Thymic involution

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One of the major characteristics of vertebrate immunology is thymic involution, the shrinking (involution) of the thymus with age, resulting in changes in the architecture of the thymus and a decrease in tissue mass. [1] This process is genetically regulated, with the nucleic material responsible being an example of a conserved sequence — one maintained through natural selection (though the pressures shaping this are unclear as will be discussed) since it arose in a common ancestor of all species now exhibiting it, via a phenomenon known to bioinformaticists as an orthologic sequence homology. The thymus involutes in almost all vertebrates, from birds, teleosts, amphibians to reptiles, though the thymi of a few species of sharks are known not to involute. [1] [2] T-cells are named for the thymus where T-lymphocytes migrate from the bone marrow to mature. Its regression has been linked to the reduction in immunosurveillance [3] and the rise of infectious disease and cancer incidence in the elderly (in some cases risk is inversely proportional to thymus size). [4] Though thymic involution has been linked to immunosenescence, it is not induced by senescence as the organ starts involuting from a young age: [5] in humans, as early as the first year after birth. [6]

Contents

Progression

Neonatal period

Though the thymus is fully developed before birth, [7] newborns have an essentially empty peripheral immune compartment immediately after birth. [8] [9] Hence, T lymphocytes are not present in the peripheral lymphoid tissues, where naïve, mature lymphocytes are stimulated to respond to pathogens. [1] In order to populate the peripheral system, the thymus increases in size and upregulates its function during the early neonatal period. [1]

Age-relatedness

Though some sources[ which? ] continue to cite puberty as the time of onset, studies have shown thymic involution to start much earlier. [1] The crucial distinction came from the observation that the thymus consists of two main components: the true thymic epithelial space (TES) and the perivascular space (PVS). [6] Thymopoiesis, or T-cell maturation, only occurs in the former. In humans, the TES starts decreasing from the first year of life at a rate of 3% until middle age (35–45 years of age), whereupon it decreases at a rate of 1% until death. [6] Hypothetically, the thymus should stop functioning at around 105 years of age; [10] but, studies with bone marrow transplant patients have shown that the thymi of the majority of patients over forty were unable to build a naïve T cell compartment. [11]

Effects of the involution

The ability of the immune system to mount a strong protective response depends on the receptor diversity of naive T cells (TCR). Thymic involution results in a decreased output of naïve T lymphocytes – mature T cells that are tolerant to self antigens, responsive to foreign antigens, but have not yet been stimulated by a foreign substance. In adults, naïve T-cells are hypothesized to be primarily maintained through homeostatic proliferation, or cell division of existing naïve T cells. Though homeostatic proliferation helps sustain TCR even with minimal to nearly absent thymic activity, it does not increase the receptor diversity. [12] For yet unknown reasons, TCR diversity drops drastically around age 65. [12] Loss of thymic function and TCR diversity is thought to contribute to weaker immunosurveillance of the elderly, including increasing instances of diseases such as cancers, autoimmunity, and opportunistic infections. [13]

Acute thymic involution and treatment implications

There is growing evidence that thymic involution is plastic and can be therapeutically halted or reversed in order to help boost the immune system. In fact, under certain circumstances, the thymus has been shown to undergo acute thymic involution (alternatively called transient involution). [1] For example, transient involution has been induced in humans and other animals by stresses [14] such as infections, [15] [16] pregnancy, [17] and malnutrition. [16] [18] [19] The thymus has also been shown to decrease during hibernation and, in frogs, change in size depending on the season, growing smaller in the winter [20] Studies on acute thymic involution may help in developing treatments for patients, who for example are unable to restore immune function after chemotherapy, ionizing radiation, or infections like HIV. [13] IShown that castrated men and women exhibit a slower rate of thymus involution implicating testosterone. The results of Greg Fahy TRIIM trial showed clinically significant reversal of thymus involution using human growth hormone (HGH), Dehydroepiandrosterone (DHEA) and metformin. [21] The two results could mean that HGH and mTOR inhibition in autophagy reverses thymus involution with testosterone advancing thymus involution. [22]

Unknown selective pressures

Thymic involution remains an evolutionary mystery since it occurs in most vertebrates despite its negative effects. Since it is not induced by senescence, many scientists have hypothesized that there may have been evolutionary pressures for the organ to involute. A few hypotheses are as follows: Developing T cells that interact strongly with antigen being presented within the thymus are induced to undergo programmed cell death. The intended effect is deletion of self-reactive T cells. This works well when the antigen being presented within the thymus is truly of self origin, but antigen from pathogenic microbes that happens to infiltrate the thymus has the potential to subvert the entire process. Rather than deleting T cells that would cause autoimmunity, T cells capable of eliminating the infiltrating pathogen are deleted instead. It has been proposed that one way to minimize this problem is to produce as many long-lived T cells as possible during the time of life when the thymus is most likely to be pristine, which generally would be when organisms are very young and under the protection of a functional maternal immune system. [23] Thus, in mice and humans, for example, the best time to have a prodigiously functional thymus is prior to birth. In turn, it is well known from Williams' [24] theory of the evolution of senescence that strong selection for enhanced early function readily accommodates, through antagonistic pleiotropy, deleterious later occurring effects, thus potentially accounting for the especially early demise of the thymus. The disposable soma hypothesis and life history hypothesis say similarly that tradeoffs are involved in thymic involution. Since the immune system must compete with other bodily systems, notably reproduction, for limited physiological resources, the body must invest in the immune system differentially at different stages of life. There is high immunological investment in youth since immunological memory is low. [1] There are also hypotheses that suggest that thymic involution is directly adaptive. For example, some hypotheses have proposed that thymic involution may help in avoidance of autoimmunity or other dangers, [25] prevention of infection, [10] and production of an optimal repertoire of T-cells. [26] Zinc deficiency may also play a role. [27]

Related Research Articles

Thymus Endocrine gland

The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or T cells mature. T cells are critical to the adaptive immune system, where the body adapts specifically to foreign invaders. The thymus is located in the upper front part of the chest, in the anterior superior mediastinum, behind the sternum, and in front of the heart. It is made up of two lobes, each consisting of a central medulla and an outer cortex, surrounded by a capsule.

T cell Type of lymphocyte

A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system, and play a central role in the adaptive immune response. T cells can be easily distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

Cytotoxic T cell T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell is a T lymphocyte that kills cancer cells, cells that are infected, or cells that are damaged in other ways.

T helper cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the immune system, particularly in the adaptive immune system. As their name suggests, they "help" the activity of other immune cells by releasing cytokines, small protein mediators that alter the behavior of target cells that express receptors for those cytokines. These cells help to polarize the immune response into the appropriate kind depending on the nature of the immunological insult (virus vs. extracellular bacterium vs. intracellular bacterium vs. helminth vs. fungus vs. protist). They are generally considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils.

Major histocompatibility complex Cell surface proteins, part of the acquired immune system

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

The regulatory T cells, formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Tregs are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Tregs express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4 cells. Because effector T cells also express CD4 and CD25, Tregs are very difficult to effectively discern from effector CD4+, making them difficult to study. Recent research has found that the cytokine TGFβ is essential for Tregs to differentiate from naïve CD4+ cells and is important in maintaining Treg homeostasis.

Central tolerance, also known as negative selection, is the process of eliminating any developing T or B lymphocytes that are reactive to self. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.

Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

A Thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood. Thymopoiesis describes the process which turns thymocytes into mature T cells according to either negative or positive selection. This selection process is vitally important in shaping the population of thymocytes into a peripheral pool of T cells that are able to respond to foreign pathogens but remain tolerant towards the body's own antigens. Positive selection selects cells which are able to bind MHC class I or II molecules with at least a weak affinity. This eliminates those T cells which would be non-functional due to an inability to bind MHC. Negative selection destroys thymocytes with a high affinity for self peptides or MHC. This eliminates cells which would direct immune responses towards self-proteins in the periphery. Negative selection is not 100% effective, and some autoreactive T cells escape and are released into the circulation. Additional mechanisms of peripheral tolerance exist to silence these cells, but if these fail, autoimmunity may arise.

MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a T cell can interact with a self-major histocompatibility complex molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule.

A naive T cell is a T cell that has differentiated in the thymus, and successfully undergone the positive and negative processes of central selection in the thymus. Among these are the naive forms of helper T cells (CD4+) and cytotoxic T cells (CD8+). A naive T cell is considered immature and, unlike activated or memory T cells, has not encountered its cognate antigen within the periphery.

Intraepithelial lymphocyte

Intraepithelial lymphocytes (IEL) are lymphocytes found in the epithelial layer of mammalian mucosal linings, such as the gastrointestinal (GI) tract and reproductive tract. However, unlike other T cells, IELs do not need priming. Upon encountering antigens, they immediately release cytokines and cause killing of infected target cells. In the GI tract, they are components of gut-associated lymphoid tissue (GALT).

Immunosenescence refers to the gradual deterioration of the immune system brought on by natural age advancement. The adaptive immune system is affected more than the innate immune system.

Peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease.

Gamma delta T cells are T cells that have a distinctive T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, gamma delta (γδ) T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells, but are at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

Clonal deletion is the removal through apoptosis of B cells and T cells that have expressed receptors for self before developing into fully immunocompetent lymphocytes. This prevents recognition and destruction of self host cells, making it a type of negative selection or central tolerance. Central tolerance prevents B and T lymphocytes from reacting to self. Thus, clonal deletion can help protect individuals against autoimmunity. Clonal deletion is thought to be the most common type of negative selection. It is one method of immune tolerance.

Thymic nurse cells (TNCs) are large epithelial cells found in the cortex of the thymus and also in cortico-medullary junction. They have their own nucleus and are known to internalize thymocytes through extensions of plasma membrane. The cell surfaces of TNCs and their cytoplasmic vacuoles express MHC Class I and MHC Class II antigens. The interaction of these antigens with the developing thymocytes determines whether the thymocytes undergo positive or negative selection.

Medullary thymic epithelial cells (mTECs) represent a unique stromal cell population of the thymus which plays an essential role in the establishment of central tolerance. Therefore, mTECs rank among cells relevant for the development of functional mammal immune system.

Virtual Memory T cells (TVM) are a subtype of T lymphocytes. These are cells that have a memory phenotype but have not been exposed to a foreign antigen. They are classified as memory cells but do not have an obvious memory function. They were first observed and described in 2009. The name comes from a computerized "virtual memory" that describes a working memory based on an alternative use of an existing space.

References

  1. 1 2 3 4 5 6 7 Shanley D.P.; Danielle A.W.; Manley N.R.; Palmer D.B.; et al. (2009). "An evolutionary perspective on the mechanisms of immunosenescence". Trends in Immunology . 30 (7): 374–381. doi:10.1016/j.it.2009.05.001. PMID   19541538.
  2. Zakharova L.A. (2009). "Evolution of adaptive immunity". Seriya Biologicheskaya. 2: 143–154. PMID   19391473.
  3. Linton P.J.; Dorshkind K. (2004). "Age-related changes in lymphocyte development and function". Nature Immunology. 5 (2): 133–139. doi:10.1038/ni1033. PMID   14749784.
  4. Palmer S.; Albergante L.; Blackburn C.C.; Newman T.J. (2018). "Thymic involution and rising disease incidence with age". Proceedings of the National Academy of Sciences of the United States of America . 115 (8): 1883–1888. doi:10.1073/pnas.1714478115. PMC   5828591 . PMID   29432166.
  5. Taub D.D.; Long D.L. (2005). "Insights into thymic aging and regeneration". Immunological Reviews. 205: 72–93. doi:10.1111/j.0105-2896.2005.00275.x. PMID   15882346.
  6. 1 2 3 Steinmann G.G.; Klaus B.; Muller-Hermelin H.K.; et al. (1985). "The involution of the aging human thymic epithelium is independent of puberty. A morphometric study". Scandinavian Journal of Immunology. 22 (5): 563–75. doi:10.1111/j.1365-3083.1985.tb01916.x. PMID   4081647.
  7. Parham, P. 2005. The immune system: Second edition Garland Science.
  8. Min B.; McHugh R.; Sempowski G.D.; Mackall C.; Foucras G.; Paul W.E.; et al. (2003). "Neonates support lymphopenia-induced proliferation". Immunity . 18 (1): 131–140. doi:10.1016/S1074-7613(02)00508-3. PMID   12530982.
  9. Schuler T.; Hammerling G.J.; Arnold B.; et al. (2004). "Cutting edge: IL-7-dependent homeostatic proliferation of CD8+ T cells in neonatal mice allows the generation of long-lived natural memory T cells". Journal of Immunology . 172 (1): 15–19. doi: 10.4049/jimmunol.172.1.15 . PMID   14688303.
  10. 1 2 George A.J.; Ritter M.A. (1996). "Thymic involution with ageing: obsolescence or good housekeeping?". Immunology Today . 17 (6): 267–272. doi:10.1016/0167-5699(96)80543-3. PMID   8962629.
  11. Hakim F.; Memon S.; Cepeda R.; Jones E.; Chow C.; Kasten-Sportes C.; Odom J.; Vance B.; Christensen B.; et al. (2005). "Age-dependent incidence, time course, and consequences of thymic renewal in adults". Journal of Clinical Investigation . 115 (4): 930–939. doi:10.1172/JCI22492. PMC   1064981 . PMID   15776111.
  12. 1 2 Naylor K.; Li G.; Vallejo A.N.; Lee W.W.; Koetz K.; Bryl E.; Witkowski J.; Fulbright J.; Weyand C.M.; et al. (2005). "The influence of age on T cell generation and TCR diversity". Journal of Immunology . 174 (11): 7446–7452. doi: 10.4049/jimmunol.174.11.7446 . PMID   15905594.
  13. 1 2 Lynch H.E.; Goldberg G.L.; Chidgey A.; Boyd R.; Sempowski G.D.; et al. (2009). "Thymic involution and immune reconstitution". Trends in Immunology . 30 (7): 366–373. doi:10.1016/j.it.2009.04.003. PMC   2750859 . PMID   19540807.
  14. Dominguez-Gerpe L; Rey-Mendez M (2003). "Evolution of the Thymus Size in Response to Physiological and Random Events Throughout Life". Microscopy Research and Technique . 62 (6): 464–476. doi:10.1002/jemt.10408. PMID   14635139.
  15. Savino W (2006). "The thymus is a common target organ in infectious diseases". PLOS Pathogens. 2 (6): 472–483. doi:10.1371/journal.ppat.0020062. PMC   1483230 . PMID   16846255.
  16. 1 2 Savino W; Dardenne M; Velloso LA; Silva-Barbosa SD (2007). "The thymus is a common target in malnutrition and infection". British Journal of Nutrition . 98: S11–S16. doi: 10.1017/s0007114507832880 . PMID   17922946.
  17. Kendall M.D.; Clarke A.G. (2000). "The thymus in the mouse changes its activity during pregnancy: a study of the microenvironment". Journal of Anatomy . 197 (3): 393–411. doi:10.1046/j.1469-7580.2000.19730393.x. PMC   1468141 . PMID   11117626.
  18. Cromi A.; Ghezzi F.; Raffaelli R.; Bergamini V.; Siesto G.; Bolis P.; et al. (2009). "Ultrasonographic measurement of thymus size in IUGR fetuses: a marker of the fetal immunoendocrine response to malnutrition". Ultrasound in Obstetrics & Gynecology . 33 (4): 421–426. doi:10.1002/uog.6320. PMID   19306477.
  19. Howard J.K.; Lord G.M.; Matarese G.; Vendetti S.; Ghatei M.A.; Ritter M.A.; Lechler R.I.; Bloom S.R.; et al. (1999). "Leptin protects mice from starvation induced lymphoid atrophy and increases thymic cellularity in ob/ob mice" (PDF). Journal of Clinical Investigation . 104 (8): 1051–1059. doi:10.1172/JCI6762. PMC   408574 . PMID   10525043.
  20. Wytycz, B., Mica, J., Jozkowir, A. & Bigaj J. 1996. Letters: Plasticity of thymuses of ectothermic vertebrates. Immunology Today (Comment). 442: No.9.
  21. "Reversing Thymic Involution – Intervene Immune" . Retrieved 2020-12-31.
  22. Sutherland, Jayne S.; Goldberg, Gabrielle L.; Hammett, Maree V.; Uldrich, Adam P.; Berzins, Stuart P.; Heng, Tracy S.; Blazar, Bruce R.; Millar, Jeremy L.; Malin, Mark A.; Chidgey, Ann P.; Boyd, Richard L. (2005-08-15). "Activation of Thymic Regeneration in Mice and Humans following Androgen Blockade". The Journal of Immunology. 175 (4): 2741–2753. doi: 10.4049/jimmunol.175.4.2741 . ISSN   0022-1767. PMID   16081852.
  23. Turke P (1995). "Microbial parasites versus developing T cells: an evolutionary arms race with implications for the timing of thymic involution and HIV pathenogenesis". Thymus. 24 (1): 29–40. PMID   8629277.
  24. Williams G. C. (1957). "Pleiotropy, natural selection, and the evolution of senescence". Evolution. 11 (4): 398–411. doi:10.2307/2406060. JSTOR   2406060.
  25. Aronson M (1991). "Hypothesis: involution of the thymus with aging–programmed and beneficial". Thymus. 18 (1): 7–13. PMID   1926291.
  26. Dowling M.R.; Hodgkin P.D. (2009). "Why does the thymus involute? A selection-based hypothesis". Trends in Immunology . 30 (7): 295–300. doi:10.1016/j.it.2009.04.006. PMID   19540805.
  27. Mocchegiani E, Muzzioli M, Cipriano C, Giacconi R (1998). "Zinc, T-cell pathways, aging: role of metallothioneins". Mechanisms of Ageing and Development. 106 (1–2): 183–204. doi:10.1016/S0047-6374(98)00115-8. PMID   9883983.