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Try out PMC Labs and tell us what you think. Learn More. Sex differences are well-recognized in ischemic stroke, a disease mainly affecting the elderly. Stroke in robust activation of central and peripheral immune responses which contributes to functional outcome. Despite that sex differences are well-documented in immunity and inflammation, few studies have focused on sex differences in inflammatory responses after ischemic stroke and even fewer in the context of aging.
T cells offer an attractive therapeutic target due to their relatively delayed infiltration into the ischemic brain. This review will focus on T cell immune responses in ischemic stroke, highlighting studies examining the effects of aging and biological sex. Ischemic stroke is a leading cause of mortality and morbidity in the elderly. There are considerable sex differences in stroke incidence across the lifespan, with earlier onset in men [ 1 ]. However stroke risk in middle-aged females and females above 85 years of age is higher than in men [ 1 , 2 ].
Hormonal effects due to early life exposure to sex hormones organizational effects and acute effects of circulating hormones during the reproductive years are thought to play a role in this sexual dimorphism. There has been increasing recognition of the contribution of the sex chromosomes XX vs.
XY and X-linked genes to ischemic sensitivity, especially after reproductive senescence [ 3 — 5 ]. Using the four core genotype FCG mouse model, studies indicate that the ischemic phenotype, and whether female neuroprotection is present, is hormone-dependent in young mice while it is chromosomal-dependent in aged mice [ 4 , 5 ].
Males and females show different immunological responses to foreign and self-antigens. The majority of pre-clinical studies have not included a sex-specific de or analysis [ 8 ], and are often underpowered to detect sex differences. Historically, female subjects have also been underrepresented in clinical trials [ 9 ] but due to policy changes by the FDA in that required efficacy and safety of new drugs to be evaluated in both sexes, female s have increased and the overall participation of men and women is comparable [ 10 , 11 ].
Women are still underrepresented in phase I clinical trials and in certain areas such as cardiovascular trials, however this was correlated to age of enrollment as age-sex differences in cardiovascular disease prevalence are well-known [ 12 ]. Differences in drug efficacy and side-effects led to the withdrawal of eight out of ten prescription drugs in the US between and because they posed greater risks for women than men [ 13 ]. In ischemic stroke, the anti-inflammatory drug minocycline affords neuroprotection in male mice but not in females [ 14 ].
Sex differences in ischemic stroke have also been reported in clinical trials , e. The inflammatory cascade that is activated acutely after stroke continues for weeks and months after the injury, and contributes to outcome and recovery [ 16 , 17 ]. An increasing of studies highlight an important role for T lymphocytes in the pathophysiology and recovery after ischemic stroke, yet our understanding of sex differences in these responses are limited.
In this review, we highlight recent work on sex differences in T cell immune responses and how they are affected by aging and ischemic stroke. It is well-documented that immune responses differ by sex Table 1 , which is emphasized by the higher proportion of females with multiple autoimmune diseases in which female to male ratios can approach [ 18 ].
Differential responses to infection and vaccines exist in that females mount a stronger antigenic response, are less susceptible to a wide variety of pathogens, and have superior clearance of pathogens [ 3 , 19 ]. Sex differences and sex hormone effects on these different T cell subsets have been described [ 6 ], and they have been implicated in pathophysiology and recovery after stroke [ 24 — 26 ], which will be discussed in later sections. Mon et al. Short-lived effector cells are more terminally differentiated, express high levels of cytokines and cytolytic molecules, hence phenotypically are more apoptotic and largely responsible for elimination of infected cells during an infection [ 28 ].
Memory precursor cells on the other hand, are less responsive during infection but transition into the long-lived memory pool and respond to repeat infections. Sex differences in T cells are evident also in the absence of stimuli like vaccines and pathogens. Estrogens, progesterones and androgens are the major gonadal hormones. All have numerous well-documented effects on the immune system that mediate many of the known sex differences in immunity reviewed in detail in [ 6 ]. Estrogens promote the expansion of Tregs in mice and healthy women [ 38 ], induce T H 2-type responses and decrease production of interleukin by T H 17 cells [ 39 ].
In response to estrogen fluctuations throughout the course of the menstrual cycle, the of Tregs undergo ificant changes and will affect overall immunity accordingly as Tregs regulate the peripheral T cell pool and the response to infections [ 40 ]. Interestingly, the impact of ischemic stroke in young cycling female mice vary throughout the estrous cycle and neuroprotection is seen primarily during proestrus when estradiol levels are high [ 41 ].
However, Treg and effector T cell levels throughout the estrous cycle have not been investigated in relation to neuroprotection in ischemic stroke. Besides the classical aling of hormone and hormone receptors, non-classical direct aling occur in immune cells between ERs and ERE-independent transcription factors including nuclear kappa beta and activator protein 1. In addition, estrogens can bind to the membrane associated estrogen G protein-coupled receptor 30 GPR30 to provide more rapid aling [ 42 ].
Similar to estradiol, a GPRspecific agonist G1 was shown to be neuroprotective in ischemic stroke and improved immunosuppression by partially restoring splenocyte s in female mice [ 43 ]. Progesterone receptors are found on many different immune cells, including T cells and Natural Killer NK cells [ 44 ]. The hormonal milieu in males and females change as we age, with a rapid decline in females and a more gradual decrease in males which parallels a functional decline in the immune system of both sexes.
Hormones are not the only contributors to sex differences in immunity; sex chromosome effects are also important modulators [ 48 ]. This is exemplified by Klinefelter and Turner syndromes, where males have an extra X chromosome Klinefelter syndrome and women have only one X chromosome or major X chromosome deletions, Turner syndrome. On the other hand, women with Turner syndrome have lower immunoglobulin and T cell levels and are less susceptible to systemic lupus erythematosus SLE [ 50 , 51 ]. Both patients with Klinefelter syndrome and patients with Turner syndrome show increased susceptibility to autoimmune disorders speaking for an important role for the X chromosome in influencing autoimmunity [ 52 ].
Genes on the X chromosome have to be inactivated to ensure only one copy functions in each sex, a process initiated by the X-inactive specific transcript XIST gene. The impact of sex chromosomes can be studied using the FCG mouse model where the sex determining gene SRY is placed on an autosome [ 53 ]. Gonadectomy in these mice unmask sex chromosome effects including susceptibility to autoimmune diseases and viral infections [ 54 ]. In ischemic stroke, aged mice with a second X chromosome male or female had ificantly larger infarct volumes and a larger population of infiltrating lymphocytes compared to XY-females or XY-males [ 4 ].
However, changes in specific T cell populations and phenotypes after stroke using this model have yet to be studied. Aging is associated with a decreased function of the adaptive immune system and profound changes in T cell function have been reported. The thymus is critical for maturation and development of a diverse T cell repertoire. As we age thymic involution occurs, a process that is shaped by sex hormones [ 55 ].
This is detrimental as a diverse TCR is vital for protection from viral infections, and explains, in part, why older individuals are more susceptible to infection [ 58 ]. Not all T cell subtypes becomes impaired as we age, for instance mouse and human Tregs increase in and function with aging, and might be higher in males [ 59 — 62 ]. Although aging affects the adaptive immune system in both males and females, aging may be occurring at an accelerated rate in males. For example, during the process of aging, females better maintain the proliferative capacity of T cells [ 63 ].
These sex differences in the aging immune system are likely to affect age-related diseases such as ischemic stroke. In fact, Ritzel et al. In the next section we will first give an overview of known T cell responses after ischemic stroke, unfortunately most are from studies performed exclusively in young male animals. Ischemic stroke triggers multiple inflammatory cascades in the brain and periphery. T cells are integral to the pathophysiology of stroke and are a key component of the adaptive immune system [ 16 , 65 , 66 ].
The time-course and extent of T cell infiltration after ischemic stroke vary depending on the experimental stroke model used permanent vs transient and the age of the animals. The distinction between early and late T cell responses after stroke is likely related to antigen-independent and antigen-dependent mechanisms which is a subject of debate discussed in a later section.
Nevertheless, the delayed profile of T cell migration and its potential for an extended time-window for ischemic stroke offer an attractive therapeutic target. In contrast, existing data point to a regulatory and protective role for B cells through interleukin IL secretion thereby limiting neuroinflammation and neurological deficits 48 hours post-stroke [ 70 ]. It has been suggested that delayed infiltration of B cells contribute to cognitive impairment 7 weeks post-stroke [ 71 ]. Further evidence for the importance of T cells in the evolution of ischemic brain injury has been shown after treatment with an immunomodulatory drug, FTY fingolimod , used in multiple sclerosis patients, that inhibits migration of T cells into inflamed tissues [ 24 ].
Liesz et al. Overall inhibition of leukocyte infiltration through blockade of very late antigen-4 VLA-4, CD49d reduced stroke size 7 days post-stroke in both a permanent and transient model of ischemic stroke. DNTs increased in brain and blood of stroke patients and mice subjected to experimental stroke, and were found in close proximity to microglia.
The authors suggested that DNTs are critical for microglia-induced neuroinflammation after ischemic stroke. Autoimmune responses can occur when T cells react to brain antigens, either within the brain itself or systemically, as the blood brain barrier becomes compromised after ischemic stroke allowing for lymphocyte entry and leakage of brain antigens from injured neurons and glia.
Development of autoimmunity to brain antigens such as myelin basic protein and related peptides in stroke remains controversial in regards to whether it is beneficial or detrimental [ 16 , 65 , 76 ]. Interestingly, elevated immunoreactivity to neuronal-derived antigens was associated with smaller infarcts and better long-term outcome, whereas greater reactivity to myelin basic protein correlated to worse stroke severity NIHSS at admission , larger infarcts and worse functional outcomes at 3 months in stroke patients [ 77 ].
Adoptive transfer of lymphocytes specific for myelin proteins in rats and mice worsens stroke outcomes indicating the presence of autoreactive T cells is merely not just a consequence of worse outcome [ 78 , 79 ]. Clonal T cell expansion can be detected in the mouse brain at day 7 and 14 after stroke, making it unlikely that early T cell responses after stroke is antigen-dependent [ 80 , 81 ].
Ortega et al. This highlights the importance of considering the time-course of immune cell infiltration when distinguishing between antigen-independent and antigen-dependent mechanisms. Early deleterious effects of T cells in ischemic stroke are most likely antigen-independent. Whether brain antigen specific T cells are protective or not could also depend on the time-course of the concomitant activation of regulatory T cells.
Work by Becker and others have demonstrated that increased tolerance to myelin basic protein characterized by a Treg responses improves outcomes after stroke in pre-clinical models [ 83 — 86 ]. These cells are pro-homeostatic during healthy conditions and upon injury act to limit extensive inflammation.
In ischemic stroke, Tregs have been suggested to be major neuroprotective modulators through IL aling [ 25 ]. In these experiments, in vivo depletion of Tregs with a CDspecific antibody administered 48 hours prior to stroke resulted in increased delayed brain injury at 7 days and worsened sensorimotor function. In contrast, Kleinschnitz et al. A large of Tregs accumulate in the brain by day 14 after stroke and continue to increase thereafter [ 87 , 88 ]. Post-stroke depletion of Tregs using DEREG mice and application of diphtheria toxin on day 7, 9 and 11 resulted in worsened neurological recovery without affecting the infarct volume on day 14 [ 87 ].
In this study Ito et al. Overall, the majority of studies point to a neuroprotective role of Tregs in ischemic stroke. While it has become evident that T cell responses are major determinants of acute and long-term stroke outcome in males, the contributions of age and sex to T cell-mediated inflammation after ischemic stroke remains mainly unknown. Similar to observations in human stroke patients, sex differences are apparent in experimental stroke [ 89 ]. Young female animals sustain smaller ischemic brain injury and have less neurological deficits than age-matched males, which is largely due to sex hormones, primarily estrogens, as ovariectomy OVX abolishes the sex differences and estrogen-replacement restores the female protection reviewed in detail by Ahnstedt et al.
Some of the protective effects of estrogens have been linked to its immunomodulatory actions; here we will focus on the effect of sex hormonal and chromosomal on T cell immune responses after ischemic stroke see Table 2. It has been established from work by Offner and Hurn that stroke induces a massive, rapid activation of the peripheral immune system [ 90 ]. Stroke le to splenic atrophy characterized by a reduction in organ size and in the of splenocytes.
In OVX females, estradiol administration partly restored the drastic reduction in splenocytes after ischemic stroke [ 43 ]. In stroke patients, higher serum IL levels correlated with poor acute 24 hours and long-term outcomes 3, 12 months in women but not in men [ 94 ]. However, after controlling for cofounders, IL was not an independent predictor of functional outcome suggesting IL levels are related to other factors such as age and stroke severity.Mature women sex Lages
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