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Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response
i n d i a n j o u r n a l o f r h e u m a t o l o g y x x x ( 2 0 1 4 ) 1 e7
ScienceDirect Available online at www.indianjrheumatol.com and www.sciencedirect.com
Review Article
Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response Subir Roy* article info
abstract
Article history:
Not many years ago achieving remission in rheumatoid arthritis was difficult due to lack of
Received 28 August 2013
effective treatment. With the advent of biologics, remission is very much within reach. But
Accepted 30 January 2014
biologics are expensive. And not all patients respond adequately to biologics. Hence it will
Available online xxx
be useful if we have a marker which predicts response to any disease modifying antirheumatic drug (DMARD), whether conventional or biologic. Expansion of CD28-ve T
Keywords:
cells is characteristically seen in RA. Both CD28-ve T Cells and RA are believed to be linked
CD28-ve
to immunosenescence. The available evidences are suggestive of an intimate relationship
Immunosenescence
between RA and clonal expansion of CD28-ve T cells. Newer biomarkers are constantly
Biomarker
being looked at and CD28-ve T cells is one of them. In this review I will discuss in brief the
Rheumatoid arthritis
relationship between immune disorders like RA and immunosenescence and discuss significance of CD28-ve T cells in RA. Copyright ª 2014, Indian Rheumatology Association. All rights reserved.
1.
Introduction
Management of rheumatoid arthritis (RA) has seen tremendous and rapid evolution. Not many years ago achieving remission was an elusive aim due to lack of effective treatment options. With the advent of biologics, remission is very much within reach and should be aimed early in a patient with RA before the patient develops RA related deformities or co morbidities.1 But biologics are expensive and not all patients respond adequately to biologics. One-third of RA patients do not respond to tumor necrosis factor a (TNF-a) inhibitors.2 Patient and disease related variables probably play a role in drug response.3 Hence it will be useful if we have a biomarker which predicts response to disease modifying anti-rheumatic drug (DMARD), whether conventional or biologic.
Expansion of CD28 negative T cells is seen in RA.4 Both CD28 negative T Cells and RA are thought to be linked to immunosenecence.5 The available evidence suggests an intimate relationship between RA and clonal expansion of CD28 negative T cells. In this review the relationship between immune disorders like RA and immunosenescence, and significance of CD28 negative T cells in RA as regards disease activity and as predictors of response to therapy, will be discussed.
2.
Immunity and immunosenescence
RA is an autoimmune disorder resulting from disruption in the immune system’s discrimination of self and non-self.6 It is generally believed that in autoimmunity there is overactive immune system that responds to a slight aberration of the self-peptides with sustained immune response resulting in
* Tel.: þ91 9930830118. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.injr.2014.01.011 0973-3698/Copyright ª 2014, Indian Rheumatology Association. All rights reserved.
Please cite this article in press as: Roy S, Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/j.injr.2014.01.011
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tissue damage.7 But, this perspective might not be true. A large set of data suggests that RA might be a result of immunosenescence.8,5
2.1.
What is immunosenescence?
Normally, primary adaptive immune response is induced when antigen presenting cells (APCs) take up antigens and present them to the naı¨ve T cells via major histocompatibility complex (MHC).9 T cells bearing T cell receptors (TCRs) specific to the antigens presented undergo clonal expansion and differentiate into effector T cells including cytotoxic CD8þ T cells and helper CD4þ T cells. A few of these activated T cells go on to become memory T cells.5 The adaptive immune system can distinguish between the self and the non-self. This selfenon self discrimination is generated at central and peripheral level. Central T cell tolerance occurs in the thymus where T cell differentiation and maturation takes place. Here, newly generated T cells undergo selection mechanisms resulting in survival and maturation of only those T cells who’s TCRs interact weakly with self-peptide/ self- MHC complexes (referred to as self tolerant and self MHC restricted)5 (Fig. 1). Peripheral tolerance mechanism includes the two signal model of T cell activation.5 Signal one is generated by binding of TCR with the antigen/MHC complex delivered by APC. Signal two is generated when CD28 receptor on T cell surface binds with B7 molecule expressed by APC. Without costimulatory signal, T cell activation does not happen.10 When there is no infection/inflammation, APCs do not express B7. This means that when a mature T cell interacts with a selfpeptide/MHC complex, signal two is not generated. This lack of signal two results in either the death of interacting T cell or makes it refractory to activation (also known as anergy). However a weak interaction between TCR and self-peptide/ MHC complexes is needed in the periphery for survival and physiological multiplication of mature T cells.5 The naı¨ve and memory T cells represent a pool which undergoes constant proliferation, influx and apoptosis. The
balance of naı¨ve and memory T cells is driven by homeostatic and antigen- driven requirements.11 Approximately 3 109 T cells are generated each day as a part of homeostatic churning of T cells.7 Homeostatic proliferation of memory T cells is more as compared to naı¨ve T cells. Though, this raises the possibility that memory T cells might outcompete naı¨ve T cells leading to compromise of the naı¨ve T cell compartment, homeostatic mechanisms seem to control this demise of naı¨ve T cell compartment.11 New memory T cells are generated from the naı¨ve T cell compartment whenever there is priming from new exogenous antigen. Naı¨ve T cells can be generated either via precursor T cells which are derived from haemato-poietic stem cells (HSCs) in the thymus or via self-proliferation wherein naı¨ve T cells serve as their own precursors11 (Fig. 2). With aging there is decline in the supply of new T cells from thymus.5 This decline in generation of T cells is a result of age related defective HSC replication and progressive involution of thymus.5,12 It is known that thymic function rapidly declines with age. Thymic epithelial space (TES) is considered as the best biologic correlate of functionally active thymic tissues. This TES goes down from about 7 cm3 in the young adult to about 1 cm3 in the 55e65-year-old. Thymic function is minimal after the age of 40 years. Hence, after the age of 40 years, the homeostasis of the T cell compartment nearly completely depends on peripheral mechanisms which regulate the proliferation and survival of naı¨ve and memory T cells.11,13 Also, with age, both antigenic load and duration of exposure to specific antigen increase. These result in compensatory proliferation of peripheral naı¨ve and memory T cells, leading to predominance of memory T cells (since memory T cells proliferate much faster as compared to the naı¨ve T cells).5,11 Such kind of proliferation is accompanied by changes at the level of receptor expression and consequently on functions. One such change is contraction of T cell repertoire.5 This contraction seems to get accelerated markedly at around the age of 65 years after which around 95% of diversity in T cells is lost.14 Why? One reason is that any proliferation which is not happening due to stimulation via any foreign antigens is dependent on interaction between the TCR and the self-peptideeMHC complex that the specific TCR had weakly reacted to during positive selection of the T cell in the thymus. Since this is now happening in the peripheral compartment, there is no positive/negative selection process which happens in thymus. The consequences are grave. There is competitive exclusion of TCRs because of the differences in the TCR affinity for the self peptides inducing proliferation. Those TCRs which have more avidity towards self-peptide MHC complex now get selected. The immune system gets biased to self antigens and makes the system susceptible to develop autoimmunity.5
3. Significance of CD28 negative T cells and their characteristics
Fig. 1 e Selection process of T cells in thymus.5
A cellular change that has been consistently noted with aging is progressive loss of CD28 receptor expression. Both CD4þ and CD8þ T cells are affected, but is more common with CD8þ T cells.5
Please cite this article in press as: Roy S, Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/j.injr.2014.01.011
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Fig. 2 e Maintenance of naı¨ve T cell supply.11
It has been noted that T cell activation always leads to CD28 downmodulation. If there is repeated stimulation by the same antigen, it leads to progressive loss of CD28 ultimately resulting in formation of CD28 eve T cells. Hence it seems logical why loss of CD28 is seen commonly with aging as well as in chronic infection. Loss of CD28 is also very common in autoimmune diseases.15 Since CD28 is a crucial for delivery of costimulation, theoretically it may sound that CD28 negative T cells are inactive and silent. But in reality, CD28 negative T cells are actually highly potent as effector cells.16 and have tissue damaging properties. CD4þCD28 T cells have been reported to be autoreactive. CD4þCD28 T cells store large amounts of interferon g in their cytoplasm and they also express CD161. CD161 facilitates tissue invasion. This makes them similar to proinflammatory lymphocytes. Unlike normal activated T cells, they do not require high amounts of IL-2 to survive. Interestingly though, CD4þCD28 T cells are able to produce large amounts of IL-2. CD4þCD28 T cells also acquire a variety of killer cell Ig-like receptors (KIRs). KIRs are generally seen in natural killer (NK) cells. NKG2D is another receptor associated with CD4þCD28 T cells. NKG2D is an NK-related receptor which can contribute to the survival of autoreactive CD4þCD 28 T cells.16 CD8þCD28 T cells are reactive to viruses like EpsteineBarr virus (EBV), cytomegalovirus (CMV) etc. Clonal expansion of CD8þCD28 T cells are common in patients suffering from acquired immunodeficiency syndrome (AIDS). These CD8þCD28 T cells represent terminally differentiated effector lymphocytes. Unlike their CD4þ counterparts, CD8þCD28 T cells are unable to produce their own IL-2. Receptor expression is similar to that of CD4þCD28 T cells when it comes to the NK- related receptors like KIR, NKG2D, CD94, CD56, and Fc-g receptor IIIA.16 Data suggest that CD8þCD28 T cells are the first ones to respond to any acute infection.17,18 Evidence also show that
they are representatives of either an aging process or chronic antigen stimulation, indicating that they represent immunosenescence.16,5 Cellular senescence is always defined by the presence altered function, resistance to apoptosis and telomere shortening leading to proliferative arrest (Table 1).14 As discussed, loss of thymic supply of new T cells via HSCs coupled with antigen stimulation accelerates proliferation of peripheral T cells, which then lose CD28 expression indicating replicative senescence of the T cells. It has been conclusively shown that loss of CD28 is an indicator of oligoclonality,19 which means that the same T cell is repeatedly proliferating. This process then should lead to telomere erosion. Telomere length, which is considered as a biomarker of biological age, is highly truncated in CD28 negative T cells.16,20 Taken together, CD28 negative T cells fit the definition of cellular senescence. This prompts us to believe that when our body faces any antigenic challenge as an immediate measure the threat is dealt by peripheral multiplication of T cells which leads to downmodulation of CD28 expression. Downmodulation of CD28 expression leads to increased reactivity but decreased specificity which helps dealing with the impending threat on a short term basis. This is then complimented and controlled by the adaptive immunity which is more specific and controlled. The fine balance between the immediate action in the form of CD28 negative T cells and mature response via CD28 mediated costimulation determines normalcy in our immune response.
Table 1 e What’s common between RA and aging?
Decreased thymic output Defective HSC replication Expansion of CD28 negative T cell population Contraction of T cell repertoire Eroded telomeres in T cells Low T cell receptor excision circle numbers
Please cite this article in press as: Roy S, Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/j.injr.2014.01.011
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This normalcy can get disturbed if there is defective replication of HSCs or defect in the thymus or chronic antigenic stimulus; either or a combination of these individual events can lead to unrestricted generation of CD28 negative T cells tipping the homeostatic balance towards autoimmunity. If this theory holds true then there has to be differences in the characteristics of CD28 negative T cells generated as a result of normal T cell activation and those generated due to immunosenescence. In 1999 Vallejo et al15 in their classic experiment noted that there exists distinct mechanisms that lead to CD28 down-regulation following T cell activation and during replicative senescence. In their experiment Vallejo et al noted that while activation-induced down-regulation of CD28 expression equally affected CD4 and CD8 T cells, the gradual loss of CD28 expression during continuous culture was more pronounced in the CD8 cells. This type of cell culture is representative of replicative senescence. This is in line with the observation that during aging and chronic infections there is characteristic increase in the frequencies of CD8þCD28 T cells and that loss of CD28 expression is less common with CD4þ T cells.4,15 Infact clonal expansion of CD8þCD28 T cells with loss of CD28 receptor expression can occur due to normal aging or pathologic immunosenescence, but loss of CD28 expression in both CD4þ and CD8þ T cells is more common in autoimmune conditions like rheumatoid arthritis.19 This indicates that autoimmune diseases might be an immunosenescent process where chronic inflammation and premature aging play a tandem of vicious cycle exhausting the integrity of immune system.
4. Rheumatoid arthritis (RA) and immunosenescence Rheumatoid arthritis is an autoimmune disease driven by several cytokines acting sequentially and/or in parallel.21 One of the best known cytokine imbalances is overexpression of tumour necrosis factor (TNF). Interleukin-6 is also one such cytokine known to drive inflammation and joint damage. These cytokine imbalances result due to a complex interaction among T and B lymphocytes, fibroblast and macrophages.21,22 Clinical improvement in RA patients receiving anti-CD20 antibodies like Rituximab highlights the role of B cells in RA pathology.23 Available data suggest that RA is a T cell mediated autoimmune disease.24e26 Abnormal T cell activation occurs early in RA which stimulates the monocytes and macrophages to secrete cytokines and enzymes that cause bone destruction in RA.20 RA is characterized by clonal expansion of CD28 negative T cells. These CD28 negative T cells are autoreactive, have markedly contracted repertoire and show highly eroded telomere.5 As discussed, CD28 negative T cells indicate immunosenescence. This observation therefore makes us ponder if RA is a case of immunosenescence.7,14,27,28 Thymic involution occurs very early in patients with RA.28 There exists an inverse relationship between thymic capacity and incidence of RA.7 In patients with RA, output of T cells via thymus is inappropriately low for age. It matches that of healthy individuals 20e30 years older, and the TCR repertoire
of naive and memory T cell populations is smaller.5 This will become clearer when we compare the T-cell receptor excision circles (TREC) numbers between patients of RA and healthy controls (Fig. 3). TRECs are extra-chromosomal byproducts that are generated during recombination of V(D)J gene segments of TCR. Since they do not replicate, they get diluted with every cell division. TREC content of peripheral blood mononuclear cells (PBMCs) can be used to determine thymic output. As compared to the age matched healthy controls, TREC numbers are significantly lower in RA patients (Fig. 3). As expected, in both patients with RA and healthy controls, TREC numbers in PBMCs decline progressively with age.28 Lower thymic output in RA is complimented by replicative stress on peripheral T cells. Highly eroded telomeres, rising frequencies of CD28 negative T cells and contraction of repertoire diversity with oligoclonality are all indicative of terminal expansion of peripheral T cells in the absence of supply of new T cells from thymus.14
5. What comes first: RA or immunosenescence? An interesting question to ponder upon is what comes firstRA or immunosenescence? First clue comes from an interesting difference in the nature of immunosenescence in RA as compared to normal aging. CD8þCD28 T cells are common with increasing age, but rising numbers of CD4þCD28 is unusual and is usually seen with RA. This means that in RA, there will be an age unmatched expansion of CD8þCD28 T cells along with hyperproliferation of CD4þCD28 T cells.19 This may suggest that forces driving RA pathogenesis are much different than that of aging, and RA might not be a case of mere early immunosenescence; there is more to it. Second clue comes from understanding the cause of decreased supply of new T cells from thymus. It is known that thymic involution is accelerated in RA, thus potentially compromising the supply of new T cells. Another source of such compromise can be a genetic defect in the HSCs, since they are the ultimate source of precursor T cells to thymus. We know that there is a high degree of genetic association between HLA-DRB1*04 alleles and RA.29 In a study conducted by Schonland et al, the authors
Fig. 3 Age-wise comparison of number of TRECs in healthy controls vs RA patients. Adapted from Weyand CM, Fulbright JW, Goronzy JJ. Immunosenescence, autoimmunity, and rheumatoid arthritis. Exp Gerontol. 2003.
Please cite this article in press as: Roy S, Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/j.injr.2014.01.011
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noted that in healthy individuals, presence of HLA-DRB1*04 alleles were associated with excessive loss of telomeres in CD4þ T cells. This telomere erosion was accelerated in the first 2 decades of life leading to reduced homeostatic T cell during adulthood. The authors also found that the primary target for such a telomere loss were HSCs.30 Telomere erosion is seen even in peripheral T cells from RA patients (Fig. 4). This shows that repeated replication is not the only reason for loss of telomeres. Telomerase activity is required to maintain telomeres. Normally on induction via any antigen, T cells upregulate telomerase formation so that loss of telomere is decelerated. But in a study conducted by Hiroshi Fujii et al, it was conclusively proven that naive CD4þ T cells from patients with RA are defective in inducing telomerase when primed with an antigen.31 As noted earlier, oligoclonality (loss of CD28 is a marker of oligoclonality19) of CD8þ T cells is fairly common with increasing age, but is not so common for CD4þ T cells except in diseases like RA. Sibpair studies have indicated that oligoclonality in CD4 compartment is equally frequent in affected and unaffected siblings in RA multicase families. This indicates presence of a common genetic link to the defect.19,32 Also interesting is that CD28 negative T cells do not appear only after RA development; rather they precede disease onset.19 Thus it seems that in patients with RA there is a genetic component which makes our immune system incapable of handling antigen stress. Consider a prospective patient of RA who is now healthy and has no clue that he might develop RA in future. The patient’s immune system is already coping with accelerated thymic involution, defective HSC replication, defective telomerase induction; introduction of antigenic stress triggers the development of RA. This antigen stress can be from various sources, including citrullinated peptides due to smoking or infections like Porphyromonas gingivalis or maybe a viral infection.33e35 When faced with such an antigenic stress, peripheral T cells expand with limited support from thymus ultimately leading to formation of autoreactive CD28 negative T cells. These autoreactive CD28 negative T cells have a contracted repertoire and may cross react with antigens similar to the priming antigen (e.g. citrullinated
Fig. 4 Age-wise comparison of Telomere length in healthy controls vs RA patients. Adapted from Weyand CM, Fulbright JW, Goronzy JJ. Immunosenescence, autoimmunity, and rheumatoid arthritis. Exp Gerontol. 2003.
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peptide). This leads to inflammation at the site of attack (e.g. joint synovium). Inflammation leads to release of peptidylarginine deiminase (PAD) enzymes, causing citrullination of more peptides and hence generation of more neo- antigens.36 This generates a vicious cycle, leading to formation of increased number of autoreactive T cells whose self-peptide targets keep on increasing as RA progresses, a phenomenon referred to as epitope spreading37 (Fig. 5). In short, in RA patients, immune system is not genetically fit to last long; when faced by a prolonged antigenic stress it just burns out fast. This is like an aging star; when it nears its own demise it explodes leading to supernova, consuming and destroying the members of its own solar system!!38
6. CD28 negative T cells: markers of disease activity in RA? As noted earlier, expansion of CD28 negative T cells precede RA disease onset. This loss of CD28 is not only limited to CD8þ T cells but is also seen with CD4þ T cells. In their study, A. Fasth et al suggested that tissues other than joint might be the primary homing sites for CD4þCD28 T cells. This might mean that CD4þCD28 T cells can be responsible for extra- articular manifestations in RA including cardiovascular disease.39 Schmidt et al19 found that increased frequency of CD4þCD28 T cells in RA was associated with development of extra- articular manifestations. CD4þCD28 T cells are also expanded in patients with unstable angina and were infrequent in patients with stable angina.40 The frequency of CD4þCD28 T cells was significantly higher in RA patients than in control subjects.41 These data are in unison with the fact that CD4þCD28 T cells express CD161which can facilitate tissue invasion.16 Since any antigen stress in RA patients will further add to the population of CD28 negative T cells. It has been long known that chronic viral infections need constant immune surveillance, which requires clonal expansion of immune cells.5 Presence of anti-CMV antibodies is associated with increase in the number of CD28 T cells.42 Though there was no significant difference between RA patients and healthy controls with regards to anti CMV antibodies but anti-CMV antibodies in RA patients were associated with an increased frequency of CD4þCD28 T cells and such patients developed more advanced joint damage.43 In end stage renal disease (ESRD) patients, Cytomegalovirus seropositivity is associated with an increased risk for cardiovascular disease,44 which can be linked to resultant increase in CD4þCD28 T cell population.45 Indeed, these data seems to corroborate that the number of CD4þCD28 T cells may serve as a marker of disease activity in RA. Can this information be used to predict response while managing a patient with RA? It has been observed that ligation of CD80/86 with CD28 leads to downmodulation of CD28.46 Abatacept is a humanized CTLA-4-immunoglublin-Fc (CTLA4-Ig) fusion protein designed to selectively inhibit T-cell activation by binding to the natural ligands CD 80 and CD86. In consequence, CD80 and CD86 cannot interact with CD28 on the T lymphocyte.47 Hence, theoretically, it is conceivable to believe that preventing CD28 to bind with CD80/86 using Abatacept will prevent generation of CD28 negative T cells.48
Please cite this article in press as: Roy S, Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/j.injr.2014.01.011
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Fig. 5 e Proposed model of immunosenescence and RA.
Available data shows that Abatacept treatment decreases CD28 negative T cell population along with other effector cells and this decrease correlates with clinical response. Such decrease in the number of CD28 T cells might have beneficial effects on cardiovascular risks associated with RA.49 Can the number of circulating CD28 T cells can be used as a predictor of clinical response to Abatacept in patients with RA? One study showed that patients having low baseline numbers of CD8þCD28 T cells (below 87 cells/ml) had a more than 4-fold higher probability of achieving remission within 6 months than patients with higher levels of these cells. What was more interesting to note was that the numbers of CD28 T cells at the time of remission is similar irrespective of whether the remission is achieved before or after 6 months.48 This suggests that the baseline number of CD28 T cells is useful in predicting time to achieve response, rather than indicating responsiveness to Abatacept. Higher the baseline CD28 T cells number, more will be the time taken to show response.48 Since CD4þCD28 T cells have built- in power for tissue invasion, number of CD4þCD28 T cells can indicate how aggressively RA is going to behave. We would need long term studies to evaluate this hypothesis. In summary, RA is a disease of genetic predilection towards accelerated immunosenescence, a process that is triggered and accelerated by antigenic stress. This process leads to formation of autoreactive CD28 negative T cells which orchestrate autoimmune damage including extra- articular manifestations of RA. This damage is directly proportional to the population of CD28 negative T cells. Success of management of RA will therefore depend on controlling CD28 negative T cells and
response can be predicted by checking if the intervention has been able to decrease this population or not.
Conflicts of interest The author has none to declare.
references
1. Salliot C, Finckh A, Katchamart W, et al. Indirect comparisons of the efficacy of biological antirheumatic agents in rheumatoid arthritis in patients with an inadequate response to conventional disease-modifying antirheumatic drugs or to an anti-tumour necrosis factor agent: a meta-analysis. Ann Rheum Dis. 2011;70:266e271. 2. Hyrich KL, Lunt M, Watson KD, Symmons DPM, Silman AJ, Register BS for RB. Outcomes after switching from one antietumor necrosis factor a agent to a second antietumor necrosis factor a agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum. 2007;56:13e20. 3. Emery P, Do¨rner T. Optimising treatment in rheumatoid arthritis: a review of potential biological markers of response. Ann Rheum Dis. 2011;70:2063e2070. 4. Broux B, Markovic-Plese S, Stinissen P, Hellings N. Pathogenic features of CD4þCD28 T cells in immune disorders. Trends Mol Med. 2012;18:446e453. 5. Lindstrom TM, Robinson WH. Rheumatoid arthritis: a role for immunosenescence? J Am Geriatr Soc. 2010;58:1565e1575.
Please cite this article in press as: Roy S, Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/j.injr.2014.01.011
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6. Goronzy JJ, Weyand CM. Rheumatoid arthritis. Immunol Rev. 2005;204:55e73. 7. Weyand CM, Fulbright JW, Goronzy JJ. Immunosenescence, autoimmunity, and rheumatoid arthritis. Exp Gerontol. 2003;38:833e841. 8. Koetz K, Bryl E, Spickschen K, O’Fallon WM, Goronzy JJ, Weyand CM. T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci U S A. 2000;97:9203e9208. 9. Goldrath AW, Bevan MJ. Selecting and maintaining a diverse T-cell repertoire. Nature. 1999;402:255e262. 10. Jin L-P, Fan D-X, Li D-J. Regulation of costimulatory signal in maternalefetal immune tolerance. Am J Reprod Immunol. 2011;66:76e83. 11. Goronzy JJ, Lee W-W, Weyand CM. Aging and T-cell diversity. Exp Gerontol. 2007;42:400e406. 12. Hakim FT, Memon SA, Cepeda R, et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest. 2005;115:930e939. 13. Goronzy JJ, Shao L, Weyand CM. Immune aging and rheumatoid arthritis. Rheum Dis Clin North Am. 2010;36:297e310. 14. Goronzy JJ, Weyand CM. Aging, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity - catalysts of autoimmunity and chronic inflammation. Arthritis Res Ther. 2003;5:225e234. 15. Vallejo AN, Brandes JC, Weyand CM, Goronzy JJ. Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence. J Immunol. 1999;162:6572e6579. 16. Vallejo AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev. 2005;205:158e169. 17. Manjunath N, Shankar P, Stockton B, Dubey PD, Lieberman J, von Andrian UH. A transgenic mouse model to analyze CD8þ effector T cell differentiation in vivo. Proc Natl Acad Sci U S A. 1999;96:13932e13937. 18. Trimble LA, Kam LW, Friedman RS, Xu Z, Lieberman J. CD3zeta and CD28 down-modulation on CD8 T cells during viral infection. Blood. 2000;96:1021e1029. 19. Schmidt D, Martens PB, Weyand CM, Goronzy JJ. The repertoire of CD4þ CD28- T cells in rheumatoid arthritis. Mol Med. 1996;2:608e618. 20. Costenbader KH, Prescott J, Zee RY, De Vivo I. Immunosenescence and rheumatoid arthritis: does telomere shortening predict impending disease? Autoimmun Rev. 2011;10:569e573. 21. Boissier M-C. Cell and cytokine imbalances in rheumatoid synovitis. Joint Bone Spine. 2011;78:230e234. 22. Scott DL, Wolfe F, Huizinga TWJ. Rheumatoid arthritis. Lancet. 2010;376:1094e1108. 23. Andersson AK, Li C, Brennan FM. Recent developments in the immunobiology of rheumatoid arthritis. Arthritis Res Ther. 2008;10:204. 24. Buckley CD. Science, medicine, and the future. Treatment of rheumatoid arthritis. BMJ. 1997;315:236e238. 25. Struyk L, Hawes GE, Chatila MK, Breedveld FC, Kurnick JT, van den Elsen PJ. T cell receptors in rheumatoid arthritis. Arthritis Rheum. 1995;38:577e589. 26. Klareskog L, Ro¨nnelid J, Holm G. Immunopathogenesis and immunotherapy in rheumatoid arthritis: an area in transition. J Intern Med. 1995;238:191e206. 27. Goronzy JJ, Henel G, Sawai H, et al. Costimulatory pathways in rheumatoid synovitis and T-cell senescence. Ann N Y Acad Sci. 2005;1062:182e194. 28. Thewissen M, Linsen L, Somers V, Geusens P, Raus J, Stinissen P. Premature immunosenescence in rheumatoid arthritis and multiple sclerosis patients. Ann N Y Acad Sci. 2005;1051:255e262.
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29. Fugger L, Svejgaard A. Association of MHC and rheumatoid arthritis: HLA-DR4 and rheumatoid arthritis e studies in mice and men. Arthritis Res. 2000;2:208e211. 30. Schonland SO, Lopez C, Widmann T, et al. Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages. Proc Natl Acad Sci U S A. 2003;100:13471e13476. 31. Fujii H, Shao L, Colmegna I, Goronzy JJ, Weyand CM. Telomerase insufficiency in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2009;106:4360e4365. 32. Waase I, Kayser C, Carlson PJ, Goronzy JJ, Weyand CM. Oligoclonal T cell proliferation in patients with rheumatoid arthritis and their unaffected siblings. Arthritis Rheum. 1996;39:904e913. 33. Luban S, Li Z-G. Citrullinated peptide and its relevance to rheumatoid arthritis: an update. Int J Rheum Dis. 2010;13:284e287. 34. Wegner N, Lundberg K, Kinloch A, et al. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol Rev. 2010;233:34e54. 35. Munz C, Lunemann JD, Getts MT, Miller SD. Antiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol. 2009;9:246e258. 36. Suzuki A, Yamada R, Yamamoto K. Citrullination by peptidylarginine deiminase in rheumatoid arthritis. Ann N Y Acad Sci. 2007;1108:323e339. 37. Sokolove J, Bromberg R, Deane KD, et al. Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS One. 2012;7. 38. Kirshner RP. Supernova: death of a star. Natl Geogr Mag. 1988;173:618e647. 39. Fasth AE, Snir O, Johansson AA, et al. Skewed distribution of proinflammatory CD4þCD28null T cells in rheumatoid arthritis. Arthritis Res Ther. 2007;9:R87. 40. Liuzzo G, Goronzy JJ, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation. 2000;101:2883e2888. 41. Gerli R, Schillaci G, Giordano A, et al. CD4þCD28 T lymphocytes contribute to early atherosclerotic damage in rheumatoid arthritis patients. Circulation. 2004;109:2744e2748. 42. Vasto S, Colonna-Romano G, Larbi A, Wikby A, Caruso C, Pawelec G. Role of persistent CMV infection in configuring T cell immunity in the elderly. Immun Ageing. 2007;4:2. 43. Pierer M, Rothe K, Quandt D, et al. Association of anticytomegalovirus seropositivity with more severe joint destruction and more frequent joint surgery in rheumatoid arthritis. 2012;64:1740e1749. 44. Shlipak MG, Fried LF, Cushman M, et al. Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors. JAMA. 2005;293:1737e1745. 45. Betjes MG, de Wit EE, Weimar W, Litjens NH. Circulating proinflammatory CD4posCD28null T cells are independently associated with cardiovascular disease in ESRD patients. Nephrol Dial Transplant. 2010;25:3640e3646. 46. Linsley PS, Bradshaw J, Urnes M, Grosmaire L, Ledbetter JA. CD28 engagement by B7/BB-1 induces transient downregulation of CD28 synthesis and prolonged unresponsiveness to CD28 signaling. J Immunol. 1993;150:3161e3169. 47. Von Kempis J, Dudler J, Hasler P, et al. Use of abatacept in rheumatoid arthritis. Swiss Med Wkly. 2012 May;142:w13581. 48. Scarsi M, Ziglioli T, Airo’ P. Baseline numbers of circulating CD28-negative T cells may predict clinical response to abatacept in patients with rheumatoid arthritis. J Rheumatol. 2011;38:2105e2111. 49. Scarsi M, Ziglioli T, Airo` P. Decreased circulating CD28negative T cells in patients with rheumatoid arthritis treated with abatacept are correlated with clinical response. J Rheumatol. 2010;37:911e916.
Please cite this article in press as: Roy S, Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/j.injr.2014.01.011
ScienceDirect Available online at www.indianjrheumatol.com and www.sciencedirect.com
Review Article
Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response Subir Roy* article info
abstract
Article history:
Not many years ago achieving remission in rheumatoid arthritis was difficult due to lack of
Received 28 August 2013
effective treatment. With the advent of biologics, remission is very much within reach. But
Accepted 30 January 2014
biologics are expensive. And not all patients respond adequately to biologics. Hence it will
Available online xxx
be useful if we have a marker which predicts response to any disease modifying antirheumatic drug (DMARD), whether conventional or biologic. Expansion of CD28-ve T
Keywords:
cells is characteristically seen in RA. Both CD28-ve T Cells and RA are believed to be linked
CD28-ve
to immunosenescence. The available evidences are suggestive of an intimate relationship
Immunosenescence
between RA and clonal expansion of CD28-ve T cells. Newer biomarkers are constantly
Biomarker
being looked at and CD28-ve T cells is one of them. In this review I will discuss in brief the
Rheumatoid arthritis
relationship between immune disorders like RA and immunosenescence and discuss significance of CD28-ve T cells in RA. Copyright ª 2014, Indian Rheumatology Association. All rights reserved.
1.
Introduction
Management of rheumatoid arthritis (RA) has seen tremendous and rapid evolution. Not many years ago achieving remission was an elusive aim due to lack of effective treatment options. With the advent of biologics, remission is very much within reach and should be aimed early in a patient with RA before the patient develops RA related deformities or co morbidities.1 But biologics are expensive and not all patients respond adequately to biologics. One-third of RA patients do not respond to tumor necrosis factor a (TNF-a) inhibitors.2 Patient and disease related variables probably play a role in drug response.3 Hence it will be useful if we have a biomarker which predicts response to disease modifying anti-rheumatic drug (DMARD), whether conventional or biologic.
Expansion of CD28 negative T cells is seen in RA.4 Both CD28 negative T Cells and RA are thought to be linked to immunosenecence.5 The available evidence suggests an intimate relationship between RA and clonal expansion of CD28 negative T cells. In this review the relationship between immune disorders like RA and immunosenescence, and significance of CD28 negative T cells in RA as regards disease activity and as predictors of response to therapy, will be discussed.
2.
Immunity and immunosenescence
RA is an autoimmune disorder resulting from disruption in the immune system’s discrimination of self and non-self.6 It is generally believed that in autoimmunity there is overactive immune system that responds to a slight aberration of the self-peptides with sustained immune response resulting in
* Tel.: þ91 9930830118. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.injr.2014.01.011 0973-3698/Copyright ª 2014, Indian Rheumatology Association. All rights reserved.
Please cite this article in press as: Roy S, Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/j.injr.2014.01.011
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tissue damage.7 But, this perspective might not be true. A large set of data suggests that RA might be a result of immunosenescence.8,5
2.1.
What is immunosenescence?
Normally, primary adaptive immune response is induced when antigen presenting cells (APCs) take up antigens and present them to the naı¨ve T cells via major histocompatibility complex (MHC).9 T cells bearing T cell receptors (TCRs) specific to the antigens presented undergo clonal expansion and differentiate into effector T cells including cytotoxic CD8þ T cells and helper CD4þ T cells. A few of these activated T cells go on to become memory T cells.5 The adaptive immune system can distinguish between the self and the non-self. This selfenon self discrimination is generated at central and peripheral level. Central T cell tolerance occurs in the thymus where T cell differentiation and maturation takes place. Here, newly generated T cells undergo selection mechanisms resulting in survival and maturation of only those T cells who’s TCRs interact weakly with self-peptide/ self- MHC complexes (referred to as self tolerant and self MHC restricted)5 (Fig. 1). Peripheral tolerance mechanism includes the two signal model of T cell activation.5 Signal one is generated by binding of TCR with the antigen/MHC complex delivered by APC. Signal two is generated when CD28 receptor on T cell surface binds with B7 molecule expressed by APC. Without costimulatory signal, T cell activation does not happen.10 When there is no infection/inflammation, APCs do not express B7. This means that when a mature T cell interacts with a selfpeptide/MHC complex, signal two is not generated. This lack of signal two results in either the death of interacting T cell or makes it refractory to activation (also known as anergy). However a weak interaction between TCR and self-peptide/ MHC complexes is needed in the periphery for survival and physiological multiplication of mature T cells.5 The naı¨ve and memory T cells represent a pool which undergoes constant proliferation, influx and apoptosis. The
balance of naı¨ve and memory T cells is driven by homeostatic and antigen- driven requirements.11 Approximately 3 109 T cells are generated each day as a part of homeostatic churning of T cells.7 Homeostatic proliferation of memory T cells is more as compared to naı¨ve T cells. Though, this raises the possibility that memory T cells might outcompete naı¨ve T cells leading to compromise of the naı¨ve T cell compartment, homeostatic mechanisms seem to control this demise of naı¨ve T cell compartment.11 New memory T cells are generated from the naı¨ve T cell compartment whenever there is priming from new exogenous antigen. Naı¨ve T cells can be generated either via precursor T cells which are derived from haemato-poietic stem cells (HSCs) in the thymus or via self-proliferation wherein naı¨ve T cells serve as their own precursors11 (Fig. 2). With aging there is decline in the supply of new T cells from thymus.5 This decline in generation of T cells is a result of age related defective HSC replication and progressive involution of thymus.5,12 It is known that thymic function rapidly declines with age. Thymic epithelial space (TES) is considered as the best biologic correlate of functionally active thymic tissues. This TES goes down from about 7 cm3 in the young adult to about 1 cm3 in the 55e65-year-old. Thymic function is minimal after the age of 40 years. Hence, after the age of 40 years, the homeostasis of the T cell compartment nearly completely depends on peripheral mechanisms which regulate the proliferation and survival of naı¨ve and memory T cells.11,13 Also, with age, both antigenic load and duration of exposure to specific antigen increase. These result in compensatory proliferation of peripheral naı¨ve and memory T cells, leading to predominance of memory T cells (since memory T cells proliferate much faster as compared to the naı¨ve T cells).5,11 Such kind of proliferation is accompanied by changes at the level of receptor expression and consequently on functions. One such change is contraction of T cell repertoire.5 This contraction seems to get accelerated markedly at around the age of 65 years after which around 95% of diversity in T cells is lost.14 Why? One reason is that any proliferation which is not happening due to stimulation via any foreign antigens is dependent on interaction between the TCR and the self-peptideeMHC complex that the specific TCR had weakly reacted to during positive selection of the T cell in the thymus. Since this is now happening in the peripheral compartment, there is no positive/negative selection process which happens in thymus. The consequences are grave. There is competitive exclusion of TCRs because of the differences in the TCR affinity for the self peptides inducing proliferation. Those TCRs which have more avidity towards self-peptide MHC complex now get selected. The immune system gets biased to self antigens and makes the system susceptible to develop autoimmunity.5
3. Significance of CD28 negative T cells and their characteristics
Fig. 1 e Selection process of T cells in thymus.5
A cellular change that has been consistently noted with aging is progressive loss of CD28 receptor expression. Both CD4þ and CD8þ T cells are affected, but is more common with CD8þ T cells.5
Please cite this article in press as: Roy S, Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/j.injr.2014.01.011
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Fig. 2 e Maintenance of naı¨ve T cell supply.11
It has been noted that T cell activation always leads to CD28 downmodulation. If there is repeated stimulation by the same antigen, it leads to progressive loss of CD28 ultimately resulting in formation of CD28 eve T cells. Hence it seems logical why loss of CD28 is seen commonly with aging as well as in chronic infection. Loss of CD28 is also very common in autoimmune diseases.15 Since CD28 is a crucial for delivery of costimulation, theoretically it may sound that CD28 negative T cells are inactive and silent. But in reality, CD28 negative T cells are actually highly potent as effector cells.16 and have tissue damaging properties. CD4þCD28 T cells have been reported to be autoreactive. CD4þCD28 T cells store large amounts of interferon g in their cytoplasm and they also express CD161. CD161 facilitates tissue invasion. This makes them similar to proinflammatory lymphocytes. Unlike normal activated T cells, they do not require high amounts of IL-2 to survive. Interestingly though, CD4þCD28 T cells are able to produce large amounts of IL-2. CD4þCD28 T cells also acquire a variety of killer cell Ig-like receptors (KIRs). KIRs are generally seen in natural killer (NK) cells. NKG2D is another receptor associated with CD4þCD28 T cells. NKG2D is an NK-related receptor which can contribute to the survival of autoreactive CD4þCD 28 T cells.16 CD8þCD28 T cells are reactive to viruses like EpsteineBarr virus (EBV), cytomegalovirus (CMV) etc. Clonal expansion of CD8þCD28 T cells are common in patients suffering from acquired immunodeficiency syndrome (AIDS). These CD8þCD28 T cells represent terminally differentiated effector lymphocytes. Unlike their CD4þ counterparts, CD8þCD28 T cells are unable to produce their own IL-2. Receptor expression is similar to that of CD4þCD28 T cells when it comes to the NK- related receptors like KIR, NKG2D, CD94, CD56, and Fc-g receptor IIIA.16 Data suggest that CD8þCD28 T cells are the first ones to respond to any acute infection.17,18 Evidence also show that
they are representatives of either an aging process or chronic antigen stimulation, indicating that they represent immunosenescence.16,5 Cellular senescence is always defined by the presence altered function, resistance to apoptosis and telomere shortening leading to proliferative arrest (Table 1).14 As discussed, loss of thymic supply of new T cells via HSCs coupled with antigen stimulation accelerates proliferation of peripheral T cells, which then lose CD28 expression indicating replicative senescence of the T cells. It has been conclusively shown that loss of CD28 is an indicator of oligoclonality,19 which means that the same T cell is repeatedly proliferating. This process then should lead to telomere erosion. Telomere length, which is considered as a biomarker of biological age, is highly truncated in CD28 negative T cells.16,20 Taken together, CD28 negative T cells fit the definition of cellular senescence. This prompts us to believe that when our body faces any antigenic challenge as an immediate measure the threat is dealt by peripheral multiplication of T cells which leads to downmodulation of CD28 expression. Downmodulation of CD28 expression leads to increased reactivity but decreased specificity which helps dealing with the impending threat on a short term basis. This is then complimented and controlled by the adaptive immunity which is more specific and controlled. The fine balance between the immediate action in the form of CD28 negative T cells and mature response via CD28 mediated costimulation determines normalcy in our immune response.
Table 1 e What’s common between RA and aging?
Decreased thymic output Defective HSC replication Expansion of CD28 negative T cell population Contraction of T cell repertoire Eroded telomeres in T cells Low T cell receptor excision circle numbers
Please cite this article in press as: Roy S, Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/j.injr.2014.01.011
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This normalcy can get disturbed if there is defective replication of HSCs or defect in the thymus or chronic antigenic stimulus; either or a combination of these individual events can lead to unrestricted generation of CD28 negative T cells tipping the homeostatic balance towards autoimmunity. If this theory holds true then there has to be differences in the characteristics of CD28 negative T cells generated as a result of normal T cell activation and those generated due to immunosenescence. In 1999 Vallejo et al15 in their classic experiment noted that there exists distinct mechanisms that lead to CD28 down-regulation following T cell activation and during replicative senescence. In their experiment Vallejo et al noted that while activation-induced down-regulation of CD28 expression equally affected CD4 and CD8 T cells, the gradual loss of CD28 expression during continuous culture was more pronounced in the CD8 cells. This type of cell culture is representative of replicative senescence. This is in line with the observation that during aging and chronic infections there is characteristic increase in the frequencies of CD8þCD28 T cells and that loss of CD28 expression is less common with CD4þ T cells.4,15 Infact clonal expansion of CD8þCD28 T cells with loss of CD28 receptor expression can occur due to normal aging or pathologic immunosenescence, but loss of CD28 expression in both CD4þ and CD8þ T cells is more common in autoimmune conditions like rheumatoid arthritis.19 This indicates that autoimmune diseases might be an immunosenescent process where chronic inflammation and premature aging play a tandem of vicious cycle exhausting the integrity of immune system.
4. Rheumatoid arthritis (RA) and immunosenescence Rheumatoid arthritis is an autoimmune disease driven by several cytokines acting sequentially and/or in parallel.21 One of the best known cytokine imbalances is overexpression of tumour necrosis factor (TNF). Interleukin-6 is also one such cytokine known to drive inflammation and joint damage. These cytokine imbalances result due to a complex interaction among T and B lymphocytes, fibroblast and macrophages.21,22 Clinical improvement in RA patients receiving anti-CD20 antibodies like Rituximab highlights the role of B cells in RA pathology.23 Available data suggest that RA is a T cell mediated autoimmune disease.24e26 Abnormal T cell activation occurs early in RA which stimulates the monocytes and macrophages to secrete cytokines and enzymes that cause bone destruction in RA.20 RA is characterized by clonal expansion of CD28 negative T cells. These CD28 negative T cells are autoreactive, have markedly contracted repertoire and show highly eroded telomere.5 As discussed, CD28 negative T cells indicate immunosenescence. This observation therefore makes us ponder if RA is a case of immunosenescence.7,14,27,28 Thymic involution occurs very early in patients with RA.28 There exists an inverse relationship between thymic capacity and incidence of RA.7 In patients with RA, output of T cells via thymus is inappropriately low for age. It matches that of healthy individuals 20e30 years older, and the TCR repertoire
of naive and memory T cell populations is smaller.5 This will become clearer when we compare the T-cell receptor excision circles (TREC) numbers between patients of RA and healthy controls (Fig. 3). TRECs are extra-chromosomal byproducts that are generated during recombination of V(D)J gene segments of TCR. Since they do not replicate, they get diluted with every cell division. TREC content of peripheral blood mononuclear cells (PBMCs) can be used to determine thymic output. As compared to the age matched healthy controls, TREC numbers are significantly lower in RA patients (Fig. 3). As expected, in both patients with RA and healthy controls, TREC numbers in PBMCs decline progressively with age.28 Lower thymic output in RA is complimented by replicative stress on peripheral T cells. Highly eroded telomeres, rising frequencies of CD28 negative T cells and contraction of repertoire diversity with oligoclonality are all indicative of terminal expansion of peripheral T cells in the absence of supply of new T cells from thymus.14
5. What comes first: RA or immunosenescence? An interesting question to ponder upon is what comes firstRA or immunosenescence? First clue comes from an interesting difference in the nature of immunosenescence in RA as compared to normal aging. CD8þCD28 T cells are common with increasing age, but rising numbers of CD4þCD28 is unusual and is usually seen with RA. This means that in RA, there will be an age unmatched expansion of CD8þCD28 T cells along with hyperproliferation of CD4þCD28 T cells.19 This may suggest that forces driving RA pathogenesis are much different than that of aging, and RA might not be a case of mere early immunosenescence; there is more to it. Second clue comes from understanding the cause of decreased supply of new T cells from thymus. It is known that thymic involution is accelerated in RA, thus potentially compromising the supply of new T cells. Another source of such compromise can be a genetic defect in the HSCs, since they are the ultimate source of precursor T cells to thymus. We know that there is a high degree of genetic association between HLA-DRB1*04 alleles and RA.29 In a study conducted by Schonland et al, the authors
Fig. 3 Age-wise comparison of number of TRECs in healthy controls vs RA patients. Adapted from Weyand CM, Fulbright JW, Goronzy JJ. Immunosenescence, autoimmunity, and rheumatoid arthritis. Exp Gerontol. 2003.
Please cite this article in press as: Roy S, Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/j.injr.2014.01.011
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noted that in healthy individuals, presence of HLA-DRB1*04 alleles were associated with excessive loss of telomeres in CD4þ T cells. This telomere erosion was accelerated in the first 2 decades of life leading to reduced homeostatic T cell during adulthood. The authors also found that the primary target for such a telomere loss were HSCs.30 Telomere erosion is seen even in peripheral T cells from RA patients (Fig. 4). This shows that repeated replication is not the only reason for loss of telomeres. Telomerase activity is required to maintain telomeres. Normally on induction via any antigen, T cells upregulate telomerase formation so that loss of telomere is decelerated. But in a study conducted by Hiroshi Fujii et al, it was conclusively proven that naive CD4þ T cells from patients with RA are defective in inducing telomerase when primed with an antigen.31 As noted earlier, oligoclonality (loss of CD28 is a marker of oligoclonality19) of CD8þ T cells is fairly common with increasing age, but is not so common for CD4þ T cells except in diseases like RA. Sibpair studies have indicated that oligoclonality in CD4 compartment is equally frequent in affected and unaffected siblings in RA multicase families. This indicates presence of a common genetic link to the defect.19,32 Also interesting is that CD28 negative T cells do not appear only after RA development; rather they precede disease onset.19 Thus it seems that in patients with RA there is a genetic component which makes our immune system incapable of handling antigen stress. Consider a prospective patient of RA who is now healthy and has no clue that he might develop RA in future. The patient’s immune system is already coping with accelerated thymic involution, defective HSC replication, defective telomerase induction; introduction of antigenic stress triggers the development of RA. This antigen stress can be from various sources, including citrullinated peptides due to smoking or infections like Porphyromonas gingivalis or maybe a viral infection.33e35 When faced with such an antigenic stress, peripheral T cells expand with limited support from thymus ultimately leading to formation of autoreactive CD28 negative T cells. These autoreactive CD28 negative T cells have a contracted repertoire and may cross react with antigens similar to the priming antigen (e.g. citrullinated
Fig. 4 Age-wise comparison of Telomere length in healthy controls vs RA patients. Adapted from Weyand CM, Fulbright JW, Goronzy JJ. Immunosenescence, autoimmunity, and rheumatoid arthritis. Exp Gerontol. 2003.
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peptide). This leads to inflammation at the site of attack (e.g. joint synovium). Inflammation leads to release of peptidylarginine deiminase (PAD) enzymes, causing citrullination of more peptides and hence generation of more neo- antigens.36 This generates a vicious cycle, leading to formation of increased number of autoreactive T cells whose self-peptide targets keep on increasing as RA progresses, a phenomenon referred to as epitope spreading37 (Fig. 5). In short, in RA patients, immune system is not genetically fit to last long; when faced by a prolonged antigenic stress it just burns out fast. This is like an aging star; when it nears its own demise it explodes leading to supernova, consuming and destroying the members of its own solar system!!38
6. CD28 negative T cells: markers of disease activity in RA? As noted earlier, expansion of CD28 negative T cells precede RA disease onset. This loss of CD28 is not only limited to CD8þ T cells but is also seen with CD4þ T cells. In their study, A. Fasth et al suggested that tissues other than joint might be the primary homing sites for CD4þCD28 T cells. This might mean that CD4þCD28 T cells can be responsible for extra- articular manifestations in RA including cardiovascular disease.39 Schmidt et al19 found that increased frequency of CD4þCD28 T cells in RA was associated with development of extra- articular manifestations. CD4þCD28 T cells are also expanded in patients with unstable angina and were infrequent in patients with stable angina.40 The frequency of CD4þCD28 T cells was significantly higher in RA patients than in control subjects.41 These data are in unison with the fact that CD4þCD28 T cells express CD161which can facilitate tissue invasion.16 Since any antigen stress in RA patients will further add to the population of CD28 negative T cells. It has been long known that chronic viral infections need constant immune surveillance, which requires clonal expansion of immune cells.5 Presence of anti-CMV antibodies is associated with increase in the number of CD28 T cells.42 Though there was no significant difference between RA patients and healthy controls with regards to anti CMV antibodies but anti-CMV antibodies in RA patients were associated with an increased frequency of CD4þCD28 T cells and such patients developed more advanced joint damage.43 In end stage renal disease (ESRD) patients, Cytomegalovirus seropositivity is associated with an increased risk for cardiovascular disease,44 which can be linked to resultant increase in CD4þCD28 T cell population.45 Indeed, these data seems to corroborate that the number of CD4þCD28 T cells may serve as a marker of disease activity in RA. Can this information be used to predict response while managing a patient with RA? It has been observed that ligation of CD80/86 with CD28 leads to downmodulation of CD28.46 Abatacept is a humanized CTLA-4-immunoglublin-Fc (CTLA4-Ig) fusion protein designed to selectively inhibit T-cell activation by binding to the natural ligands CD 80 and CD86. In consequence, CD80 and CD86 cannot interact with CD28 on the T lymphocyte.47 Hence, theoretically, it is conceivable to believe that preventing CD28 to bind with CD80/86 using Abatacept will prevent generation of CD28 negative T cells.48
Please cite this article in press as: Roy S, Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/j.injr.2014.01.011
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Fig. 5 e Proposed model of immunosenescence and RA.
Available data shows that Abatacept treatment decreases CD28 negative T cell population along with other effector cells and this decrease correlates with clinical response. Such decrease in the number of CD28 T cells might have beneficial effects on cardiovascular risks associated with RA.49 Can the number of circulating CD28 T cells can be used as a predictor of clinical response to Abatacept in patients with RA? One study showed that patients having low baseline numbers of CD8þCD28 T cells (below 87 cells/ml) had a more than 4-fold higher probability of achieving remission within 6 months than patients with higher levels of these cells. What was more interesting to note was that the numbers of CD28 T cells at the time of remission is similar irrespective of whether the remission is achieved before or after 6 months.48 This suggests that the baseline number of CD28 T cells is useful in predicting time to achieve response, rather than indicating responsiveness to Abatacept. Higher the baseline CD28 T cells number, more will be the time taken to show response.48 Since CD4þCD28 T cells have built- in power for tissue invasion, number of CD4þCD28 T cells can indicate how aggressively RA is going to behave. We would need long term studies to evaluate this hypothesis. In summary, RA is a disease of genetic predilection towards accelerated immunosenescence, a process that is triggered and accelerated by antigenic stress. This process leads to formation of autoreactive CD28 negative T cells which orchestrate autoimmune damage including extra- articular manifestations of RA. This damage is directly proportional to the population of CD28 negative T cells. Success of management of RA will therefore depend on controlling CD28 negative T cells and
response can be predicted by checking if the intervention has been able to decrease this population or not.
Conflicts of interest The author has none to declare.
references
1. Salliot C, Finckh A, Katchamart W, et al. Indirect comparisons of the efficacy of biological antirheumatic agents in rheumatoid arthritis in patients with an inadequate response to conventional disease-modifying antirheumatic drugs or to an anti-tumour necrosis factor agent: a meta-analysis. Ann Rheum Dis. 2011;70:266e271. 2. Hyrich KL, Lunt M, Watson KD, Symmons DPM, Silman AJ, Register BS for RB. Outcomes after switching from one antietumor necrosis factor a agent to a second antietumor necrosis factor a agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum. 2007;56:13e20. 3. Emery P, Do¨rner T. Optimising treatment in rheumatoid arthritis: a review of potential biological markers of response. Ann Rheum Dis. 2011;70:2063e2070. 4. Broux B, Markovic-Plese S, Stinissen P, Hellings N. Pathogenic features of CD4þCD28 T cells in immune disorders. Trends Mol Med. 2012;18:446e453. 5. Lindstrom TM, Robinson WH. Rheumatoid arthritis: a role for immunosenescence? J Am Geriatr Soc. 2010;58:1565e1575.
Please cite this article in press as: Roy S, Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/j.injr.2014.01.011
i n d i a n j o u r n a l o f r h e u m a t o l o g y x x x ( 2 0 1 4 ) 1 e7
6. Goronzy JJ, Weyand CM. Rheumatoid arthritis. Immunol Rev. 2005;204:55e73. 7. Weyand CM, Fulbright JW, Goronzy JJ. Immunosenescence, autoimmunity, and rheumatoid arthritis. Exp Gerontol. 2003;38:833e841. 8. Koetz K, Bryl E, Spickschen K, O’Fallon WM, Goronzy JJ, Weyand CM. T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci U S A. 2000;97:9203e9208. 9. Goldrath AW, Bevan MJ. Selecting and maintaining a diverse T-cell repertoire. Nature. 1999;402:255e262. 10. Jin L-P, Fan D-X, Li D-J. Regulation of costimulatory signal in maternalefetal immune tolerance. Am J Reprod Immunol. 2011;66:76e83. 11. Goronzy JJ, Lee W-W, Weyand CM. Aging and T-cell diversity. Exp Gerontol. 2007;42:400e406. 12. Hakim FT, Memon SA, Cepeda R, et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest. 2005;115:930e939. 13. Goronzy JJ, Shao L, Weyand CM. Immune aging and rheumatoid arthritis. Rheum Dis Clin North Am. 2010;36:297e310. 14. Goronzy JJ, Weyand CM. Aging, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity - catalysts of autoimmunity and chronic inflammation. Arthritis Res Ther. 2003;5:225e234. 15. Vallejo AN, Brandes JC, Weyand CM, Goronzy JJ. Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence. J Immunol. 1999;162:6572e6579. 16. Vallejo AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev. 2005;205:158e169. 17. Manjunath N, Shankar P, Stockton B, Dubey PD, Lieberman J, von Andrian UH. A transgenic mouse model to analyze CD8þ effector T cell differentiation in vivo. Proc Natl Acad Sci U S A. 1999;96:13932e13937. 18. Trimble LA, Kam LW, Friedman RS, Xu Z, Lieberman J. CD3zeta and CD28 down-modulation on CD8 T cells during viral infection. Blood. 2000;96:1021e1029. 19. Schmidt D, Martens PB, Weyand CM, Goronzy JJ. The repertoire of CD4þ CD28- T cells in rheumatoid arthritis. Mol Med. 1996;2:608e618. 20. Costenbader KH, Prescott J, Zee RY, De Vivo I. Immunosenescence and rheumatoid arthritis: does telomere shortening predict impending disease? Autoimmun Rev. 2011;10:569e573. 21. Boissier M-C. Cell and cytokine imbalances in rheumatoid synovitis. Joint Bone Spine. 2011;78:230e234. 22. Scott DL, Wolfe F, Huizinga TWJ. Rheumatoid arthritis. Lancet. 2010;376:1094e1108. 23. Andersson AK, Li C, Brennan FM. Recent developments in the immunobiology of rheumatoid arthritis. Arthritis Res Ther. 2008;10:204. 24. Buckley CD. Science, medicine, and the future. Treatment of rheumatoid arthritis. BMJ. 1997;315:236e238. 25. Struyk L, Hawes GE, Chatila MK, Breedveld FC, Kurnick JT, van den Elsen PJ. T cell receptors in rheumatoid arthritis. Arthritis Rheum. 1995;38:577e589. 26. Klareskog L, Ro¨nnelid J, Holm G. Immunopathogenesis and immunotherapy in rheumatoid arthritis: an area in transition. J Intern Med. 1995;238:191e206. 27. Goronzy JJ, Henel G, Sawai H, et al. Costimulatory pathways in rheumatoid synovitis and T-cell senescence. Ann N Y Acad Sci. 2005;1062:182e194. 28. Thewissen M, Linsen L, Somers V, Geusens P, Raus J, Stinissen P. Premature immunosenescence in rheumatoid arthritis and multiple sclerosis patients. Ann N Y Acad Sci. 2005;1051:255e262.
7
29. Fugger L, Svejgaard A. Association of MHC and rheumatoid arthritis: HLA-DR4 and rheumatoid arthritis e studies in mice and men. Arthritis Res. 2000;2:208e211. 30. Schonland SO, Lopez C, Widmann T, et al. Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages. Proc Natl Acad Sci U S A. 2003;100:13471e13476. 31. Fujii H, Shao L, Colmegna I, Goronzy JJ, Weyand CM. Telomerase insufficiency in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2009;106:4360e4365. 32. Waase I, Kayser C, Carlson PJ, Goronzy JJ, Weyand CM. Oligoclonal T cell proliferation in patients with rheumatoid arthritis and their unaffected siblings. Arthritis Rheum. 1996;39:904e913. 33. Luban S, Li Z-G. Citrullinated peptide and its relevance to rheumatoid arthritis: an update. Int J Rheum Dis. 2010;13:284e287. 34. Wegner N, Lundberg K, Kinloch A, et al. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol Rev. 2010;233:34e54. 35. Munz C, Lunemann JD, Getts MT, Miller SD. Antiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol. 2009;9:246e258. 36. Suzuki A, Yamada R, Yamamoto K. Citrullination by peptidylarginine deiminase in rheumatoid arthritis. Ann N Y Acad Sci. 2007;1108:323e339. 37. Sokolove J, Bromberg R, Deane KD, et al. Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS One. 2012;7. 38. Kirshner RP. Supernova: death of a star. Natl Geogr Mag. 1988;173:618e647. 39. Fasth AE, Snir O, Johansson AA, et al. Skewed distribution of proinflammatory CD4þCD28null T cells in rheumatoid arthritis. Arthritis Res Ther. 2007;9:R87. 40. Liuzzo G, Goronzy JJ, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation. 2000;101:2883e2888. 41. Gerli R, Schillaci G, Giordano A, et al. CD4þCD28 T lymphocytes contribute to early atherosclerotic damage in rheumatoid arthritis patients. Circulation. 2004;109:2744e2748. 42. Vasto S, Colonna-Romano G, Larbi A, Wikby A, Caruso C, Pawelec G. Role of persistent CMV infection in configuring T cell immunity in the elderly. Immun Ageing. 2007;4:2. 43. Pierer M, Rothe K, Quandt D, et al. Association of anticytomegalovirus seropositivity with more severe joint destruction and more frequent joint surgery in rheumatoid arthritis. 2012;64:1740e1749. 44. Shlipak MG, Fried LF, Cushman M, et al. Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors. JAMA. 2005;293:1737e1745. 45. Betjes MG, de Wit EE, Weimar W, Litjens NH. Circulating proinflammatory CD4posCD28null T cells are independently associated with cardiovascular disease in ESRD patients. Nephrol Dial Transplant. 2010;25:3640e3646. 46. Linsley PS, Bradshaw J, Urnes M, Grosmaire L, Ledbetter JA. CD28 engagement by B7/BB-1 induces transient downregulation of CD28 synthesis and prolonged unresponsiveness to CD28 signaling. J Immunol. 1993;150:3161e3169. 47. Von Kempis J, Dudler J, Hasler P, et al. Use of abatacept in rheumatoid arthritis. Swiss Med Wkly. 2012 May;142:w13581. 48. Scarsi M, Ziglioli T, Airo’ P. Baseline numbers of circulating CD28-negative T cells may predict clinical response to abatacept in patients with rheumatoid arthritis. J Rheumatol. 2011;38:2105e2111. 49. Scarsi M, Ziglioli T, Airo` P. Decreased circulating CD28negative T cells in patients with rheumatoid arthritis treated with abatacept are correlated with clinical response. J Rheumatol. 2010;37:911e916.
Please cite this article in press as: Roy S, Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/j.injr.2014.01.011