Autoimmunity Reviews 20 (2021) 102893 Contents lists available at ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev Review Immunosenescence in multiple sclerosis: the identification of new therapeutic targets María Dema a, b, c, Herena Eixarch a, b, c, Luisa M. Villar c, d, Xavier Montalban a, b, c, Carmen Espejo a, b, c, * a Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya, Vall d’Hebron Institut de Recerca, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035, Barcelona, Spain b Universitat Autònoma de Barcelona, 08193, Bellaterra, Cerdanyola del Vallès, Spain c Red Española de Esclerosis Múltiple (REEM), Spain d Servicio de Inmunología, Hospital Universitario Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain A R T I C L E I N F O A B S T R A C T Keywords: The number of elderly multiple sclerosis (MS) patients is growing, mainly due to the increase in the life ex­ Immunosenescence pectancy of the general population and the availability of effective disease-modifying treatments. However, Ageing current treatments reduce the frequency of relapses and slow the progression of the disease, but they cannot stop Autoimmunity the disability accumulation associated with disease progression. One possible explanation is the impact of Multiple sclerosis immunosenescence, which is associated with the accumulation of unusual immune cell subsets that are thought to have a role in the development of an early ageing process in autoimmunity. Here, we provide a recent overview of how senescence affects immune cell function and how it is involved in the pathogenesis of auto­ immune diseases, particularly MS. Numerous studies have demonstrated age-related immune changes in experimental autoimmune encephalomyelitis models, and the premature onset of immunosenescence has been demonstrated in MS patients. Therefore, potential therapeutic strategies based on rejuvenating the immune system have been proposed. Senolytics and regenerative strategies using haematopoietic stem cells, therapies based on rejuvenating oligodendrocyte precursor cells, microglia and monocytes, thymus cells and senescent B and T cells are capable of reversing the process of immunosenescence and could have a beneficial impact on the progression of MS. 1. Introduction immunosenescence, generally result in a higher susceptibility to in­ fections, a reduced response to vaccines [3] and a higher prevalence of The world’s population is rapidly ageing. By 2050, it is estimated autoimmunity [4] and neurodegenerative disorders [5]. The immuno­ that 22% of people will be over 60 years old [1]. Ageing is broadly senescence process is the consequence of a series of events that affect the defined as a progressive functional decline that leads to impaired bio­ differentiation and maturation processes of different immune cell sub­ logical functions, which are the main cause of multiple human pathol­ types as well as their functionality. ogies, such as cancer, diabetes, cardiovascular disorders and Immunosenescence is defined by a set of immune markers known as neurodegenerative diseases. Several hallmarks define the process of the immune risk phenotype, which includes the inversion of the CD4: ageing, including genomic instability, telomere attrition, epigenetic al­ CD8 ratio, the expansion of CD8+CD28− T cells, the presence of cyto­ terations, the loss of proteostasis, deregulated nutrient sensing, mito­ megalovirus (CMV) seropositivity, poor T cell proliferation and low B chondrial dysfunction, stem cell exhaustion, altered intercellular cell numbers. In fact, immune risk phenotype features are associated communication and cellular senescence [2]. The age-related changes with increased morbidity and mortality in elderly individuals [6]. In that take place in the immune system, a process known as addition, recent studies have revealed that the ageing process is also * Corresponding author at: Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya, Vall d’Hebron Institut de Recerca, Hospital Uni­ versitari Vall d’Hebron, Pg. Vall d’Hebron 119-129 (Ed. Collserola, Lab. 149), 08035, Barcelona, Spain E-mail addresses: maria.dema@vhir.org (M. Dema), herena.eixarch@vhir.org (H. Eixarch), luisamaria.villar@salud.madrid.org (L.M. Villar), xavier.montalban@ cem-cat.org (X. Montalban), carmen.espejo@vhir.org (C. Espejo). https://doi.org/10.1016/j.autrev.2021.102893 Received 25 April 2021; Accepted 2 May 2021 Available online 5 July 2021 1568-9972/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). M. Dema et al. Autoimmunity Reviews 20 (2021) 102893 associated with an increased activity of immunosuppressive cells such as 2. Ageing of the immune system: immunosenescence regulatory T (Treg) cells, regulatory B (Breg) cells and myeloid-derived suppressor cells (MDSCs) [7]. Numerous changes have already been The events that take place in the aged immune system result in poor described to occur in the adaptive immune system during immunose­ immune responses in older adults (Table 1). Indeed, these events affect nescence; however, fewer studies have been performed to determine the not only the functionality of immune cells but also the number and impact of immunosenescence on innate immunity. Innate immunity frequency of certain immune cells due to decreased haematopoiesis and seems to be more preserved with age, although recent reports point to progressive atrophy of the thymus. Immune cells are generated in the age-associated impaired functionality of innate immune cells [8]. bone marrow from haematopoietic stem cells (HSCs), which are able to Multiple sclerosis (MS) is a chronic neurodegenerative, inflamma­ self-renew and differentiate into any of the lineages of the immune tory and demyelinating disease of the central nervous system (CNS) system. The ageing of HSCs is characterized by impaired telomerase characterized by the formation of demyelinating lesions. Although the activity, which leads to telomere shortening with each division; as a immunopathological events occurring in the initial stages of the disease consequence, the pool of HSCs is progressively reduced due to decreased are not yet well understood, it is clear that the immune system is self-renewal capacity. Moreover, immunosenescence bears other con­ involved in the destruction of myelin sheaths that ultimately leads to sequences involving the commitment of progenitors, since myeloid neurological disability in patients. Taking this into account, many ex­ differentiation is potentiated over lymphoid differentiation [10]. perts point to an autoimmune origin of MS [9]. Several studies suggest that autoimmunity itself as well as MS progression could be associated 2.1. Adaptive immunity with premature immunosenescence. Thus, an understanding of the mechanisms underlying immunosenescence is a challenging objective in T cell changes are the most described in the immunosenescence the field of MS to determine the possible efficacy of already approved process. One of the main consequences of ageing is the progressive therapies that have the capacity to reverse the process of immunose­ involution of the thymus, which deeply affects the maturation of naïve T nescence. This review gives an overview of recent research findings on cells and the diversity of the T cell receptor (TCR) repertoire [11,12]. immunosenescence features and links the events that cause immunose­ These two features bear important consequences in T cell-mediated nescence with MS immunopathogenesis. Finally, the possible beneficial immunity. Moreover, the involution of the thymus also involves a impact of currently approved therapies aiming to rejuvenate the im­ decrease in the detection of T cell receptor excision circles (TRECs), mune system on MS progression is discussed. which are circular DNA products generated from the rearrangement of TCR genes in the thymus. TRECs are detected only in naïve T cells, so their content has been suggested as a biomarker of the naïve T cell pool state and thymic function in immune ageing [13]. Although the overall T cell population is maintained in older adults, the number of naïve T cells in the periphery is reduced (especially the number of CD8+ T cells) Table 1 [14,15]. Terminally differentiated memory T cells (especially CD8+ T Age-related alterations in innate and adaptive immunity. cells) are expanded and accumulate due to persistent infections, most Immune cell type Age-related alterations References commonly with CMV [16,17]. As a consequence of the lower number of naïve T cells and their decreased diversity in the TCR repertoire, the T cells ↓ naïve cells, ↑ memory cells [14–17] ↓ TCR repertoire diversity, ↓ TRECs [11–13] normal function of the T cell-mediated immune response is also ↓ CD28 co-stimulatory receptor, ↓ CD40L, ↓ [19,23,24] impaired, presenting a decreased ability to respond properly to in­ helper ability fections and vaccination [18]. Senescent cells lack the CD28 co- ↑ TIGIT and PD1 inhibitory receptors [20] stimulatory molecule and express CD57 and KLRG1 senescence ↑ CD57 and KLRG-1 senescent markers [17] ↑ SASP cytokines [21] markers. This phenotype is commonly associated with terminally ↑ NK receptors, ↑ cytotoxic response [28–30] differentiated memory CD8+ T cells in elderly individuals [17]. Termi­ ↑ autoreactivity [22,23] nally differentiated memory CD8+ T cells that tend to accumulate with B cells ↓ naïve cells, ↑ memory cells [34] age present an impaired capacity to proliferate, more resistance to un­ ↓ BCR repertoire diversity [33] dergo apoptosis and shortened telomeres, which are typical features of ↓ class switch, ↓ AID enzyme [37,38] ↑ autoantibodies [40] cellular senescence [19]. There is evidence that senescent CD8+ T cells ↑ ABCs [39,40] also express inhibitory receptors such as T cell immunoglobulin and ↑ inflammation recruitment [36] immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and Monocytes/ ↑ M2 macrophages [45] PD1, which are characteristic of not only senescent T cells but also macrophages ↓ MHC-II receptor, ↓ TLR receptors, ↑ TAM [44,46,47] receptors exhausted T cells [20]. Although these terminally differentiated memory ↓ antiviral response, ↓ inflammation [43] CD8+ T cells could fight against persistent infections in older adults recruitment [17], senescent T cells are also characterized by the secretion of a DCs ↓ DC responsiveness [50] determinate cytokine profile termed the senescence-associated secretory ↑ ROS, ↓ phagocytosis, ↓ cross-presentation [48] profile (SASP) [21], which could contribute to tissue damage. ↓ stimulation of CD8+ T cells, ↓ IFN-γ [49] NK cells ↓ CD56bright immunoregulatory cells, ↑ [51,52] Although major changes are observed in the CD8+ T cell compart­ CD56dim cytotoxic cells ment, CD4+ T cells also experience modifications with age, but to a ↓ mature NK cells in periphery [53] lesser extent. Terminally differentiated CD4+ T cells present senescence ↓ degranulation capacity [52] features that are similar to those of terminally differentiated CD8+ T Neutrophils ↓ ROS, ↓ NETs [54] ↓ phagocytosis [55,56] cells, since they also accumulate with age due to persistent antigen ↓ inflammation recruitment [56] stimulation with pathogens or self-antigens, present shortened telo­ meres, produce a high number of pro-inflammatory cytokines, express Abbreviations: T cell receptor (TCR); T cell receptor excision circle (TREC); CD57 and KLRG1 senescence markers and lose CD28 co-stimulatory Tyrosine-based inhibitory motif domain (TIGIT); Senescence-associated secre­ tory profile (SASP); B cell receptor (BCR); Activation-induced cytidine deami­ molecule. Particularly, in senescent CD4+ T cells, there is an increased nase (AID); Age-associated B cell (ABC); Major histocompatibility complex number of autoreactive cells [19,22,23]. Furthermore, the loss of CD28 (MHC); Toll-like receptor (TLR); Tyro3, Axl, and Mer (TAM); Dendritic cell (DC); leads to a deficiency in the induced expression of CD40L, impeding Reactive oxygen species (ROS); Natural killer (NK); Neutrophil extracellular trap CD4+ T cells from interacting with CD40 molecules present on the (NET). surface of B cells; consequently, CD4+ T cells lose their helper ability to 2 M. Dema et al. Autoimmunity Reviews 20 (2021) 102893 induce B cell proliferation and the production of antibodies. Moreover, negatively regulate the immune responses mediated by TLRs and, in senescent CD4+ T cells lose their helper ability to induce somatic turn, inhibit inflammation [44]. Macrophages are considered the main hypermutation on B cells and the formation of germinal centres, which is phagocytes of potential pathogens and are capable of initializing and a T cell-dependent process that negatively interferes with the humoral regulating inflammation. Polarization to alternatively activated anti- immune response in older adults [23,24]. inflammatory M2 macrophages, rather than pro-inflammatory M1 It is well reported that a subset of CD8+ T cells constitutively express macrophages, is predominant in the tissues of older mice [45]. More­ the NK-associated receptor NKG2D in humans and upon stimulation in over, age negatively impacts the expression of TLRs and major histo­ mice, as NKG2D serves as an activating receptor in cytotoxic cells [25]. compatibility complex II (MHC-II), which probably contributes to However, CD8+ T cells with a senescent-like phenotype, lacking CD28 impaired antigen presentation and the activation of CD4+ T cells expression, accumulate NK receptors with age [26]. Despite their [46,47]. inability to respond to TCR-mediated signals, CD8+ senescent T cells DCs are the most important antigen-presenting cells, thereby acting mediate cytotoxic immune responses through NKG2D and other NK as a link between innate and adaptive immunity. Age-related alterations receptors instead. The switch from TCR- to NK-receptor-mediated in DCs, such as mitochondrial dysfunction and increased reactive oxy­ cytotoxicity probably increases their capacity for immune surveillance gen species (ROS) production, have specific deleterious effects on the and the elimination of senescent cells in aged tissues as well as tumour phagocytosis and cross-presenting capacity of DCs [48]. The alteration cells [27]. In contrast, CD4+ CD28− T cells express NK receptors de of the antigen processing and presentation machinery specifically con­ novo, and these cells are expanded in certain pathological conditions, tributes to an impaired stimulation and cytotoxic response of CD8+ T including acute coronary syndrome [28] and rheumatoid arthritis [29]. cells, together with lower secretion of IFN-γ [49]. Moreover, circulating In aged individuals, CD4+CD28− T cells with senescent features that plasmacytoids (pDCs) and myeloid DCs (mDCs) are less represented and specifically express the NKG2D receptor are expanded and, moreover, less responsive to TLR stimulation in elderly women [50]. have been suggested as a differentiation marker in the CD4+ T cell NK cells are the main innate cell subtype responsible for killing cells compartment in elderly individuals [30]. Innate-like properties in se­ infected by viruses, which have altered self or missing self-antigens. nescent T cells confer beneficial adaptation mechanisms to mediate Unlike T and B cells, the absolute number of NK cells is slightly faster effector functions, suggesting that the limits between the innate increased in elderly individuals, which could be associated with a and adaptive immune systems may not be as distinct as was first thought redistribution of NK cell subtypes. There is a decrease in CD56bright [31]. immunoregulatory cells and an increase in CD56dim cytotoxic cells; Numbers of peripheral B cells are not deemed with age, but many however, older subjects show a defective degranulation capacity changes are observed in the composition of the different compartments [51,52]. In contrast, the maturation of NK cells in the bone marrow of and in the functional features of B cell subtypes, mainly due to a deficit mice was shown to be impaired with age and is associated with reduced in CD4+ T helper cells, as mentioned above. The production of B cells in proliferation, resulting in reduced numbers of mature circulating cells in the bone marrow is decreased in elderly individuals [32], as well as the peripheral tissues [53]. Taken together, these data highlight the need for diversity of the B cell receptor (BCR) repertoire in the bone marrow, more studies on how ageing affects NK cells. lymph nodes and peripheral blood [33]. Moreover, a shift from naïve to Neutrophils are the first cells recruited against bacterial and fungal memory B cells has been described, which is consistent with the infections and they produce many degradative enzymes, antimicrobial decrease in IgD levels observed [34]. Late memory B cell numbers are peptides and ROS for their activity. Aged neutrophils display a reduced increased in older people and express markers associated with migration ability to target infected tissue, as these cells present a lower capacity to to sites of inflammation [35,36]. Another age-associated feature is the generate ROS and neutrophil extracellular traps (NETs) [54]. In elderly decreased isotype switch from IgM to IgG, IgE or IgA [37], possibly due individuals, alterations in surface molecules of neutrophils, such as to a decrease in the expression of activation-induced cytidine deaminase CD11b or CD16, have been reported, affecting phagocytosis and intra­ (AID) [38]. Age-associated B cells (ABCs) are antigen-experienced B vascular adhesion to the endothelium and, consequently, the recruit­ cells with features of memory B cells that are activated through Toll-like ment of immune cells to the infected tissue [55,56]. receptor (TLR) 7 and TLR9 and not by BCR stimulation alone [39,40]. ABCs continuously expand with age and are hardly detectable in youth. 3. Age-related autoimmunity However, ABCs are particularly expanded at earlier ages in individuals with autoimmune diseases, and ABCs often produce antibodies recog­ One of the most important features of immunosenescence is nizing self-antigens [41]. inflammaging, a chronic low-grade inflammation characterized by a gradual increase in pro-inflammatory mediators, including TNF-α, IL-6 2.2. Innate immunity and IL-1β, which results from an imbalance between pro-inflammatory and anti-inflammatory networks during ageing [57]. Pro-inflammatory Although alterations induced by age in the adaptive response are responses can confer not only a high resistance to infectious diseases well established, changes in the innate immune response in human but also an increased susceptibility to inflammatory-based diseases. On ageing are not well understood. Most studies suggest that the total the other hand, anti-inflammatory responses not only can increase sus­ numbers of different innate immune cell populations do not change ceptibility to infectious diseases but also can provide a survival advan­ dramatically; however, recent findings support that many of their tage in older individuals. In fact, centenarians seem to deal with this functions, such as cytotoxicity, phagocytosis, antigen presentation and chronic low-grade inflammation through an anti-inflammatory response the secretion of inflammatory cytokines, are altered. called anti-inflammaging, which may be one of the secrets of longevity Monocytes play an important role as starters of the inflammatory [58]. The principal stimulus involved in the progression of inflammag­ response, as they are circulating cells that are recruited to the site of ing is the accumulation of cell debris and self-antigens derived from inflammation, where they can differentiate into macrophages or into cellular stress or viral infections. The mechanisms devoted to cleaning DCs in certain inflammatory situations [42]. Aged monocytes stimulated cell debris and misfolded self-antigens become defective with age, with agonists of pattern recognition receptors show differences at the leading to an overexposure of the immune system to these products and transcriptional and functional levels, resulting in reduced production of sustained low-grade inflammation, which favours autoimmunity [59]. IFN-α, IFN-γ, IL-1β, CCL20 and CCL8, which participate in antiviral re­ Immune tolerance is a mechanism of the unresponsiveness of the sponses and in the recruitment of monocytes to the sites of inflammation immune system to antigens and is aimed at discriminating self from non- [43]. Monocytes in elderly individuals also express more TAM (Tyro3, self-antigens. However, some autoreactive lymphocytes escape all Axl and Mer) tyrosine kinase receptors, a family of receptors that tolerance mechanisms, leading to the expansion of autoreactive T cells 3 M. Dema et al. Autoimmunity Reviews 20 (2021) 102893 and the production of autoantibodies. Most likely related to a higher ABCs are also implicated in the pathogenesis of this syndrome, as they exposure to exogenous factors, elderly people show an increased prev­ are elevated in the blood of SjS patients. ABCs remain unresponsive in alence of autoantibodies such as rheumatoid factor, anti-neutrophil peripheral blood and are probably activated through TLRs, breaking cytoplasm and anti-nuclear antibodies, among others [60,61]. tolerance and leading to B cell lymphoproliferation [75]. Ageing is associated with the emergence of unusual cell subsets that are thought to have a role in the development of autoimmunity. Se­ 4. Immunosenescence in MS nescent CD4+CD28− T cells were originally isolated in the context of an autoimmune disease and were found to be outgrowths and autoreactive MS is a chronic neurodegenerative, inflammatory and demyelinating to self-antigens [22]. Their autoreactive properties and inability to serve disease of the CNS that is probably of autoimmune origin. MS affects as helpers in B cell responses are very similar to the deficiencies found in approximately 2.5 million people worldwide, and MS is the primary senescent CD4+ T cells from aged individuals [23]. Furthermore, se­ cause of non-traumatic disability in young adults [76]. MS typically nescent CD8+CD28− T cells expressing NK receptors can be found not initiates between 20 and 40 years of age, with a higher prevalence in only in elderly individuals but also in patients suffering from autoim­ women than men (2.3–3.5:1), a ratio that is increasing over time [77]. mune diseases, who present alterations in the number and function of Clinically isolated syndrome (CIS) is the first clinical acute episode that these cells [26]. ABCs continuously expand with age and are hardly shows inflammatory demyelination; however, CIS does not fulfil clinical detectable in youth; however, they are particularly expanded at earlier and radiological criteria to be considered definite MS, and not all pa­ ages in people with autoimmune diseases presenting enriched autoan­ tients with CIS necessarily develop MS. Most patients present a tibody production [40]. There are other factors that might accelerate relapsing-remitting (RR) form of MS, the most frequent form of the immunosenescence and contribute to the onset of autoimmune diseases, disease (80%), characterized by episodes of neurological dysfunction, like genetic factors such as the human leucocyte antigen (HLA) haplo­ and the majority of these patients (65%) progressively accumulate type and environmental factors such as persistent viral infections and disability with time, developing secondary progressive (SP) forms of MS. high consumption of different medications in elderly individuals [62]. A minority of patients (20%) present a progressive disease course from Systemic lupus erythematosus (SLE) has immune features that the onset, known as primary progressive (PP) MS [78]. overlap with features of ageing, suggesting the presence of premature Although the aetiology of MS remains unknown, MS is known to immunosenescence, such as telomere attrition and a generally lower result from an interplay between genetic and environmental risk factors. phagocytic capacity [63,64]. The clearance of apoptotic bodies is Genome-wide association studies have identified 233 independent as­ mediated by macrophages and its deregulation could generate danger sociations that are significantly linked to MS susceptibility, the majority signals and the exposure of self-antigens to DCs [65], which present an of which were found in the autosomal non-MHC genome [79–81]. affected tolerance and a greater autoreactivity with age [66]. In addi­ Nonetheless, the main genetic risk factors are related to HLA genes, with tion, ABCs are significantly increased in these patients and positively the variants DRB1*15:01, DRB5*01:01 and DQA1*01:02 being associ­ correlate with high anti-chromatin antibody production [67]. Moreover, ated with an increased risk of developing MS, while HLA-A*02 is asso­ ABCs are B cell activating factor (BAFF)-dependent, and the blockade of ciated with protection from the disease [82]. Sex, living in high-latitude this cytokine has been proven to be effective in SLE patients, which areas, smoking, low vitamin D levels caused by insufficient sun exposure confirms the implication of ABCs in the disease [68]. Furthermore, or dietary intake, obesity during adolescence, commensal microbiota autoreactive B and T cells are thought to be activated after infection by composition and EBV infection have been identified as possible envi­ CMV or Epstein-Barr virus (EBV) with pathogen antigens that share ronmental risk factors related to MS development, whereas the use of structural similarities with self-antigens. This cross-recognition mecha­ oral nicotine or alcohol, seropositivity to CMV and high coffee con­ nism principally provokes the production of anti-nuclear autoanti­ sumption are related to a reduced risk [83,84]. Among these risk factors, bodies, which are also found in healthy elderly individuals [69]. EBV is strongly associated with the development of MS. Several myelin As in ageing, in rheumatoid arthritis (RA), it is well established that antigens, including myelin basic protein (MBP), myelin oligodendrocyte CD4+CD28− T cells accumulate and show signs of senescence; in fact, glycoprotein (MOG) and proteolipid protein (PLP), have been proposed this population of cells was first identified in RA patients [22]. Senescent as the principal candidate autoantigens involved in the development of T cells no longer require a CD28 co-stimulatory signal for complete MS [85]; however, other non-myelin antigens have been identified to activation, and at the same time, they acquire cytotoxic properties [62]. trigger immune attack on myelin components [86]. The most accepted In addition, a novel CD4+ CD28− T cell subset has been described in RA hypothesis to explain the immunopathogenesis of MS involves an initial patients, revealing features of both Treg cells and senescent T cells. immune activation in the periphery of CD4+ T cells reactive to myelin These CD4+CD28− FoxP3+ Treg-like cells insufficiently suppress the antigens. Then, activated autoreactive CD4+ T cells infiltrate the CNS, proliferation of effector T cells and induce a pro-inflammatory cytokine where they are reactivated by the recognition of myelin antigens pre­ profile [70]. sented by microglial cells, initiating a series of immune events that It is known that age-related gene expression profiles overlap with contribute to demyelination and tissue damage. These immune events gene expression profiles in tissues affected by autoimmune thyroid provoke the activation of astrocytes and microglia, the apoptosis of ol­ disease (AITD), suggesting that there is also a relation between prema­ igodendrocytes and axonal loss in both the white matter and the grey ture immunosenescence and autoimmunity in the thyroid gland. These matter of the brain and the spinal cord. In addition, the release of pro- changes include the downregulation of genes related to mitochondrial inflammatory mediators facilitates the permeabilization of the blood- and proteasomal functions and the upregulation of genes related to the brain barrier (BBB), attracting monocytes and additional lymphocytes, immune response [71]. AITD patients present a peripheral T cell thus sustaining the inflammatory process that leads to progressive tissue phenotype reminiscent of findings in elderly patients and patients with degeneration [87]. The analysis of the autoimmune response showed other autoimmune diseases. There is a significant increase in structural homology between MBP and EBV peptides presented by HLA- CD4+CD28− T cells associated with CMV seropositivity in individuals DRB1*15:01, as well as the presence of T cells with specificity for both with Hashimoto’s disease [72] and an increase in CD4+CD28− T cells antigens. Altogether, molecular mimicry with EBV antigens is one of the producing IFN-γ in individuals with Graves’ disease [73], which might main mechanisms involved in MS pathogenesis [88]. drive the destruction of thyroid tissue. The prevalence of MS and the age of affected patients are increasing The most frequent causes of Sjögren syndrome (SjS) are the chronic due to the increasing longevity of the general population and the use of medications and viral infections [74], which are both common availability of effective disease-modifying treatments. Patients with features in elderly individuals, suggesting a relationship between pre­ PPMS normally have a later disease onset than those with RRMS, the mature ageing of the immune system and the developmentof the disease. majority of whom develop SPMS over time. However, current 4 M. Dema et al. Autoimmunity Reviews 20 (2021) 102893 treatments reduce the frequency of relapses and slow the progression of and this transition is dependent on age rather than disease duration the disease, but they cannot stop the disability accumulation associated [101]. Neuroinflammation mechanisms such as synaptopathy and syn­ with disease progression [89]. These facts support the idea that there are aptic plasticity impairments are exacerbated and accelerate with age in differences between the processes driving relapses and those driving MS patients [102]. In particular, disease progression is characterized by chronic progression commonly in elderly individuals, which could be a marked decrease with age in the CD8+ T cell response to EBV-infected due to the impact of age on the immune system. Indeed, there are B cells, which may result from the deletion of EBV-specific T cells numerous studies in the animal model of MS experimental autoimmune through exhaustion mechanisms that occur during chronic viral in­ encephalomyelitis (EAE) and in MS patients that demonstrate the impact fections [103]. of immunosenescence on the disease [90]. 4.3. Premature ageing of the immune system in MS 4.1. Age-related immune changes in EAE Patients suffering from MS are also characterized by premature EAE is a well-established animal model used for the study of MS that immunosenescence [104] and reduced immune function that resembles has provided helpful information about various pathological processes, that of healthy elderly individuals. The reduced immune function can be including inflammation, demyelination, axonopathy and neuron loss a consequence of the diminished proliferative capacity of bone-marrow- mediated by immune cells [91]. However, there are some differences in derived cells and the shortening of telomeres, which are both observed immunopathology between EAE and MS, since CD4+ T cells predomi­ in MS patients [105]. Telomere length reduction and increased oxidative nate in the inflammatory infiltrate in EAE, while in MS lesions, CD4+ T stress have been suggested as premature ageing markers in many cells are much less frequent, with CD8+ T cells and macrophages being autoimmune diseases, including MS. The shortened telomeres and the predominant infiltrating cells [92,93]. oxidative stress found in PPMS patients may reflect the most severe state A key mediator in central tolerance is the autoimmune regulator of the disease and may also be associated with greater disability and (Aire), a transcription factor highly expressed in medullary thymic brain atrophy [106,107]. Furthermore, RRMS and PPMS patients also epithelial cells (TECs) that promotes ectopic expression of peripheral- present prematurely reduced immune functions related to thymic tissue-specific self-antigens, leading to central tolerance. Some autor­ dysfunction, including a contraction of naïve T cells, Treg cell eactive T cells escape this process, but they are regulated by peripheral dysfunction and decreased signal joint TRECs [108]. Similar alterations tolerance mechanisms, including immune regulation by Treg cells. in T cell homeostasis are observed in paediatric MS patients, confirming There is an age-related association between Aire and Treg cells in sus­ the presence of an early thymic involution [109]. The main common ceptibility to EAE. The resistance of young Aire-knockout (KO) mice to characteristic between ageing and MS is the accumulation of EAE correlated with an elevated percentage of peripheral Treg cells, CD4+CD28− T cells. These effector memory T cells result from repeated whereas older Aire-KO mice presented more severe disease and no dif­ viral antigenic stimulation, typically CMV and EBV, before migrating to ferences in the frequency of Treg cells in the periphery, demonstrating the CNS, which contributes to tissue damage, thereby causing the age-related impaired peripheral tolerance [94]. A spontaneous EAE release of self-antigens. IL-15 produced by peripheral B cells, astrocytes mouse model also showed a decrease in intrinsic regulatory mechanisms and infiltrating macrophages in CNS inflammatory lesions is known to involved in the maintenance of self-tolerance and Treg cell suppressive enhance the cytotoxic properties of CD4+CD28− T cells [110]. Alter­ function with age [95]. EAE rats show an age-associated alteration in the ations in B cell subsets are also found in the cerebrospinal fluid of MS autoimmune response, while young rats show an anti-MBP antibody patients with acute relapse, as there is a higher frequency of non- response during the acute period, no epitope dominance was detected in switched memory B cells in paediatric patients and class-switched the older rats [96]. memory B cells in adults [111]. However, B cell participation in MS Little is known about the age effect on BBB disruption in EAE, a goes beyond the production of antibodies. ABCs are increased in MS critical step in the development of the disease, as myelin-specific T cells patients as well, corroborating the presence of early ageing [112]. infiltrate the CNS by crossing the BBB. Several molecules are altered in MS is primarily mediated by adaptive immune responses, while response to BBB disruption, such as nicotinamide adenine dinucleotide chronic stages are believed to be mediated by compartmentalized innate phosphate oxidase, matrix metalloproteinases and cell adhesion mole­ immune responses in the CNS [9]. Therefore, a complete understanding cules. These molecules were elevated with age in a non-relapse EAE of the impact of age on the immune system and disease progression, as mouse model, suggesting that they play a role in BBB disruption and the well as the premature immune ageing observed in MS patients, needs to subsequent autoreactive T cell infiltration that leads to neuro­ be achieved to develop effective immunotherapies against immunose­ degeneration [97]. However, age not only is a risk factor for neuro­ nescence in MS. degeneration but also influences neuroregeneration. Using a focal EAE rat model, immunization with MOG followed by localized injections of 5. Rejuvenation of the immune system as a therapy for MS cytokines in the spinal cord to generate focal demyelinating injury increased vulnerability to axonal injury and reduced the efficiency of Currently, there is no cure for MS and no effective therapy options remyelination in older animals compared with young animals. More­ available that can stop disability accumulation in individuals with over, remyelination in aged rats was mediated by Schwann cells, while progressive forms of the disease, who represent the majority of patients in younger rats, oligodendrocytes mediated the regeneration process over 65 years of age. Food and Drug Administration (FDA)-approved [98]. therapies for RRMS have failed to demonstrate efficacy as a treatment for PPMS, and there are few disease-modifying therapy options for SPMS 4.2. Age-related immune changes in MS [113,114]. In addition, emerging data suggest that premature immu­ nosenescence strongly influences MS progression; thus, several thera­ Age, sex and viral infections are known to influence the phenotype peutic strategies based on rejuvenating the immune system have been and function of the immune system. The frequencies of immune cells proposed to reverse this phenomenon (Fig. 1). depend on lifetime exposure to pathogens such as CMV, which leads to late differentiation and the accumulation of senescent immune cells with 5.1. Senolytics and HSC regenerative strategies age [99]. Indeed, senescent neurons and glial cells also accumulate in the nervous system with age, predisposing individuals to the appearance Senescent cells accumulate with age in the CNS and contribute to and aggravation of neurodegenerative events [100]. Furthermore, the disease progression. Senolytic drugs have been developed to selectively evolution from RRMS to SPMS normally occurs over time at older ages, remove senescent cells by targeting anti-apoptotic pathways, and 5 M. Dema et al. Autoimmunity Reviews 20 (2021) 102893 Fig. 1. Senolytics and regenerative strategies using haematopoietic stem cells (A), therapies based on rejuvenating oligodendrocyte precursor cells, microglia and monocytes (B), thymus cells (C) and senescent B and T cells (D) are capable of reversing the process of immunosenescence and could have a beneficial impact on the progression of MS. Abbreviations: Oligodendrocyte precursor cell (OPC); Haematopoietic stem cell (HSC); T cell receptor (TCR); Regulatory T cell (Treg); Thymic epithelial cell (TEC); Age-associated B cell (ABC); Natural killer (NK). senolytics have recently been suggested as potential rejuvenation stra­ CNS has the capacity to remyelinate axons and, thus, prevent neuro­ tegies against progressive MS [115]. The use of the tyrosine kinase in­ degeneration, the efficiency of CNS remyelination declines with age, and hibitor dasatinib and quercetin in combination decreased the age-related failure of OPCs to differentiate into myelinating oligoden­ accumulation of senescent cells and increased survival in older mice. drocytes is particularly involved. The fasting mimetic drug metformin Moreover, these drugs showed immunomodulatory effects on MS when reverses the poor differentiation and maturation of OPCs and restores used separately [116–118]. Another important senolytic drug is navi­ remyelination and neuroregeneration in aged rodents [124]. Further­ toclax, or ABT263, which is able to induce apoptosis in senescent bone more, older mice with a focal demyelination exposed to a youthful marrow HSCs, reduce myeloid bias and improve haematopoietic func­ systemic milieu through heterochronic parabiosis (a young mouse sur­ tionality [119]. In fact, HSC ageing is related to reduced self-renewal gically joined to an aged partner) could recruit young macrophages and capacity, which leads to altered immune cell numbers and functions. rejuvenate OPCs, suggesting that youthful monocyte transplantation The ageing of the HSC compartment was initially considered to be could be considered a remyelination therapy [125]. Microglia and irreversible; however, recent findings show rejuvenating strategies that macrophages are essential for remyelination, as both are responsible for are capable of reversing HSC dysfunctions related to ageing, including the phagocytosis of myelin debris that inhibits remyelination and for the prolonged fasting and pharmacological targeting to inhibit molecules release of growth factors necessary for OPC maturation. With age, a such as mTOR (rapamycin) [120], CDC42 (CASIN) [121] and p38 decline in the phagocytic clearance of myelin debris occurs, a phe­ MAPK (TN13 and SB203580) [122,123]. These strategies are capable of nomenon that has also been observed in MS patients. Given that retinoid enhancing the regenerative capacity of HSCs, reducing ROS levels and X receptor activation in monocytes enhances myelin debris clearance in re-establishing an immune system similar to that of young organisms MS, the agonist bexarotene was found to reverse phagocytosis defects (Fig. 1A). and lead to a younger state of these cells [126]. In addition, with age, a decrease in the expression of CD36 by microglia occurs, which is also involved in myelin debris clearance by phagocytosis. Daily treatment of 5.2. Rejuvenation of oligodendrocyte precursor cells (OPCs), microglia old microglia with niacin or vitamin B3 upregulates CD36 expression and monocytes and enhances phagocytosis, which leads to remyelination. Thus, niacin can stimulate innate immunity and represents a regenerative therapy for MS progressive forms are characterized by accumulative neuro­ chronic demyelination, which is an interesting therapeutic strategy for degeneration due to persistent demyelination of axons. Although the 6 M. Dema et al. Autoimmunity Reviews 20 (2021) 102893 MS [127]. MCC950 regulates innate immunity by specifically inhibiting restoration of helper function in senescent CD4+ T cells can be partially the NLRP3 inflammasome and subsequently reducing IL-1β production. achieved when CD4+ T cells are exposed to the cytokine IL-12 [138]. A MCC950 attenuated the severity of EAE, improved the histopathology of similar functional restoration and production of IL-2 was shown in se­ the CNS and protected against axonal damage in organotypic cerebellar nescent CD8+ T cells by CD28 gene transduction [139]. Both strategies cultures. Therefore, MCC950 could be considered an anti-inflammaging can delay or reverse the ageing effects of the loss of the CD28 co- therapy for MS [128,129] (Fig. 1B). stimulatory molecule. In addition, the expression of innate receptors such as NKG2D on CD4+ T cells is characteristic of ageing and regulates 5.3. Rejuvenation of the thymus the cytotoxic functions of these cells by promoting pro-inflammatory cytokine production. Treatment with a blocking anti-NKG2D antibody Recently, many potential rejuvenation therapeutic strategies have ameliorates EAE inflammation, making this receptor a promising ther­ been developed to restore aged thymic function and, consequently, de­ apeutic target for MS treatment [140] (Fig. 1D). fects in negative selection and in the generation of Treg cells. As the FOXN1 transcription factor is strongly implicated in the differentiation 6. Conclusions of TECs cells and is responsible for the ectopic expression of peripheral- tissue-specific self-antigens that lead to tolerance, it has been proposed Overall, the evidence presented here demonstrates that age-related as a target for several rejuvenation strategies against thymic involution immune changes are observed in EAE and MS patients, as well as pre­ [130]. Because thymic atrophy is related to a failure in the thymic mature ageing of the immune system in MS patients. Therefore, we microenvironment and consequently in thymopoiesis, targeting this propose different therapeutic strategies based on rejuvenating the im­ process could also reverse the observed thymus dysfunction in MS pa­ mune system, which could reverse the process of immunosenescence tients. There is evidence that an age-related decrease in the expression of and have a beneficial impact on the treatment of MS, as potential add-on IL-7 is involved in thymus involution. Treatment with IL-7 promotes the treatments to current FDA-approved therapies. Moreover, therapies maturation of thymocytes to naïve T cells, enhances TCR diversity and focused on the rejuvenation of the immune system could provide new results in higher numbers of memory CD8+ T cells [131]. Another therapeutic opportunities for the PP form of the disease. A broad cytokine involved in thymopoiesis is IL-22, which was shown to knowledge of the impact of age on the immune system and disease enhance thymic recovery after the depletion of CD4+CD8+ double- progression in MS patients would facilitate the development of new positive thymocytes [132]. Keratinocyte growth factor is important effective immunotherapies against immunosenescence in MS. for the maintenance of TECs and has been proven to increase thymo­ poietic capacity in aged mice by restoring the function of TECs [133]. Funding However, thymic involution results in not only decreased numbers of naïve T cells but also increased output of potential autoreactive T cells to This work was supported by the Fondo de Investigación Sanitaria, the periphery and consequently to higher susceptibility to developing Instituto de Salud Carlos III, and co-funded by the European Union autoimmune diseases such as MS. The most promising rejuvenation (European Regional Development Fund/European Social Fund), “A way immunotherapies focused on targeting these autoreactive T cells are to build Europe”, under Grant PI18/01146 and RD16/0015/004 and the therapeutic vaccinations that include TCR peptides, MBP-based DNA, “Agència de Gestió d’Ajuts Universitaris i de Recerca” (AGAUR; Gen­ altered peptide ligands and attenuated autoreactive T cells [134]. eralitat de Catalunya) under Grant 2017SGR527. Among them, T cell vaccines have shown clinical efficacy in clinical trials, as they induce an anti-idiotypic response against MBP-reactive T Declaration of Competing Interest cells and restore Treg cell function in MS patients, making them a po­ tential strategy against MS [135]. Additionally, a fasting-mimicking MD, HE, LMV and CE: None. diet, a very low-calorie and low-protein diet, prevents autoimmunity in XM has received speaking honoraria and travel expenses for partic­ an EAE model by reducing the levels of autoreactive T cells and ipation in scientific meetings and has been a steering committee member increasing the production of Treg cells, which are both cell subsets that of clinical trials or has participated in advisory boards of clinical trials in are altered with immunosenescence [136]. 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