Thymic senescence develops in every person, although at different pace. Thymic senescence significantly lowers the production of naive T cells, leading to increased incidence of infections, cancer and autoimmune diseases. Certain external factors can accelerate thymic senescence. These include chemicals (copper-chelators), hor-mones (androgens), infections (viruses, fungi, protozoa). Others may slow the aging process of the thymus including perturbations to the hormonal (sex-steroid) system, genetic alterations (PPARgamma deficiency) or chemical compounds (PPARgamma antagonists). Thymic senescence research may provide insight to underlying molecular events and potentially appoint novel therapeutic targets for senescence interven-tion strategies. These hold promise to postpone thymus senescence and enhance T cell production. That would result in a decreased incidence of infections, cancer and autoimmune diseases, currently affecting the elderly. The attributed drop in healthcare costs and gain in quality of life share tremendous economic and social interest.
Thymus is a ductless, highly organized, bilobed encapsulated gland of the lymphoid organs that contributes in thymopoiesis. Thymus plays an important function in the assortment, progress and profusion of T cells. The mature subsets of thymus dependent lymphocytes linked with the thymic epithelial and other cells developed the microstructure that protect the body from the harmful foreign micro-organism. Most of the thymic lobular areas experienced the parenchymal cells hypoplasia, undergone infiltration of stromal FCT and experienced thymic atrophy with age progression. As the host gets adult, the regression of the thymus and the thymopoiesis occurs, which ultimately boost the vulnerable situations of the host and open a gateway to autoimmune diseases. Since past decades, scientists are intensely investigated to develop some tactics for the improvements of the thymus performance including T-cell regeneration and maturation with age progression. This unique organ is continuously altered morphologically with age and disease; however, this microarchitectural alteration and its possible modulations is not yet clear. Therefore, the main purpose of this chapter is to highlight the microstructural compartments and physiological modification of the thymus with age. Also, the chapter is suggesting the possible alternative ways to improve its durable physio-morphology in vertebrates.
Where, when, and why of the thymusThe pharynx is regarded as a part of the digestive system.It is, however, attached to the respiratory system and, thus, is referred to as the conducting zone of the respiratory system as well.The pharyngeal apparatus groups together five pharyngeal arches, four pharyngeal pouches, four pharyngeal clefts, and pharyngeal membranes that occur during 4-5 weeks of human development [1].Within the developmental context, the thymus is closely related to parathyroid glands [2] since both are derived from the endodermal-lined pharyngeal pouches-the thymus develops from the ventral portion of pouch 3, and the inferior and superior parathyroid glands arise from the dorsal portions of pouches 3 and 4, respectively.Late in the 4th week, the primordia of the thymus begin to form but remain attached to that of the inferior parathyroid glands for a time [3].By the 7th week, they migrate to the position where they should reside and be functional-the thymus is located midline in the upper chest just behind the sternum between the lungs and above the heart, and the inferior parathyroid glands descend along the inferior border of the thyroid.However, it takes about 12 weeks to form the definitive structure of the thymus, a bilobed organ that is covered by a mesenchymal capsule and is composed of two internal layers: the cortex and the medulla.The cortex is the outer layer of the thymus in which cortical thymic epithelial cells (cTECs) are found.The medulla is located in the center of the thymus.It is where medullary thymic epithelial cells (mTECs) and Hassall's (thymic) corpuscles are present.The thymus is seen as of high value, due to its functions as a part of the neuroendocrine system in addition to its actions to provide a primary lymphoid microenvironment that efficiently carries T cell differentiation and selection.The first evidence that the thymus can have immune and endocrine functions was provided from athymic nude animals and/or animals undergoing thymectomy showing impairments in their cell-mediated immunity, growth pattern, and puberty and developing organ-specific autoimmune diseases.These impairments were consistent with their relative reduction in levels of thyroxin, testosterone, progesterone, and 17-β-estradiol, whereas corticosterone levels were elevated.Of particular note was that the passive transfer of lymphocytes and thymus implantation at birth were effective in transferring cell-mediated immunity to nude mice [4].The endocrine defects could be, in part, healed by thymus implantation at birth as well but remain stable following passive transfer of lymphoid cells [4].
Age-related thymic atrophy or involution, a hallmark of thymic aging, takes place both in humans and animals.In this chapter, we will discuss age-related thymic atrophy, outlining the underlying cellular and molecular mechanisms of its occurrence.We will also address the downstream influences on the aged T cell immune system, not only regarding insufficiency against pathogens, but also hyper-reactivity to self.Particularly, we will focus on how thymic atrophy disrupts efficient establishment of central T cell immune tolerance primarily via impairment of thymocyte negative selection, resulting in an increased number of self-reactive conventional T cells, and on thymic-derived regulatory T cell generation.Finally, we will provide a framework for understanding the significant role that the atrophied thymus plays in shaping inflammaging: a chronic, low-grade, systemic inflammatory phenotype observed in aged individuals in the absence of acute infection.The involvement of T cell adaptive immunity in mediating inflammaging plays a crucial role in the progression of many age-related neurological and cardiovascular diseases.
The thymus, a retrosternal lymphoid tissue, develops from the third and fourth pharyngeal pouches like the parathyroid glands at the sixth week of gestational age. The thymus is usually located in the anterior mediastinum, although it can be found anywhere in the thymopharyngeal path. The thymus has a bilobed or quadrilateral shape; however, it can be found in other shapes. Limited information is available about the precise epidemiology of thymic congenital anomalies. Since these anomalies are not symptomatic, it may be more common than the available reports. There are various reports available about the prevalence of thymic diseases and anomalies ranging from 4.45 to 30%. In this chapter we tried to have a review on epidemiology, definition, and management of congenital anomalies of the thymus.
Despite advances in applied sciences, myasthenia gravis (MG) remains a challenging disorder to diagnose and treat. The clinical presentation results in either transient or persistent painless weakness and abnormal fatigability of any (ocular, bulbar, limbs, trunk, respiratory) or all voluntary (skeletal) muscles; however, it is usually not to the same extent. Several scoring systems of MG signs or the global state of the patient have been proposed in an attempt to provide a standard scheme for use by all investigators. Some patients may have non-muscle-related complaints due to different disorders which may be associated with MG (thymoma, thyroid disorders, other autoimmune diseases, etc.).
Air pollution is a high-risk factor in megacities' dwellers because of its effects on health.One of the most important components of the pollution is particulate matter (PM) on which metals are adhered.One element adhered to its surfaces is vanadium (V), and through this route, PM reaches the respiratory system, then the systemic circulation and the rest of the organs.Vanadium is released in the atmosphere as a consequence of the combustion of fossil fuels.Vanadium pentoxide is the compound liberated after the combustion and adhered into PM.Previous studies from our group have reported effects on diverse systems in a mouse model.Besides the morphological changes in the spleen and the decreased function of the immune humoral response, the thymus was also affected.Vanadium inhalation diminished thymic dendritic cells (DCs) and the biomarkers: CD11c and MHCII; in addition, thymic cytoarchitecture changed, demonstrated by cytokeratin-5, and also, modification in the expression of 3-nitrotyrosine was observed.Our findings suggest that autoreactive T cells could be released into the systemic circulation and favor the increase in autoimmune diseases in cities with high concentrations of PM.
Essential oils (EO) are volatile compounds produced by the secondary metabolism of aromatic plants. They are complex mixtures whose main components are synthesized by the mevalonic acid and the methyl erythritol phosphate pathways, which lead to the biosynthesis of terpenes, and the shikimic acid pathway, responsible for the biosynthesis of phenylpropanoid compounds. In nature, EOs are stored in the aerial parts of the plant, being of vital importance for their survival due to their antimicrobial properties. In addition, EOs provide protection against herbivores to the aromatic plants and allow them to repel or attract insects because of their strong fragrance, as well as compete with other plants of the same environment. Humans have exploited the properties of their EOs since ancient times, being used as medicinal remedies, among other uses. Currently, aromatic plants are used in pharmaceutical and food industries. One of the most commonly used aromatic plants is thyme. Thyme is a perennial aromatic plant, taxonomically belonging to the genera Thymus and Thymbra, belonging to the family Lamiaceae. These plants are very abundant in the Mediterranean Region. In this review, we focus on the study of the properties and use of EOs of Thymbra capitata (L) Cav. and Thymus hyemalis Lange., whose EOs are rich in phenolic monoterpenes. These compounds are responsible for their antioxidant, anti-inflammatory, anticarcinogenic, antibacterial, antifungal, and antiparasitic properties.
Thymic ID cells are involved in the differentiation of mature T cells which are resistant against apoptosis. TRX/ADF is a potent thiol-related reducing agent, acts as a redox regulator, and it can attenuate the induction of apoptosis of T lineage lymphocytes. In the present study, 42 thymoma-free thymus and 40 thymoma samples were examined to identify the expression of TRX/ADF in human thymic tissue. TRX/ADF high-producer (TRXh) cells with cytoplasmic protrusions were found distributed in the thymic medulla. These TRXh cells were negative for CD3, a lymphocyte marker, keratin, an epithelial cell marker, and CD68 or lysozyme, macrophage/monocyte markers, but were positive for S100 protein and HLA-DR complex. Our results revealed that the TRXh cells in the thymic medulla were ID cells. As TRX/ADF has an important and fundamental role in cellular responses acting against oxidative stress, TRX/ADF may provide an explanation of cellular interaction between the medullary ID cells and the mature T cells.
The presence of Nerve Growth Factor (NGF) and the expression of low-and high-affinity NGF receptor were investigated in prenatal, postnatal and pregnant rats. Using ELISA and immunohistochemistry it was found that both NGF and its receptors are present in the medulla of the thymus and are more strongly expressed in pre-and early postnatal life and nearly absent in adult and ageing rats. It was also found that during pregnancy, which is characterised by an involution of the cortex and hypertrophy of the medulla, the level of NGF in the thymus increases. The present study showed not only that NGF is produced in a specific compartment of the thymus, the medulla, but that its synthesis declines with age, following thymus involution. These results suggest that NGF may be critically involved in the proliferation and differentiation of thymic cells.
Part of the apoptotic process in lymphocytes involves the Fas receptor, which can transduce a cell death signal after interaction with its ligand, FasL. Many studies concerning expression of Fas and FasL in the thymus have been performed, but no detailed information about in situ expression patterns of mRNA inside the thymus is available. In the present study the expression of Fas and FasL was evaluated by non-radioactive in situ hybridization in the thymi of normal mice and compared with the results of lpr- and gld-mice, the two mouse models with mutations of Fas and FasL, respectively. In the thymi of normal and gld-mice, Fas mRNA was found only in the medulla. In lpr-mice, no Fas mRNA expression could be detected. The expression pattern changes as the mice get older. No specific signals for FasL mRNA were detected in any of the mice (normal, lpr, gld) tested. Together, these results are consistent with absence of a role for the Fas-FasL interaction in thymocyte apoptosis.
We have examined the expression of a panel of cytokines in thymic epithelial cells and CD4(-)CD8(-) (DN) thymocytes following cell to cell lymphostromal interaction, in an experimental model which enhances in vitro thymocyte maturation. Since retinoic acid (RA) has been previously shown to be an inhibitor of thymocyte maturation process in this model, we wanted to analyse cytokine expression in DN thymocytes and thymic epithelial cells following the RA-induced impairment of in vitro thymocyte maturation. Cell to cell lymphostromal interaction results in increased IL2 and decreased IL7 expression in thymocytes while the expression of IL1 beta and IL7 increased and decreased, respectively, in thymic epithelial cells. Addition of RA to lympho-stromal cell co-culture results in the enhancement of IL6 and IL7 expression in thymocytes while in thymic epithelial cells IL1 alpha decreased and IL6 and IL7 increased. These data indicate that discrete patterns of cytokine expression are present in thymocyte precursors and in thymic epithelial cells during in vitro T-cell development. They furthermore suggest that specific cytokine modulation might contribute to the RA-induced impairment of thymocyte differentiation.
Memory T cells are considered to be less dependent on costimulation and to respond more vigorously to TCR triggering compared to their naive counterparts. We and others, however, observed that memory CD4 T cells display nonresponsiveness to a variety of stimuli, including superantigens and soluble anti-CD3. We now report that CD28-derived costimulation can revert the nonresponsive state of antigen-exposed CD4 T cells. Interestingly, the rescuing effect of CD28 can be completely negated by CTLA-4 engagement. The malfunction of memory T cells is related to increased cell death; the viability can be restored by CD28 engagement and is negatively regulated by CTLA-4 engagement. Importantly, it has been reported that antigen-exposed T cells express lower levels of the anti-apoptotic mediator Bcl-2. In addition, CD28 costimulation was reported to upregulate the expression levels of Bcl-xL. We therefore examined the possible role of Bcl-2 family proteins in the nonresponsiveness of antigen-exposed CD4 T cells, and determined whether CTLA-4, in analogy to CD28, mediates its negative regulatory effects via the Bcl-2 family of apoptotic mediators. Our data indicate that neither the nonresponsiveness nor the susceptibility to CTLA-4 of antigen-experienced CD4 T cells are related to the expression levels of Bcl-2 or Bax. The rescuing effects of CD28, however, may be related to increased Bcl-xL levels. Addition of IL-2 normalizes the nonresponsiveness of memory CD4 T cells and renders these cells resistant to the negative effects of CTLA-4 engagement. Impaired IL-2 production is therefore likely to be the cause of the malfunction and CTLA-4 susceptibility of memory CD4 T cells.
Natural killer (NK) cells have been shown to play a role in the phenomenon of resistance to transplantation of allogeneic stem cells. To explore and prevent such resistance, we treated severe combined immunodeficiency mice (SCID) with anti-NK antibodies and analysed the improved engraftment of stem cells induced by this treatment. Two groups of nine SCID mice (H-2d) were compared: group A received two injections of anti-asialo GM1 rabbit antibodies (anti-NK) on days 1 and 4; group B received two injections of normal rabbit serum. All mice were injected intravenously with 7 x 10(6) fetal liver cells from B6 mice (H-2b) on day 2. One month after fetal liver cell transplantation, all mice from group A demonstrated engraftment and chimerism; at this time, donor cells accounted for more than 50% of peripheral blood mononuclear cells (PBMC). In contrast, in group B, only one mouse had 26% of donor cells among PBMC and all other mice had less than 10%. At two months, results were virtually identical in group A (over 72% of donor cells among PBMC from all mice) and slightly improved in group B (0-38% of donor cells). After the third month and continuously until the 12th month, the stability of chimerism was established in group A (over 55% of donor cells in 7 of the 9 mice) but had virtually disappeared in group B (0-2% of donor cells in all mice). Tissue analysis demonstrated the improved reconstitution of the thymus and the spleen in mice from group A. The proliferative responses of spleen cells to phytomitogens were significantly higher in all mice from group A than in any mouse from group B. Skin allografts from a third party (H-2k) were rejected within 10 days by group A mice but not by group B mice, one year after fetal liver cell transplantation. On the whole, anti-NK antibodies were able to improve engraftment, chimerism and stability of allogeneic stem cell transplants.
T-cell mediated cytotoxicity play an important role in the control of human immunodeficiency virus (HIV) infection. The polyclonal cytotoxic T lymphocyte (CTL) response against target cells infected with a recombinant vaccinia virus expressing Env,Gag, Nef or reverse transcriptase (RT) proteins has been studied in four groups of individuals: acquired immune deficiency syndrome (AIDS) patients, AIDS-related complex (ARC) patients, HIV-1 seropositive subjects and seronegative controls. CTL lines have been generated by non-specific stimulation with phytohemagglutinin and interleukin-2 and target cells have been prepared from autologous B lymphocytes. CTL from asymptomatic and ARC individuals recognized most of the various proteins of HIV-1 but those from AIDS patients had very low or absent responses to the majority of proteins, with the anti-Nef cytotoxic activity decreasing first. Two of 10 AIDS patients had demonstrable recognition of Gag p24, one of RT and eight patients had no recognition of any of the proteins. The effector cells were demonstrated to be predominantly of the CD8(+) phenotype, using the appropriate monoclonal antibodies. When heterologous target cells were substituted for autologous cells, the cytotoxic response was abrogated in the vast majority of cases demonstrating its human leucocyte antigen (HLA) class I restriction. Among the 10 HIV-seronegative subjects, nine had no CTL activity against the various HIV-1 proteins but one subject was able to recognize Env and RT. In the evolution of HIV infection from the seropositive stage to AIDS, CTL polyclonal activities progressively decrease, with Nef responses disappearing first, then Env and Gag p55, followed by RT and Gag p24.
We investigated the capacity of the Staphylococcal enterotoxin (SE) B, a superantigen (SAg) specific for TCR V beta domain, to modulate V beta 8+ thymocytes selection in adult mice. Thymocytes were collected at various time intervals after SEB injection (10 and 100 micrograms) and V beta 8+ modulation was analysed by three color flow cytometry. SEB failed to affect V beta 8+ thymocytes comprised in the less mature compartments, namely, CD4+8+ and CD4-CD8-, whereas it selectively affected V beta 8+CD4+8+ (downward modulation) and V beta 8+CD4-8+ thymocytes (upward modulation). The different response to SEB challenge between CD4+8- and CD4-8+ thymocytes appeared dependent on the CD4/MHC class II interaction, as V beta 8+CD4-8+ thymocytes carrying a transgenic CD4 molecule capable of interacting with MHC class II showed the same response of V beta 8+CD4+8- thymocytes. At variance with thymocytes, however, V beta 8+CD4+8- and V beta 8+CD4-8+ splenic T lymphocytes responded to SAg challenge in identical manner (upward modulation) highlighting the importance of maturation status and/or microenvironment in SAg response. V beta 8+ thymocytes remaining in the thymus were assessed for their capacity to respond to a SAg challenge. Thus, thymocytes were obtained at various time intervals after SEB injection and cultured in the presence of SEB or SEA, a Sag specific for V beta 10 as control. A reduced mitotic response to SEB but not to SEA was noticed irrespective of the number of V beta 8+ responding cells present in culture. It is concluded that SAgs affect TCR specific thymocytes by conditioning their redistribution and inducing an anergic status.
The presence or absence of CD4, CD8, Thy-1, RT6 and CD45RC revealed a number of T-cell subpopulations in the rat. Vascular thymus transplantation was used in RT7 congenics to establish the lineage relationship between these subpopulations by following phenotypic changes after thymus emigration. We found that recent thymic emigrants exhibit the Thy-1+/RT6-/CD45RC- phenotype and express either CD4 or CD8. Within 11 days after emigration, these cells differentiated into Thy-1-/RT6+/CD45RC+ cells. From 33 to 76 days following transplantation, a proportion of the latter lost RT6 and/or CD45RC expression, suggesting further differentiation. The pathway of 'mature' T-cell differentiation could be reconstructed from these data and analysis of the differences between T-cell subsets in thymectomized and normal control rats. End-stages of post-thymic T-cell differentiation in the rat were most likely to be Thy-1-/RT6+/CD45RC- and Thy-1-/RT6-/CD45RC+ T cells.
A decrease in natural killer (NK) cell activity is a common feature of the immune dysfunction found in patients with human immunodeficiency virus (HIV)-induced acquired immune deficiency syndrome (AIDS). The present study was aimed at exploring the NK and the lymphokine-activated killer (LAK) cell activities of lymphocytes from HIV-seropositive subjects. The in vitro production of interleukins (IL-2 and IL-10) in response to mitogens was also studied. Two groups of HIV-seropositive subjects were studied: asymptomatic and AIDS patients. Controls were normal blood donors. The NK cell activity in peripheral blood mononuclear cells (PBMC) from AIDS patients was significantly lower than that in PBMC from both HIV-seronegative subjects and asymptomatic patients. There was no significant difference between asymptomatic patients and controls. Exposure of PBMC from all three groups of individuals to an optimal dose of IL-2 in vitro enhanced LAK cell activity. At all three effector: target cell ratios, the LAK activity in AIDS patients remained below that in normal subjects. However, the proportional increase of lytic activity with IL-2 was slightly higher in AIDS patients than in HIV-seronegative subjects. The mitogen-induced production of IL-2 was especially reduced in AIDS patients. In contrast, very high levels of mitogen-induced production of IL-10 were found in the AIDS group, as compared to asymptomatic subjects or to controls. We therefore conclude that the alteration of NK cell activity occurs at an advanced stage of HIV infection, that the reduction of cytotoxic activity is partially restored by exogenous IL-2, and that decreased production of IL-2 and increased production of IL-10 may account for part of this reduction in cytotoxicity.
