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 Table of Contents  
REVIEW ARTICLE
Year : 2012  |  Volume : 8  |  Issue : 4  |  Page : 520-527

Autoimmunity in the elderly: Implications for cancer


1 Department of Internal Medicine and Systemic Pathologies, University of Catania, Italy
2 Department of Biomedical Sciences, University of Catania, Italy

Date of Web Publication29-Jan-2013

Correspondence Address:
Erika Cristaldi
Department of Internal Medicine and Systemic Pathologies, Azienda Ospedaliera "Cannizzaro", via Messina 829, 95124 Catania
Italy
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Source of Support: None, Conflict of Interest: None


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 > Abstract 

Immunosenescence is the aging process involving the immune system competencies. These changes imply a reduced level of immunosurveillance against cancer onset and the occurrence of autoimmune phenomena. The clinical presentation of autoimmune diseases in the elderly is characterized in most cases by atypical features, insidious presentation and poor specificity of laboratory parameters. The role of autoimmune reactivity in the elderly either as a consequence of or as a risk factor for cancer development has aroused great interest among clinicians and researchers, as well as the influence of a chronic inflammatory state as a predisposing factor for autoimmunity and cancer occurrence. Particularly, we have investigated the pathogenetic effect of two cell subsets, Treg cells and Th17 lymphocytes, involved in the control mechanisms both of autoimmune reactions and cancer onset, as the possible future approach to treat cancer in older adults.

Keywords: Autoimmunity, cancer, elderly, lymphoma, Th17 cells, treg cells


How to cite this article:
Malaguarnera M, Cristaldi E, Romano G, Malaguarnera L. Autoimmunity in the elderly: Implications for cancer. J Can Res Ther 2012;8:520-7

How to cite this URL:
Malaguarnera M, Cristaldi E, Romano G, Malaguarnera L. Autoimmunity in the elderly: Implications for cancer. J Can Res Ther [serial online] 2012 [cited 2019 Sep 17];8:520-7. Available from: http://www.cancerjournal.net/text.asp?2012/8/4/520/106527


 > Introduction Top


The aging process is a biological phenomenon that affects every human being as well as all species of animals and plants; it has been discussed as a result of damage due to the influence of free radicals, glycosylation process as well as intrinsic and extrinsic factors, causing DNA breakdown. Other theories are based on the assumption of genetic determination of aging resulting in a limited number of possible cell divisions depending on the age of the donor. [1]

An important aspect of human aging is the loss of the immune system's ability to distinguish self-antigens from non-self-antigens. [2] Hypothetically, during the aging process the decline in naïve T-cells and the accumulation of memory T-cells may lead to their activation against "neoantigens", thus causing the development of autoimmune conditions; furthermore, a decrease in T-cell function implies a decline in defense function, favoring the tumor growth. Both changes may be due to a chronic inflammatory state set off by a diminished apoptosis and altered T-cell homeostasis. [3] The role of autoimmune reactivity in the elderly either as a consequence of or as a risk factor for cancer development has aroused great interest, since a high level of autoimmunity is unhealthy, a low level of autoimmunity may actually be beneficial, thereby autoimmune reaction may be considered as a defense process played by the host against tumor.


 > Immunosenescence: Changes of The Immune System of Older People Top


The alterations in the elderly have been observed predominantly in the cellular immunity, indicating a loss of age-related functionality [Table 1]. The primary responsibility of this functional decline has been attributed to thymic involution, which begins at puberty, reducing in size and being replaced by fat.

All thymic T-cell intermediates are present, and the rearrangement of T-cell receptor (TCR) gene still goes on, but there is an imbalance between naïve and memory T-cells. [4] Naïve T-lymphocytes' output declines with thymic atrophy, leading to a compensatory proliferation of peripheral T-cells, the so-called memory cells that have yet encountered the antigen.
Table 1: Changes of innate and acquired immunity in elderly people

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The T-cells' subsets are affected by the aging process, too. Thus, it can be observed in peripheral blood a decrease in the CD4/CD8 ratio.. [5]

The predominance of these expansions within the CD8 T-cell subset implies that their generation possibly represents the outcome of normal proliferative responses to viral or tumor antigens. [6]

Both CD4 and CD8 T-cells need the expression on their surface of a co-stimulatory molecule, CD28, that intervenes as a complement in the transduction of signals, after the T cell receptor (TCR) activation as well as in the cytokine production, such as interleukin (IL)-2 and interferon (IFN)-γ. Clonal T-cell populations lacking CD28 show shortened telomeres, thus indicating that they have undergone multiple rounds of cell division.

Moreover, the persistence in humans of CD8 + CD28 - T-cells in vivo might be due to their increased resistance to apoptosis. [1]

If the altered clonal expandability and homing patterns of CD8 + CD28 - T-cells result in diminished protective function, they could play a role in the increased morbidity and mortality that are due to infections and cancer. [7]

CD28 - T-cells have a remarkable role in the chronic inflammatory state, since they release large amounts of interferon-γ; [8] in addition they possess autoreactive abilities, thus influencing the occurrence of autoimmune disorders in the elderly people. [9]

Furthermore, the cytokines' patterns show some alterations during the aging process, which deals with a shift between Th1 and Th2 cytokines' profile, with a reduced production of Th1 (e.g. reduced IL-2) and higher levels of Th2 cytokines as IL-4. [10]

Qualitative alteration is the defect in IL-2 production by memory CD4 + T-cells that are generated in aged mice: though memory CD4+ T-cells are deficient in IL-2 production, it has been seen that the presence of exogenous IL-2 can restore the young naïve cell cytokine levels. [11]

Also, the B-cells' compartment is affected by aging, showing a reduction of the proportion of B-cells in the peripheral blood. The bone marrow of aged mice contains increased proportions of mature B- and T-cells, which suggests that a compensatory effect exists for reduced functions of peripheral lymphoid tissues. [11]

The B-cell repertoire is further influenced by aging during an immune response, where the spectrum of expressed immunoglobulin genes as well as the frequency of somatic mutations, affect the quality, though not necessarily the quantity, of the antibody response [Table 1]. Here too, what appears as an intrinsic defect in somatic mutations is caused by suppressive influences exerted in vivo by aged CD4 T-cells, possibly reflecting the shift from T-helper 1 cell (Th1) to Th2 cytokine patterns associated with age. Finally, one of the most dramatic examples of age-associated repertoire changes is the appearance of oligoclonal expansions of CD5 B-cells producing antibodies against self-antigens, though with un-known pathophysiological consequences. [12]


 > Autoimmune Diseases in The Elderly Top


Systemic autoimmune diseases are a heterogeneous group of disorders influenced by genetic and environmental factors. At present, there are few studies focused on the clinical presentation of autoimmune diseases in the elderly, characterized in most cases by atypical features, insidious presentation and poor specificity of laboratory parameters.

A large proportion of elderly people may show both organ-specific and non-specific autoantibodies in the absence of an autoimmune disease; although this phenomenon has been recognized for many years, its biological significance is still debated. [13] The increased concentration and frequency of auto-antibodies has been explained by a higher exposure to exogenous factors, such as viral infection and drugs. Some medications may affect the production of auto-antibodies and, in some cases, may mimic the features of autoimmune diseases (i.e., drug-induced lupus-like syndrome). [13] However, as a consequence of the low immune response in older adults, it may originate altered cells which are not removed, and then the immune cells may cross-react with the normal cell constituents, leading to the autoimmune response. [14]

Also, autoantibodies might play a role in the general deterioration of aging individuals through their participation in subclinical chronic tissue damage. [15] The higher levels of autoantibodies present in the elderly do not show any clinical relevance, until tolerance mechanisms keep down their number, thereby autoantibodies, like rheumatoid factor and antibodies to nuclear antigens, can be detected in a significant proportion of elderly people without necessarily causing pathology. [16]

One of the most frequent autoantibodies described in the elderly, with a frequency of 9-48% according to different series, is rheumatoid factor (RF). [16] Until specific antibody production is activated, it is possible that the production of Immunoglobulin M -RF represents a first line of defense against bacterial or viral infections, since a correlation between RF and high levels of gammaglobulins has been described in populations with a high prevalence of chronic infections. [17] However, Gordon et al., have suggested that the autoreactive clones accumulated with age were of restricted specificity. [15]

In the elderly, the presence of antinuclear antibodies (ANA) is less frequent than RF, but not less considerable among the non-organ-specific autoantibodies' repertoire, [16] because of the possible role played in immunosurveillance against tumors. [18] Naschitz et al., found circulating ANA in 30% of patients with cancer, some of whom developed autoimmune disorders. [19]

Analyzing differences in the patterns of nuclear staining of ANA and their antigenic specificities, it has been found that ANA in the aged are persistent and directed toward chromatin elements, sharing major histocompatibility complex (MHC) associations with autoimmune diseases. [14]

Furthermore, ANA were found associated with anticardiolipin (aCL) antibodies, [20] these are positive in 28% of the elderly patients studied. [16] It still remains unclear if it may be attribute a pathogenetic role to aCL antibodies or if these antibodies may be considered the result of associated conditions in the elderly, such as malignancy and drug treatment. [16]

A remarkable association between immunosenescence and autoimmune disorders, and the age-related changes in the immune system may be considered as a predisposing factor to develop reactivity against self-antigen.

The major susceptibility to autoimmune disorders in elderly people has been explained by the lesser efficiency of physical barriers, decreased protection against invasive pathogens, and by the exposure of previously hidden antigens in the body tissues.

Tumors may contribute to the inappropriate exposure of these antigens to the immune system. Therefore, it should be considered the additional potential role of cumulative responses against infections and cancers in the generation of autoimmune disorders. [21]

In the elderly, the autoimmune diseases seem to occur very frequently, although they show a lower reactivity toward novel antigen. [3] An explanation about the increased occurrence of autoimmunity diseases in the elderly has been given by Stacy et al., [22] which hypothesized that memory B-cells, initially activated by an antigen exposure when young, become re-stimulated and begin to produce autoreactive antibodies later in life, promoting late-onset autoimmune disease, (e.g. after having encountered the novel antigen released during the aging process); or the impairment of tolerance with aging would allow autoreactivity development. [22] The initial B-cell response may have targeted a foreign antigen, and late-onset autoreactivity may then arise owing to cross-recognition of a self-antigen that is newly exposed, because of tissue damage accumulated during the lifetime. Also, it may be due to newly formed antigens, because of inflammation-mediated modification of a self-peptide, as it was seen in the pathogenesis of RA, after exposure of normally sequestered self-antigens, owing to tissue damage or cartilage destruction. [23]

Aging of the immune system is also characterized by several changes in T-cell function and phenotype. [24] Upon repeated activation, T-cells progressively down-regulate CD28 expression, finally leading to CD28 - T-cells. [5] These cells have gained pro-inflammatory capacities and cytotoxic function and they are resistant to apoptosis, too. [25] The percentage of CD4 + CD28 - T-cells is increased in the circulation of elderly individuals. [26] However, this unusual subset of pro-inflammatory, cytotoxic CD4 + T-cells is also increased in a subset of patients with autoimmune disease. [27] Their presence in autoimmune diseases and their unusual functional characteristics imply their active involvement in the pathogenesis of autoimmunity.

Maintaining self-tolerance requires a functioning immune system, able to distinguish self from non-self antigens. But, typical alterations of aged people, observed in T-cells, negatively affect this immunocompetence, contributing to autoimmune manifestations as rheumatoid arthritis, systemic lupus erythematosus and Sjogren's syndrome. [28]

As observed, older humans often develop oligoclonal expansion of CD8 + T-cells, correlating with CD8 + cell senescence, likely due to chronic antigenic stimulation. The activation-induced cell death (AICD) is one of the major mechanisms to avoid expansion of unwanted cell lines, and a malfunction in this process may lead to an accumulation of clonal T-cells. [3]

Studies on age-related apoptosis in humans have shown both an increase [29] and decrease [1] in T-cell susceptibility to apoptosis. These alterations in apoptosis of T-cells may have an important role in control mechanisms of autoimmune disease and immunosenescence. [30]

Lymphocytes from elderly subjects undergo apoptosis, either spontaneously or following in vitro stimulation. [31] Type 1 cytokines can prevent such activation-induced apoptosis, whereas Type 2 cytokines increase it. Interestingly, Th-1-like, but not Th-2-like cells are likely to be selective targets for apoptosis as the former express higher amounts of CD95 ligand, therefore the interaction between CD95 and its ligand induces apoptosis of mature lymphocytes. This should lead to a progressive loss in the proportion of Th-1 cells and a progressive enrichment of Th-2 cells, as confirmed by the experimental data of Lio et al., [32] which have demonstrated that the production of IL-5 by phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMNC) is normal or even increased in the elderly, strengthening previous suggestions that the Type 2 cytokine pattern is not defective in old age. They also investigated the production of IL-12 which is considered as a key molecule for the induction of a Th1-type response. The results showed that IL-12 production by PHA-stimulated PBMNC from older subjects was significantly decreased because of defects in cell expression of activation molecules that may affect the IL-12 secretion. [32]

The decreased production of Th-1 type cytokines in the presence of a normal or even increased production of Th-2 type cytokines might account for a pattern of immune response which may be observed in the elderly, i.e. a normal or increased humoral response, including the autoimmune one, in the face of a low cellular-mediated immune response. In fact, the Type 2 cytokine profile can be directly involved in the inhibition of Type 1 cytokines, activation of autoreactive B-cells and alteration of antigen-presenting cell functions. [33]

Nevertheless, the inflammatory state of older humans, mainly due to the cytokines' shift toward the Th2 pattern, allows autoantibodies to act in a pathogenetic manner, [22] as it has been seen in old mice, that are more vulnerable to SLE after IL-12 administration. [34]

Also, in rheumatic arthritis, the aging of T-cells, characterized by the loss of CD28, shortened telomeres, reduction of TCR excision circles (TREC) containing naïve cells, may lead to altered control of auto-reactivity and tissue injury, with onset of autoimmune diseases. [35]


 > Autoimmunity and Cancer in The Elderly Top


The mechanisms arranged by the immune system to control tumor development and to limit the autoimmune reaction seem to be overlapping [Table 2]. A common explanation given for the coincidence of autoimmune diseases and cancer is based on the regeneration of damaged tissues at inflammatory sites by rapid cell division due to inflammatory responses which characterized autoimmunity. [36] However, many data report that malignancies are associated with the induction of autoimmunity diseases, which often appear like early clinical manifestations of cancer, as in the paraneoplastic syndromes. [37]
Table 2: More frequent association between autoimmune diseases and hematological malignancies and solid tumors

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The presentation of autoimmune disorders in the elderly and their association with malignancies is an interesting topic So far it is not well known if the autoimmune diseases have a pathogenetic role in the development of cancer or whether it is a consequence.

Studies carried out on two consecutive series of patients, reported the prevalence of malignancies in 20% and 17%. All these patients were positive to anticardiolipin antibodies. [38] However, it is not clear if aCL antibodies play a pathogenetic role or their presence is the result of diseases associated with the elderly, as cancer or of drug therapy. [39]

It has been documented the association of anti-phospholipid antibodies both with solid tumors of lung, colon, prostate, ovary and breast, and with lymphoproliferative malignancies. [40]

Numerous studies have found a higher incidence of neoplastic disorders in elderly patients with dermatomyositis (DM) and polymyositis (PM) and some patients develop muscular disorders 5-10 years after the occurrence of malignancies. [41]

The higher risk of cancer in patients with DM may be demonstrated by the fact that these patients had a cancer at the time of diagnosis or they develop tumors after DM diagnosis, particularly involving the ovary, lungs, pancreas, stomach, colon and non-Hodgkin's lymphoma. [40]

A recent study reports a very common association between DM and malignancies, in patients over 40 years of age. The most common malignancy associated with DM was nasopharyngeal cancer, followed by lung cancer. Malignancy was often detected within the first year after the onset of DM. Other malignancies associated with DM included liver, ovarian, cholangial, esophageal cancer, colon, laryngeal, renal, and tongue cancer, as well as lymphoma and cervical lymph node metastases of unknown origin. [42]

A considerable body of data suggests that the incidence of cancer increases exponentially with age. [43] The neoplasm in elderly people may persist asymptomatically in a dormant state for many years, therefore the tumor will be detected during autopsy evaluation, as it happens often for prostate cancer. [44] Also, the presence of minimal residual disease (MRD) detected in solid tumors as well as hematological malignancies, lead us to speculate about the involvement of immune surveillance, that allows to limit the growth of the tumor, thereby the presence of autoimmunity reactions in elderly people may be seen as a defense mechanism against tumor growth.

The cell immunity is mostly affected by the aging process, however, the humoral immunity may compensate T-cells in the anti-tumor activity.

The age-related elevation in the production of antinuclear autoantibodies (ANA) and the possible resultant enhancement of Ab-dependent cellular cytotoxicity (ADCC) mechanisms with aging lead us to assume that ANA may serve as anti-neoplastic immune-surveillance agents. [45]

Patients with multiple myeloma, macroglobulinemia, and chronic lymphocytic leukemia show a large number of autoantibodies, which acquire rheumatoid factor activity, and autoantibody activity, resulting from the malignant transformation of B-cells that produce autoantibodies. [46] Also, since in the sera of patients with solid and hematological malignancies autoantibody activity has been detected, it may be reasonable that the anti-tumor immune response may result in elicitation of autoantibodies against various autoantigens, including self-antigens expressed in tumor cells, which are a large group of autoantigens defined as tumor-associated autoantigens (TAA). [47]

The occurrence of malignancies in patients affected by rheumatoid arthritis indicates an increased risk for the development of lymphoproliferative disorders rather than for the development of colon-rectum cancer. [48]

The same authors found that patients with systemic sclerosis had an increased risk for developing malignancies in organs and tissues affected by fibrosis, such as lung, esophagus, breast and skin. [48] In addition, older age at the time of diagnosis may be considered as a major risk factor for the occurrence of cancer. [49]


 > Pathogenetic Role of Possible Future Therapeutic Targets: Treg Cells and Th17 Lymphocytes Top


Treg cells

The T-regulatory (Treg) cells, which represent a subpopulation of approximately 10-15% of all CD4 T-cells, play an important role both in immunological homeostasis and in identification activity of self- and non-self-antigens. [50]

They are classified into natural or induced, according to their site of origin and activation. The first type takes origin from the thymus and is long-lived, the second type develops in the periphery, following an antigenic stimulation. The natural subset could represent a distinct T-cell lineage, showing suppressive tasks, through inhibiting secretion of inflammatory cytokines and favoring the secretion of cytokines that alter the inflammatory environment. Further, they exert a negative control on cytotoxic cells, through activation-induced cell death. [51]

This population of T-lymphocytes is made up of either CD4 or CD8 T-cells, both expressing surface marker (e.g. CTLA-4 and GITR), and intracellular marker Forkhead box P3 (FOXP3). The subset of Treg cells receiving much attention is represented by CD4 + CD25 + FoxP3 that is involved in the homeostasis of the immune system. This intracellular marker is a transcription regulator required for the development and maintenance of Treg cells, as well as for allowing their suppressor function. [52] The loss or a reduced expression of FOXP3 on Treg cells may lead to turn into effector T-cells, losing specific properties, such as the production of Treg cells cytokines. [53] Furthermore, mice with mutations in this gene can display deregulated immunity and can develop multiorgan inflammatory diseases. [54]

The removal of Treg cells from normal mice or transfer of T-helper cells into lymphopenic hosts can cause autoimmune diseases that are tissue-specific, including thyroiditis, oophoritis, gastritis, and inflammatory bowel disease. [55] However, depletion of Treg cells with an antibody to CD25 can enhance tumor protection against umor-associated antigens that are expressed as self-antigens. [56]

The impairment of the function of Treg cells seems to be associated with different autoimmune diseases like systemic lupus erythematosus, Type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. [57]

Since an increased frequency of Treg cells with suppressive activity has been observed, it is reasonable that Treg cells play an important role in malignant tumor patients. [58] Blocking the function of Treg cells in murine tumor models resulted in a strong cellular anti-tumor immunity and even complete tumor destruction, [59] thus indicating a crucial role for T-regulatory cells in tumor immunity.

The abrogation of this suppressive function has been demonstrated by Ko et al., in murine models, [60] by the activation of GITR (Glucocorticoid-induced tumor necrosis factor receptor family-related protein) in concert with antigen-specific stimulation of Treg. After applying the anti-GITR antibody to the BALB/c mice, it developed a strong anti-tumor immune response followed by complete tumor eradication in all treated animals, in the absence of secondary autoimmune reactions.

In elderly people was found a quantitative increase of both memory and FOX P3 cells, which come from the memory cells' subset. Furthermore, the naïve/memory T-cell ratio as well as the naïïve/Fox P3 Treg cells ratio is decreased. As recently seen in older murine models SJL/J, these imbalances may lead to the development of Hodgkin's lymphoma-like; thereby, this model may have some influence for the explanation of cancer onset in elderly people, [61] since autoimmunity and tumor immunity may be two sides of the same immune phenomenon, and complementary to each other. [62] Therefore, Treg cells may play a critical role in the induction of tolerance to self-antigens, including those expressed by tumors. Because most tumor antigens are normal, non-mutated self-antigens, [63] it is conceivable that most tumors overexpressing self-antigens could induce tumor/self-specific Treg cells that suppress an effective anti-tumor response. [64]

A strong evidence for that can be observed when, reducing CD25 + T-cells and/or blocking CTLA-4 or GITR in vivo with antibodies, the reactivity to known self-antigens increases and tumor rejection in mice enhances. [65] Although autoimmune destruction of self-antigen-expressing tissues were readily seen, these reports did not always consider the effects that the antibodies have on CD4 + effector T-cell. [66] These experimental therapeutical approaches revealed that it may be possible to immunize against self-antigens. Therefore, the depletion or inactivation of Treg cells may substantially improve the anti-tumor immunity, as seen in some preclinical studies, [57] influencing the possible use of immunotherapy in elderly people.

Lymphocytes Th17

A differentiated subset of cells, termed Th17 have emerged as key mediators of autoimmunity and inflammation. These cells are characterized as preferential producers of IL-17A, IL-17F, IL-21, IL-22 and IL-26 in humans. The IL-17 production is required to differentiate Th17 cells from IFN-γ-producing Th1 cells, or IL-4-producing Th2 cells. [67]

For the generation of human Th17 cells in vitro and in vivo the transcription factor retinoic-acid-related orphan receptor-γτ (ROR-γτ) is necessary, which can be induced by IL-6, TGF- β, IL-1β and IL-23, [67] though the importance of IL-1β in the induction of IL-17 production is restricted to human T-cells. Th17 cells are potent inducers of tissue inflammation and dysregulated expression of IL-17 appears to initiate organ-specific autoimmunity. [67]

Cytokines like IL-17A and IL-17F, as well as IL-22 (a member of the IL-10 family) are produced by Th17 and evoke inflammation largely by stimulating fibroblasts, endothelial cells, epithelial cells, and macrophages to produce chemokines, other cytokines and matrix metalloproteinases (MMP), with the subsequent recruitment of polymorphonuclear leukocytes to inflammation sites. [68] In addition, Th17 cells have been associated with effective tumor immunity in a model of adoptive transfer of TCR transgenic CD4 + T-cells specific for the shared self-tumor antigen tyrosinase-related protein 1 (TRP1). [69] These cells have been used for the treatment of the poorly immunogenic B16 murine melanoma, as well as it has been demonstrated the therapeutic efficacy of Th1, Th17, and Th0 CD4 + T cell subsets, for tumor eradication. [69]

Monoclonal antibodies blocking CTLA-4, a key negative regulator of the immune system, induce regression of tumors in mice and humans, and are being pursued as treatment for cancer. [70]

von Euw et al., detected in patients with metastatic melanoma the possibility of regression after using cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)-blocking antibodies, that modulated the subset of Th17 cells. [71]

There is evidence that CTLA-4 is expressed in murine Th17 cells at higher levels than Th1 cells, [72] while CTLA-4 has also been demonstrated in human Th17 cells. [73] Since both tremelimumab and ipilimumab, the two CTLA-4-blocking antibodies in clinical development, inhibit CTLA-4 negative signaling without inducing ADCC, [74] it is possible that these antibodies would release negative signaling in Th17 resulting in increased number or function.

CTLA-4-blocking antibodies break tolerance to self-tissues, as clearly demonstrated by the autoimmune phenomena in CTLA-4 knock-out mice, [75] which results in autoimmune toxicities in patients.

The emerging clinical data suggest that a minority of patients with metastatic melanoma (in the range of 10%) achieve long-lasting objective tumor responses when treated with CTLA-4 blocking monoclonal antibodies, with most being relapse-free up to seven years later. However, a significant proportion of patients (in the range of 20-30%) develop clinically relevant toxicities, more often autoimmune or inflammatory-like. [70] It is more likely that the same threshold of CTLA-4 blockade may lead to activation of lymphocytes reactive to self-tissues and cancer.


 > Conclusions Top


Inflammaging is a term coined to explain that aging is accompanied by a chronic upregulation of the inflammatory response, mediated mainly by the increased circulating levels of pro-inflammatory cytokines and that the underlining inflammatory changes are also common to many age-associated diseases. Concepts of an immune-risk phenotype and alterations of the T-cell homeostasis by a chronic inflammatory state and clonal expansions (e.g. caused by chronic viral infections) help to understand the processes driving the immune system into premature senescence and promoting autoimmune conditions. Immune perturbations, including autoimmune diseases, have been associated with an increased risk of development of hematological malignancies.

As seen above the pathogenetic mechanisms that explain the relationship between autoimmunity and cancer are not fully and clearly understood. There is a fine link which correlates anti-self reactions and anti-cancer immunity, because both work for blocking abnormal growth of unknown cells. However, we think that a dysregulated immune system, as observed in older adults, might greatly influence the causal relationship between these two diseases, thus further study of this association in depth could give future improvements for treatment of cancer and autoimmune diseases in elderly people.

 
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