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Accelerated telomere shortening in rheumatic diseases: cause or consequence? Expert Rev. Clin. Immunol. 9(12), 1193–1204 (2013)

Amina ZA Dehbi1, Timothy RDJ Radstake1,2 and Jasper CA Broen*1,2 1 Laboratory of translational immunology, University Medical Center Utrecht , Lundlaan 6, 3584 EA Utrecht, The Netherlands 2 Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands *Author for correspondence: [email protected]

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Accelerated aging of the immune system (immune aging), represented by telomere shortening, has been implicated in a variety of rheumatic diseases. Studies addressing telomere shortening in rheumatic diseases so far yielded controversial results. The current review aims to provide an overview on the role of immune aging in a plethora of immune-mediated conditions including systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis. The main question this review aims to answer is whether rheumatic diseases cause accelerated aging or that accelerated aging drives rheumatic diseases. KEYWORDS: osteoarthritis • rheumatoid arthritis • SLE • systemic sclerosis • T cells • telomeres

Aging is a process that affects all cells, tissues, organs and organisms as a whole, with immune cells being some of the most noticeable targets [1]. Although not clearly understood, immunological aging seems to be linked with a variety of prominent contemporary diseases including cancer, Type 2 diabetes, cardiovascular disease and rheumatic disorders, all of which are subsequently related to both the immune system and aging [2–4]. It is well established that there is a decline in cellmediated immunity with age [5], and longevity is positively correlated with natural, healthy immunity [6]. Hence, understanding specifically how aging and immunity are related will help in laying the concrete of the path to comprehending a myriad of poorly understood diseases related to immunosenescence. Biological aging is the aging at the level of a cell, tissue or organ and can be generalized to the whole organism in some instances. As opposed to quantifying age solely by years, biological age offers a more biologically complete definition of age. It is determined by the presence and expression of molecular changes at the cellular level that need not necessarily equate with the chronological age of an individual. As a consequence, it can be used to explain interindividual variation in the rate of 10.1586/1744666X.2013.850031

aging between individuals of the same chronological age. Typically, functional capacity of immune cells would be expected to decline with increasing biological age, which is demonstrated by the inversely correlated decline inability to cope with infections with age [6]. The rate of biological aging is influenced by the levels of oxidative insult at a cellular level, which is in turn affected by factors including disease, environmental factors, lifestyle and socioeconomic factors, thereby explaining the difference in biological age among individual of similar chronological ages. One of the most used biological markers to quantify biological aging is telomere shortening. Telomeres are repetitive DNA structures, of the sequence TTAGGG, located at the ends of chromosomes offering stability and protection of the chromosomes and hence of the genome as a whole. They were primarily discovered as genes with no informative DNA at the ends of chromosomes and coined the term telogenes by Muller in 1940. It was only in the early 1970s, however, that Olovnikov explained their function as protection of crucial genetic material against the destructive effect of marginotomy [7]. Because of the end replication problem, with each DNA replication of cells, some DNA, at the ends of the chromosomes,

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Dehbi, Radstake & Broen

is lost [8]. Without telomeres, this loss per replication would be of chromosomal genetic information. With time, telomere repeats shorten in cultured somatic cells, including fibroblasts and peripheral blood lymphocytes. At a certain point, cells with short telomeres are activated to enter cellular senescence or apoptosis and therefore irreversibly lose function. As a result, telomere lengths indicate the age of cells and thus can be used as a one of the biomarkers for replicative history of individual cells or populations of cells [9]. The rate at which telomeres shorten is under both polygenic and environmental influences and is biologically dependent on the type of cell and system wherein it functions [10]. More precisely, telomere attrition rate is a function of age, oxidative stress, antioxidative defenses and cell turnover [11] and therefore telomere shortening can occur via different mechanisms. One of the nature’s ways to overcome this aging process is via a holoenzyme called telomerase, which is involved in the natural replenishment of telomere repeats in selected cell types including stem cells, sperms and lymphocytes [12]. By synthesizing novel telomeric DNA, and adding it to the ends of chromosomes, telomerase activity can circumvent the process of telomere shortening thereby increasing the cell’s proliferative lifespan. However, even in stem cells, and certainly in lymphocytes, telomerase activity is incomplete and telomere shortening still occurs progressively with age. Telomerase can also be an indicator of premature aging as implied above. Telomerase is not usually expressed by resting, untransformed somatic cells. However, transient telomerase activity can be detected in some untransformed cells of the immune system, namely progenitor cells, thymocytes, tonsillar T cells, germinal center B cells and in vitro activated peripheral blood CD4+ cells. Cellular systems that are more dependent on cell replenishment and/or cell proliferation for full functionality, and those which do not have high telomerase activity are more sensitive to telomere shortening [13] and therefore age more rapidly. The immune system is an example of such a system in which telomere length and cellular functionality are crucial, partially explaining its strong correlation with aging. Interestingly, the age of onset for most rheumatic diseases is closely linked to the age that telomere shortening becomes apparent as important hallmark of biological aging. Both processes appear often around the fifth–sixth decade of life [14]. The possible correlation between aging, altered immunity and rheumatic disorders warranted several researchers to investigate telomere shortening in rheumatic diseases. However, the answers to the direction of this correlation are often contradictory. Is decline in immunity, and development of certain rheumatic disorders, a cause or consequence of aging? Is every aged individual bound to develop such disorders, or do rheumatic disorders, propagated perhaps by genetics, lead to a higher burden on the immune system, inducing accelerated aging? Furthermore, does premature telomere shortening cause or predispose one to disease development? To examine these questions, we performed a literature review initiating with the hypothesis that the more an individual’s immune system is activated 1194

throughout life, the faster it ages. This in combination with genetics may in turn lead to a higher predisposition toward immune-related disorders. Telomere shortening, thus, would be a prelude to disease. To specifically investigate this hypothesis, we performed literature research in the following hallmark rheumatic disorders, which have been studied for their correlation with the immune system and age: rheumatoid arthritis (RA), systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and osteoarthritis (OA). Because telomeres are one of the main read-outs for accelerated aging, we explored literature on telomere length and telomerase expression for each of the hallmark disorders. A summary of the studies reviewed can be found in TABLE 1. Methods

In this review, we used two search engines: Google scholar and Pubmed. Because we were interested in telomeres and telomerase expression/activity in rheumatic disorders, and how these were perhaps related to accelerated telomere shortening, we had a list of words that we used while reviewing each disorder, and thus only modified the name of the disease in our mesh terms: SSc: • Telomere length: ‘Systemic sclerosis telomere lengths ageing’; • Telomerase activity: ‘telomerase activity systemic sclerosis’. RA: • Telomere length: ‘Rheumatoid Arthritis Telomeres Ageing’; • Telomerase activity: ‘telomerase activity Rheumatoid Arthritis’. OA: • Telomere length: ‘Osteoarthritis, telomere lengths, ageing’; • Telomerase Activity: ‘telomerase activity Osteoarthritis’; • No relevant results were found regarding studies done on telomerase expression in OA patients. SLE: • Telomere length: ‘Systemic Lupus Telomeres Ageing’; • Telomerase activity: ‘Systemic Lupus Telomerase Activity’. Only original publications were included. Studies had to describe changes in telomere length, telomerase expression or mechanisms underlying one of both to be included. Furthermore, we solely reviewed articles published after 1996. Telomeres were discovered in the 1940s and their function described in the 1970s; however, the relationship between aging, telomere length and disease only became a hot topic in the mid-late 1990s. In addition, measurement techniques have evolved, making it difficult to compare recent results with the older ones. For these reasons, we chose 1996 as our threshold for studies to review. Rheumatoid arthritis Telomere shortening in RA

RA is a chronic inflammatory, autoimmune disease characterized mainly by synovial inflammation leading to cartilage damage and Expert Rev. Clin. Immunol. 9(12), (2013)

Accelerated telomere shortening in rheumatic diseases

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Table 1. Summary of studies reviewed: summary of telomere lengths and telomerase activity in rheumatic disorders. Study (year)

Disease

Cells

Telomere length

Telomerase

Sample size (n)

Results

Ref.

Artlett et al. (1996)

SSc

Lymphocytes Fibroblasts

Yes

No

43

Significantly low TL (also in family members)

[36]

MacIntyre et al. (2008)

SSc

PBL

Yes

No

43

Longer mTRF in IssC/no TL erosion. Many patients were under NSAIDs treatment and these had longest TL

[37]

Katayama et al. (2001)

SSc

PBMCs

No

Yes

9

No difference compared with controls

[38]

Tarhan et al. (2008)

SSc SjS

PBL PBL

No No

Yes Yes

19 14

Significantly lower hTERT activity in SSc No significant difference in hTERT

[39]

Kawashima et al. (2011)

SjS

Lacrimal gland tissue

Yes

No

11

Significantly shorter TL in patients

[40]

Steer et al. (2007)

RA

Lymphocytes

Yes

No

151

Shorter TL in RA and no association with disease duration

[16]

Schonland et al. (2003)

RA

Lymphocytes HSC

Yes

No

37

HLA-DR4+ T cells significantly shorter. Significantly shorter TL of granulocytes

[17]

Koetz et al. (2000)

RA

T cells

Yes

No

51

TL not associated with age. TL significantly shorter under the age of 40 years, but not older than 40 years

[18]

Yudoh et al. (2001)

RA

PBL

No

Yes

18

RA lymphocytes had high telomerase activity. Telomerase levels correlated with clinical features

[21]

Zhai et al. (2006)

OA

PBL

Yes

No

163

Significantly shorter TL in OA

[24]

Honda et al. (2001)

SLE

PBMCs

Yes

Yes

90

Significantly increased telomerase in CD8+ CD4+ cells drive significantly low TL in early years

[29]

Haque et al. (2013)

SLE

Full blood

Yes

No

63/164

SLE patients significantly shorter telomeres. Steroid therapy patients had longer TL

[31]

Kurosaka et al. (2003)

SLE

PBMCs

Yes

Yes

30

TL did not correlate with age. Younger SLE individuals had significantly lower TL. No significant difference in older age groups

[30]

Hoffecker et al. (2003)

SLE

PBMCs

Yes

No

59

Shorter TL in SLE patients. Short telomere length was associated with vitamin B deficiency

[32]

hTERT: Human telomerase-specific reverse transcriptase; PBL: Peripheral blood leukocyte; PBMC: Peripheral blood mononuclear cell; SSc: Systemic sclerosis; SjS: Sjogren syndrome; RA: Rheumatoid arthritis.

destruction of the joint infrastructure [9]. Although the joint symptomology is eventually the predominant feature of RA, it is preceded by aberrations in the immune system, which are not necessarily joint specific, but instead systemic. These immune abnormalities are already apparent several years before actual onset of the disease, including loss of immune homeostasis and regulation [9], as well as premature immunosenescence [11]. RA development is only about 50% attributable to genetic www.expert-reviews.com

factors [15]. Environmental factors, namely smoking or infections, seem to also predispose one to RA [15]; however, exact causes and mechanisms are not known. Intriguingly, these environmental factors all have a strong effect on telomere shortening as well. Telomere loss in lymphocytes of RA patients is postulated to be partially driven by chronic inflammation; in vitro studies showed telomere loss in white blood cells is accelerated by 1195

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oxidative stress and inflammation. One study aimed to measure terminal restriction fragments (TRFs), obtained by the southern blot method, in a large, predominantly female, cohort of 151 RA patients and 1,151 healthy controls. Telomere lengths were compared between cases and controls, and the effects of the disease duration were assessed. Age- and gender-adjusted telomere lengths were found to be significantly shorter in RA patients compared to the healthy controls (p < 0.001). Noteworthy is that there was no association found between disease duration and telomere length [16]. Thus, this study elucidates that telomeres are shorter in RA patients in a disease durationindependent manner. The data does not support the hypothesis that inflammation in RA is the predominant factor promoting lymphocyte telomere shortening. The question as to whether this telomeric erosion is congenital, based on genetics, or due to abundant infections in early life is unclear; however, the data suggest that the difference in telomere lengths arises before clinical diagnosis or during a very early phase of the disease. Another study examined the effects specifically of the HLADR4 gene, a gene often associated with RA, on telomere lengths of lymphocytes. Telomere lengths of CD4+ T cells of 37 healthy individuals who expressed one of the RA-associated alleles (HLA-DR4+; aged 23–86 years) and 37 age-matched healthy controls (HLA-DR4-) were determined. Telomeres were measured using TRFs and also analyzed by Southern blotting. Results showed that HLA-DR4- CD4+ T cells displayed progressive decline in telomere lengths with age by about 50 bp/year (p < 0.001). By the second decade of life, HLADR4+ CD4+ T cells were on average about 1500 bp of telomeres shorter compared with their age-matched counterparts. In addition, HLA-DR4+ CD4 T-cell telomeres were significantly shorter than those of their age-matched controls (p = 0.002). However, progressive decline in telomeres was less pronounced in HLA-DR4+ CD4+ T cells, with an average loss of 25 bp/year, but when compared to the healthy controls, the difference was not significant (p = 0.057). Moreover, telomeres in both memory and naı¨ve T-cell subsets were significantly shorter in HLA-DR4+ individuals (p < 0.001) [17]. This study thus seems to show a confirmation of accelerated telomere shortening in T cells and elaborates by showing evidences that HLA-DR4 haplotype imposes premature replicative senescence on lymphocytes [17]. Studying an RA-related gene in non-RA affected patients is interesting considering Steer et al. [16] study elucidated the disease duration independency of telomere shortening in RA. The study by the group of Schonland et al. [17] implies an endogenous mechanism behind accelerated immunosenescence defined by genetics. Koetz et al. [18] studied T-cell generation in RA patients by measuring thymic function and T-cell telomere lengths [18]. To obtain thymic function, they used T-cell Receptor Excision Circle (TREC)-expressing peripheral T cells, which is a marker for newly generated T cells. A decline in the level of newly generated T cells, which is a consequence of age, does not only result in a decrease in TREC-containing T cells, but will also force the system to restore equilibrium by replicating the 1196

available mature T cells, leading to telomere shortening. They obtained T cells from 51 RA patients aged 13–80 years, and 47 age-matched healthy controls and measured different subsets of T cells, as well as TREC-containing ones. Telomere lengths of control individuals significantly declined progressively with age. However, this decline was not constant, contrary to prior studies. Median telomere length actually remained stable until the fourth decade of life, after which there was an accelerated reduction in telomeres until the age of 65, where this decline reached a plateau. Results estimated that between the ages of 40 and 65 years, healthy individuals had an average telomere loss of 76 bp/year. Interestingly, in RA patients, telomere length was not significantly associated with age. RA patients under the age of 40 years had shorter telomere lengths than their age-matched controls. During the phase of accelerated telomere loss in healthy controls, between ages 40 and 65, RA patients only experienced an average loss of telomeric DNA of 20 bp/year, which is much lower than the loss experienced by controls. Furthermore, patients and controls after the age of 65 reached the same plateau making them indistinguishable. In addition, TREC levels in RA patients were age inappropriately decreased. About 20- to 30-year-old RA patients had TREC levels equivalent to those of 50- to 60-year-old healthy individuals [18]. This lack of TREC positive cells could be due to the acceleration of peripheral T-cell turnover, which is often associated with disease progression. Nevertheless, abnormalities in Tcell homeostasis were apparent extremely early in disease, and strikingly, with no progression with disease duration. Therefore, this study observes no correlation between telomere shortening and disease duration, which again argues against the direct effect of chronic RA on T-cell homeostasis and premature immunosenescene. Telomere shortening has been known to occur in lymphocytes early in the pathogenesis of RA, but this telomere erosion was also found to effect granulocytes [17], which suggests that hematopoietic stem cells (HSC) might be the primary target of telomeric erosion. Hence, studies have also explored the telomere lengths in HSC as a possible explanation to immunosenescence in RA. Schonland et al.’s study [17], mentioned above, also examined whether prethymic cells were affected by accelerated telomere erosion in HLADR4+ versus HLADR4- individuals. Granulocytes have a short survival time, of only a few days and their telomere lengths closely reflect the proliferative history of bone marrow stem cells [19]. Thus, to measure HSC telomere lengths, granulocytes were used. Telomere length in granulocytes was found to correlate significantly with age, and the slopes of both the HLA-DR4+ and HLA-DR4- individuals were similar. However, HLA-DR4+ granulocytes had significantly shorter telomeres throughout the entire age range (p = 0.004). The authors reported that the survival and replication of HSC are therefore influenced by polymorphisms of the HLA-DR4 haplotype. Furthermore, the influence of the HLADR4 on telomere shortening on both HSCs and therefore on lymphocytes, coincided with the time period of maximal Expert Rev. Clin. Immunol. 9(12), (2013)

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Accelerated telomere shortening in rheumatic diseases

replicative stress for HSCs. Under normal conditions, telomeric loss of granulocytes and lymphocytes is highest within the first year of life, due to the demand for establishment of lymphoid organs and rapid increase in T-cell compartment size [20]. When studying newborns, the influence of HLA-DR4 haplotype on telomere shortening was absent, whereas by the age of 20, the difference in telomere lengths between HLA-DR4- and HLA-DR4+ individuals were maximal, indicating an additive effect of replicative stress. After the age of 20, annual telomeric loss was not accelerated in the HLA-DR4+ group, and in fact, as mentioned above, telomere loss was even less pronounced [17]. Thus, it appears that events leading to significantly shorter telomeres, and ergo higher senescence, occur in childhood and early adolescence thereby further indicating an intrinsic/early mechanism behind immunosenescence seen in RA. These studies show that telomeres are shortened in RA patients, but this shortening seems to only be apparent in the early years of life, as shown by Steer et al. [16] as well as by Koetz et al. [18], Schonland et al. [17] and Koetz et al. [18] demonstrated that telomere length might be intrinsically shorter, but does not continue to shorten as a function of age. Then both controls and patients reach the same plateau, as the disease duration does not continue to affect turnover and telomere shortening. Schonland et al. [17] touch upon the possibility of an intrinsic mechanism behind accelerated telomere loss and immunosenescence in RA but studying healthy patients carrying an RA-associated gene. Their results indicate indeed a role of genetics in the existence of shortened telomeres and premature aging. Telomerase in RA

The role of telomerase in RA has also been investigated as a possible contributor to immunosenescence in RA. However, is it more active to balance the observed effects of less telomeric erosion, or less active, further contributing to the perhaps early telomere shortening? One study aimed to comprehend the involvement of telomerase activity in the pathogenesis of RA. Peripheral blood leukocytes (PBLs), synovial infiltrating lymphocytes and synoviocytes were isolated from peripheral blood and synovial tissue of 18 RA patients. Telomerase activity in these samples was measured by a telomeric repeat application protocol assay. There was a high level of telomerase activity detected in 100% of both PBL and synovial infiltrating lymphocytes. This telomerase activity correlated with intensity of synovial lining layer hyperplasia (p = 0.006), microvessel proliferation (p = 0.0001), perivascular infiltrates (p < 0.0001) and focal aggregates (p < 0.0001) [21]. The systemic function of lymphocytes is largely dependent on cell division; substantial amounts of cell division and clonal expansion are crucial for an effective immune response. Studies have found that telomerase activity in peripheral blood T lymphocytes is induced via CD3 and CD28 activation, suggesting that telomerase plays a role in T-cell proliferation and activation [22]. The high amounts of T-cell proliferation seen in RA thus could explain or could be explained by the high activity of telomerase www.expert-reviews.com

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observed in RA lymphocytes as concluded by Yudoh et al. [21]. Furthermore, telomerase could be responsible for the proliferation and activation of lymphocytes in the pathogenic immune response in RA. Osteoarthritis

OA is the most common joint disease in middle aged and older people. It is characterized by dysfunction and pain in the joints, thought to be caused by joint degeneration, a process wherein inflammation is thought to play a lesser role compared with RA [23]. Intriguingly, although weight bearing joints are commonly involved, hands are the most frequent site suggesting that the other factors other than weight bearing pressure must be involved [24]. OA etiology has been associated with genetic factors, environmental factors and hormone replacement therapy [24]. However, age seems to be the strongest predictor of OA [25]. Thus a critical question is whether OA is truly a disease or merely a consequence of aging. In other words, does OA affect aging or is aging an inevitable predisposer to OA? To explore this, some studies have looked into the aging patterns of immune cells in patients with OA. The most flagrant cells in the pathogenesis of OA are chondrocytes, and multiple in vitro studies have shown that greater telomere shortening occurs in chondrocytes from the osteoarthritic lesional site [26]. In addition, exogenous telomerase prolongs the lifespan of chondrocytes in vitro, further suggesting telomere shortening as the responsible factor for senescence. Studies focusing on peripheral blood mononuclear cell (PBMC) telomere length also further substantiate the role of aging in OA. One study by Zhai et al. [24] observed leukocyte mean telomere lengths of patients with hand OA. They included 163 hand OA patients and 963 healthy controls. Leukocyte telomere length was measured via calculation of TRF length from venous blood samples taken after an overnight fast. Results showed that, on average, OA patients had significantly shorter leukocyte telomeres compared with the controls (p < 0.001) even after correction for sex, BMI and smoking status. When patients older than 50 were further stratified into subgroups, mean difference between controls and patients was even higher. Data on the OA feature scores of patients were gathered and compared with telomere length, which decreased in the presence of higher OA feature scores. This suggests an involvement of leukocytes in OA disease progression. The authors hypothesize that oxidative stress and inflammation are the driving forces of accelerated telomere shortening in OA patients, as they are more exposed to both factors than are healthy controls [24]. However, it is noteworthy that the participants in this study were sets of twins. As telomere length is genetically determined with heritability estimates of 36– 78% [27], and there is a genetic component in OA, the observed associations concluded in this study may be due to the shared genetic components in the participants. Hence, although this study may indicate that the disease preludes immunosenescence, this cannot be concluded considering the genetic similarities in the patients. 1197

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SLE

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Telomeres in SLE

SLE is an autoimmune disease characterized by a variety of different clinical manifestations thought to originate from the presence of antinuclear antibodies (ANAs), directed against naked DNA and entire nucleosomes. It has been stipulated that the complexes resulting from the ANA activation accumulate in vessel wall, glomeruli and joints, causing a hypersensitivity reaction Type 3. Consequently, this manifests as glomerulonephritis, arthritis and vasculitis [28]. In contrast to the previously reviewed rheumatic diseases, which most often occur late in life when the first immunosenescent features set in, SLE can occur at any age, predominantly affecting women between the ages of 15 and 44 years. A salient feature of SLE seems to be an aberrant immune regulation. In the active form of the disease, there is an imbalance between pro- and anti-inflammatory cytokines. As a result, immune responses are impaired leading to hyperactivity of lymphocytes. Recurrent endogenous immune activation seen in autoimmune disease is thought to accelerate aging of the immune system. T cells are flagrant cells in the pathogenesis of SLE. One study evaluating whether SLE patients exhibit accelerated immunosenescence in T-cell subsets included a total of 90 SLE patients and 64 unaffected, unrelated healthy controls. Subjects were all females aged between 20 and 69 years, who were free from any bacterial or viral infection at the time their blood was drawn to obtain PBMCs. After separation of T-cell subsets, DNA was extracted and telomeric DNA content (TDC) measurements were evaluated. Results showed that mTRF was significantly shorter in SLE PBMCs, more markedly in CD4+ cells, compared with controls (p = 0.00008). In addition, lymphocyte telomere shortening was more significantly different between patients and controls in younger subjects aged 55 years old; p = 0.12). Furthermore, the authors found that in addition to the significantly lower mTRF in younger SLE patients, there was also a significant increase in low molecular weight telomeric DNA fraction in the patients group. This is characteristic of senescent cells [29]. The accelerated telomeric shortening in SLE could be due to the chronic activation and proliferation characteristic of autoimmune diseases, possibly leading to premature immune senescence or another endogenous mechanism occurring early in life. There is an indication of premature cell death or exit from the cell cycle thereby contributing to the deregulation of the immune system and the low responsiveness to new antigens, which are characteristic of SLE. This offers a possible explanation of the co-occurrence in elderly individuals of telomere shortening, immune exhaustion and higher risk of autoimmune diseases. The results and conclusions drawn from Honda et al. [29] were also replicable by Kurosaka et al. [30]. This group evaluated the clinical significance of telomere length of PBMCs in 30 SLE patients and 45 healthy controls. The individuals 1198

ranged in age between 18 and 75 years and were predominantly females. DNA was extracted from isolated PBMCs, and telomere length was measured in a different way than previous studies. They used a chemiluminescence detection method to obtain TRF and thus telomere length. Results showed that when correlating age with telomere length in the two groups, they found that while controls had a significant negative correlation coefficient, that is, telomere length significantly decreased with age, SLE patients did not. To further compare the telomere lengths between patients and controls, the authors subdivided the individuals into two different age groups. They found that when comparing the PBMC telomere lengths of the younger individuals, SLE patients had significantly shorter telomere lengths. No significant differences were found in the older age group [30]. This implies that PBMC telomere length of SLE patients and controls becomes similar with increasing age, further indicating an early role of immunosenescence in disease progression. Another more recent study done by Haque et al. [31] performed a cross-sectional comparison of telomere length in full blood of 63 SLE patients and 63 age-matched controls, with a median age of 51. Telomere length was measured here using a real-time quantitative polymerase chain reaction method. Results showed that telomeres of SLE patients were significantly shorter than those of healthy controls (p = 0.0008) [31]. The authors further extended their cohort to more SLE patients (n = 164) and measured their telomere lengths and compared them to auto-antibody levels and steroid therapy. Interestingly, they found that auto-antibody levels were positively associated with shorter telomeres (p = 0.023), and steroid therapy was associated with longer telomere lengths (p = 0.046). In addition, several SLE-related factors were subsequently examined for their association with telomere length. However, no association was found between telomere length and overall SLE disease activity. [31]. From this, the authors concluded that telomere attrition is therefore not simply a reflection of immune cell turnover, that is, most often associated with inflammatory disorders. Thus, there is another mechanism behind telomere attrition, as it is not correlated with disease activity. Similarly, and equally recent, a case–control study on 59 African-American SLE patients, done by the group of Hoffecker et al. [32], examined telomere lengths of PBMCs in SLE but also examined levels of a possible trigger of SLE: vitamin D [32]. They found that indeed telomeres were shorter in patients with SLE, and further that these shortened telomeres were associated with lower vitamin D levels. A follow-up of these patients showed that those who remained vitamin D deficient continued to have shorter telomere lengths than those whose vitamin D levels were replenished, suggesting that vitamin D may be beneficial in preventing cellular aging. In addition, this group also confirmed the results indicating no correlation between disease activity and telomere length, further indicating a role for an alternative predisease mechanism. Expert Rev. Clin. Immunol. 9(12), (2013)

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Telomerase in SLE

The telomere-related molecule, telomerase, can also be an indicator of premature aging as implied above. Telomerase is not usually expressed by resting, untransformed somatic cells. However, transient telomerase activity can be detected in some untransformed cells of the immune system, namely progenitor cells, thymocytes, tonsillar T cells, germinal center B cells and in vitro-activated peripheral blood CD4+ cells. Because of its correlation with telomere length, Honda et al. [29] and Kurosaka et al. [30] also evaluated in their studies, the expression levels of telomerase to get a deeper understanding of the immune system’s aging patterns in SLE patients. The group of Honda et al. [29] (SLE patients n = 90; Healthy controls n = 64) evaluated the proliferative potential of T cells by comparing SLE PBMC subsets to those of healthy controls for the evidence of telomerase activity. T-cell subsets were isolated using mononuclear antibodies, magnetic beads and sterile columns, following monocyte and B-cell depletion. Cell replicative potential was evaluated after a 6–8 week culture period, and telomerase activity of complete cell lysates was measured with use of a modified telomeric repeat amplification protocol (TRAP) assay. Results showed that SLE-derived T cells overall underwent less mitotic cycles than did controls (p = 0.04), implying a decreased replicative capacity, which is in line with the conclusions from the previous section, which showed that these PBMCs also had shorter telomere lengths. However, when they examined the behaviors of different subsets of PBMCs separately, they found that CD28 low CD8+ T cells actually conserved telomeric DNA, displaying high replicative potential as well as high telomerase activity. Thus, the overall lower replicative potential, as well as reduced TDC described above, was primarily driven by SLE CD4+ T cells [29]. Thus, there seems to be an endogenous mechanism by which telomerase expression is modified in different subsets of immune cells, inducing an overexpression and longer lifespan of some immune cells on the one hand, and a lower life span on other cells on the other hand. Kurosaka et al. [30] also analyzed telomerase activity in PBMCs of SLE patients in addition to measuring telomere length using the same patients plus 15 more (n = 45) and controls. To measure telomerase activity, this group also used the TRAP assay. Telomerase expression is known to vary with age [33]. Therefore, telomerase expression was compared between age groups. In addition, within the SLE group, there were two subgroups: active SLE group and inactive SLE group, defined by the M-SLEDAI score, which measures clinical findings per patient. In each age group, Kruskal–Wallis rank test comparison was performed among the control group, active SLE group and inactive SLE group. For all the age groups, 20s, 30s, 40s and 50s, there was a significant difference, p = 0.022, 0.008, 0.01, 0.004, respectively. Subsequently, comparisons between two groups in each age group was carried out, ultimately indicating that PBMC telomerase activity was significantly higher in the active SLE group than the control group in all age groups. Telomerase activity was www.expert-reviews.com

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indistinguishable between the control group and inactive SLE group in age groups 20, 30 and 40, but was significantly higher in the 50s age group. Under healthy circumstances, PBMC telomerase activity decreases with age, until it becomes almost completely absent after the age of 40 years [33]. However, in SLE patients, the telomerase activity does not follow this trend with age, even in the inactive SLE group. Thus, Kurosaka et al. [30], like the group of Honda et al. [29], found an increase in telomerase activity in SLE patients. As Honda et al. [29] illustrated, this increase in telomerase activity may be due to the CD28 low, CD8+ T-cell group, which were found to have maintained telomere length. These findings are in line with literature indicating that T cells are overly active in active SLE [34]. Furthermore, the studies together suggest that telomerase activity is useful as a marker for lymphocyte activation. In summary, telomere length, which had a tendency to be shorter in younger SLE patients compared with healthy controls, became similar in aged patients. No definite conclusion can be drawn from this; however, it is possible that SLE patients develop a mechanism that prevents telomere shortening, perhaps via upregulation of telomerase expression. With this train of thought, it could be inferred that SLE patients either have congenitally shorter leukocyte telomeres, which somehow lack full functionality and thus lead to disease or the early presence of autoantibodies results in high leukocyte activation (including lymphocytes) and therefore proliferation thereby accounting for the shortened telomeres. In either case, with regards to telomere expression, shortened telomeres might signal the cell to upregulate its telomerase expression, consequently resulting in compensation for telomere loss, and thus equating with telomere lengths of healthy patients. From reviewing this data, we think that it is likely that telomere shortening and thus immunosenescence again precedes disease. However, there needs to exist a mechanism either by which autoantibodies are produced (and survive) or a mechanism by which telomeres are congenitally shorter. The former would imply that disease precedes immunosenescence, but the latter would indicate again an endogenous mechanism inducing premature immunosenescence, which then leads to disease. SSc Telomeres in SSc

One study explored telomere lengths of both lymphocytes and fibroblasts from 43 SSc patients, 182 SSc family members and 96 age-matched controls. Telomere length measurements were done using restriction fragment length polymorphism and chemiluminescent labeled probes. Results showed that there was an average loss of telomere repeats in lymphocytes of about 3 kb compared with the controls. Even after the results were corrected for age and disease duration, the results remained constant. Telomere lengths of fibroblasts were also, overall, shorter in patients than in the healthy controls; however, the difference was not significant. Thus, SSc patients indeed had shorter telomere lengths, most notable in lymphocytes. 1199

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Noteworthy, however, is that shorter telomeres were not specific to the SSc patients, as family members of the patients were also found to have shorter telomeres than healthy controls, often even shorter than those of the patients themselves. This interestingly implies a genetic influence of the premature aging seen in these patients [35,36]. Another study, addressing telomere length in SSc, investigated PBLs of 43 SSc females, aged 37–80 years, specifically with the IcSSc phenotype, along with 107 age-matched healthy controls. Telomere measurements were obtained via analysis of TRFs. Results, analyzed using regression analysis, unexpectedly showed that mean TRF of the ISSc patients were significantly longer compared with their age-matched healthy controls. In addition to this striking finding, it was also observed that these telomere of the patients showed no evidence of attrition, which would normally occur with age. Following age stratification, it was discovered that these differences were only significant beyond the fifth decade of life, whereas no differences were detected between the patients and the healthy controls below the age of 50 years. For a more detailed comprehension of these results, medication records of patients were analyzed using retrospective analysis. It was found that patients using NSAIDs (n = 3), had longer telomeres than those not using NSAIDs (n = 17) [37]. Although these results are intriguing, it is worth mentioning that using Southern blotting to measure TRF lengths, as was done in this study, inevitably included detection of subtelomeric region sequences, known to show interindividual variation. These observations may therefore indicate a subtelomeric component in lcSSc, while concealing possible telomeric TTAGGG repeat attrition, merely as a consequence of methodology. Besides methodological explanations, the differences in study outcomes might be explained by the difference in SSc clinical subsets investigated. dcSSc patients are more often ATA positive, making it tempting to conclude that the differences between the Artlett et al. and the MacIntyre et al. study is due to the presence of these antibodies, which may lead to more severe and chronic inflammation that might play a role in the rate of telomere shortening. In addition, anti-inflammatory medication might have an effect on the results. Telomerase in SSc, Sjogren syndrome & mixed connective tissue disorder

The most obvious system that is able to compensate for accelerated telomere shortening in SSc is the telomerase system. One study specifically investigating telomerase in systemic connective tissue diseases hypothesized that telomerase activation may participate in activation and proliferation of circulating lymphocytes. To address the role of telomerase activity, PBMCs from 9 female SSc patients and 10 healthy agematched females were obtained and subjected to the TRAP. In addition, PBLs from SLE, Sjogren syndrome (SjS) and mixed connective tissue disease (MCTD) were included for comparison. Telomerase activity was detected in 64.7% of SLE patients, 63.6% of MCTD, 54.5% of SS and 44.4% of SSc. 1200

Although, telomerase activity in SSc was not significantly different from the activity observed in the controls, it is important to note that high telomerase activity was detected in some patients with this disease. On the other hand, there was a significant difference observed in PBLs from patients with SLE, MCTD and SjS [38]. Another group also studied the levels of telomerase activity in connective tissue diseases. The study included PBLs from SSc (n = 19), SLE (n = 15), RA (n = 10) and SjS (n = 14) patients, as well as a control group (n = 29). Human telomerase-specific reverse transcriptase (hTERT) levels were measured in the PBLs of each patient group using an online real-time polymerase chain reaction. In addition, expression values in each patient group were correlated with clinical parameters as well as disease activity. hTERT levels were determined as a relative ratio of hTERT/housekeeping gene porphobilinogen deaminase. Strikingly, hTERT values in SSc were markedly low (2.08 ± 3.17) to the point where they were significantly lower than the control group (p = 0.0001). No such significant difference was observed in the group of SjS patients, RA, nor SLE patients [39]. The possible preliminary conclusions that can be drawn about SSc from these observations are twofold. For one, it seems improbable that SSc itself causes telomere shortening. Instead, shorter telomeres seem to be a risk factor for SSc or a secondary effect of another risk factor. Secondly, when considering the familial incidence of shortened telomeres, this other risk factor might originate in the genes, thus demonstrating that telomere shortening and immunosenescence prelude SSc. In addition, telomerase does not seem to play a role in SSc immune cells, due to its low/similar expression in comparison to controls. However, as the cohorts in all studies were rather small, it is difficult to reach reliable inferences. Telomeres in other rheumatic diseases

The above-mentioned rheumatic disorders are merely an example of the vast variety of other inflammatory diseases that most likely involve premature aging mechanisms. However, studies on other rheumatic diseases and telomere length measurements are more rare, as the diseases themselves are scarce. Only one study was found to have examined telomeres in SjS. SjS is a systemic autoimmune disease that is characterized by immune cell infiltration in exocrine glands, especially those that produce tears and saliva. Lacrimal gland tissue was taken from SjS patients, and telomere length was measured using a FISH technique, called telo-FISH. When compared with healthy controls, telomere intensity in patients was significantly lower (p = 0.02). Again, this is in line with the repetitive pattern seen with the association of telomere shortening and presence of inflammatory disorder [40]. However, whether one is a cause or consequence of the other cannot be concluded from this study alone. Expert commentary

There is a clear pattern present in the hallmark rheumatic disorders with regards to their premature aging features. TABLE 1 Expert Rev. Clin. Immunol. 9(12), (2013)

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shows a summary of all the articles reviewed for each disorder. All section conclusions reached to the postulation that immunosenescence seems to precede disease. Immunosenescence is driven by Accelerated Immunosenescence Disease aging, and in many diseases, namely telomere shortening development • Malfunctioning immune rheumatic ones, aging occurs prema• Multiple infections • Rheumatic diseases system turely. The question was whether this • Genetics • Autoimmunity premature aging of bodily systems was a consequence of disease, or if the aging itself led to disease development. By studying these rheumatic disorders and reviewing articles related to aging and telomere lengths as a biomarker, we could accept our initial hypothesis. It Figure 1. Summary of sequence of proposed conceptual framework. Sequence of events with regards to immunosenescence and rheumatic disease development. seems likely that immunosenescence, and premature aging, are a prelude to disease development. Thus we proposed a conceptual framework we saw that often disease duration did not play a role in the shown in FIGURE 1. This immunosenescence and accelerated aging acceleration of telomere loss, it is more probable that autoimcan be achieved via several mechanisms, many of which are munity could be excluded as a driving factor for the premature likely unknown. Genetics seems to be a reliable source of aging. In addition, while the pathological natures of RA and intrinsic predisposition to accelerated aging (of the immune SLE are rather different, they are rather similar diseases with system), as was outlined by Schonland et al. [17]. HLA-DR4+ regards to telomere shortening; most studies on both diseases carriers showed shorter telomere lengths than noncarriers, encountered similar results in telomere lengths as well as teloimplying that the disease is affected by telomere shortening. merase activity. This indicates an alternative, universal effect on Furthermore, telomere length in general is genetically deter- premature aging. It is also important to understand that the conclusions mined; hence, congenitally shorter telomeres seem to stimulate a higher risk for disease development. Another possible predis- drawn were, most of the time, based on cohorts of rather small poser to accelerated aging could lie in the repeated occurrence sample sizes, which may be due to the scarce nature of rheuof infections early in life. This leads to increased immune cell matic disorders. This makes the studies more open to debate, turnover and thereby drives telomere shortening. The observa- however, for the sake of attempting to understand whether a tion that disease duration had no effect on telomere shortening pattern exists regarding premature aging, some conclusions further highlights the implication that immunosenescence prel- were made, but with the full consideration of their perhaps preudes disease. Shortened telomeres are known to become geneti- sumptuous nature. An additional critical point that can be cally unstable, or signal a cell into senescence. This feature and made regarding the reviewed studies is that they are all retropower of telomeres are likely to drive a system into spective studies. That is, all the studies involved the collection of blood from both already ill patients and measured the telodisease development. In some studies, we saw that telomere length was actually mere lengths of their PBMCs. Prospective studies, wherein increased, namely in the SSc study by MacIntyre et al. [37]. blood would in this case be collected prior to disease developThis could either be driven by the consumption of NSAIDs, ment, are more reliant when one aims to understand whether a which are suggested to prevent telomere shortening [37], or phenomenon is a cause or consequence of the disease; however, hyperexpression of telomerase to compensate for the telomere they are indeed more difficult to conduct, and under this speloss. Another observation from these studies was the high cific topic of rheumatic disorders and telomere length, no prospective studies were found. In the study by Schonland et al. expression of telomerase seen in both RA and SLE. It is essential to note that the diseases included in this review [17], subjects had not been diagnosed with RA at the time of have similarities as well as differences among each other. Most blood collection but were positive for the gene often associated of the diseases are autoimmune, with the exception of OA, with RA, HLA-DR4. If these patients were to develop RA in which does not seem to express presence of autoantibodies or the future, a follow-up on them would indeed be interesting other hallmarks of autoimmune disease, but of course OA does and rather informative. Information on these subjects was not pertain an inflammatory component, which contributes to a found unfortunately. Nonetheless, retrospective studies are still higher burden on the immune system, similar to that found in a liable option when studying diseases with low incidence, or autoimmune diseases [41]. Thus, with that in mind, and with for those with a long developmental time, such as rheumatic oxidative stress as a known cause for telomere shortening, it diseases. Although there was a pattern with regards to shorter telomere could indeed be that the telomere shortening is driven by chronic inflammation caused by autoimmunity. However, as length being associated with disease, there were some www.expert-reviews.com

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inconsistencies that provoked some questions. Some studies in fact found not shorter telomeres in patients, but either longer or equal to those of healthy controls. There could be two explanations for this observed phenomenon. Either some individuals develop a protective mechanism by upregulating their telomerase activity, as seen in the Koetz et al. [18] study on RA patients, or there is some exogenous influence on telomere length such as the administration of NSAIDs, as seen in the study of Macintyre et al. [37] or administration of steroids, as seen in the study by Haque et al. [31]. If accelerated telomere shortening, or premature aging, is indeed the predecessor to disease development, the causes for its shortening, which vary among disease, and even among individuals, should be studied more elaborately. As eluded to earlier, causes include genetics, age, oxidative stress/DNA damage and cellular turnover. If one could indicate which cause is relevant in each disease, or in each patient, perhaps new insights on disease prevention can be incurred. Five-year view

The conclusions we reached in this review are not limited to rheumatic disorders. Telomere loss and premature aging are also present in other diseases including cancer [42], diabetes [43] and cardiovascular disease [44]. With disease comes cell turnover and imposed cellular pressure, thus telomere loss naturally occurs at a much faster rate than in healthy individuals, perhaps further contributing to worsening of healthy and disease progression. However, could it be the case that telomere

shortening also precedes other diseases? It would be fascinating to study this question, as if this is the case, disease can be predicted and more efficiently prevented. Hence studying telomeres, telomerase activity and premature aging in general can contribute greatly to the medical sciences. Not only could it be used to prevent disease development, or at least severe disease progression, but can also be used to predict comorbidity in rheumatic diseases. For example, cardiovascular disease is often associated with RA and is the leading cause of death in RA patients [45]. RA patients are twice as likely to have myocardial infarctions, with this risk increasing to nearly threefold after 10 years of disease [45]. Shorter leukocyte telomere length is also implicated in chronic heart failure patients [46], and this shortening is thought to correlate with disease severity. Perhaps, this is due to accelerated telomere shortening, inducing aged cells of middle-aged patients to act similarly to those in elderly individuals. Thus, studying telomere shortening and its relationship to disease development and comorbidities can greatly aid the future of medicine. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Accelerated biological aging of the immune system is thought to correlate with diseases. • Telomere length and telomerase activity can be used to measure biological aging, and be compared with chronological age to compare rate of biological aging between healthy controls and patients. • The main question of this review is whether accelerated telomere shortening is a cause or consequence of disease. • The rheumatic diseases rheumatoid arthritis, systemic lupus erythmatosus, osteoarthritis and systemic sclerosis are used to review whether accelerated aging drives their development or whether their mere existence causes accelerated aging. Literature indicates that telomere length often is shorter in patients, but does not correlate with disease duration. • Healthy relatives of patients have similarly short telomere length compared with patients. • There seems to be a prelude of accelerated telomere shortening, which poses some at a higher risk for disease development. Thus, accelerated telomere shortening is suggested to be a cause and not a consequence of disease development.

References

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Papers of special note have been highlighted as: • of interest •• of considerable interest

Holt SE, Shay JW, Wright WE. Refine telomere-telomerase hypothesis of aging and cancer Nat. Biotechnol. 14(836), (1996).

4

Sampson MJ, Hughes DA. Chromosomal Telomere Attrition as a mechanism for increased risk of epithelial cancers and senescent phenotype in type 2 diabetes. Diabetologia 49 (2006).

1

Miller RA. The aging immune system: primer and perspectus. Science 273(5271), (1996).

2

Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science 273(5271), (1996).

1202

5

Yung R, Julius A. Epigenetics, aging, and autoimmunity. Autoimmunity 41(4), (2008).

6

Zahava V, Haj T, Kessel A, Toubi, E. Age related autoimmunity. Biomed. Central. 11 (2013).

7

Olovnikov A. A theory of marginotomy: the incomplete copying of template margin in Enzymatic synthesis of polynucleotides and biological significance of phenomenon. J. Theor. Biol. 41 (1973).

8

Blackburn E. The structure and function of telomeres. Nature 350(6319), (1991).

9

Goronzy J, Shao L, Weyand CM. Immune aging and rheumatoid arthritis. Rheum. Dis. Clin. North Am. 36(2), (2010).

10

Carrero JJ, Stenvinkel P, Fellstrom B et al. Telomere attrition is associated with inflammation, low fetuin A levels, and high

Expert Rev. Clin. Immunol. 9(12), (2013)

Accelerated telomere shortening in rheumatic diseases

Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Michigan University on 11/04/14 For personal use only.

11

Costenbader K, Prescott J, Zee RY. Immunosenescence and rheumatoid arthritis: Does Telomere Shortening Predict Impending Disease? Autoimmunity Rev. 10(9), (2011).

12

Hodes RJ, Hathcock KS, Weng NP. Telomeres in T and B cells. Nat. Rev. Immunol. 2(9), (2002).

13

Naylor K, Guangijn L, Vallejo AN et al. The influence of age on T-cell generation and TCR diversity. J.Immunol. 174 (2005).

15

Scott DL, Wolfe F, Huizinga T. Rheumatoid arthritis. Lancet 376(9746), (2010).

16

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17

Steer SE, Williams B, Kato JP et al. Reduced telomere length in rheumatoid arthrtitis is independent of disease activity and duration. Ann. Rheum. Dis. 66(4), (2007). Studies telomere lengths of rheumatoid arthritis (RA) patients and observes that telomere length is shorter in RA patients. Interestingly, they also found that telomere length in RA patients did not correlate with disease duration. Schonland SO, Lopez C, Widmann T et al. Premature telomeric loss in rheumatoid arthritis is genetically determined and involved in both myeloid and lymphoid lineages. PNAS 100(23), (2003).



Outlines the genetic influence of accelerated immunosenescence in HLA-DR4 positive healthy controls.

18

Koetz K, Bryl E, Spickschen K et al. T-cell homeostasis in patients with rheumatoid arthritis. PNAS 97(16), (2000).



Indicates that shortened telomere length preludes disease development, as telomere length in RA patients was found to be shorter in younger patients, under the age of 40 years, but indistinguishable from healthy controls after the age of 40 years.

19

20

21

Robertson JD, Gale RE, Wynn RF et al. Dynamics of telomere shortening in neutrophils and T lymphocytes during ageing and the relationship to skewed X chromosome inactivation patterns. Br. J. Haematol. 109 (2000). Rufer N, Brummendorf TH, Kolvraa S et al. Telomere fluoresensce measurements in granulocytes and T-lymphocyte subsets point to a higher turnover of HSC and memory

www.expert-reviews.com

Yudoh K, Matsuno H, Nakazawa F, Katayama R, Kimura T. Reconstituting Telomerase activity using the telomerase catalytic subunit prevents the telomere shortening and replicative senescence in human osteoblasts. J. Bone Miner. Res. 16 (2001).

31

Haque S, Rakieh C, Marriage F et al. Shortened telomere length in patients with systemic lupus erythematosus. Arthritis Rheum. 65(5), (2013).

32

Hoffecker BM, Raffield LM, Kamen DL, Nowling TK. Systemic lupus erythematosus and Vitamin D deficiency are associated with shorter telomere length amonth african americans : a case control study. PLoS ONE 8(5), (2013).

33

Iwama H, Ohyashiki K, Ohyashiki JH. Telomeric length and telomerase activity vary with ae in peripheral blood cells obtained from normal individuals. Hum. Genet. 102 (1998).

22

Weng NP, Levine BL, June CH,Hodes RJ. Regulated expression of telomerase activity in human T-lymphocyte development and activation. J. Exp. Med. 183 (1996).

23

Buckwalkter JA, Saltzman C, Brown T. The Impact of osteoarthritis: implications for research. Clin. Ortho. Relat. Res. 427 (2004).

24

Zhai G, Aviv A, Hunter DJ et al. Reduction of leukocyte telomere length in radiographic hand osteoarthritis: a population based study. Ann. Rheum.Dis. 65 (2006).

34

Hishikawa T, Tokano Y, Sekigawa I. HLA-DP T-cells and deficient IL-2 production in patents with systemic lupus erthematosus. Clin. Immunol. Immunopathol. 55 (1990).

25

Oliveria SA, Felson DT, Reed JI, Cirillo PA, Walker AM. Incidence of symptomatic hand, hip, and knee osteoarthritis among patients in a health maintenance organization. Arthritis Rheum. 38 (1995).

35

Jimenez SA, Derk CT. Following molecular pathways towards an understanding of the pathogenesis of systemic sclerosis. Ann. Intern. Med. 140 (1), (2004).

36

26

Martin JA, Buckwalter JA. Telomere erosion and senescence in human articular cartilage chrondocytes. J.Gerontol. 56(4), 2001.

27

Andrew T, Aviv A, Falchi M et al. Mapping genetic loci that determine leukocyte telomere length in a large sample of unselected female sibling pairs. Am. J. Hum. Genet. 78 (2006).

Artlett CM, Black CM, Briggs DC, Stevens CO, Welsh KI. Telomere reduction in scleroderma: a possible cause for chromosomal instability. Br. J. Rheumatol. 35(8), (1996).

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Shows that SSc patients have significantly shorter telomere lengths, as do their healthy family members.

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MacIntyre A, Brouilette SW, Lamb K et al. Assocaition of increased telomere lengths in limited scleroderma with a lack of age related telomere erosion. Ann. Rheum. Dis. 67(12), (2008).

38

Katayama Y,Kohriyama K. Telomerase activity in peripheral blood mononuclear cells of systemic connective tissue diseases. J. Rheumatol. 28(2), (2001).

39

Tarhan F, Vural F, Kosova B et al. Telomerase activity in connective tissue diseases: elevated in rheumatoid arthritis, but markedly decreased in systemic sclerosis. Rheumatol. Int. 28 (2008).

40

Kawashima M, Kawakita T, Maida Y et al. Comparison of Telomere Length and association with progenitor cell markers in lacrimal gland between Sjogren Syndrom and non Sjogren Syndrom dry eye patients. Mol. Vis. 17 (2011).

41

Berenbaum F. Osteoarthritis as an inflammatory disease. Osteoarthritis Cartilage. 21(1), (2013).

Goronzy J, Hiroshi F, Weyand CM. Telomeres, immune aging, and autoimmunity. Exp. Gerontol. 41 (2006).

14

predisease existence of short telomere length.

T-cells in eary childhood. J. Exp. Med. 190 (1999).

mortality in prevalent haemodyalysis patients. J. Intern. Med. 263(3), (2007).

Review

28

Napirei M, Karsunsky H, Stephan H, Mannherz-Georg H, Moroy T. Features of systemic lupus erythematosis in Dnase 1 deficient Mice. Nat. Gen. 25 (2000).

29

Honda M, Mengesha E, Albano S. Telomere shortening and decreased replicative potential constrasted by continued proliferation of telomerase positive CD8+ CD28 (lo) T cells in patients with systemic lupus erythematosus. Clin. Immunol. 99 (2001).



Demonstrates that SLE patients have significantly shorter telomere lengths.

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Kurosaka D, Yasuda J, Yoshida K et al. Telomerase activity and telomere length of peripheral blood mononuclear cells in SLE patients. Lupus 12 (2003).



Confirms that SLE patients have a significantly shorter telomere length than healthy controls, but only in the young age group, whereas in the older age group, this difference was not observed. This implies a

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Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nat. Rev. Gen. 6 (2005).

43

Morocutti A, Earle K, Sethi M et al. Premature senescence of skin fibroblasts from insulin depedent diabetic patients. Kidney Int. 50 (1996).

44

Fitzpatrick A, Kronmal RA, Gardner JP et al. Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. Am. J. Epidemiol. 165(1), (2006).

45

Dhawan S, Quiyummi A. Rheumatoid arthritis and cardiovascular disease. Curr. Artheroscler. Rep. 10(2), (2008).

46

Harst P, Steege G, Boer Rd et al. Telomere Length of circulating leukocytes is decreased in patients with chronic heart failure. J. Am. Coll. Cadiol. 49(13), (2007).

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Accelerated telomere shortening in rheumatic diseases: cause or consequence?

Accelerated aging of the immune system (immune aging), represented by telomere shortening, has been implicated in a variety of rheumatic diseases. Stu...
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