic division. However, this telomere loss is
not a linear process over time since, in older people, it is
possible to find significant telomere erosion. In fact, several
studies have shown a decline in the length of telomeres with
and endogenous retroviral sequences. On top of this, a study aging [17]. A lot has been written regarding the relationship
of monozygotic twins showed that, for other young people, between aging, thymic degeneration, and changes in the
they retain similarmethylation profileswhile other twinswho bone marrow cells [18–20]. However, we will focus only on
were between 50 and 60 years old had different methylation immune senescence with an emphasis on circulating cell
profiles and an H3 and H4 differential acetylation state [10]. populations.
Another mechanism related to epigenetic changes in There are reports about age-related changes in peripheral
aging involves chromatin remodeling. This includes H3K9, blood cell populations: increase in monocytes, decreased
H3K27, and H4K20 trimethylation, decreased H3K9 acetyla- lymphocytes, decrease in naı̈ve cells, and increase in mem-
tion, and increased H3S10 phosphorylation [11]. A decrease ory cells (Table 1) [21]. Curiously, memory T cells (CD4
+-
CD45RO+ and CD8+-CD45RO+in H3K27 methylation together with an augmentation in ) increase with age and are
H3S10 phosphorylation supports the idea of a change in the preferentially located in tissue, whereas there is a similar
heterochromatin and euchromatin dynamics in aging cells. proportion ofCD45RA
+ andCD45RO+ subsets in peripheral
In addition, there are several chromatin remodeling-related blood [22]. Unlike somatic cells, lymphocytes have a robustcapability to proliferate given their clonal expansion and
proteins that suffer alterations during aging.These include the present an overexpression in the telomerase. This process
histone deacetylases (HDACs), the sirtuin 1 (SIRT1) protein, ensures no significant telomere shortening during each divi-
and the histone methyltransferases [12]. sion. Interestingly, T cells possess several special features
Finally, several studies in both murine and humans have regarding their phenotype and their telomere length. T-cell
shown that miRNAs may influence aging and longevity. Re- memory cells have shorter telomeres than näıve T cells, and
cently, multiplemiRNAs related to aging have been described CD28+ T cells have longer telomeres than CD28− T cells.
including lin-4, miR-1, miR-145, miR-140, miR-34a, andmiR- Immune aging or immunosenescence not only affects
449th, and some of them modulate cell senescence critical adaptive response but also has implications in the innate
molecules such as class I HDAC, SIRT1, p21, p53, and response (Table 1) [23]. It has been found that older individu-
pRb. Another important miRNA related to TCR signaling als who exhibit a breakdown of their innate immune barriers
(miR181a) has serious implications in elderly people and such as epithelial skin barriers, lungs, and gastrointestinal
autoimmunity (this topic will be discussed later). Recently, tract could be vulnerable to a pathogen attack. Among the
Liu et al. summarized themiRNAs involved in cell senescence cell types involved in innate response, there are neutrophils,
[13]. macrophages, and natural killer (NK) cells, which also suffer
Autoimmune Diseases 3
Table 1: Age-associated changes in immune cell populations and functions.
Cell type Characteristics References
Innate immunity
↓ Phagocytic chemotaxis capability
Neutrophils ↓ Superoxide anion production [23, 70, 87, 140]
↓ Ability to respond to soluble factors (GM-CSF) and bacteria (LPS and fMLP)
↓Molecule recruitment into lipid raft, apoptosis, and signal transduction
↓ Cell number, antigen presentation, TLR-mediated signaling, IFN I/III production,
Dendritic cells chemotaxis, and endocytosis [23, 102, 141]
↓ Ability to stimulate lymphocytes in the ill elderly
↑ Function in the healthy elderly
↓ Phagocytic activity and chemotaxis
↑ Synthesis of proinflammatory cytokines (IL-6, IL-8, TNF-𝛼, and IL-1𝛽)
Macrophages ↓ Apoptosis, superoxide production, and signal transduction [23, 87, 142]
↓ TLR expression and function
↑ PGE2 production
↓MCH class II production
↑ CD56dimCD57+ population
↓ Function of cytotoxicity
NK cells ↓ Secretion of IFN-𝛾 induced by Interleukin 2 (IL-2) [72, 143, 144]
↓HLA-DR, IFN-𝛼, CD57, and CD95
↓ Cell proliferation
↑ Production of IL-1, IL-4, IL-6, IL-8, and TNF-𝛼
Adaptive immunity
Cellular response
Thymus Involution from age of 9 months, thymic remnant after 50 years [20, 145]
Variable number (↓ proliferation to PHA, varying age, and health status)—HLA
B8/DR3 associated with high proliferative responses
↑ Proportion of memory cells (CD45RO+), especially tissue CD8+
↓ Proportion of naı̈ve cells (CD45RA+)
↓ Proliferative capacity
↓ Synthesis of IL-2 receptor and IL-2 in memory cells
↓ CD28+
↑ CD28− T cells—mainly CD8+ CD28− (characterized by oligoclonal expansion,
shortening of telomeres, potentially decreased proliferation, resistance to apoptosis,
T Cells and increased production of TNF-𝛼 and IL-6) [14, 145–147]
↓ CD4 T lymphocytes
Change fromTh1 response to Th2 response with ↓ cell-mediated responses directed
against intracellular bacteria (Th1 function) and relative preservation of humoral
response (Th2 function)
↓ Treg population (CD4+ CD25+) that plays a role in the manifestations of
autoimmunity
Impaired immunological synapse formation and signaling pathways (calcium
response and phosphorylations)
↓ CD4/CD8 rate
Humoral response
↓ Pre-B lymphocytes with peripheral B lymphocyte count unchanged
↑ CD5+ B cells (CD19+ CD5+ clones B) that produce low affinity antibodies without
cooperation of T cell
B Cells ↓ Näıve B cells [14, 33, 50, 53, 145, 148]
Accumulation of memory B cells with ↓ diversity and affinity of antibodies
Reaching primary humoral response (dependent T cell cooperation).
Conserved secondary humoral response
4 Autoimmune Diseases
Table 1: Continued.
Cell type Characteristics References
↑ Serum levels of IgA and IgG (IgG1, IgG2, and IgG4).
Immunoglobulins Monoclonal immunoglobulin production by CD19
+ CD5+ clones. [51, 113]
Secretion of non-organ-specific self-antibodies (rheumatoid factor, antinuclear
antibodies, antiphospholipid antithyroglobulines, and parietal cells).
↓ IL-2 production because of the following:
Interleukins ↓ cooperation of T cells with antibody producer B cells, [14, 106, 145]
↑ production of IL-4, IL-6, IL-8, IL-10, and TNF-𝛼,
↓ production of IL-1 and IFN-𝛾.
functional alterations through aging (Table 1). Immunose- T cells. Changes in surface molecules may have a negative
nescence also affects the response to immunization.There are impact onT-cell activation by increasing phosphatase expres-
several reports indicating low response to infectious agents in sion such as DUSP family. Furthermore, a study evaluated the
elderly individuals [24, 25]. Latent proinflammatory status in effect of aging on surfacemolecule gene expression and found
old subjects is due to involution of thymus with subsequent that IL-6R, CD8, CD27, and CD28 are downregulated while
alteration of function and balance of näıve, effector, and ILT2 (CD85j), KLRG,KIR, CD44, CD96, Klrf1, andCD94 are
memory cells. This status combined with the presence of upregulated [30, 31]. Some of these molecules (ILT, KLRG,
common and cumulative viral infections in the elderly (such and KIR) function as negative regulators of TCR activation
as cytomegalovirus and Epstein-Barr virus) produces overall and proliferation (at least in murine models) or as specific
responses, loss of ability to control infectious diseases, and molecules of particular T cells such as cytomegalovirus
decreased response to vaccinations. The cytokine environ- (CMV) peptide-specific T cells (KIR and ILT2). They also
mental balance (i.e., decline in the INF𝛾 : IL-10 ratio) in appear to be related to T-cell exhaustion although the rela-
challenge condition (i.e., influenza or other viral infections) tionship between aging, senescent, and exhausted T-cell gene
could decline the CD8+ cytotoxic ability, thus conducing to expressions seems to be different (Figure 2). An excellent
high IL-10 response to virus challenge. Therefore, vaccines review of this topic was done by Cavanagh et al. [32].
that arouse inflammatory cytokines would be expected to In addition to surface molecule gene expression alter-
enhance protection in elderly subjects. ation, there are other processes related to TCR signaling
alteration and aging. For instance, it is well known that a
3.1. Adaptive Immune Response cell-intrinsic environment (ROS species, DNA damage) and
a cell-extrinsic environment (cytokines) both modulate TCR
3.1.1. T Cells. T lymphocytes suffer alterations due to aging. responses, and they are also altered in the elderly. Moreover,
Most of the observed changes are attributed to alterations studies have shown that increased oxidative stress produces
during the initial activation step of the T-cell receptor (TCR). displacement of LAT from the cell membrane, thus inhibiting
There is evidence of alteration in the downstream signaling TCR signaling. Along with this, activated CD4 T cells from
of the TCR in the case of elderly people. This includes a aging humans express increased levels of metallothoineins,
decrease in intracellular free calcium, deficiencies in protein which are an important redox system [34]. Additionally, there
kinase C translocation, low Lck, ZAP70 activation, NFAT are alterations in molecules that participate in nuclear and
impairment, NF-𝜅B translocation, low ras-mitogen activated cytoplasmic signaling pathways such as DNA repair kinases
protein kinase (MAPK) pathways, and a decrease in protea- (ATM, ATR, and DNA-PKCs), which are activated not only
some activity, [26].These alterations have been demonstrated by DNA double-strand breaks (DSB) but also by telomere
in both näıve and memory T cells [27]. attrition (as we will see later). Both of them are related to
TCR has the function to discriminate between self- activation of DNA repair kinases (ATM, ATR and DNA-
antigens and respond to foreign peptides.This is caused by its PKcs) [35].
activation threshold level, and therefore, the loss of TCR sen- Host environment and specific cytokine profiles have
sitivity is closely related to aging. As mentioned before, there enormous implications in the T-cell signaling threshold.
is an importantmicroRNA—namedmiR-181a—implicated in Some cytokines such as IL-7, IL-21, and IL15 have been
this phenomenon which controls the expression of several studied in this regard. These cytokines signal through PI3K,
phosphatases related to the negative regulation of proximal STAT3, and STAT5 [36] and participate in ERK pathway
CD4 TCR signaling events. Indeed, in a murine model, activation. Note that IL-7 and IL-15 have profound impli-
miR181a overexpression lowers TCR activation threshold and cations in lymphopenia development in RA animal models.
restores TCR ability to respond to autoantigens [28]. Note This has been shown through the fact that when animals are
that miR-181a expression declines throughout life and shows primed with IL-7 or IL-15, T-cell response to autoantigens
a significant loss after the age of 70 [29]. is enabled. In addition, another cytokine implicated in sig-
Another interesting point is that there are reports indi- naling alteration during aging is the IL-6. This cytokine has
cating changes in gene expression of surface molecules on implications in the JAK-STAT pathway through activation of
Autoimmune Diseases 5
Acute infection
Chronic TCR stimulation
Reinfection or molecular mimicry Memory Rapid reexpression of TNFRSF 
Homeostatic cytokine receptors CD45RO
Chronic latent infection Senescent
Memory Telomere erosion 
T cell DNA damage responseKLRG1, CD85
KIRs
Chronic TCR stimulation ↓ CD28 
Exhausted
PD-1
CTLA-4, TIM-3, LAG-3
Chronic acute infection ↓ Homeostatic cytokine receptors
Chronic TCR stimulation
Aged naı̈ve
Näıve No exposure to antigen CD28
T cell CD27TCR  stimulation Homeostatic cytokine receptors
cross-reactivity to self-antigen CD45RA
Figure 2: Changes in the T-cell pool and individual cells during aging. A Proportion of T subsets depends on individual infection antecedents
and the environment. Memory T-cell subset can change to senescence by a chronic latent infection and chronic TCR stimulation. Meanwhile,
exhausted T cells are produced by the same type of stimulation and the chronic acute infection. Aged näıve cells are generated from näıve
cells stimulated by self-antigen exposure (adapted from [32]).
First division Second division n divisions telomerase activity on the periphery. However, the telom-
erase is activated by lymphocyte stimulation. The level of
telomerase activity decreases during successive stimulations
of the lymphocyte (Figure 3) [38]. The rate of telomere
Telomeres shortening seems to be different among CD4+ and CD8+
Centromere cells, and it has been estimated to be 33 bp/year for CD4+
T cells and 26 bp/year for CD8+ T cells. One of the most
Chromosome outstanding features of aged CD4+ näıve T cells is their
Näıve T inability to produce significant levels of IL-2 after stimulation
lifespan T-cellBim of their T-cell receptor (TCR). This inability subsequently
leads to poorTh1/Th2 polarization. However, these cells may
retain their ability to suffer Th17 differentiation [39, 40],
Age which, in turn, could favor an inflammatory and autoimmune
Figure 3: Schematic representation of T-cell divisions and their phenotype development. On the other hand, the number
implication in telomere erosion and aging. Constantly dividing cells of CD4+CD25+FOXP3+ regulatory T cells (Treg) increases
are accompanied by a decrease in their telomere length, which is (2.4-fold), and they retain and gain functions during aging.
related to aging phenotype: decreased Bim expression, increased Nonetheless, their ability to produce IL-10 is low. They may
näıve lifespan, and important functional changes. also contribute toTh17 bias (production of high levels of IL-17,
IL-21, and IL-22) and show a decrease in antitumor responses
too [40]. Meanwhile, aging CD8+ lymphocytes show a reduc-
SOCS3 transcription. Note that STAT molecules are highly tion in the diversity of the TCR repertoire, low antitumor
phosphorylated in elderly humans, a phenomenon that also response, and marked clonal expansion development but
occurs through type I interferon T-cell activation [35]. without the ability to replicate after stimulation [26]. Note
As was discussed previously, telomere attrition is very that Th2 inflammatory cytokines favor antibody production
frequent in elderly people and it is also known that T-cell by B cells, and this condition could explain autoantibodies in
replication is important for maintaining lymphocyte func- the aged population.
tion. This suggests that T-cells employ the best mechanisms One of the most important traits of immune aging is the
for telomere maintenance during clonal expansion. Indeed, loss of theCD28 surfacemarker. CD28 is one of themolecules
there is evidence that telomerase activity is highly regulated expressed inT cells that provide costimulatory signals that are
during T lymphocyte development and differentiation [37]. required for T-cell activation, T-cell proliferation, cytokine
The resting CD4+ and CD8+ and naı̈ve T cells recorded no production, and T-cell survival promotion. Loss of CD28
6 Autoimmune Diseases
Näıve ∙ Increased lifespan disease), an increase in the frequency of CD28− T cells has
∙ Reduction of Bim expression been detected [43]. It has been suggested that autoantigens
∙ Lower Ca2+ influx can lead to clonal expansion of these cells. Thus, there are
∙ Low cytokine production (IL-2)
∙ Increased IFN-𝛾 and osteopontin reports [45, 46] indicating how they can, for instance, show
∙ Reduced expansion reactivity to myelin basic protein (MBP). The presence of
CD4+ CD28− T cells in both elderly individuals and patients
Memory Restricted cytokines patterns with autoimmune diseases (ADs) has supported the concept∙
CD4+ Reduced helper response that ADs are closely related to the cell aging process. In∙
∙ Poor proliferative capacity this regard, the loss of CD28 molecule could favor CTLA-4
∙ Increased lifespan interaction with their ligands (CD80 and CD86), which are
∙ Reduced expansion implicated in autoimmune phenotype too.
The main differential and functional alterations of CD4+
+
Increased apoptosis and CD8 T-cell subsets are summarized in Figure 4.Näıve ∙
∙ Weak proliferative capacity
∙ Upregulation of activation markers
∙ Suboptimal primary response to 3.1.2. B Cells. It is known that with aging, there is a decrease
infection/vaccination in not only the frequency and absolute number of pro-
∙ Low polyfunctional production B cells but also in their ability to differentiate into pre-B
of multiple effector molecules
Reduced quantity of effector (between 60 and 90%). Nevertheless, in healthy individuals,∙
proteins produced mature peripheral B-cell numbers do not change with aging;
CD8+ ∙ Altered signal transduction instead the relationship between näıve and memory cells is
∙ Reduced Bim expression altered; that is, there is an increase in long-livedmemory cells
(homeostatic expansion of antigen-experienced or activated
Memory ∙ Memory responses are defective B cells) and a decrease in näıve cells [47]. This condition
∙ Increased clonal expansion seems to depend on different factors other than genetic ones.
∙ Low repertoire diversity A study comparing old individuals with healthy centenarian
∙ Reduced synapse formation offspring could determine that centenarian offspring have
∙ Increase in number more IgD+ CD27− näıve B cells than older people. Neverthe-
Figure 4: Aged-related functional changes in T-cell subsets. Alter- less, the double negative memory cells (IgD
− CD27− B cells)
ations are produced in both memory and naı̈ve subsets. These are only found in healthy elderly individuals, and there are
alterations depend on T-cell microenvironmental history, exposures no differences between groups [48]. Recently, studies have
to stressor agents, and stochastic events. There are differences in reported a novel peripheral B-cell subset in the elderly named
changes between CD4+ and CD8+ concerning aging, but in both aging-associatedB-cell (ABC) subset (CD19+CD11b+CD11c+)
cases, there is reduction of näıve subtype, increase in lifespan, and [49]. In vitro, the ABC subset responds only to innate stimuli
defective immune response. producing secretion of autoantibodies and cytokines, and this
subset also has the ability to potentiateTh17 polarization, thus
relating it to an autoimmune phenotype.
expression is a phenotypic change associated with senescence Another important fact is the presence of alterations in
in T lymphocytes, and it has been associated with func- the repertoire of the B-cell receptor (BCR), which exhibits
tional alterations such as enhanced cytotoxicity, suppressive a decreased affinity and diversity to the antibody response
functions, and resistance of CD4+ T cells to apoptosis. Loss with aging [33]. Indeed, elderly patients have impaired B-
of CD28 expression is characterized by telomere shortening cell proliferation and activation, possibly as a result of
and reduced proliferative ability, both ex vivo and in vitro defects in their threshold of activation [26]. Also, there is
[41, 42]. At birth, virtually all T cells express CD28, but a loss of precision in distinguishing self- from non-self-
with age, the marker decreases about 40 to 50% for CD8+ antigens due to the oligoclonal expansion of the B lymphocyte
T cells and 85 to 90% for CD4+. This reduction in the subpopulationwith a high proportion of antigen-experienced
markers is attributed to repeated antigenic stimulation in cells [50].This subpopulation expresses CD5 on their surface,
peripheral blood [43]. However, when the CD28 is lost, cells thus giving them the ability to produce low affinity antibodies
suffer reprograming and, as a consequence, they express independently of T cells. In the context of autoantibody
new receptors such as KIR, CD70, and perforin. Moreover, generation, this is important for triggering an autoimmune
phenotypic CD28− T-cell characteristics include interferon response.
gamma (IFN-𝛾) production, potent cytotoxic capability, and Moreover, the germinal centers (GC) from elderly peo-
CD158, CD158b, CD158J, DAP12, CD94, and CD244 receptor ple are small and have few cells producing IgM. In these
expression (similar to NK cell characteristics). These recep- individuals, levels of immunoglobulins, especially IgA and
tors give them the potential to interact with accessory cells IgG, are increased [51]. Furthermore, it has been shown that
such as mesenchymal cells, which include the fibroblasts of IgG+/IgA+ B-cell subsets (both CD27+ and CD27−) express
inflamed joints [44]. Furthermore, in elderly individuals with Ig mutated genes in their variable regions and high levels of
chronic viral infections and autoimmune diseases (e.g., mul- CD80 and CD86 on their surface, thus exhibiting a similar
tiple sclerosis (MS), rheumatoid arthritis (RA), andWegener’s B-cell memory phenotype [52]. According to the reports,
Autoimmune Diseases 7
Age
Bone marrow progenitors
• HSC changes
• Decreased B-cell production
• Developing repertoire shifts
• Reduced BM output
Peripheral preimmune pools
• Altered pool size
• Reduced BCR diversity and affinity
• Altered homeostatic relationship
• Increased tumor rates
Antigen-experienced pool
• Poor memory responses
• Poor response to vaccination  
  and new infections
• Increased rates of ADs  and tumors
Figure 5: Age-related changes in the generation and function of B cells. There is a reduced output of B cells in the bone marrow, which
induces accumulations in the periphery of antigen-experienced subsets with poor immune response and low diversity. HSC: hematopoietic
stem cell; BCR: B-cell receptor; BM: bone marrow (adapted from [33]).
this subtype of cells declines with aging [51]. Finally, aging such as TNF-𝛼 and IL-6 [56], and high levels of NF-𝜅B acti-
B cells have been observed to produce antibodies with low vation. However, they do not exhibit upregulation of CD86
avidity because of their somatic hypermutation deterioration and CD80 molecules on their surface, which suggests that
which leads to a gradual decline in the humoral response. they are partially activated. Another important characteristic
Nevertheless, repertory changes are not synchronous with is that they are more reactive to self-antigens compared with
aging, and decreased diversity has been related to poor health their young counterparts and display an impaired clearance
status [53]. of apoptotic cells and antigens [57]. This could produce a
An interesting study [54] done to evaluate näıve higher presentation of self-antigens and, consequently, an
(CD19+CD27−) and memory (CD19+CD27+) switch B-cell activation of autoreactive lymphocytes. An interesting point
subsets in elderly individuals showed a decrease in total B is that these partially activated DCs have a greater ability to
cells, and, although the quantity of näıve cells increased in stimulate T cells, thus indicating that their ability to induce
percentage, they decreased or remained constant in number. tolerance to self-antigens is affected.
Moreover, another striking result is that the B-cell memory Some explanations have been given regarding partially
(CD27+) increased in percentage but not significantly. In activated DCs: (1) an increased age-associated level of proin-
contrast, memory cells producing IgM subtype decreased in flammatory mediators and (2) age-associated modifications
number but not in percentage. Finally, the memory switch in autoantigens, which increase their immunogenicity [58].
cells decreased both in number and percentage with aging. Note that the functions of myeloid DCs (mDCs) such
An interesting point about memory B cells is that they have a as IL-12 production, chemotaxis, and their ability to activate
hyporesponsive state to antigen-induced activation with less näıve CD4 T cells via antigen presentation appear to be
clonal expansion or less ability to differentiate into antibody altered in elderly individuals [57]. This inability is due to
secreting cells [55]. This condition may be caused by the decreased PI3K activation [59], which leads to activation of
decreasing number of antibody high affinity B cells that NF-𝜅B, as it was previously mentioned. This subtype of DCs
elderly people have. also shows decreased capability in their antigen processing
Taken together, these results indicate that there is an and increased expression of CD86.
accumulation of antigen-experienced B subsets in aging indi- Plasmacytoid DCs (pDCs) from elderly people, in turn,
viduals. In these cases, overall B-cell numbers are unchanged, have reduced IFN I and IFN III production after stimulation
but they vary in their functional abilities (Figure 5). via Toll-like receptor (TLR) [60]. Additionally, they have an
impaired ability for antigen presentation to CD4 and CD8 T
3.2. Innate Immune Response cells.
3.2.1. Dendritic Cells. Dendritic cells (DCs) are important 3.2.2. Neutrophils. Neutrophils are the first immune cells that
because they function as a checkpoint between immunity and are recruited to the site of infection or to the tissue damage
tolerance. DCs from aging individuals display a basal level of [61]. Besides, there is a debate about whether the numbers of
activation, increased secretion of proinflammatory cytokines neutrophils change with age, but a variety of studies suggest
8 Autoimmune Diseases
that there are no number changes. However, there are reports Monocytes respond to inflammation by their differentiation
indicating several functional defects in neutrophils from the into macrophages and dendritic cells. Studies have demon-
elderly [62, 63]. The main function decreased in neutrophils strated that CD56+ monocytes subpopulation (high produc-
is the chemotaxis, followed by the phagocytic activity. Both ers of TNF-𝛼 via TLRs 2 and 4) is increased with age while
of them affect the time needed for the neutrophils to reach their counterpart (CD56−) is decreased [82]. The increment
the infection site and their ability to control the infections, of CD56+ monocytes is paradoxical with the alteration in
respectively [62, 64, 65]. These two alterations are closely macrophage TLR function. A study revealed a decrease in
related to increased infections in elderly subjects. IL-6 and TNF-𝛼 via TLR1/2 in the elderly, and this fact was
Low phagocytic activity has been associated with reduced related to the decrease of TLR1 on monocyte surface [83].
surface expression of the Fc𝛾 receptor CD16 [64]. Signaling These results are contradictory with another report which
function of other receptors involved in activation such as indicates substantial increase of the same cytokines [21].
fMLp, TLR, retinoic-acid-inducible-gene-1-protein- (RIG- Thus, this issue required further confirmation, which can
1-) like helicases (RLRs), nucleotide binding domain and be accomplished by the study of phenotype subpopulations
leucine-rich-repeat-containing proteins (NLRs), and C3b has (according to the expression levels of the receptors and
been reported to be significantly altered.This alteration is due proteins). In this regard, age-associated changes in TLRs
to changes in signaling molecules but not in the number of expression on monocytes have been performed [84]. A
their receptors [66, 67]. Some downstream signaling events particular study showed that old patients infected with West
include phosphoinositide-3 kinase (PI-3 K), MAP kinase, Nile virus have a persistent TLR3 expression onmacrophages’
Calcium, protein kinase B, and SHP-1 and Jak-STATpathways surface while young patients have reduced expression of this
[68]. Interestingly, these alterations are produced by changes receptor [85]. This feature may produce a higher inflamma-
in membrane composition including lipid rafts distribution tory response with the subsequent increased morbidity of
and their structure [69, 70]. elderly subjects.
Furthermore, there are reports about age-related upregu-
3.2.3. NK and NKT Cells. NK cells participate in the innate lation of CD80 molecule on monocytes after TLR activation
immune defense against intracellular pathogens and tumor [86] which is associated with production of a protective
cells, and theymediateMHC-independent cytotoxicity.There response to influenza vaccination.
are several studies indicating a remodeling of these cells Another important age-associated feature of both mono-
in elderly individuals. The percentage and absolute number cytes and macrophages is that several of their receptors
of NK cells are increased in healthy aging, and they are become altered, thus producing cells dysfunction. This pro-
characterized by the increment of CD57 expression and duces that clearance of free radical production and phago-
expansion of CD56dim NK cells (mature and highly differ- cytosis are reduced in monocyte/macrophages in the elderly
entiated cells) [71, 72]. Other important features of these cells [87]. Also, these alterations may lead to deregulation in
from aging subjects are decreased proliferative response to clearing of apoptotic cells by macrophages, thus precipitating
cytokines, altered expression of some NK receptors such as the exacerbation of inflammatory-aging condition.
natural cytotoxicity receptors (NCRs) [73], CD226 [74], and
KLRG-1 [75], and increased expression of HLA-specific killer 4. Infection and Immunosenescence
immunoglobulin-like receptor [73].
At functional level, cytotoxic and proliferation ability and To produce an adequate response to large numbers of
cytokines/chemokines (such as INF , RANTES, MIP1a, and pathogens throughout life, there are homeostatic mecha-𝛾
IL8) production of NK cells are reduced [76]. nisms guaranteeing competent memory and a naı̈ve cell
NKT cells are important in the clearance of bacterial and pool for prolonging the survival of memory cells. However,
viral infections as well as in regulation of immune tolerance under the conditions of advanced age, these mechanisms
and autoimmunity [77]. NKT cells are characterized by are seriously affected. As we have seen, during aging, many
expression of a TCR encoded by V𝛼14/V𝛽8.2 gene segments. changes occur in the immune system, which means that
The effects of aging on NKT cell number and function immunosenescence becomes a factor contributing signifi-
have been little studied. In general, nowadays, it is accepted cantly to a higher risk and severity of infections. The most
that the absolute number of NKTs within the lymphoid organ important diseases in the elderly are urinary tract infections,
increases [78]. In addition, there are reports that show a influenza andpneumonia, chronic viral infection reactivation
decrease of proliferative ability and low number of CD1d- (herpes virus and varicella-zoster virus), as well as bacterial
restricted NKT cells in the peripheral blood [79]. Studies (tuberculosis), fungal (candidiasis), or parasitic infections,
of inhibition of NKT cell activation demonstrated age- and,more rarely, opportunistic infections such asClostridium
associated decay of proliferative response and retarded type and Staphylococcus [88, 89]. Although the immune response
hypersensitivity responses [80]; in addition, results showed to antigens may be preserved in elderly individuals, their
that NKT cells contribute to increments of IL-4 and IL-10 ability to be immunized against new antigens is reduced.This
production and decreased IFN- may be the result of an increase in the proportion of memory𝛾 in aging subjects [81]. cells and progressive decrease in naı̈ve cells from the thymus
[90].
3.2.4. Monocyte/Macrophages. Other essential components While it is true that aging is associatedwith the emergence
of innate immune response are macrophages andmonocytes. of infectious diseases, it is also true that these infectious
Autoimmune Diseases 9
events will promote aging. It is well known that viral function-associated antigen 1 (LFA-1)—a protein which is
infections (particularly the herpes virus family) are strong associated with certain ADs—is hypomethylated with age
stressors which alter the lymphocyte phenotype and func- and thus overexpressed in aging cells [100]. Furthermore,
tionality, altered cytokine profile, resistance to apoptosis, there are other reports on elderly subjects indicating DNA
and shortened telomeres [91]. These features are similar to hypomethylation states which could lead to an increase in the
those found in the elderly; thus it is possible that viral immunogenicity [58]
infections could represent an important extrinsic factor for Another important aspect of aging that is closely related
aging by the repeated antigen stimulation characteristic of to autoimmunity in general and ADs in particular is the
persistent latent infections [92]. Furthermore, it has been increase in inflammatory cytokines and chemokines such
suggested that latent herpes virus infections are primarily as TNF-𝛼, C-reactive protein, IL-8, MCP1, and RANTES
responsible for in vivo generation of senescent CD8+ T cells, [102–104]. There is a substantial amount of evidence of age-
perhaps due to constant and prolonged virus-specific T-cell associated alterations in the T-cell cytokine profile which
proliferation [93]. Additionally, the Epstein-Barr virus (EBV) could contribute to development of ADs. Studies have shown
latent infection has also been associated with telomere short- that there is a change from Th1 to Th2 molecules (mainly
ening in antigen-specific CD8− T cells because EBV antigens IL-4 and IL-6) in the cytokine profile as age advances [105].
cause a decrease in telomerase activity associated with T- IL-6 is a potent proinflammatory cytokine closely related to
cell proliferation [94]. In contrast (and related to telomere disability in patients with RA; therefore, IL-6 represents a
erosion and its relationship with CD28molecule expression), therapeutic target for this disease [106]. In addition, there
the majority of T cells in a study done by Vescocini were are reports of an imbalance between Th17 and Treg cells. A
CD28+ unlike what was found for CMV, which were mainly considerable number of IL-17-secreting naı̈ve CD4+ T helper
CD28− [95]. During human immunodeficiency virus (HIV) cells have been detected in the elderly in contrast to reduced
infection, in turn, it has been reported that early presence IL-17-secreting memory CD4+ T helper cells [107].
of CD8+ CD28− T cells is a predictive characteristic of rapid Some ADs are very frequent in younger patients and
disease progression [96]. are not limited to elderly people although the occurrence or
These data indicate that chronic infections during aging presence of autoantibodies is greater at advanced age [108–
produce significant changes in the CD8+ cell subset. Addi- 111]. Autoantibody production such as rheumatoid factor, as
tionally, this shows that expansion of CD28− T cells is age well as antinuclear, antiphospholipid, and antithyroglobulin
dependent, and they have a positive correlation with proin- antibodies, is present during aging [109, 112]. Autoanti-
flammatory cytokines. At the same time, these cytokines body production has been attributed to altered T- and B-
are heavily involved in the pathogenesis of immunological cell functions [113], especially to the decrease in antibody
disorders which could favor the emergence of different affinity maturation. This evidence supports the idea that
pathologies including ADs. autoantibody levels may be closely related to the clinical
characteristics of the elderly and to patients with ADs.
5. Autoimmune Disease One of the important causes of dysfunctional immune
responses is telomere abnormalities which may lead to
Currently, it is clear that changes occurring in the immune autoimmunity.This observation is significant since numerous
system during aging affect the onset of ADs. This is due to studies have shown an association between mean telomere
the fact that aging is related to increased reactivity to self- length in peripheral blood mononuclear cells (PBMCs) and
antigens and loss of tolerance. The overall tendency supports different diseases [91]. This evidence suggests an increase in
this hypothesis because elderly people experience general CD8+ CD28− T-cell proportions in several pathologies such
systemic inflammation and, at the same time, they aggravate as in the case of some ADs.
degenerative diseases [97], which, in turn, increase the risk of Moreover, there are reports of telomere length alteration
developing ADs [98, 99]. Proinflammatory cytokines on gen- in patients with ADs such as RA [114, 115], scleroderma (SSc)
eral systemic inflammation (produced by viral infection) lead [116], systemic lupus erythematosus (SLE) [117], polyangiitis
to a state called inflammaging, which corresponds to the loss with granulomatosis [118], psoriasis, and atopic dermatitis
of equilibrium between adequate inflammatory response and [119], suggesting an excessive cell replication with their
efficient anti-inflammatory control in the elderly condition. corresponding telomere erosion. These findings have been
Later, in normal aging, this control fails to fully neutralize the interpreted as evidence of T-cell accelerated proliferation in
inflammatory processes. the autoimmune process.
In addition to this, it is important to remember (as we At present, it is believed that there are differences among
have seen previously) the epigenetic changes occurring in telomere abnormalities and various ADs. Some of these
elderly people and how these may affect important genes differences could be explained by the genetic background
involved in autoimmune disorder development [100]. In this of the individuals studied. For example, a study performed
regard, there are reports in which some genes associated with in patients with SSc and their family members reported
ADs are hypermethylated but others are hypomethylated. short telomeres [116]. The idea of a genetic predisposition to
For instance, FoxP3, a hypermethylated gene, is a member telomere shortening is also suggested in patients with RA,
of the forkhead transcription regulator family [101] and who exhibit telomere erosion in not only memory cells but
is associated with the development of multiple ADs. In also in näıve cells.Moreover, this evidence shows acceleration
contrast, the gene coding for the CD11a chain of lymphocyte in telomere erosion occurring at the precursor cell level [120].
10 Autoimmune Diseases
Lupus in older adults
Associated with ↑ RF and antinucelar
Sjögren’s syndrome antibodies
Milder disease course
Frequency of 3–18% Ocurrence of serositis
compared to all SLE and pulmonary
cases involvement
F/M sex ratio
from 2.5 to 9
Figure 6: General characteristics of late-onset SLE.There are different manifestations of older SLE patients compared to young patients. RF:
rheumatoid factor; F/M: female/male.
Another striking fact is that the genetic predisposition to by different reasons: ethnicity, sample size, methodology, and
short telomeres is strongly related to HLA-DR4 haplotype so forth.
which is shared by RA and T1D in some individuals [121, 122]. An important fact is that the severity of the disease
appears to decrease with age. It has been reported that
5.1. Late-Onset Systemic Lupus Erythematous. Although SLE late-onset SLE patients have milder disease course which is
is considered a disease of the reproductive stage of women, reflected in a small number of relapses per patient. Addition-
there is evidence that it occurs between 3 and 18% in ally, it was found that the prevalence of lupus nephritis and
individuals older than 50 years [123]. Despite that there are nephrotic syndrome also is lower in elderly patients.
aged SLE patients, their clinical manifestations, response to Currently, it is not clear if there is a relationship between
treatment, prognosis, and course of the disease are different telomere loss and SLE. Some studies have shown an increased
in these individuals (Figure 6). For example, clinical man- telomere erosion in SLE patients [100, 101, 131, 132], while
ifestations such as malar rash, renal disease, arthritis, and others report normal telomere length when compared with
photosensitivity are less frequent in them, while serositis, healthy controls [102, 103]. Nevertheless, it is clear that
cytopenias, and pulmonary involvement are more frequent there is a reduction in telomerase activity in näıve CD4+ T
[124–127]. In addition, it has been shown that female/male cells and an increased activity in B cells [101, 103]. In this
(F/M) sex ratio declines with age. Studies report F/M ratio regard, a recent study showed a differential expression of
from 2.5 to 9 in elderly individuals compared to from 9.1 to shelterin complexmolecules in patients with lupus [104], but,
14.4 in young people [126, 128]. unfortunately, it was not done cell specific.
A striking feature of these patients is the differential According to the report of [132], shorter telomeres are
diagnosis due to the SLE overlapping with other diseases. associated with Ro antibodies while longer ones with steroid
Late-onset rheumatoid arthritis, endocarditis, tuberculosis, therapy and increased body mass index. However this study
neoplasia, polymyalgia rheumatica, temporal arteritis, and also showed that short telomeres are not related to disease
Sjögren’s Syndrome (SS) had been described is these patients activity or immune cell turnover, but they could be good
[124, 127]. In the particular case of SS, elderly patients with predictors of premature aging.
SLE and without SS have low frequency of compromising Related to this topic, previous studies have indicated that
renal disease, lymphadenopathy, and thrombocytopenia and bone marrow mesenchymal stem cells (BMSCs) from SLE
high frequency of Raynaud’s phenomenon [129]. patients exhibit not only increased apoptosis and senescence
Besides changes in clinical and serological profiles, sero- but also impaired capacity of differentiation, immune mod-
logical profiles of aged SLE patients also exhibit alterations ulation, proliferation, and secretion of cytokines. Apoptosis
[124]. Compared to younger individuals, elderly patients and senescence in BMSCs fromSLE patients appear, to be due
with SLE have high frequency of rheumatoid factor (33% to increased favorable conditions for these processes. There
versus 20%) and antinuclear antibodies but low frequency of were described increased levels of p16INK4A, Bax, caspase 8,
antiribonucleoprotein (anti-RNP, 10% versus 21%) and anti- Fas and tumor necrosis factor-a receptor 1, and the respective
Sm (9% versus 17%). There are reports that indicate contra- ligands of the two last.There is also a decreased expression of
dictory results [130], but these differences can be explained Bcl-2, CDK4, CDK6, and p-Rb [133, 134].
Autoimmune Diseases 11
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