Thymic Involution Research Articles

Predicting model of mild and severe types of COVID-19 patients using Thymus CT radiomics model: A preliminary study.

To predict COVID-19 severity by building a prediction model based on the clinical manifestations and radiomic features of the thymus in COVID-19 patients. We retrospectively analyzed the clinical and radiological data from 217 confirmed cases of COVID-19 admitted to Xiangyang NO.1 People's Hospital and Jiangsu Hospital of Chinese Medicine from December 2019 to April 2022 (including 118 mild cases and 99 severe cases). The data were split into the training and test sets at a 7:3 ratio. The cases in the training set were compared in terms of clinical data and radiomic parameters of the lasso regression model. Several models for severity prediction were established based on the clinical and radiomic features of the COVID-19 patients. The DeLong test and decision curve analysis (DCA) were used to compare the performances of several models. Finally, the prediction results were verified on the test set. For the training set, the univariate analysis showed that BMI, diarrhea, thymic steatosis, anorexia, headache, findings on the chest CT scan, platelets, LDH, AST and radiomic features of the thymus were significantly different between the two groups of patients (P < 0.05). The combination model based on the clinical and radiomic features of COVID-19 patients had the highest predictive value for COVID-19 severity [AUC: 0.967 (OR 0.0115, 95%CI: 0.925-0.989)] vs. the clinical feature-based model [AUC: 0.772 (OR 0.0387, 95%CI: 0.697-0.836), P < 0.05], laboratory-based model [AUC: 0.687 (OR 0.0423, 95%CI: 0.608-0.760), P < 0.05] and model based on CT radiomics [AUC: 0.895 (OR 0.0261, 95%CI: 0.835-0.938), P < 0.05]. DCA also confirmed the high clinical net benefits of the combination model. The nomogram drawn based on the combination model could help differentiate between the mild and severe cases of COVID-19 at an early stage. The predictions from different models were verified on the test set. Severe cases of COVID-19 had a higher level of thymic involution. The thymic differentiation in radiomic features was related to disease progression. The combination model based on the radiomic features of the thymus could better promote early clinical intervention of COVID-19 and increase the cure rate.

Mesenchymal Stem Cells: A Promising Treatment for Thymic Involution.

The thymus is the main immune organ in the body. However, the thymus gradually degenerates in early life, leading to a reduction in T-cell production and a decrease in immune function. Mesenchymal stem cells (MSCs) are a promising alternative for the treatment of thymus senescence due to their homing ability to the site of inflammation and their paracrine, anti-inflammatory, and antioxidant properties. However, the heterogeneity, difficulty of survival in vivo, short residence time, and low homing efficiency of the injected MSCs affect the clinical therapeutic effect. This article reviews strategies to improve the efficacy of mesenchymal stem cell therapy, including the selection of appropriate cell doses, transplantation frequency, and interval cycles. The survival rate of MSCs can be improved to some extent by improving the infusion mode of MSCs, such as simulating the in vivo environment, applying the biological technology of hydrogels and microgels, and iron oxide labeling technology, which can improve the curative effect and homing of MSCs, promote the regeneration of thymic epithelial cells, and restore the function of the thymus.

An enlarged fetal thymus may be the initial response to intrauterine inflammation in pregnant women at risk for preterm birth

Fetal thymus involvement in prematurity has been studied, and this study aimed to evaluate its relationship with short cervix and amniotic fluid sludge in the second trimester of pregnancy. In this prospective cross-sectional study, 79 pregnant women (19+0 to 24+6 weeks) were included, and cervical length and the presence or absence of amniotic fluid sludge were evaluated. In the three-vessel view of the fetal thorax, the thymus was identified, and its perimeter and transverse diameter were measured and transformed to a zeta score based on gestational age. Data from 22 women with short cervix (<25 mm) and 57 patients with normal cervix (≥25 mm) were analyzed. The transverse diameter of the fetal thymus was significantly greater in the short cervix group compared to that of the normal cervix group (z-score 2.708 vs. -0.043, p=0.003). There were no significant differences in the perimeter (z-score -0.039 vs. -0.071, p=0.890) or the transverse diameter (z-score 1.297 vs. -0.004, p=0.091) of the fetal thymus associated with the presence (n=21) or absence of sludge (n=58). A short cervix is associated with an increased transverse diameter of the fetal thymus during the second trimester of gestation.

Restored Thymic Output after Androgen Blockade Participates in Antitumor Immunity.

The thymus is a hormone-sensitive organ, which involutes with age in response to production of sex steroids. Thymic involution leads to a decrease in the generation of recent thymic emigrants (RTEs), resulting in a reduced response to immune challenges such as cancer. Interestingly, the standard of care for prostate cancer patients is androgen deprivation therapy (ADT), which leads to thymic regeneration and an increase in thymic output. It remains unknown whether these newly produced T cells can contribute to the antitumor immune response. This study defines the kinetics of thymic regeneration in response to ADT in mice, determining that thymic epithelial cell proliferation is critical for the increase in RTE output. Using a mouse model to track RTE in vivo, we demonstrate that these newly generated RTEs can traffic to tumors, where they become activated and produce effector cytokines at levels similar to more mature T cells. Collectively, these data suggest that RTEs produced from ADT-induced thymic regeneration could be harnessed for the antitumor immune response.

Immune system modulation in aging: Molecular mechanisms and therapeutic targets.

The function of the immune system declines during aging, compromising its response against pathogens, a phenomenon termed as "immunosenescence." Alterations of the immune system undergone by aged individuals include thymic involution, defective memory T cells, impaired activation of naïve T cells, and weak memory response. Age-linked alterations of the innate immunity comprise perturbed chemotactic, phagocytic, and natural killing functions, as well as impaired antigen presentation. Overall, these alterations result in chronic low-grade inflammation (inflammaging) that negatively impacts health of elderly people. In this review, we address the most relevant molecules and mechanisms that regulate the relationship between immunosenescence and inflammaging and provide an updated description of the therapeutic strategies aimed to improve immunity in aged individuals.

Thymic involution caused by repeated cocaine administration includes apoptotic cell loss followed by ectopic adipogenesis.

Cocaine abuse has a negative impact on the immune system. To investigate the adverse effects of binge cocaine administration on lymphoid organs such as thymus and spleen, we examined the effects of repeated intravenous (i.v.) administration of cocaine on rats. Sprague Dawley rats (male, 8 weeks old) received 20 mg/kg body weight of cocaine hydrochloride per day for 7 or 14 days. In addition to a significant loss in the weight of the spleen, consistent with our previous intraperitoneal (i.p.) injection model of binge cocaine abuse (50 mg/kg cocaine for 7 days), we also found a significant loss of weight as well as apparent shrinkage of the thymus in the cocaine group. Transcriptome analysis of the thymus revealed increased expressions of genes involved in apoptosis, such as Ifi27 and Traf2, as well as decreased expressions of several genes related to lipid metabolism, such as Cd36, Adipoq, Scd1, and Fabp4, in the thymus of the cocaine group (7 days), suggesting an apoptotic loss of thymic cells as well as alterations in lipid metabolism. Paradoxically, cocaine activates PPARγ, a key transcriptional factor activating lipid metabolism, although ectopic adipogenesis was scarcely observed in the thymus. Further analysis of rats administered 20 mg/kg cocaine for 14 days revealed ectopic adipogenesis, which was accompanied with the activation of PPARγ as well as increased expression of Adipoq and Fabp4, in the thymus. Taken together, these results indicate that repeated cocaine administration induces thymic involution, which is initiated by the loss of thymic cells through apoptosis and subsequent ectopic adipocyte development.

Age-Related Immune Cell Dynamics Influences Outcomes after Allogeneic Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation (HCT) holds a pivotal place in the setting of therapeutic algorithms for hematological disorders. Its therapeutic index is principally related to the immunogenic graft-versus-leukemia (GvL) effect that, together with an efficient immune reconstitution ensures the success of the procedure, contributing to disease control and immune competence. Factors influencing recipient immune recovery have been largely investigated across multiple cohorts issuing heterogenous results. Differences in outcomes in adult and pediatric populations suggest an age-related contribution to post-transplant immune reconstitution, however it is unclear how this parameter may affect the dynamics of single immune cells. Here we conducted a monocentric prospective study questioning on the modifications of immune cell recovery in a cohort of 176 patients (58 children and 118 adults) with hematological disorders receiving a HCT between 2015 and 2020 and followed at our institution. Complete flow-based immune reconstitution data on T-CD4, T-CD8, NK and B cell populations were collected at defined time-points (+1, 3, 6 and 12 months post-HCT). After ascertaining the dynamics in adult and pediatric populations of each cell component, the effect of a set of baseline clinico-biological variables on late (>6 months) reconstitution for each cell population was tested through univariable and multivariable linear or logistic regression models. First, we analyzed the linear relationship existing between recipient and donor age and each cell compartment. Interestingly, while donor age did not impact on any of the parameters in study, CD4- T (Adj R2 0.4, p=5.7x 10-15) and, in minor part, B cell post-transplant increments (Adj R2 0.05, p=0.004) were inversely correlated with recipient age, which instead did not influence CD8-T nor NK cell reconstitution. Results of stepwise multivariable analyses showed that CD8-T cell reconstitution was positively impacted by recipient positive CMV serostatus (p=0.00009) while donor CMV serostatus positively influenced CD4-T cell recovery (p=0.017). This effect was likely dependent from the expansion of CMV related T cell clonotypes in case of previous CMV immunity. The inverse correlation between CD4-T cells and recipient age was confirmed in multivariable analysis (p=0.0148). Donor EBV positive serostatus resulted instead to be a negative predictor of B cell recovery (p=0.0442). Interestingly none of the parameters analyzed influenced NK cell recovery. The impact on age mirrored a different kinetics of immune reconstitution in adult and pediatric patients (<18 years). Therefore, while early after HCT immune cell composition was similar in the two groups, with NK cells representing the largest component, followed by CD8-T and CD4-T, and minimal B cell contribution, in later phases we assisted to a faster expansion of CD4-T arm in children whereas CD8-T remained the major contributor of the immune recovery processes in adults still one year after transplant. B cell reconstitution was also faster in children, with a better immunoglobulin levels recuperation (measured on IgM to avoid bias of prophylactic IgG infusions) despite no differences in post-transplant pre-emptive rituximab utilization. When looking at different outcomes of pediatric and adult patients, both overall and event free survival were significantly higher in children (p=0.00062 and p=0.0062). While no difference in acute grade III-IV GvHD, adults experienced a significantly higher cumulative incidence (CI) of chronic GvHD (p=0.0258) and of specific infections, including EBV (p=0.031) and fungi (p=0.007). Although CI of relapse was not different, children experienced later relapses as compared to adults (median of 294 vs. 139 days, p=0.039), indicating a better disease control at least at early post-transplant stages. Here, starting from immune reconstitution data prospectively collected for patients transplanted at our institution, we dissected the effect of age on post-transplant immune cells. A faster CD4-T and B cell recovery in children may be the driver of a better immune competence underpinning superior outcomes in pediatric populations. If age-related thymus involution may reflect suboptimal CD4-T cell differentiation in adults, younger donor selection does not seem to improve recipient post-transplant immune reconstitution.

High-Throughput Screening to Elucidate In Vivo Oncogenicity of Loss-of-Function Alterations in Lymphoid Malignancies

Large-scale genetic studies utilizing next-generation sequencing have identified many recurrently altered genes and revealed their overall picture in lymphoid malignancies. Although limited genes mutated at high frequency have been extensively investigated using genetically engineered mouse models, less attention has been directed to hundreds of rarely mutated genes (so-called long tail driver genes). Here we performed in vivo CRISPR loss-of-function screening to examine oncogenicity of somatic alterations, cooperability between them, and association between genotype and lineage in lymphoid malignancies. As many driver candidates mutated with various frequencies have been reported in diffuse large B-cell lymphomas (DLBCL), we constructed a custom lentiviral CRISPR library targeting 86 genes (12 sgRNAs each) in which loss-of-function alterations (mutations and deletions) are recurrently (> 5%) observed in DLBCL. These sgRNA-targeted genes also covered the majority of driver candidates of other precursor and mature lymphoid neoplasms, such as 71% and 87% of those observed in B-acute lymphoblastic leukemia (B-ALL/LBL) and peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). Transplantation of the CRISPR library-transduced murine hematopoietic stem/progenitor (Lin-c-Kit+Sca-1+) cells caused a variety of hematologic malignancies in 180 (90%) out of 199 recipient mice, resulting in earlier death (with a median of 228 [range, 37‒476] days) of transplanted mice than control mice. Hematologic, immunophenotypic, and pathologic analyses of 132 tumors revealed that these malignancies consisted of B- and T-cell lymphomas (17% and 20%), B- and T-ALL/LBL (14% and 15%) and myeloid malignancy (14%) according to Bethesda criteria, although the diagnosis of 22 (17%) tumors could not be determined. sgRNA sequencing of 109 tumors showed that at least 1 sgRNA-targeted genes were detected in almost all (>99%) tumors, with a median of 3 (range, 1‒10) genes per tumor. Enrichment analysis of sgRNA-targeted genes demonstrated significant overrepresentation of 13 genes, such as Trp53 and Irf2bp2, pointing to stronger oncogenic capacity of these driver genes. These sgRNA-targeted genes showed lineage and tissue specificity, such as Pax5, Kmt2d, Atm, and S1pr2 for B-cell lineage and Zc3h12a and Socs1 for T-cell lineage, while only weak enrichment was observed in myeloid neoplasms. These tumors showed characteristic disease phenotype according to sgRNA-targeted genes: Pax5-targeted tumors were usually B-ALL/LBL, whereas Kmt2d-targeted tumors developed as B-cell lymphomas with earlier onset than those harboring other targeted genes. All of Zc3h12a-targeted tumors were T-cell lymphoma with CD4+CD8- immunophenotype and low clonality, while Socs1-targeted tumors primarily developed as T-ALL/LBL with CD4+CD8+ immunophenotype and frequent thymus involvement. Whole-exome sequencing (n = 108) not only confirmed targeted disruption by sgRNAs but also identified additional driver alterations in 76% and 40% of B-cell and T-cell neoplasms, respectively, suggesting the necessity of second-hit alterations in these tumors. These additional driver alterations were associated with a specific lineage. Frequent C-terminal truncating mutations of Notch1 and loss-of-function mutations of Ikzf1 were found in T-cell malignancies, while Jak1 and Jak3 hotspot missense mutations and Flt3 internal tandem duplications were common in B-cell malignancies, suggesting cooperative relationship between specific alterations and their association with lineage. In addition, hierarchical clustering of RNA-sequencing data (n = 105) identified several clusters associated with disease phenotypes and sgRNA-targeted genes. These clusters showed distinct expression signatures, including germinal center B-cell-like signatures in Kmt2d-targeted tumors, MYC target signatures in Pax5-targeted tumors, and inflammation-related signature in Zc3h12a-targeted tumors. In summary, our in vivo CRISPR loss-of-function screening enables high-throughput evaluation of the tumorigenic potential of many genetic abnormalities, their cooperability and association with lineage in lymphoid malignancies. Such approach accelerates understanding of genotype-phenotype association and discovery of potential therapeutic targets. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

IL-33 induces thymic involution-associated naive T cell aging and impairs host control of severe infection

Severe infection commonly results in immunosuppression, which leads to impaired pathogen clearance or increased secondary infection in both humans and animals. However, the exact mechanisms remain poorly understood. Here, we demonstrate that IL-33 results in immunosuppression by inducing thymic involution-associated naive T cell dysfunction with aberrant expression of aging-associated genes and impairs host control of infection in mouse disease models of schistosomiasis or sepsis. Furthermore, we illustrate that IL-33 triggers the excessive generation of medullary thymic epithelial cell (mTEC) IV (thymic tuft cells) in a Pou2f3-dependent manner, as a consequence, disturbs mTEC/cortical TEC (cTEC) compartment and causes thymic involution during severe infection. More importantly, IL-33 deficiency, the anti-IL-33 neutralizing antibody treatment, or IL-33 receptor ST2 deficient thymus transplantation rescues T cell immunity to better control infection in mice. Our findings not only uncover a link between severe infection-induced IL-33 and thymic involution-mediated naive T cell aging, but also suggest that targeting IL-33 or ST2 is a promising strategy to rejuvenate T cell immunity to better control severe infection.

Sex-dependent worsening of NMDA-induced responses, anxiety, hypercortisolemia, and organometry of early peripheral immunoendocrine impairment in adult 3xTg-AD mice and their long-lasting ontogenic modulation by neonatal handling

The neuroimmunomodulation hypothesis for Alzheimer’s disease (AD) postulates that alterations in the innate immune system triggered by damage signals result in adverse effects on neuronal functions. The peripheral immune system and neuroimmunoendocrine communication are also impaired. Here we provide further evidence using a longitudinal design that also studied the long-lasting effects of an early life sensorial intervention (neonatal handling, from postnatal day 1–21) in 6-month-old (early stages of the disease) male and female 3xTg-AD mice compared to age- and sex-matched non-transgenic (NTg) mice with normal aging. The behavioral patterns elicited by the direct exposure to an open field, and the motor depression response evoked by NMDA (25 mg/kg, i.p) were found correlated to the organometry of peripheral immune-endocrine organs (thymus involution, splenomegaly, and adrenal glands’ hypertrophy) and increased corticosterone levels, suggesting their potential value for diagnostic and biomonitoring.The NMDA-induced immediate and depressant motor activity and endocrine (corticosterone) responses were sensitive to sex and AD-genotype, suggesting worse endogenous susceptibility/neuroprotective response to glutamatergic excitotoxicity in males and in the AD-genotype. 3xTg-AD females showed a reduced immediate response, whereas the NTg showed higher responsiveness to subsequent NMDA-induced depressant effect than their male counterparts. The long-lasting ontogenic modulation by handling was shown as a potentiation of NMDA-depressant effect in NTg males and females, while sex × treatment effects were found in 3xTg-AD mice. Finally, NMDA-induced corticosterone showed sex, genotype and interaction effects with sexual dimorphism enhanced in the AD-genotype, suggesting different endogenous vulnerability/neuroprotective capacities and modulation of the neuroimmunoendocrine system.

Thymic changes as a contributing factor in the increased susceptibility of old Albino Oxford rats to EAE development

The study was aimed to examine putative contribution of thymic involution to ageing-associated increase in susceptibility of Albino Oxford (AO) rats to the development of clinical EAE, and vice versa influence of the disease on the progression of thymic involution. To this end we examined (i) the parameters of thymocyte negative selection efficacy, the thymic generation of CD4+CD25+Foxp3+ T regulatory cells (Tregs) and thymic capacity to instruct/predetermine IL-17-producing T-cell differentiation, and thymopietic efficacy-associated accumulation of “inflammescent” cytotoxic CD28- T cells in the periphery, and (ii) the key underlying mechanisms in young and old non-immunised AO rats and their counterparts immunised for EAE (on the 16th day post-immunisation when the disease in old rats reached the plateau) using flow cytometry analysis and/or RT-qPCR. It was found that thymic involution impairs: (i) the efficacy of negative selection (by affecting thymocyte expression of CD90, negative regulator of selection threshold and the expression of thymic stromal cell integrity factors) and (ii) Treg generation (by diminishing expression of cytokines supporting their differentiation/maturation). Additionally, the results suggest that thymic involution facilitates CD8+ T-cell differentiation into IL-17-producing cells (previously linked to the development of clinical EAE in old AO rats). Furthermore, they confirmed that ageing-related decrease in thymic T-cell output (as indicated by diminished frequency of recent thymic emigrants in peripheral blood) resulted in the accumulation of CD28- T cells in peripheral blood and, upon immunisation, in the target organ. On the other hand, the development of EAE (most likely by increasing circulatory levels of proinflammatory cytokines) contributed to the decline in thymic output of T cells, including Tregs, and thereby to the progression/maintenance of clinical EAE. Thus, in AO rats thymic involution via multi-layered mechanisms may favour the development of clinically manifested autoimmunity, which, in turn, precipitates the thymus atrophy.

The unilateral involution in the thymus of a 96-year-old male leads to the preservation of structural integrity in one thymic lobe, as assessed by the expression of medullar and cortical antigens and the presence of CD3+ cells

The process of thymic involution begins soon after birth and continues through adult life. Although evolutionary conserved in all vertebrates, the thymic involution has no defined kinetics. Little is known about the pace of its regression in humans, except that there is a marked increase of thymic involution after puberty. This report describes the unusual structural findings in the thymus of a 96-year-old male. The morphological parameters of the organ were evaluated using H&E and immunohistochemistry (IHC) techniques. The macroscopic examination showed a typical organ's weight and size, except that the right thymic lobe presented a well-preserved organ and the left lobe was significantly adiposed. The H&E staining of the thymic sections from the left and right lobes confirmed advanced thymic adiposity in the left lobe and preserved thymic epithelial space containing hematoxylin-stained cells in the right lobe. The multiplex immunostaining of the right lobe sections with antibodies specific to cytokeratins -14 and -8, CD3, and CD4 revealed the presence of medullar and cortical epithelium and mix population of CD3+/CD4+ and CD3+/CD4- T cells. The T cells were associated with the medulla but not with the cortex of the thymus. The immunostaining with an antibody to FoxN1 showed that the protein was expressed in the thymic epithelium. Taken together, we provide evidence that the thymus of a 96-year-old man involuted different kinetics in each of the two thymic lobes. Furthermore, the presence of CD3+/CD4+ and CD3+/CD4-cells gives a hand to the hypothesis that a pool of T-cells may associate with this primary lymphatic organ for as long as there is the available thymic epithelium and be a source of lymphocytes aiding adaptive immune responses to old age.

Characterization of circular RNA expression profiles in the age-related thymic involution of Magang goose

The thymus is a vital immune organ, but its function gradually declines with age. Circular RNAs (circRNAs) are related to the development of tissues and organs. In this study, bioinformatics analysis showed that 1329, 755, and 417 circRNAs were differentially expressed between the comparison groups of 6-month age (M6) and 20-embryo age (E20), 3-day post-hatch (P3), and 3-month age (M3) Magang geese, respectively. Among them, 167 circRNAs were differentially co-expressed between thymic development (E20, P3, and M3) and involution (M6). Functional analysis showed significant enrichment of phosphorylation and positive regulation of GTPase activity. Furthermore, pathway analysis has shown that glycerolipid metabolism and the Wnt signaling pathway are critical pathways in the thymic involution process. Finally, we constructed the competitive endogenous RNA (ceRNA) network. The results of this study suggest that circRNAs may be involved in the age-related thymic involution of the Magang goose.

Blood levels of T-Cell Receptor Excision Circles (TRECs) provide an index of exposure to traumatic stress in mice and humans

Exposure to stress triggers biological changes throughout the body. Accumulating evidence indicates that alterations in immune system function are associated with the development of stress-associated illnesses such as major depressive disorder and post-traumatic stress disorder, increasing interest in identifying immune markers that provide insight into mental health. Recombination events during T-cell receptor rearrangement and T-cell maturation in the thymus produce circular DNA fragments called T-cell receptor excision circles (TRECs) that can be utilized as indicators of thymic function and numbers of newly emigrating T-cells. Given data suggesting that stress affects thymus function, we examined whether blood levels of TRECs might serve as a quantitative peripheral index of cumulative stress exposure and its physiological correlates. We hypothesized that chronic stress exposure would compromise thymus function and produce corresponding decreases in levels of TRECs. In male mice, exposure to chronic social defeat stress (CSDS) produced thymic involution, adrenal hypertrophy, and decreased levels of TRECs in blood. Extending these studies to humans revealed robust inverse correlations between levels of circulating TRECs and childhood emotional and physical abuse. Cell-type specific analyses also revealed associations between TREC levels and blood cell composition, as well as cell-type specific methylation changes in CD4T + and CD8T + cells. Additionally, TREC levels correlated with epigenetic age acceleration, a common biomarker of stress exposure. Our findings demonstrate alignment between findings in mice and humans and suggest that blood-borne TRECs are a translationally-relevant biomarker that correlates with, and provides insight into, the cumulative physiological and immune-related impacts of stress exposure in mammals.

Oxidative stress in Hashimoto's thyroiditis: possible adjuvant therapies to attenuate deleterious effects.

A number of studies have shown that oxidative stress is related to the pathogenesis of several immunological diseases, such as Hashimoto's thyroiditis (HT), although there is no plausible mechanism to explain it. Thus, we aimed at hypothesizing and providing some possible mechanisms linking oxidative stress to autoimmunity aspects and its implications for HT, as well as adjuvant therapeutic proposals to mitigate the deleterious effects. Our hypothesis is that deficient eating habits, autoimmune regulator gene predisposing gene, dysbiosis and molecular mimicry, unfolded proteins and stress in the endoplasmic reticulum, and thymus involution appear to be the main potential factors leading to HT oxidative stress. Likewise, we show that the use of minerals selenium and zinc, vitamins D and C, as well as probiotics, can be interesting adjuvant therapies for the control of oxidative damage and poor prognosis of HT. Further clinical trials are needed to understand the real beneficial and side effects of these supplements.

Effect of mifepristone under acute stress on thymocyte apoptosis in mice

In 1936, the Canadian pathologist Hans Selye, in experiments with adrenalectomy, has shown adrenal cortex hormones to be involved in development of thymic acute involution under stress. By 1970s, the idea of lysis of lymphoid cells by glucocorticoids dominated among researchers as the main mechanism of these changes. Later on, increased migration of T lymphocytes from thymus as well as decreased migration of bone marrow precursors to the thymus were considered. Since 1990s, apoptosis induced by glucocorticoids was also studied in this respect. To elucidate the in vivo contribution of glucocorticoids these events, a convenient tool was developed in experimental endocrinology and pharmacology, i.e., treatment of male rats or mice with antagonist of glucocorticoid and progesterone receptors mifepristone, also known as RU-38486 or RU-486. The purpose of this work is to investigate the effect of mifepristone on thymocyte apoptosis in mice under acute stress. Experimental studies were performed in male white noninbred mice. Mifepristone was injected once subcutaneously 30 min before immobilization at a dose of 50 mg/kg body weight prepared in olive oil solution. Control mice and the animals from comparison group were injected once subcutaneously with an equivalent amount of the drug solvent. A classical model of 24-hour immobilization stress in a plastic restrainer (supine position) was used for experimental simulation of acute stress. Thymocyte apoptosis was assessed by flow laser cytometry with BD PE Annexin V Apoptosis Detection Kit I (BD Pharmingen) reagent kit adapted for Guava EasyCyte flow laser cytometer by Millipore Corporation. It was found that acute stress induced by 24-hour immobilization of mice leads to an increase in the total relative number of 7-AAD-positive cells as well as proportion of cells stained with 7-AAD, but not annexin V-PE (nuclear debris, annexin V(-), 7-AAD (+)). Administration of mifepristone alleviated these changes, thus confirming involvement of glucocorticoids in increasing number of necrotic thymocytes. The number of thymocytes in early apoptosis (i.e., annexin V-PE-positive, 7-AAD-negative), as well as total relative number of cells with phosphatidylserine exposed at the surface (annexin V-PE-positive thymocytes) under acute stress and at stress on the background of the introduction of mifepristone did not differ from the control.

Effects of sex steroids on thymic epithelium and thymocyte development.

Sex steroid hormones have major effects on the thymus. Age-related increases in androgens and estrogens and pregnancy-induced increases in progestins all cause dramatic thymic atrophy. Atrophy can also be induced by treatment with exogenous sex steroids and reversed by ablation of endogenous sex steroids. Although these observations are frequently touted as evidence of steroid lymphotoxicity, they are often driven by steroid signaling in thymic epithelial cells (TEC), which are highly steroid responsive. Here, we outline the effects of sex steroids on the thymus and T cell development. We focus on studies that have examined steroid signaling in vivo, aiming to emphasize the actions of endogenous steroids which, via TEC, have remarkable programming effects on the TCR repertoire. Due to the dramatic effects of steroids on TEC, especially thymic involution, the direct effects of sex steroid signaling in thymocytes are less well understood. We outline studies that could be important in addressing these possibilities, and highlight suggestive findings of sex steroid generation within the thymus itself.

Aging is accompanied by T-cell stiffening and reduced interstitial migration through dysfunctional nuclear organization.

Age-associated changes in T-cell function play a central role in immunosenescence. The role of aging in the decreased T-cell repertoire, primarily because of thymic involution, has been extensively studied. However, increasing evidence indicates that aging also modulates the mechanical properties of cells and the internal ordering of diverse cell components. Cellular functions are generally dictated by the biophysical phenotype of cells, which itself is also tightly regulated at the molecular level. Based on previous evidence suggesting that the relative nuclear size contributes to variations of T-cell stiffness, here we examined whether age-associated changes in T-cell migration are dictated by biophysical parameters, in part through nuclear cytoskeleton organization and cell deformability. In this study, we first performed longitudinal analyses of a repertoire of 111 functional, biophysical and biomolecular features of the nucleus and cytoskeleton of mice CD4+ and CD8+ T cells, in both naive and memory state. Focusing on the pairwise correlations, we found that age-related changes in nuclear architecture and internal ordering were correlated with T-cell stiffening and declined interstitial migration. A similarity analysis confirmed that cell-to-cell variation was a direct result of the aging process and we applied regression models to identify biomarkers that can accurately estimate individuals' age. Finally, we propose a biophysical model for a comprehensive understanding of the results: aging involves an evolution of the relative nuclear size, in part through DNA-hypomethylation and nuclear lamin B1, which implies an increased cell stiffness, thus inducing a decline in cell migration.

Gallic acid ameliorates thymic involution via activating Sox2 and Nanog

AbstractThymic ageing precedes other organs, which is mainly caused by the gradual loss of thymic epithelial cells, and the thymic epithelial progenitor cells have been found in human and adult mouse. Stem cell transcription factors, sex‐determining region Y‐box2 (Sox2) is strongly involved in organogenesis. Homeobox transcription factor Nanog (Nanog) has been applied in cell reprogramming to generate induced multipotential stem cells for its related pluripotency, and its functions in the thymus remain undefined. Gallic acid, one of the natural products of polyphenols, has been used to counter ageing. In this study, we investigated the alteration of Nanog and Sox2 in the thymus of the natural ageing and D‐galactose‐induced accelerated ageing mice and further explored the effects of gallic acid on their expression. 5‐bromo‐2′‐deoxyuridine (BrdU)‐retaining assay was also performed to trace the thymic progenitor cells. Our study indicated that Nanog and Sox2 showed age‐dependent decrease in the thymus of mice. Nanog, Sox2 and BrdU‐positive cells were also found to be abundant in the area of cortex‐medulla junction (CMJ) of the thymus, which suggested that thymic adult stem cells/progenitor cells may exist in this position. Gallic acid can upregulate the expression of Nanog and Sox2, which suggested it may promote thymus regeneration from age‐related atrophy and D‐galactose‐induced damage by activating the thymic progenitor cells and increasing the expression of Nanog and Sox2.

Age-related thymic involution: Mechanisms and functional impact.

The thymus is the primary immune organ responsible for generating self‐tolerant and immunocompetent T cells. However, the thymus gradually involutes during early life resulting in declined naïve T‐cell production, a process known as age‐related thymic involution. Thymic involution has many negative impacts on immune function including reduced pathogen resistance, high autoimmunity incidence, and attenuated tumor immunosurveillance. Age‐related thymic involution leads to a gradual reduction in thymic cellularity and thymic stromal microenvironment disruption, including loss of definite cortical‐medullary junctions, reduction of cortical thymic epithelial cells and medullary thymic epithelial cells, fibroblast expansion, and an increase in perivascular space. The compromised thymic microenvironment in aged individuals substantially disturbs thymocyte development and differentiation. Age‐related thymic involution is regulated by many transcription factors, micro RNAs, growth factors, cytokines, and other factors. In this review, we summarize the current understanding of age‐related thymic involution mechanisms and effects.