Immunologic models of rheumatoid arthritis (RA) have to take into account that the disease occurs at an age when immunocompetence is declining and in a host whose immune system shows evidence of accelerated immune aging. By several immune aging biomarkers, the immune system in patients with RA is prematurely aged by more than 20 years. One major pathogenetic mechanism is a defect in telomere maintenance and DNA repair that causes accelerated cell death. These findings in RA are reminiscent of murine autoimmunity models, in which lymphopenia was identified as a major risk factor for autoimmunity. Progress in the understanding of how accelerated immune aging is pathogenetically involved in RA may allow development of new therapeutic approaches that go beyond the use of anti-inflammatory agents and eventually could open new avenues for preventive intervention.
Rheumatoid arthritis (RA) is a chronic inflammatory disease that manifests predominantly as synovial inflammation leading to cartilage damage and destruction of the joint infrastructure. Although the joint symptomatology is eventually dominant, the disease is preceded by immune abnormalities that are not joint-specific, but systemic and already apparent many years before onset of the disease. The best defined autoimmune phenomena are antibody responses against immunoglobulin (Ig)G and against citrullinated peptides, self-antigens, or neoantigens that are ubiquitously expressed. Although the focus of research in the 1990s was on identifying a tolerance defect to a joint-specific antigen, the last decade has seen a shift to the model that patients with RA have a fundamental breakdown in self-tolerance and that patients are not able to induce or maintain tolerance to neoantigens. This breakdown in tolerance occurs in the second half of life, suggesting that it is acquired. Most patients who develop disease are postmenopausal women; indeed the incidence of the disease continues to rise at least into the seventh decade of life and possibly even beyond that. The relationship between RA incidence and age is inverse to that of immunocompetence and age as illustrated in Fig. 1 for thymic epithelial space (TES) and frequency of recent thymic emigrants.
Aging as a risk factor for autoimmunity
The age relationship of RA is different from that of organ-specific autoimmune diseases, such as diabetes mellitus or systemic lupus erythematosus that peak earlier in life. RA does not stand alone in this aspect, however; age is a major risk factor in many other chronic inflammatory diseases, most notable in giant cell arteritis. This important role of age in the development of selected autoimmune diseases raises questions whether immune aging is a contributing factor and tolerance defects are part of the degenerative process of the immune system. Indeed, autoantibodies are a common finding in healthy elderly. Of interest, many of these autoantibodies are specific for common autoantigens, such as rheumatoid factor and antinuclear antibodies, while tissue-specific antibodies do not appear to be a normal by-product of immune aging. Studies on the frequency of anti-cyclic citrullinated peptide (CCP) antibodies with age are not yet available. In general, the age-related rheumatoid factors are low titered, but otherwise not different from the autoantibodies in autoimmune diseases.
The concept that autoimmune disease is a consequence of immune aging is counterintuitive. In general, the aged immune system is less responsive to antigenic challenges; it is more difficult in the elderly to elicit an immune response to an antigen than in young adult. As a consequence, vaccine responses decline with age. Autoantigens, perhaps with the exception of neoantigens, are by definition low-affinity antigens, because high affinity receptors have been purged from the repertoire by negative selection. How, therefore, can an immune system that is insufficient to generate an adaptive immune response to an exogenous antigen, such as a vaccine, be able to overcome tolerance and generate immune responses to auto- or neoantigens? As always in science, identifying an obvious paradox and overcoming its conundrum provide an opportunity to take a qualitative pivotal step in understanding the mechanisms of a disease.
Immune aging—what do we know?
The immunologic evidence of immune aging is illustrated best by the increasing incidence and morbidity of infections, the failure to mount vaccine responses and the reactivation of chronic viral infections with age. Epidemiologic data suggest that clinical evidence of immune aging is already present, albeit subtle, in the middle-aged adult. Examples include the incidence of herpes zoster reactivation that starts to increase after the age of 50 years, the increased hospitalization and mortality rates of influenza infections that also increase after the age of 50, and also vaccine responses such as the response to hepatitis B vaccination, which already starts to decline after the age of 40 years. Thus, immune aging is not only a feature of the very elderly, but emerges as a clinical complication already in the middle-aged adult, approximately at the same age when the susceptibility to develop RA increases. Immune failure becomes severe in the eighth decade of life in healthy individuals. If autoimmunity is a consequence of immune aging, but still requires a functional immune system, one would predict that the incidence of autoimmune diseases will start to dip again in the very elderly.
Immune aging affects both the innate and the adaptive immune systems. The innate immune system is constitutively activated in the elderly and the concentration of inflammatory cytokines, in particular interleukin (IL)-6, increases. This proinflammatory environment accelerates and complicates numerous degenerative diseases; the classical example is the inflammation in the atherosclerotic plaque that leads to plaque rupture and acute coronary syndromes. The mechanisms underlying this innate immune activation are not clear, but possibly are a consequence of the declining adaptive immune response. Most studies of immune senescence have focused on the adaptive system, and several defects have been described. It has been hypothesized that the defect in T-cell immunity is causatively related to the declining thymic generation of new naïve cells. By the age of 40 to 50 years, thymic activity is severely limited, and the homeostasis of the T-cell compartment entirely depends on peripheral mechanisms that regulate the proliferation and survival of naïve and memory T-cells. As a consequence, the frequency of naïve T-cells declines with age, a phenomenon that is markedly more pronounced in the CD8 than the CD4 compartment. The replicative stress associated with immune responses to exogenous antigen, but also due to the homeostatic proliferation to maintain a full peripheral T-cell compartment in the absence of thymic production, is associated with decline in telomere lengths, and epigenetic changes, and accumulation of effector subpopulations, in particular in the CD8 compartment. Individual T-cells are still responsive to stimulation by exogenous antigen. Although signaling defects have been described in elderly T-cells, they alone are usually not sufficient to suppress an immune response. It is this environment in which RA and its autoimmune manifestations develop.
Immune aging—what do we know?
The immunologic evidence of immune aging is illustrated best by the increasing incidence and morbidity of infections, the failure to mount vaccine responses and the reactivation of chronic viral infections with age. Epidemiologic data suggest that clinical evidence of immune aging is already present, albeit subtle, in the middle-aged adult. Examples include the incidence of herpes zoster reactivation that starts to increase after the age of 50 years, the increased hospitalization and mortality rates of influenza infections that also increase after the age of 50, and also vaccine responses such as the response to hepatitis B vaccination, which already starts to decline after the age of 40 years. Thus, immune aging is not only a feature of the very elderly, but emerges as a clinical complication already in the middle-aged adult, approximately at the same age when the susceptibility to develop RA increases. Immune failure becomes severe in the eighth decade of life in healthy individuals. If autoimmunity is a consequence of immune aging, but still requires a functional immune system, one would predict that the incidence of autoimmune diseases will start to dip again in the very elderly.
Immune aging affects both the innate and the adaptive immune systems. The innate immune system is constitutively activated in the elderly and the concentration of inflammatory cytokines, in particular interleukin (IL)-6, increases. This proinflammatory environment accelerates and complicates numerous degenerative diseases; the classical example is the inflammation in the atherosclerotic plaque that leads to plaque rupture and acute coronary syndromes. The mechanisms underlying this innate immune activation are not clear, but possibly are a consequence of the declining adaptive immune response. Most studies of immune senescence have focused on the adaptive system, and several defects have been described. It has been hypothesized that the defect in T-cell immunity is causatively related to the declining thymic generation of new naïve cells. By the age of 40 to 50 years, thymic activity is severely limited, and the homeostasis of the T-cell compartment entirely depends on peripheral mechanisms that regulate the proliferation and survival of naïve and memory T-cells. As a consequence, the frequency of naïve T-cells declines with age, a phenomenon that is markedly more pronounced in the CD8 than the CD4 compartment. The replicative stress associated with immune responses to exogenous antigen, but also due to the homeostatic proliferation to maintain a full peripheral T-cell compartment in the absence of thymic production, is associated with decline in telomere lengths, and epigenetic changes, and accumulation of effector subpopulations, in particular in the CD8 compartment. Individual T-cells are still responsive to stimulation by exogenous antigen. Although signaling defects have been described in elderly T-cells, they alone are usually not sufficient to suppress an immune response. It is this environment in which RA and its autoimmune manifestations develop.
Accelerated immune aging in RA
The epidemiologic data clearly show that age is an important risk factor for developing RA. The obvious next question then is what the biologic age of a patient with RA is. Is the aging of the adaptive immune system age-appropriate? Is it decelerated, leading to better-preserved T-cell immune responsiveness in an otherwise aging host? Or is it accelerated such that immune responses already have declined beyond the actual age of the individual? Early evidence from T-cell depletion studies already suggested that RA patients have difficulty in regenerating the immune system. In general, therapeutic T-cell depletion yielded only moderate benefits, but significant adverse effects. This was most evident for patients treated with an anti-CD52 antibody (alemtuzumab) that very effectively depletes T-cells. Many of these treated patients stayed lymphopenic for a long period of time after treatment, and in those patients who had a sizable recovery of T-cells, the population was highly oligoclonal, suggesting that the T-cells were derived from a few progenitor cells. The same clonally expanded populations that were present in the peripheral blood also were found in the synovial tissue of RA patients who maintained disease activity. Longitudinal studies in these patients showed that the lymphopenia in these patients persisted over decades. Of interest, other autoimmune phenomena developed in some of the anti-CD52-treated patients, consistent with the view that tolerance is more difficult to maintain in a lymphopenic host.
Subsequent studies have shown that impaired T-cell regenerative capacity and evidence for replicative stress in the peripheral T-cell compartment are already features in RA patients who have not undergone T-cell depletion. The frequency of T-cell receptor excision circles (TRECs), frequently used as a surrogate measurement for thymic activity, declines in normal healthy individuals between the age of 20 and 65 by about 95%. TRECs are episomes generated during T-cell receptor rearrangements and are likely to persist in nonproliferating cells, but are not transmitted to all daughter cells during division. TREC frequencies are therefore the net result of two events: generation of new TREC-positive cells from the thymus and loss of TREC-positive T-cells by peripheral proliferation or cell loss. RA patients have an age-inappropriate decrease in TREC frequencies, suggesting that they either have reduced thymic output, increased peripheral T-cell apoptosis and proliferation, or a combination of both. Obviously, these two processes do not need to be independent, because decreased thymic production has to be compensated with increased peripheral proliferation to maintain the size of the compartment. Indeed, the peripheral T-cell compartment in RA patients exhibits evidence for replicative stress. T-cells, like other cells that proliferate, lose sequence stretches at their chromosomal ends, called telomeres, with each division. They also change their phenotype and function; in particular, they lose the expression of the costimulatory molecule CD28. When assessed using any or all of these senescence markers, the repertoire of T-cells in patients with RA is pre-aged by approximately 20 years. Telomeric ends are shortened; frequencies of CD28-negative T-cells are increased, and T-cell repertoire diversity is contracted, consistent with excessive T-cell loss and oligoclonal expansion. Similar evidence for accelerated immune aging also has been shown for some, but not all, other autoimmune diseases. Most notable is multiple sclerosis, which is also associated with reduced TREC numbers and increased frequency of CD28-negative cells. Other chronic inflammatory diseases, such as the spondylarthropathies (which often begin in early adulthood), do not show any evidence for accelerated immune aging.
Accelerated immune aging—a primary or secondary event?
In any inflammatory disease, the question arises whether observed findings are a primary event involved in the pathogenesis of the disease or a secondary event caused by disease-induced inflammation. Several studies have shown that accelerated immune aging is a phenomenon found in patients with early RA and is not influenced by disease duration or treatment. Also, in longitudinal studies, the frequency of CD28-negative T-cells early in the disease is predictive of severity in joint erosion on follow-up and the frequency of extra-articular disease manifestations in cross-sectional studies. These observations have been interpreted in favor of immune aging as a primary event involved in disease pathogenesis and not as a consequence of the presence of inflammatory cytokines. Exceptions to this interpretation do exist (eg, transcription of the CD28 gene in young T-cells can be significantly down-regulated by TNF-α). The mechanism of TNF-mediated gene repression is the same as that which occurs with replicative T-cell aging. Under the influence of TNF, naïve T-cells lose the expression of an initiation factor that is necessary to induce CD28 transcription. However, the TNF-mediated CD28 repression is not complete and is readily reversible, which is in contrast to the CD28 loss that is seen with replicative senescence or in RA patients. All T-cells from patients with RA have reduced cell surface expression of CD28 when measured by flow cytometry, while only few have a complete CD28 loss. Full CD28 expression recovers in CD28-low T-cells with short-term cultures in vitro or with anti-TNF treatment in vivo. In contrast, CD28 loss in most cases is not reversible with anti-TNF-α. On the contrary, CD28 expression in at least some cells can be restored by another inflammatory cytokine, IL-12.
The most convincing evidence that accelerated immune aging is primary (or at least not exclusively secondary) comes from genetic studies. Increased loss of CD28 on peripheral T-cells has been found to be associated with the HLA-DRB1*04 genotype, which also predisposes to RA. In healthy individuals, the frequencies of CD28-negative cells have been found to be correlated to cytomegalovirus (CMV) infection. This correlation is maintained in patients with RA, suggesting that CMV infection and accelerated aging rather than activity of the rheumatic disease are key risk factors that lead to senescence of the cell population. HLA-DRB1*04 also is associated with accelerated telomeric shortening in healthy controls. Schönland and colleagues have shown that HLA-DRB1*04-positive individuals have shorter telomeres in several hematopoietic stem cell-derived populations including neutrophils and naïve and memory T-cells. This telomeric shortening was cell-specific for hematopoietic lineages and not found in sperm cells of HLA-DRB1*04-positive donors. The difference in telomere lengths is acquired, since no HLA-related difference was seen in cord blood T-cells. These studies led to the interpretation that the major disease risk gene for RA, HLA-DRB1*04, predisposes for at least two aging features in normal individuals, telomere shortening in hematopoietic stem cell lineages and loss of CD28 in peripheral T-cell memory cell populations. In contrast, the HLA-DR4 haplotype was not associated with reduced frequency of TRECs as a marker of thymic activity or peripheral cell death, suggesting that the features of accelerated aging observed in RA patients are at least partially independent and may be additive or even synergistic.
Mechanism of accelerated immune aging in RA
One of the most striking markers of aging in a highly proliferative compartment is telomeric erosion. Telomeres are protein-DNA complexes at the end of eukaryotic chromosomes that protect from fusion and degradation. Telomeric DNA is composed of repeats of G-rich sequences that are packed with a number of DNA-binding proteins involved in protection and repair. In the absence of the enzyme telomerase, telomeric sequences are duplicated incompletely, with loss of 40 to 200 base pairs during each cell division. Telomeric lengths therefore can be taken as a marker of the replicative history of individual cells or a population of cells. Critically short telomeres become uncapped and recruit components of the DNA damage repair machinery, such that cells enter replicative senescence or apoptosis. Telomeric erosion is counteracted by an enzyme, telomerase, that only is expressed in selected cell types, including stem cells, sperms, and lymphocytes. Even in stem cells, and certainly in lymphocytes, telomeric repair is incomplete, and telomeric erosion occurs progressively with age.
The age-inappropriate accelerated telomeric erosion found in lymphocytes of patients with RA could be caused by several mechanisms, either acting alone or in concert. Telomeric erosion could reflect an increased proliferative history of lymphocytes or their precursor cells, or be caused by defective telomerase expression or activity. Alternatively, telomeric shortening could be the result of excessive DNA damage rather than replication-induced telomeric loss ( Fig. 2 ). Data on patients with RA indicate that all three of these different mechanisms play a role. Frequencies of hematopoietic stem cells in RA patients are age-inappropriately reduced, and their telomeres are already shortened, indicating that the hematopoietic stem cell system is under replicative stress. Increased proliferation of peripheral naïve and memory T-cells may aggravate this defect. In support of this interpretation, the reduced frequency of TREC-positive cells either indicates reduced thymic activity or accelerated peripheral death of TREC-positive cells; both would increase homeostatic proliferation to maintain the compartment size. It is of interest to note that telomeric erosion in hematopoietic stem cells, but not a reduced number of TRECs, is also found in healthy HLA-DRB1*04-positive individuals, suggesting that two independent age-related mechanisms contribute to the accelerated immune aging in RA patients, one of them influenced by the disease-associated major histocompatability complex (MHC) region.
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